TB/HIV: a clinical manual - libdoc.who.int - World Health Organization

WHO/HTM/TB/2004.329TB HIVA CLINICAL MANUALsecond editionWORLD HEALTH ORGANIZATION

WHO/HTM/TB/2004.329TB/HIVA CLINICAL MANUALSecond editionStop TB DepartmentDepartment of HIV/AIDSDepartment of Child and Adolescent Health and DevelopmentWorld Health OrganizationGenevaWriting team:Anthony HarriesAdviser to National Tuberculosis Control Programme, Lilongwe, MalawiDermot MaherStop TB Department,World Health Organization, Geneva, SwitzerlandStephen GrahamWellcome Trust Research Laboratories, Blantyre, Malawi andLiverpool School of Tropical Medicine, Liverpool, EnglandWith contributions from:Mario Raviglione and Paul NunnStop TB DepartmentCharles GilksDepartment of HIV/AIDSShamim Qazi and Martin WeberDepartment of Child and Adolescent Health and DevelopmentWorld Health OrganizationEric van PraagFamily Health International,Washington DC, USAAnd forewords by:Dr JW Lee (2 nd edition)Sir John Crofton (1 st edition)Acknowledgments:We gratefully acknowledge the helpful comments and suggestions ofDrs Kevin de Cock, Robert Colebunders, Peter Donald,Malgosia Grzemska, Fabio Scano, Robert Scherpbier, Jeffrey Starke andMukund Uplekar who reviewed the manuscript.

WHO Library Cataloguing-in-Publication DataTB/HIV: a clinical manual / writing team:Anthony Harries, Dermot Maher and Stephen Graham. - 2nd ed.1.Tuberculosis, Pulmonary 2.Tuberculosis 3.HIV infections 4.AIDS-relatedopportunistic infections 5.Antitubercular agents 6.Anti-retroviral agents7.Delivery of health care, Integrated 8.Manuals I. Harries,AnthonyII.Maher, Dermot. III.Graham, Stephen.ISBN 92 4 154634 4 (NLM classification:WF 200)© World Health Organization 2004All rights reserved. Publications of the World Health Organization can beobtained from Marketing and Dissemination,World Health Organization, 20Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +4122 791 4857; email: bookorders@who.int). Requests for permission toreproduce or translate WHO publications – whether for sale or fornoncommercial distribution – should be addressed to Publications, at theabove address (fax: +41 22 791 4806; email: permissions@who.int).The designations employed and the presentation of the material in thispublication do not imply the expression of any opinion whatsoever on thepart of the World Health Organization concerning the legal status of anycountry, territory, city or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries. Dotted lines on maps representapproximate border lines for which there may not yet be full agreement.The mention of specific companies or of certain manufacturers’ productsdoes not imply that they are endorsed or recommended by the WorldHealth Organization in preference to others of a similar nature that are notmentioned. Errors and omissions excepted, the names of proprietaryproducts are distinguished by initial capital letters.The World Health Organization does not warrant that the informationcontained in this publication is complete and correct and shall not be liablefor any damages incurred as a result of its use.The named authors alone are responsible for the views expressed in thispublication.Printed in China

CONTENTSForeword to second edition. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Foreword to first edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Preface to second edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Glossary and abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Background information on tuberculosisand human immunodeficiency virus . . . . . . . . . . . . 231.1 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231.1.1 Basic facts about TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231.1.2 Pathogenesis of TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251.2 Human immunodeficiency virus . . . . . . . . . . . . . . . . . . . . 271.2.1 Introduction: HIV and AIDS . . . . . . . . . . . . . . . . . . . . . . . 271.2.2 HIV/AIDS epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . 281.2.3 HIV transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281.2.4 Prevention of HIV transmission in health units . . . . . . . . 291.2.5 Immunopathogenesis of HIV infection . . . . . . . . . . . . . . 301.2.6 Natural history of HIV infection . . . . . . . . . . . . . . . . . . . 311.2.7 Clinical staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321.2.8 Epidemiological surveillance of AIDS . . . . . . . . . . . . . . . . 351.3 HIV-related TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361.3.1 Epidemiology of coinfection of HIV and M tuberculosis. . . 361.3.2 HIV infection and risk of TB. . . . . . . . . . . . . . . . . . . . . . . 371.3.3 TB in the course of HIV progression . . . . . . . . . . . . . . . . 371.3.4 Consequence of HIV/M tuberculosis coinfection . . . . . . . . 371.3.5 Impact of HIV on TB control . . . . . . . . . . . . . . . . . . . . . . 371.3.6 Patterns of HIV-related TB . . . . . . . . . . . . . . . . . . . . . . . . 381.3.7 Impact of TB on HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392 An expanded framework for effectivetuberculosis control. . . . . . . . . . . . . . . . . . . . . . . . . . . 412.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412.2 Components of expanded TB control framework . . . . . . 412.2.1 Goals of TB control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422.2.2 Targets for TB control (cure and case detection). . . . . . . 422.2.3 TB control policy package (the DOTS strategy) . . . . . . . 43TB/HIV:A CLINICAL MANUAL3

2.2.4 Key operations for DOTS implementation. . . . . . . . . . . . 442.2.5 Indicators to measure NTP progress in TB control . . . . . 452.3 Directly observed treatment . . . . . . . . . . . . . . . . . . . . . 452.4 TB/HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462.5 DOTS-Plus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Diagnosis of pulmonary tuberculosis in adults . . . . 493.1 Diagnostic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493.2 Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503.3 Diagnostic sputum smear microscopy . . . . . . . . . . . . . . . 513.4 Differential diagnosis of pulmonary TB. . . . . . . . . . . . . . . 543.5 Chest X-ray in diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . 553.6 Radiographic abnormalities seen in pulmonary TB . . . . . . 553.7 Differential diagnosis of chest X-ray findings . . . . . . . . . . 563.8 The place of mycobacterial culture in the diagnosis of TB 573.9 Sepsis and concomitant TB . . . . . . . . . . . . . . . . . . . . . . . 573.10 Distinguishing other HIV-related pulmonary diseasesfrom pulmonary TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 Diagnosis of pulmonary tuberculosis in children . . 614.1 Epidemiology of childhood TB . . . . . . . . . . . . . . . . . . . . . 614.2 How does TB in children differ from TB in adults? . . . . . 624.3 Approach to diagnosis of TB . . . . . . . . . . . . . . . . . . . . . . 634.4 Score system for diagnosis of TB in children . . . . . . . . . . 664.5 Tuberculin skin test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674.6 The decision to start TB treatment in children . . . . . . . . 684.7 Impact of HIV on the diagnosis of TB in children . . . . . . . 694.8 Differential diagnosis of pulmonary TB inHIV-infected children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704.9 Management of child contacts of infectious adults . . . . . . 715 Diagnosis of extrapulmonary tuberculosis inadults and children . . . . . . . . . . . . . . . . . . . . . . . . . . . 755.1 Diagnostic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755.2 Tuberculous lymphadenopathy . . . . . . . . . . . . . . . . . . . . . 755.3 Miliary (disseminated) TB. . . . . . . . . . . . . . . . . . . . . . . . . 785.4 Tuberculous serous effusions (pleural, pericardial, ascites) 795.5 Tuberculous meningitis. . . . . . . . . . . . . . . . . . . . . . . . . . . 845.6 Other forms of extrapulmonary TB . . . . . . . . . . . . . . . . . 875.7 Further information on spinal, gastrointestinaland hepatic TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884 CONTENTS

6 Diagnosis of HIV infection in adultswith tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916.1 Clinical recognition of HIV infection in TB patients . . . . . 916.2 HIV testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926.2.1 HIV antibody tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926.2.2 Tests to detect the virus itself . . . . . . . . . . . . . . . . . . . . . 936.2.3 Objectives of HIV antibody testing in TB patients . . . . . . 946.2.4 Strategy for HIV antibody testing in TB patients . . . . . . . 946.2.5 Diagnosis of HIV infection in individual TB patients . . . . . 956.3 HIV counselling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957 Diagnosis of HIV infection in children withtuberculosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997.1 Clinical recognition of HIV infection in children with TB . 997.2 HIV testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007.3 Counselling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018 Standardized tuberculosis case definitionsand treatment categories. . . . . . . . . . . . . . . . . . . . . 1058.1 Standardized case definitions . . . . . . . . . . . . . . . . . . . . . 1058.1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1058.1.2 Questions and answers about case definitions . . . . . . . . 1058.1.3 Case definitions by site and result of sputum smear . . . 1068.1.4 Category of TB patient for registration on diagnosis . . . 1078.2 Standardized dignostic categories. . . . . . . . . . . . . . . . . . 1089 Management of patients with tuberculosis . . . . . . 1119.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119.2 Modes of action of anti-TB drugs. . . . . . . . . . . . . . . . . . 1129.3 TB treatment regimens . . . . . . . . . . . . . . . . . . . . . . . . . 1139.3.1 New cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149.3.2 Re-treatment cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149.3.3 Standard code for TB treatment regimens . . . . . . . . . . . 1149.3.4 Recommended treatment regimens . . . . . . . . . . . . . . . . 1159.3.5 Use of streptomycin in areas of high HIV prevalence . . . 1179.3.6 Use of TB drugs in children . . . . . . . . . . . . . . . . . . . . . . 117TB/HIV:A CLINICAL MANUAL5

9.4 TB treatment regimens: questions and answers . . . . . . . 1189.5 Use of anti-TB drugs in special situations . . . . . . . . . . . 1209.6 The role of adjuvant steroid treatment: questionsand answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219.7 Monitoring of TB patients during treatment. . . . . . . . . . 1229.7.1 Monitoring of patients with sputum smear-positive PTB . 1229.7.2 Recording treatment outcome . . . . . . . . . . . . . . . . . . . 1239.7.3 Cohort analysis: questions and answers . . . . . . . . . . . . . 1249.8 Response of HIV-positive TB patients toanti-TB treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12410 Side-effects of anti-tuberculosis drugs . . . . . . . . . . 12910.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12910.2 Prevention of side-effects . . . . . . . . . . . . . . . . . . . . . . . 12910.3 Where to manage drug reactions . . . . . . . . . . . . . . . . . 12910.4 When to stop anti-TB drugs . . . . . . . . . . . . . . . . . . . . . 12910.5 Side-effects of anti-TB drugs . . . . . . . . . . . . . . . . . . . . . 13010.5.1 Side-effects of anti-TB drugs in HIV-positive TB patients 13110.6 Symptom-based approach to management ofdrug side-effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13210.7 Management of skin itching and rash . . . . . . . . . . . . . . 13210.7.1 Treatment regimen includes thioacetazone . . . . . . . . . . 13310.7.2 Treatment regimen does not include thioacetazone. . . . 13310.8 Desensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13410.9 Management of hepatitis . . . . . . . . . . . . . . . . . . . . . . . . 13511 Antiretroviral therapy for the treatment ofHIV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13711.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13711.2 Antiretroviral drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13811.3 Principles of ART . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386 CONTENTS

11.4 Principles of a public health approach to ART . . . . . . . . 13911.5 Initiation of ART. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13911.5.1 Adults and adolescents with documented HIV infection 14011.5.2 Infants and children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14011.6 Recommended doses of ARV drugs . . . . . . . . . . . . . . . . 14111.6.1 Adults and adolescents . . . . . . . . . . . . . . . . . . . . . . . . . 14111.6.2 Children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14211.7 Choice of ART regimen . . . . . . . . . . . . . . . . . . . . . . . . . 14911.7.1 Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14911.7.2 Children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15011.8 Monitoring the efficacy of ART. . . . . . . . . . . . . . . . . . . . 15111.9 Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15111.10 Interactions between ARV drugs and drugs used toprevent or treat opportunistic infections . . . . . . . . . . . . 15311.11 Antiretroviral drugs and TB treatment . . . . . . . . . . . . . 15311.11.1 Drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15311.11.2 Treating TB and HIV together . . . . . . . . . . . . . . . . . . . . 15311.11.3 Immune reconstitution syndrome . . . . . . . . . . . . . . . . . 15411.11.4 Options for ART in patients with TB . . . . . . . . . . . . . . . 15412 Treatment and prevention of other HIV-relateddiseases in TB/HIV patients . . . . . . . . . . . . . . . . . . . 15712.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15712.2 Clinical spectrum of HIV-related disease . . . . . . . . . . . . 15712.3 Sexually transmitted infections. . . . . . . . . . . . . . . . . . . . 15812.3.1 Syndromic management . . . . . . . . . . . . . . . . . . . . . . . . . 15812.3.2 Treatment regimens for common STIs. . . . . . . . . . . . . . 15912.4 Skin and mouth problems . . . . . . . . . . . . . . . . . . . . . . . 16112.5 Respiratory problems . . . . . . . . . . . . . . . . . . . . . . . . . . 16512.5.1 Respiratory problems in adults . . . . . . . . . . . . . . . . . . . 16512.5.2 Respiratory problems in children. . . . . . . . . . . . . . . . . . 16712.6 Gastrointestinal problems . . . . . . . . . . . . . . . . . . . . . . . 16712.6.1 Dysphagia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16712.6.2 Diarrhoea in adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16812.6.3 Diarrhoea in children. . . . . . . . . . . . . . . . . . . . . . . . . . . 170TB/HIV:A CLINICAL MANUAL7

12.7 Neurological problems in adults. . . . . . . . . . . . . . . . . . . 17112.7.1 Acute confusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17112.7.2 Chronic behaviour change . . . . . . . . . . . . . . . . . . . . . . . 17212.7.3 Persistent headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17212.7.4 Difficulty in walking . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17412.7.5 Poor vision. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17512.7.6 Burning sensation in the feet . . . . . . . . . . . . . . . . . . . . . 17512.8 Neurological problems common in children . . . . . . . . . 17512.9 Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17612.9.1 Approach to management . . . . . . . . . . . . . . . . . . . . . . . 17612.9.2 Disseminated infection. . . . . . . . . . . . . . . . . . . . . . . . . . 17612.10 Other HIV-related problems . . . . . . . . . . . . . . . . . . . . . 17712.11 Prevention of HIV-related opportunistic infections. . . . . 17912.11.1 General measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17912.11.2 Immunizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17912.11.3 Primary chemoprophylaxis in adults. . . . . . . . . . . . . . . . 18012.11.4 Primary chemoprophylaxis in children . . . . . . . . . . . . . . 18112.11.5 Secondary chemoprophylaxis in adults. . . . . . . . . . . . . . 18113 Coordinated care in different settings . . . . . . . . . . 18513.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18513.2 The expanded scope of a new approach to decreasethe burden of TB/HIV . . . . . . . . . . . . . . . . . . . . . . . . . . 18513.3 Referral to local HIV/AIDS care services . . . . . . . . . . . . 18613.4 Benefits of support from local HIV/AIDS care services . 18613.5 A framework for HIV/AIDS care that incorporatesinterventions to address TB . . . . . . . . . . . . . . . . . . . . . . 18713.5.1 Home and community care . . . . . . . . . . . . . . . . . . . . . . 18713.5.2 Primary care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18813.5.3 Secondary care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18913.5.4 Tertiary care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18913.6 The private sector . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19113.6.1 Private medical practitioners . . . . . . . . . . . . . . . . . . . . . 19113.6.2 Traditional practitioners. . . . . . . . . . . . . . . . . . . . . . . . . 19113.7 Operational research aimed at improving integratedTB and HIV/AIDS prevention and care . . . . . . . . . . . . . 1928 CONTENTS

13.7.1 Promoting voluntary counselling and testing (VCT)for HIV as an entry point to better TB care . . . . . . . . . 19213.7.2 The Practical Approach to Lung Health (PAL) . . . . . . . . 19214 Prevention of tuberculosis in HIV-infectedindividuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19514.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19514.2 Protection of HIV-positive persons against exposureto TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19514.2.1 Environmental control . . . . . . . . . . . . . . . . . . . . . . . . . . 19514.2.2 Face-masks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19614.2.3 Patient education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19614.2.4 Pulmonary TB suspects . . . . . . . . . . . . . . . . . . . . . . . . . 19614.2.5 Patients with sputum smear-positive pulmonary TB . . . . 19714.2.6 Patients with multidrug-resistant TB (MDR-TB) . . . . . . . 19714.3 Role of BCG in preventing TB in HIV-infected individuals. 19714.3.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19714.3.2 BCG protection against TB in HIV-infected children. . . . 19814.3.3 BCG safety in HIV-infected children. . . . . . . . . . . . . . . . 19814.3.4 WHO recommended policy on BCG and HIV. . . . . . . . 19814.4 The role of the Expanded Programme onImmunization (EPI). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19914.5 Preventive treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . 19914.5.1 Target groups for preventive treatment . . . . . . . . . . . . . 20014.5.2 Role of isoniazid preventive treatment in HIV-positiveindividuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20114.5.3 WHO/UNAIDS recommendations on preventivetherapy against TB in HIV-positive persons. . . . . . . . . . . 201Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205TB/HIV:A CLINICAL MANUAL9

FOREWORD TO SECOND EDITIONWHO is committed to achieving major progress in global public health.Goals for tuberculosis include a worldwide cure rate of 85% and a casedetection rate of 70% by 2005. Goals for human immunodeciciency virusinclude treating 3 million people with HIV infection in developingcountries with antiretroviral drugs by 2005. The MillenniumDevelopment Goals include targets for improved child health andsurvival and for improved control of priority communicable diseases(including TB and HIV) by 2015. Progress in improving TB/HIV clinicalcare will contribute to achieving these goals. Clinicians have a vitalcontribution to make, not only to the clinical care of patients, but alsoto public health.The public health foundation of TB control is good clinical care, throughidentification and effective treatment of TB patients. A cornerstone ofpublic health activities for HIV prevention is to increase the proportionof HIV-infected people who choose to know their HIV status. One ofthe benefits of testing positive for HIV should be access to good clinicalcare. This is crucial in promoting community confidence in HIV/AIDScare, and therefore encouraging the uptake of HIV testing.This manualprovides practical guidance on the clinical care of patients of all ageswith HIV infection, including the treatment of HIV infection withantiretroviral drugs and of HIV-related diseases, including TB.TB and HIV are overlapping epidemics. For clinicians, the patient is at thecentre of public health activities to tackle TB/HIV. For example, cliniciansare usually in a good position to offer TB patients voluntary counsellingand testing for HIV. When patients with TB find out they are HIVpositive,clinicians are well placed to ensure directly or by referral thatthey receive lifelong care. Lifelong care should comprise the following:treatment of HIV infection; prevention and treatment of HIV-relateddiseases; support to decrease risk of HIV transmission; and social andpsychological support.This manual provides valuable guidance for clinicians caring for patientswith TB/HIV. Their efforts are crucial to the collective achievement ofglobal public health goals.Dr JW LeeDirector-General,World Health OrganizationGeneva, Switzerland11

FOREWORD TO FIRST EDITIONDoctors and other health professionals working in sub-Saharan Africawill be only too aware of the many patients they encounter with TB.They will also be all too well aware of the epidemic of HIV infection andthe effect this has had on dramatically increasing the TB burden.They willknow that in many patients development of clinical TB is the first sign ofunderlying HIV infection. This excellent book is designed for the busyclinician. It summarizes the characteristics of both diseases and of theirinteractions. It concentrates particularly on the clinical problems ofdiagnosis and management, both in adults and children. It summarizesthe other HIV-related diseases which the clinician may encounter inTB/HIV patients. It provides a most useful review to those new to theproblems and a handy reference for the experienced clinician whenfaced with some particular difficulty. It is well set out and easy to use.The modern treatment of TB in HIV-infected patients is highly successful.This not only benefits the patient but reduces the spread of TB tofamilies and the community. Other treatments can help to improve orcontrol many HIV-related diseases.This book well summarizes the rangeof treatments available. It also provides useful guides on counselling andon interagency cooperation, both essential components of TB/HIVmanagement.The enormous problems of HIV and TB in sub-Saharan Africa are nowalso increasing in Asia and South America, where the book should proveequally useful.I congratulate WHO on deciding to produce this valuable book and theauthors on the imaginative and practical way they have presented theproblems and their management.Sir John CroftonProfessor Emeritus of Respiratory Diseases and TuberculosisUniversity of Edinburgh, Scotland12

PREFACE TO SECOND EDITIONRecognition of the impact of HIV on the clinical management of TBprompted WHO to publish the first edition of this manual in 1996. Inresponse to popular demand, the manual was adapted for differentregions and translated into many languages.The total number of copiesdistributed has run to well over 100000. Recognition of the strengthsand weaknesses of the first edition and developments in the TB/HIV fieldhave now prompted a second edition.There is increasing attention to the need to ensure high quality care ofchildren with TB within National TB Programmes.Therefore this secondedition provides improved guidance on dealing with TB in children.HIV fuels the TB epidemic in populations where there is overlapbetween those infected with HIV and those infected with Mycobacteriumtuberculosis. Intense transmission of M. tuberculosis increases the pool ofHIV-infected people exposed to, and subsequently infected with, M.tuberculosis. In populations with high HIV prevalence, many peopleinfected with HIV develop TB, and many TB patients are coinfected withHIV. Unfortunately, at present a very small proportion of all peopleinfected with HIV have access to antiretroviral treatment. However, thisproportion is sure to increase and clinicians involved in managing TBpatients need to know about antiretroviral treatment. For these reasonsthis edition includes a new chapter on antiretroviral drugs in thetreatment of HIV infection.The new expanded framework for TB control and the strategicframework to control TB/HIV reflect the development of TB controlpolicies since 1996. Chapter 2 incorporates these new policies.With the above changes, the manual provides up-to-date guidance onclinical management of patients with TB and HIV.This manual is mainly for doctors and other health professionalsworking in district hospitals and health centres in high HIV and TBprevalence countries. It deals mainly with sub-Saharan Africa, since thisis the region most badly affected by HIV and HIV-related TB. However,we hope it will also be helpful in other parts of the world facing similarproblems.Facilities vary from hospital to hospital and from health centre to healthcentre. In this manual we assume your hospital has a small laboratoryand X-ray service. Even if you do not have these facilities, the manual13

should still be useful. Health professionals who care for TB patients nowneed to know how to diagnose and treat TB, the principles of diagnosisand treatment of HIV and other HIV-related diseases. This manual willhelp you in this task.The manual fits into a white coat pocket so you can use it on the ward,in the clinic and at home.There is not enough room in a pocket manualfor all the possible information you may want to know about TB amongHIV-infected people. So, at the end of each chapter there are suggestionsfor further reading. These suggestions include relevant books,background material, reviews and recent articles in journals.Since English is not the first language of many of the people using thismanual, the writing style is deliberately simple.You are welcome to sendany comments on the manual to WHO.We will use your comments tohelp improve future editions. Many of the references in the manual areto WHO publications.To order copies of WHO publications, you shouldcontact Marketing and Dissemination,World Health Organization, 1211Geneva 27, Switzerland.14 PREFACE TO SECOND EDITION

GLOSSARY AND ABBREVIATIONSThis glossary explains the abbreviations and acronyms and some of theterms used in this book.ambulatory able to walkacquired resistance resistance of Mycobacterium tuberculosis to anti-TBdrugs in a TB patient who has previously receivedanti-TB treatmentadherence to treatment the patient taking the medicines as directedadjuvant treatment an addition to other treatmentAFBAcid-Fast Bacilliagranulocytosis absence of polymorph white blood cellsAIDSAcquired ImmunoDeficiency Syndromeanorexialoss of appetite for foodARCAIDS-Related ComplexARTAntiRetroviral TherapyARVAntiRetroViral (drug)atypical mycobacteria nontuberculous mycobacteriabactericidal kills bacteriabacteriostatic stops bacteria from growingBCGBacille Calmette-Guerinbronchiectasis irreversibly dilated bronchi with persistentlyinfected sputumbuboswollen, pus-containing lymph nodecaseationtissue breakdown by TB bacilli, forming yellowwhite,cheese-like materialchemotherapy treatment with drugs, e.g. anti-TB chemotherapymeans treatment with anti-TB drugsCAT or CT (scan) Computerized Axial TomographyCD4 cells subgroup of T-lymphocytes carrying CD4 antigensCDCCenters for Disease Control and Prevention (USA)CMVCytoMegaloVirusCNSCentral Nervous Systemcoinfection infection with different pathogens at the sametime, e.g. Mycobacterium tuberculosis and HIVcontactspeople (often family members) close to a TBpatient and at risk of infectioncotrimoxazole trimethoprim/sulfamethoxazole (TMP/SMX)counselling face-to-face communication in which one personTB/HIV:A CLINICAL MANUAL15

CSFCXRdactylitisdefaultdesensitizationdisseminateddormantDOTdyspnoeaDTOEDLEIAerythema nodosumempirical treatmentEPIEPTBexudatefalse-negativetest resultfalse-positivetest resultFBCFDCfluorochrome stainGDFgibbusHAARThaemoptysisHEPAhilarhilumHIV(counsellor) helps another (patient/client) tomake decisions and act on themCerebroSpinal Fluidchest X-rayinflammation of the fingerspatient stopping treatment before completionway of overcoming hypersensitivity to a drug in apatient by gradual re-exposure to the drugspread throughout the body to many differentorganssleeping or inactiveDirectly Observed Treatment (supporter watchespatient to ensure the patient takes the tablets)shortness of breathDistrict TB OfficerEssential Drugs ListEnzyme ImmunoAssaypainful, tender, red nodules over the front of the legstreatment for a certain condition without exactdiagnostic confirmation by testsExpanded Programme on Immunizationextrapulmonary TB;TB outside the lungsfluid with a high protein content and inflammatorycells in an area of diseasea negative test result, when the true result is infact positivea positive test result, when the true result is infact negativeFull Blood CountFixed-Dose Combinationstain shines brightly under ultraviolet lightGlobal Drug Facilityan acute angle in the spine due to vertebralcollapse from TBHighly Active AntiRetroviral Therapycoughing up of blood-stained sputumHigh Efficiency Particulate Air (filter mask)at the root of the lungthe root of the lungHuman Immunodeficiency Virus16GLOSSARY

HIV-negativeHIV-positiveHIV-related TBHIV statusHIV testhome carehypersensitivityreactionIECIMCIi.m. injectionimmunosuppressantdrugsincidenceindurationinfantinitial resistanceIPTIUATLDJVPKSlatentlesionLIPLFTsMACMCVMDR-TBmeningismmonotherapymutant bacilliabsence of (antibodies against) HIVpresence of (antibodies against) HIVTB occurring in somebody infected with HIVpresence or absence of HIVblood test for antibodies against HIVcare for a patient at home rather than in hospitalimmunological reaction to even a small amount ofa drug or other antigen, e.g. tuberculinInformation, Education and CommunicationIntegrated Management of Childhood Illnessintramuscular injectiondrugs that suppress normal immunitythe number of new cases of a disease in apopulation in a given time (usually one year)thickening, e.g. of the skin in a tuberculin testchild less than 12 months of ageresistance of Mycobacterium tuberculosis to anti-TBdrugs in a TB patient who has never beforereceived anti-TB drugsIsoniazid Preventive TreatmentInternational Union Against Tuberculosis and LungDiseaseJugular Venous PressureKaposi Sarcomasomething that is there but not obvious (it canbecome obvious later)an area of damage or injury to a tissue or organLymphocytic (lymphoid) Interstitial PneumonitisLiver Function TestsMycobacterium Avium intraCellulare (one of theatypical mycobacteria)Mean Corpuscular VolumeMultidrug-resistant TBpresence of clinical features suggestive ofmeningitis, e.g. headache, neck-stiffness, positiveKernig's signtreatment with one drugbacilli that suddenly change genetically andbecome different from the rest of the populationTB/HIV:A CLINICAL MANUAL17

mutationa sudden genetic change, e.g. a bacillus becomingdrug-resistantNGONonGovernmental OrganizationNNRTInon-nucleoside reverse transcriptase inhibitorNsRTInucleoside reverse transcriptase inhibitorNtRTInucleotide reverse transcriptase inhibitorNSAIDNon-Steroidal Anti-Inflammatory DrugNTPNational TB Programmeopportunistic infection an infection that "takes the opportunity" to causedisease when a person's immune defence is weakPALPractical Approach to Lung Healthpassive case-finding detection of TB cases by active testing (sputumsmear) of TB suspectspathogenesis how a disease arisesPCPPneumocystis Carinii Pneumonia (now known asPneumocystis jiroveci)pericardial effusion accumulation of fluid in the pericardial cavityphlyctenular painful hypersensitivity reaction of the conjunctivaconjunctivitis to primary TB infection, with inflammation andsmall red spots where the cornea meets thescleraPGLPersistent Generalized LymphadenopathyPHCPrimary Health CarePIProtease inhibitorpleural effusion accumulation of fluid in the pleural spacePLWHPeople Living With HIVPMLProgressive multifocal lenkoencephalopathypneumothorax accumulation of air in the pleural spacePPDPurified Protein Derivative (tuberculin)preventive treatment treatment aimed at preventing disease, e.g.isoniazid for the prevention of TB in certaincircumstancesPTBPulmonary TuBerculosisPTB suspect patient presenting with features that make thehealth worker think the patient may have PTB,most importantly cough of more than 3 weeks'durationregimena drug, or several drugs, given in certain doses fora stated durationrelapsedisease starting again after a patient was declaredcured18GLOSSARY

RNARTISCCscrofulasensitivity testseroconversionseroprevalenceslim diseasespinal blocksputum smearnegativesputum smearpositiveSTIStevens-JohnsonsyndromesyndromeTBTB suspectTB/HIVTB/HIV patientTENthrombocytopeniaT-lymphocytesTMP-SMXtuberclestuberculintuberculomaUNICEFVCTWHOwindow periodZN stainRibonucleic acidReverse transcriptase inhibitorShort-Course Chemotherapytuberculous lymph nodes in the necktest of TB bacilli for sensitivity or resistance toanti-TB drugsthe first appearance of HIV antobodies in theblood, usually about 3 months after HIV infectionthe proportion of people testing seropositive (e.g.for HIV) in a population at any one timeHIV-related chronic diarrhoea and weight lossobstruction to normal flow of CSF around thespinal cordabsence of AFBs on sputum microscopypresence of AFBs on sputum microscopySexually Transmitted Infectiona characteristic rash with "target lesions" andinflammation of the mucous membranesa group of symptoms and signsTuBerculosispatient with symptoms suggestive of TBTB and HIV coinfectionHIV-infected TB patientToxic Epidermal Necrolysislow platelet counttype of lymphocyte providing cellular immunityTriMethoPrim-SulfaMethoXazolesmall rounded areas of TB diseaseprotein extracted from TB bacilli (PPD)rounded area of TB disease, usually 1cm or morewideUnited Nations Children's FundVoluntary Counselling and Testing (for HIV)World Health Organizationthe gap of about 3 months between the timewhen a person becomes infected with HIV andthe time when antibodies first appear in the bloodZiehl-Neelsen stainTB/HIV:A CLINICAL MANUAL19

INTRODUCTIONUntreated HIV infection leads to progressive immunodeficiency andincreased susceptibility to infections, including TB. HIV is driving the TBepidemic in many countries, especially in sub-Saharan Africa and,increasingly, in Asia and South America.TB in populations with high HIVprevalence is a leading cause of morbidity and mortality.TB programmesand HIV/AIDS programmes therefore share mutual concerns.Prevention of HIV should be a priority for TB control; TB care andprevention should be priority concerns of HIV/AIDS programmes. TBand HIV programmes provide support to general health serviceproviders. Previously TB programmes and HIV/AIDS programmes havelargely pursued separate courses. However, a new approach to TBcontrol in populations with high HIV prevalence requires collaborationbetween these programmes.HIV infection increases the demands on TB programmes, which arestruggling to cope with the increased TB case load. The impact of HIVexposes any weaknesses in TB control programmes. The rise in TBsuspects is putting a strain on diagnostic services. Extrapulmonary andsmear-negative pulmonary TB cases, which are more difficult todiagnose, account for an increased proportion of total cases.There aremore adverse drug reactions.There is a higher morbidity and mortality,partly due to other, curable, HIV-related infections. The risk of TBrecurrence is higher. The diagnosis of TB in young children has alwaysbeen difficult and is even more so with HIV.The objectives of a TB control programme are to decrease morbidity,mortality and transmission of TB, while avoiding the emergence of drugresistance. Up to now, the efforts to tackle TB among HIV-infectedpeople have mainly focused on implementing the DOTS strategy for TBcontrol. At the heart of this strategy is the identification and cure ofinfectious TB cases (among patients presenting to general healthservices).This targets the final step in the sequence of events by whichHIV fuels TB, namely the transmission of Mycobacterium tuberculosisinfection by infectious TB cases. The expanded scope of the newapproach to TB control in populations with high HIV prevalencecomprises interventions against TB and interventions against HIV (andtherefore indirectly against TB). Implementing this approach depends onTB and HIV programmes continuing their core activities and, in addition,collaborating in joint activities.These activities address areas of mutualinterest, e.g. staff training, public education, drug supply, case detectionand management, and surveillance.21

BACKGROUND INFORMATION ONTUBERCULOSIS AND HIVIThis chapter provides background information on tuberculosis (TB),human immunodeficiency virus and acquired immunodeficiencysyndrome, and the interaction between them.1.1 TUBERCULOSIS1.1.1 Basic facts about TBMycobacterium tuberculosisTB is a bacterial disease caused by Mycobacterium tuberculosis (andoccasionally by Mycobacterium bovis and Mycobacterium africanum).Theseorganisms are also known as tubercle bacilli (because they cause lesionscalled tubercles) or as acid-fast bacilli (AFB). When sputum containingtubercle bacilli is stained with certain dyes and examined under themicroscope, the bacilli look red.This is because they are acid-fast (theyhave kept the dye even after being washed with acid and alcohol).Tubercle bacilli can remain dormant in tissues and persist for many years.Tuberculous infection and tuberculosisTuberculous infection occurs when a person carries the tubercle bacilliinside the body, but the bacteria are in small numbers and are dormant.These dormant bacteria are kept under control by the body’s defencesand do not cause disease. Many people have tuberculous infection andare well.Tuberculosis is a state in which one or more organs of the bodybecome diseased as shown by clinical symptoms and signs. This isbecause the tubercle bacilli in the body have started to multiply andbecome numerous enough to overcome the body’s defences.Sources of infectionThe most important source of infection is the patient with TB of thelung, or pulmonary TB (PTB), and who is coughing. This person is usuallysputum smear-positive (see Chapter 3). Coughing produces tinyinfectious droplet nuclei (infectious particles of respiratory secretionsusually less than 5 µm in diameter and containing tubercle bacilli). Asingle cough can produce 3000 droplet nuclei. Droplet nuclei can also bespread into the air by talking, sneezing, spitting and singing, and canremain suspended in the air for long periods. Direct sunlight killstubercle bacilli in 5 minutes, but they can survive in the dark for longperiods.Transmission therefore generally occurs indoors. Droplet nucleiare so small that they avoid the defences of the bronchi and penetrateTB/HIV:A CLINICAL MANUAL23

into the terminal alveoli of the lungs, where multiplication and infectionbegin. Two factors determine an individual's risk of exposure: theconcentration of droplet nuclei in contaminated air and the length oftime he or she breathes that air.TB of cattle (bovine TB) occurs in some countries. Milk-borne M. bovismay infect the tonsils presenting as scrofula (cervical lymphadenitis), orthe intestinal tract, causing abdominal TB.Routes by which TB is not transmittedTB is not transmitted through food and water or by sexual intercourse,blood transfusion, or mosquitoes.Risk of infectionAn individual's risk of infection depends on the extent of exposure todroplet nuclei and his or her susceptibility to infection. The risk ofinfection of a susceptible individual is high with close, prolonged, indoorexposure to a person with sputum smear-positive PTB. The risk oftransmission of infection from a person with sputum smear-negative PTBis low, and even lower from someone with extrapulmonary TB (EPTB).Risk of progression of infection to diseaseInfection with M. tuberculosis can occur at any age. Once infected with M.tuberculosis, a person can stay infected for many years, probably for life.The vast majority (90%) of people without HIV infection who areinfected with M. tuberculosis do not develop TB. In these, asymptomaticbut infected individuals, the only evidence of infection may be a positivetuberculin skin test.Infected persons can develop TB at any time.The disease can affect mosttissues and organs, but especially the lungs. The chance of developingdisease is greatest shortly after infection and steadily lessens as timegoes by. Infected infants and young children are at greater risk ofdeveloping disease than older people because they have an immatureimmune system.TB is also more likely to spread from the lungs to otherparts of the body in this age group. Children who develop disease usuallydo so within two years following exposure and infection. Most do notdevelop disease in childhood but may do so later in life.Various physicalor emotional stresses may trigger progression of infection to disease.The most important trigger is weakening of immune resistance,especially by HIV infection.Natural history of untreated TBWithout treatment, by the end of 5 years 50% of PTB patients will be24 BACKGROUND INFORMATION ON TB AND HIV

dead, 25% will be healthy (self-cured by a strong immune defence) and25% will remain ill with chronic infectious TB.EpidemiologyM. tuberculosis infects a third of the world's population. In 2000 therewere an estimated 8.3 million new cases of TB worldwide. 95% of TBcases and 98% of TB deaths are in developing countries. 75% of TB casesin developing countries are in the economically productive age group(15–50 years). In 2000, Sub-Saharan Africa had the highest TB incidencerate (290/100000 per year) and the highest annual rate of increase ofcases (6%).There were 1.8 million deaths from TB in 2000, with 226000attributable to HIV (12%).TB deaths comprise 25% of all avoidable adultdeaths in developing countries.IA direct consequence of increasing numbers of adults with TB is anincrease in childhood TB. Neonatal BCG immunization has had limitedeffect in preventing childhood TB in developing countries. Infants andyoung children (less than 5 years) are at particular risk for infection anddisease. Accurate definition of the burden of childhood TB is difficultbecause of difficulties with diagnosis, particularly in regions wherechildhood HIV infection is common. Chapter 4 deals with these issuesin more detail.1.1.2 Pathogenesis of TBPrimary infectionPrimary infection occurs in people who have not had any previousexposure to tubercle bacilli. Droplet nuclei, which are inhaled into thelungs, are so small that they avoid the mucociliary defences of thebronchi and lodge in the terminal alveoli of the lungs. Infection beginswith multiplication of tubercle bacilli in the lungs.The resulting lesion isthe Ghon focus. Lymphatics drain the bacilli to the hilar lymph nodes.The Ghon focus and related hilar lymphadenopathy form the primarycomplex. Bacilli may spread in the blood from the primary complexthroughout the body. The immune response (delayed hypersensitivityand cellular immunity) develops about 4–6 weeks after the primaryinfection.The size of the infecting dose of bacilli and the strength of theimmune response determine what happens next. In most cases, theimmune response stops the multiplication of bacilli. However, a fewdormant bacilli may persist.A positive tuberculin skin test would be theonly evidence of infection. In a few cases the immune response is notstrong enough to prevent multiplication of bacilli, and disease occurswithin a few months.TB/HIV:A CLINICAL MANUAL25

Outcomes of primary infectionno clinical diseasepositive tuberculin skin test(usual outcome: 90% of cases)hypersensitivity reactionse.g. erythema nodosumphlyctenular conjunctivitisdactylitisprimarycomplexpulmonary and pleural complicationse.g. tuberculous pneumoniahyperinflation and collapse/consolidationpleural effusionPRACTICAL POINTdisseminated diseaselymphadenopathy (usually cervical)meningitispericarditismiliary diseaseFollowing primary infection, rapid progression to intra-thoracicdisease is more common in children less than 5 years of age.Chest X-Ray (CXR) may show intrathoracic lymphadenopathyand lung infiltrates.Post-primary TBPost-primary TB occurs after a latent period of months or yearsfollowing primary infection. It may occur either by reactivation of thedormant tubercle bacilli acquired from a primary infection or byreinfection. Reactivation means that dormant bacilli persisting in tissuesfor months or years after primary infection start to multiply.This may bein response to a trigger, such as weakening of the immune system by HIVinfection. Reinfection means a repeat infection in a person who haspreviously had a primary infection.The immune response of the patient results in a pathological lesion thatis characteristically localized, often with extensive tissue destruction andcavitation. Post-primary TB usually affects the lungs but can involve anypart of the body.The characteristic features of post-primary PTB are thefollowing: extensive lung destruction with cavitation; positive sputum26 BACKGROUND INFORMATION ON TB AND HIV

smear; upper lobe involvement; usually no intrathoraciclymphadenopathy. Patients with these lesions are the main transmittersof infection in the commmunity.IPost-primary TBPulmonary TBe.g. cavitiesupper lobe infiltratesfibrosisprogressive pneumoniaendobronchialExtrapulmonary TBCommonPleural effusionLymphadenopathy(usually cervical)Central nervous system(meningitis, cerebral tuberculoma)Pericarditis(effusion/constrictive)Gastrointestinal(ileocaecal, peritoneal)Spine, other bone and jointLess commonEmpyemaMale genital tract(epididymitis, orchitis)Female genital tract(tubo-ovarian, endometrium)KidneyAdrenal glandSkin(lupus vulgaris, tuberculids, miliary)PRACTICAL POINTPost-primary infection with pulmonary disease usually occursin adults and leads to microscopy-positive sputum smears.1.2 HUMAN IMMUNODEFICIENCY VIRUS1.2.1 Introduction: HIV and AIDSSince the first description of AIDS in 1981, researchers have identifiedtwo types of HIV, the cause of AIDS. HIV-1 is the predominant typeworldwide. HIV-2 occurs most commonly in West Africa, and occasionalTB/HIV:A CLINICAL MANUAL27

infections have occurred in East Africa, Europe, Asia and Latin America.Both types cause AIDS and the routes of transmission are the same.However, HIV-2 transmission is slightly less easy and the progression ofHIV-2 infection to AIDS may be slower.1.2.2 HIV/AIDS epidemiologyBy the end of 2002, there were an estimated 42 million adults andchildren living with HIV or AIDS. Of these, 28.5 million (68%) were livingin sub-Saharan Africa, and 6 million (14%) in South and South-East Asia.In 2002, an estimated 5 million adults and children became infected withHIV, and an estimated 3.1 million adults and children died fromHIV/AIDS. 2.4 million (77%) of these deaths occurred in sub-SaharanAfrica. Sub-Saharan Africa is the region with the highest overall HIVseroprevalence rate in the general adult (15–49 years) population (9% asof end 2002).Of 25 countries with an adult HIV seroprevalence rate above 5% in 2001,24 are in sub-Saharan Africa. The only other country with an adult HIVseroprevalence greater than 5% is Haiti. In 9 countries (all in SouthernAfrica), the adult HIV seroprevalence rate is 15% or above. Sub-SaharanAfrica thus bears the largest burden of the HIV/AIDS epidemic. However,certain countries in other regions are also badly affected by HIV, with anadult HIV seroprevalence of 1–5%, e.g. Cambodia, Myanmar and Thailand(South-East Asia) and Belize, Guatemala, Guyana, Haiti, Honduras, Panama,and Suriname (the Americas). HIV seroprevalence appears to be stabilizingin sub-Saharan Africa but is still increasing in some other large populations,e.g. in the Russian Federation.1.2.3 HIV transmissionWorldwide the most common route of HIV transmission is throughsexual intercourse. Other sexually transmitted infections (especiallythose that cause genital ulcers) increase the risk of HIV transmission.The main routes of HIV transmission vary between regions. The mainroutes of transmission of HIV in sub-Saharan Africa are through sexualintercourse, blood and from mother to infant. In most low-incomecountries roughly equal numbers of men and women are HIV-infected.Bloodborne HIV transmission occurs through contaminated bloodtransfusion, injections with contaminated needles and syringes, and theuse of non-sterile skin-piercing instruments. The commonest route ofHIV transmission in the fast-growing HIV epidemics in the RussianFederation and Ukraine is through injecting drug use.28 BACKGROUND INFORMATION ON TB AND HIV

About one-third of children born to HIV-infected mothers are also HIVinfected,with infection occurring mainly around the time of birth.Thereis a smaller risk of HIV transmission through breastfeeding. However, inmany low-income countries breastfeeding is still safer than bottle feeding.IThere is no evidence that HIV transmission occurs through everydaycontact, hugging or kissing, food or drink, or the bites of mosquitoes orother insects.1.2.4 Prevention of HIV transmission in health unitsTransmission to patientsPatients may potentially be at risk of HIV infection from HIV-positivestaff and HIV-positive patients. Known HIV-positive staff should notperform surgery or invasive diagnostic or therapeutic procedures onpatients. Cross-infection between patients can occur from contaminatedmedical, surgical or dental equipment. It is vital to follow recommendedsterilization procedures. When and where possible, reducing injectionshelps to decrease the risk of cross-infection.Transmission to staffMost HIV-positive health workers acquire HIV infection outside theworkplace, by sexual transmission from an HIV-positive partner orspouse.The risk of HIV transmission from patients to staff is small if staffobserve standard infection control procedures.The risk is less than thatof hepatitis B transmission. Less than 0.5% of health workers exposed bya needle-stick injury to the blood of an HIV-positive patient haveacquired HIV infection. Contaminated “sharps” pose a risk of HIVtransmission to health staff. Therefore handle all “sharps” carefully andfollow local guidelines for their disposal. If you have a needle-stick injury,squeeze the wound to encourage blood flow and wash well with soapand water. In areas of high HIV prevalence, assume that all blood andbody fluids are potentially infectious. The table on page 30 indicatesmeasures to prevent transmission of HIV to health workers. Whereavailable, start postexposure prophylaxis with antiretroviral drugs assoon as possible (within 24 hours) after a needle-stick injury.TB/HIV:A CLINICAL MANUAL29

Exposure to riskvenepunctureinvasive procedure,surgery, deliveryof a babyspilled blood orother body fluidsresuscitationlaundry disposalPrecautions for preventionof transmission of HIVwear glovesuse a closed vacuum system if availablediscard needle and syringe into “sharps” boxdiscard gloves and swabs into leakproofplastic bag for incinerationlabel blood bottle and request form"inoculation risk"wear gloves and apronprotect your eyes (glasses or protective goggles)discard sharps into “sharps” boxclear up as soon as possible using availabledisinfectant (e.g. glutaraldehyde, phenol,sodium hypochlorite)avoid mouth-to-mouth resuscitation(use bag and mask)wear gloves and aprondispose into leakproof plastic bagswash laundry at high temperatures or withappropriate chemical disinfectant1.2.5 Immunopathogenesis of HIV infectionHow HIV infects cellsHIV infects cells that have the CD4 antigen molecules on their surface.These cells are principally the helper subset of T-lymphocytes, which arecentral to cell-mediated immunity.They are called CD4+ T-lymphocytes. Inrecent years it has also been discovered that HIV needs other molecules,called chemokines, on the cell surface to gain entry into the cell. Patientswho do not have some of these specific chemokines (for example, CCR5)are more resistant to HIV infection. Others, who have molecular changesin these chemokine receptors, progress more slowly to AIDS.How HIV destroys the immune systemThe critical abnormality resulting from HIV infection is a progressivedecline in the number of CD4+ T-lymphocytes.These cells are the most30BACKGROUND INFORMATION ON TB AND HIV

important cells in the cell-mediated immune response. In addition thesurviving CD4+ T-lymphocytes do not perform their functions as well asthey did before infection. Progressive HIV infection therefore causesprogressive decline in immunity.I1.2.6 Natural history of HIV infectionAcute HIV infectionAcute HIV infection is also called “primary HIV infection” or “acuteseroconversion syndrome”. Between 40% and 90% of new HIVinfections are associated with symptomatic illness. The time fromexposure to onset of symptoms is usually 2–4 weeks. Some peoplepresent with a glandular-fever -like illness (fever, rash, arthralgia andlymphadenopathy). Occasionally acute neurological syndromes mayoccur, which are often self-limiting. These include aseptic meningitis,peripheral neuropathy, encephalitis and myelitis. A severe illness maypredict a worse long-term outcome. Most symptomatic patients seekmedical help. However, the diagnosis is infrequently made, for severalpossible reasons. First, the clinician may not consider HIV infection.Secondly, the nonspecific clinical features may be mistaken for anothercause, e.g. malaria. Thirdly, standard serological tests at this stage areusually negative. Serological tests first become positive about 4–12weeks after infection, with over 95% of patients “seroconverting” within6 months of HIV transmission. The diagnosis of acute HIV infection isbest established by demonstration of HIV RNA in plasma.Asymptomatic HIV infectionIn adults, there is a long, variable, latent period from HIV infection to theonset of HIV-related disease and AIDS.A person infected with HIV maybe asymptomatic for 10 years or more.The vast majority of HIV-infectedchildren are infected in the perinatal period.The period of asymptomaticinfection is shorter in children than in adults.A few infants become ill inthe first few weeks of life. Most children start to become ill before 2years of age.A few children remain well for several years.Persistent generalized lymphadenopathy (PGL)PGL is defined as enlarged lymph nodes involving at least two sites otherthan inguinal nodes. At this time, the lymph tissue serves as the majorreservoir for HIV. PGL occurs in about one-third of otherwise healthyHIV-infected people. The enlarged lymph nodes are persistent,generalized, symmetrical, and non-tender. PGL has no particularprognostic significance.TB/HIV:A CLINICAL MANUAL31

Progression from HIV infection to HIV-related disease and AIDSAlmost all (if not all) HIV-infected people, if untreated, will ultimatelydevelop HIV-related disease and AIDS. Some HIV-infected individualsprogress more quickly than others to HIV-related disease and AIDS.Therate of progression depends on virus and host characteristics. Viruscharacteristics include type and subtype: HIV-1 and certain HIV-1subtypes may cause faster progression. Host characteristics that maycause faster progression include: age less than 5 years; age more than 40years; concurrent infections; and genetic factors.Advancing immunosuppressionAs HIV infection progresses and immunity declines, patients becomemore susceptible to infections.These include TB, pneumonia, recurrentfungal infections of the skin and oropharynx, and herpes zoster. Theseinfections can occur at any stage of progression of HIV infection andimmunosuppression. Some patients may develop constitutionalsymptoms (unexplained fever and weight loss), previously known as"AIDS-related complex" (ARC). Some patients develop chronicdiarrhoea with weight loss, often known as "slim disease".Certain specific HIV-related diseases occur predominantly with severeimmunosuppression.These include certain opportunistic infections (e.g.cryptococcal meningitis) and certain tumours (e.g. Kaposi sarcoma). Atthis late stage, unless patients receive specific therapy for HIV infection,they usually die in less than 2 years.This late stage is sometimes knownas "full-blown AIDS".PRACTICAL POINTTB can occur at any point in the course of progression of HIVinfection.1.2.7 Clinical stagingWHO clinical staging system for HIV infection and HIV-relateddisease.WHO has developed a clinical staging system (originally for prognosis),based on clinical criteria.The definition of symptoms, signs and diseasesis according to clinical judgement. Clinical condition or performancescore, whichever is the higher, determines whether a patient is at clinicalstage 1, 2, 3 or 4 (see table on page 33). Clinical stage is important as acriterion for starting antiretroviral (ARV) therapy.32 BACKGROUND INFORMATION ON TB AND HIV

AdultsWHO clinical staging system for HIV infection and relateddisease in adults (13 years or older)IStage 1:º Asymptomaticº Persistent generalized lymphadenopathyPerformance scale 1: asymptomatic, normal activityStage 2:º Weight loss < 10% of body weightº Minor mucocutaneous manifestations(e.g. oral ulcerations, fungal nail infections)º Herpes zoster within the last 5 yearsº Recurrent upper respiratory tract infections(e.g. bacterial sinusitis)and/or Performance scale 2: symptomatic, normal activityStage 3:º Weight loss > 10% of body weightº Unexplained chronic diarrhoea for more than 1 monthº Unexplained prolonged fever for more than 1 monthº Oral candidiasis (thrush)º Oral hairy leukoplakiaº Pulmonary TBº Severe bacterial infections (pneumonia, pyomyositis)and/or Performance scale 3: bedridden < 50% of the dayduring the last monthStage 4:º HIV wasting syndrome, as defined by CDC aº Pneumocystis carinii pneumoniaº Toxoplasmosis of the brainº Cryptosporidiosis with diarrhoea, for more than 1 monthº Cryptococcosis, extrapulmonaryº Cytomegalovirus (CMV) disease of an organ other thanliver, spleen, lymph nodesº Herpesvirus infection, mucocutaneous for more than 1month, or visceral any durationº Progressive multifocal leukoencephalopathy (PML)º Any disseminated endemic fungal infection(e.g. histoplasmosis)TB/HIV:A CLINICAL MANUAL33

º Candidiasis of the oesophagus, trachea, bronchi or lungsº Atypical mycobacteriosis, disseminatedº Non-typhoid salmonella septicaemiaº Extrapulmonary TBº Lymphomaº Kaposi sarcomaº HIV encephalopathy, defined by CDC band/or Performance scale 4: bedridden > 50% of the day during the lastmonth(Note: both definitive and presumptive diagnoses are acceptable)a HIV wasting syndrome = weight loss > 10% of body weight, plus either unexplaineddiarrhoea for more than one month or chronic weakness and unexplained fever for morethan one month.b HIV encephalopathy = clinical findings of disabling mental or motor dysfunction,interferingwith activities of daily living, progressing over weeks and months, in the absence of aconcurrent illness or condition other than HIV infection which could explain the findings.ChildrenWHO clinical staging system for HIV infection and relateddisease in childrenStage 1:Stage 2:Stage 3:º Asymptomaticº Persistent generalised lymphadenopathyº Unexplained chronic diarrhoeaº Severe persistent or recurrent candidiasis outside theneonatal periodº Weight loss or failure to thriveº Persistent feverº Recurrent severe bacterial infectionsº AIDS-defining opportunistic infectionsº Severe failure to thriveº Progressive encephalopathyº Malignancyº Recurrent septicaemia or meningitis34BACKGROUND INFORMATION ON TB AND HIV

1.2.8 Epidemiological surveillance of AIDSAIDS is a term with an official definition used for epidemiologicalsurveillance.This means that systematic reporting of AIDS cases is usefulin helping to monitor the HIV pandemic and to plan public healthresponses.The term AIDS is not useful in the clinical care of individualpatients. In managing patients with HIV-related disease, the aim is toidentify and treat whichever HIV-related diseases are present.WHO hasrecommended case definitions for AIDS surveillance in adults andchildren where HIV testing facilities are not available.IPRACTICAL POINTThe term AIDS is used for epidemiological surveillance, notfor clinical care.WHO case definitions for AIDS surveillance in adults and childrenwhere HIV testing facilities are not availableAdultsThe case definition for AIDS is fulfilled if at least 2 major signs and atleast 1 minor sign are present.Major signsº weight loss > 10% of body weightº chronic diarrhoea for more than 1 monthº prolonged fever for more than 1 monthMinor signsº persistent cough for more than 1 month aº generalized pruritic dermatitisº history of herpes zosterº oropharyngeal candidiasisº chronic progressive or disseminated herpes simplex infectionº generalized lymphadenopathyThe presence of either generalized Kaposi sarcoma or cryptococcalmeningitis is sufficient for the case definition of AIDS.The advantages of this case definition are that it is simple to use andinexpensive. The disadvantages are its relatively low sensitivity andspecificity. For example, HIV-negative TB cases could be counted as AIDScases because of their similarity in clinical presentation.a For patients with TB, persistent cough for more than 1 month should not be considered as a minor sign.TB/HIV:A CLINICAL MANUAL35

ChildrenThe case definition for AIDS is fulfilled if at least 2 major signs and 2minor signs are present (if there is no other known cause ofimmunosuppression).Major signsº weight loss or abnormally slow growthº chronic diarrhoea for more than 1 monthº prolonged fever for more than 1 monthMinor signsº generalized lymph node enlargementº oropharyngeal candidiasisº recurrent common infections, e.g. ear infection, pharyngitisº persistent coughº generalized rashConfirmed HIV infection in the mother counts as a minor criterion.The definition for children is not very specific, particularly in poorregions where childhood malnutrition and TB are common. Further,many children present with acute HIV-related illness such as PCPwithout any clinical evidence of AIDS.1.3 HIV-RELATED TB1.3.1 Epidemiology of coinfection of HIV and M. tuberculosisBy the end of 2000, about 11.5 million HIV-infected people worldwidewere coinfected with M. tuberculosis. 70% of coinfected people were insub-Saharan Africa, 20% in South-East Asia and 4% in Latin America andthe Caribbean.Numbers of coinfected adults (15–49 years) in WHO regions byend 2000WHO Region Number of people coinfected % of globalwith TB & HIV (thousands) totalAfrica 7979 70Americas 468 4Eastern Mediterranean 163 1Europe 133 1South-East Asia 2269 20Western Pacific 427 4Total 11440 10036BACKGROUND INFORMATION ON TB AND HIV

1.3.2 HIV infection and risk of TBHIV probably increases susceptibility to infection with M. tuberculosis.HIV increases the risk of progression of M. tuberculosis infection to TBdisease. This risk increases with increasing immunosuppression. HIVincreases not only the risk but also the rate of progression of recent orlatent M. tuberculosis infection to disease. The table below shows theeffect of HIV infection on lifetime risk of an M. tuberculosis-infectedindividual developing TB.IHIV STATUSLIFETIME RISK OF DEVELOPING TBnegative 5–10%positive 50%PRACTICAL POINTHIV is the most powerful factor known to increase the riskof TB.1.3.3 TB in the course of HIV progressionTB can occur at any point in the course of progression of HIV infection.The risk of developing TB rises sharply with worsening immune status.1.3.4 Consequence of HIV/M. tuberculosis coinfectionCompared with an individual who is not infected with HIV, a personinfected with HIV has a 10 times increased risk of developing TB. TBnotifications have increased in populations where both HIV infection andM. tuberculosis infection are common. For example, some parts of sub-Saharan Africa have seen a 3–5 fold increase in the number of TB casenotifications over the past decade. HIV seroprevalence in these TBpatients is up to 75%. In sub-Saharan Africa, one-third or more of HIVinfectedpeople may develop TB.1.3.5 Impact of HIV on TB controlThe principles of TB control are the same even when there are manyHIV/TB patients. However, in populations where HIV/TB is common,health services struggle to cope with the large and rising numbers of TBpatients.TB/HIV:A CLINICAL MANUAL37

The consequences include the following:º overdiagnosis of sputum smear-negative PTB (due to difficulties indiagnosis);º underdiagnosis of sputum smear-positive PTB (due to excesslaboratory workload);º inadequate supervision of anti-TB chemotherapy;º low cure rates;º high morbidity during treatment;º high mortality rates during treatment;º high default rates because of adverse drug reactions;º high rates of TB recurrence;º increased transmission of drug-resistant strains among HIV-infectedpatients in congregate settings.1.3.6 Patterns of HIV-related TBAs HIV infection progresses, CD4+ T-lymphocytes decline in numberand function. These cells play an important role in the body’s defenceagainst tubercle bacilli. Thus, the immune system becomes less able toprevent the growth and local spread of M. tuberculosis. Disseminated andextrapulmonary disease is more common.Pulmonary TBEven in HIV-infected patients, PTB is still the commonest form of TB.Thepresentation depends on the degree of immunosuppression. The tablebelow shows how the clinical picture, sputum smear result and CXRappearance often differ in early and late HIV infection.How PTB differs in early and late HIV infectionFeatures of PTBStage of HIV infectionEarlyLateClinical picture Often resembles Often resemblespost-primary PTB primary PTBSputum smear result Often positive Often negativeCXR appearance Often cavities Often infiltrateswith no cavitiesExtrapulmonary TBThe commonest forms extrapulmonary TB are: pleural effusion,lymphadenopathy, pericardial disease, miliary disease, meningitis,disseminated TB (with mycobacteraemia).38 BACKGROUND INFORMATION ON TB AND HIV

HIV-related TB in childrenAs in adults, the natural history of TB in a child infected with HIVdepends on the stage of HIV disease. Early in HIV infection, whenimmunity is good, the signs of TB are similar to those in a child withoutHIV infection. As HIV infection progresses and immunity declines,dissemination of TB becomes more common. Tuberculous meningitis,miliary TB, and widespread tuberculous lymphadenopathy occur.I1.3.7 Impact of TB on HIVIn an individual infected with HIV, the presence of other infections,including TB, may allow HIV to multiply more quickly.This may result inmore rapid progression of HIV disease.SUGGESTIONS FOR FURTHER READINGTUBERCULOSISCrofton J, Horne N, Miller F. Clinical tuberculosis. Second edition. London,MacMillan Press Limited, 1999.Schlossberg D, ed: Tuberculosis and nontuberculous mycobacterial infections.Fourth edition. Philadelphia,WB Saunders, 1998.International Union Against Tuberculosis and Lung Disease. Tuberculosis guidefor low income countries. Fifth edition. Paris, 2000.Reider HL. Epidemiologic basis of tuberculosis control. Paris, International UnionAgainst Tuberculosis and Lung Disease, 1999.World Health Organization. Tuberculosis handbook. Geneva, 1998(WHO/TB/98.253).World Health Organization. Global tuberculosis control: surveillance, planning,financing. WHO report 2003. Geneva, 2003 (WHO/CDS/TB/2003.316).HIV/AIDSFauci AS.The AIDS epidemic. Considerations for the 21st century.New England Journal of Medicine, 1999, 341: 1046–1050.Royce RA, Sena A, Cates Jr, W Cohen, MS. Sexual transmission of HIV.New England Journal of Medicine, 1997, 336: 1072–1078.TB/HIV:A CLINICAL MANUAL39

World AIDS series. Lancet, 2000, 355: WA1–WA40.Joint United Nations Programme on HIV/AIDS (UNAIDS). Report on the globalHIV/AIDS epidemic: July 2002. Geneva, (contains country-specific estimates).Joint United Nations Programme on HIV/AIDS (UNAIDS). AIDS epidemicupdate: December 2002. Geneva, 2002.CLINICAL STAGING SYSTEM FOR HIV AND HIV-RELATEDDISEASEWorld Health Organization. Scaling up antiretroviral therapy in resource-limitedsettings. Guidelines for a public health approach. Geneva, 2002.AIDS CASE DEFINITIONS FOR SURVEILLANCEAcquired immunodeficiency syndrome (AIDS).WHO/CDC case definition forAIDS. Weekly epidemiological record, 1986, 61: 69–73. (WHO clinical casedefinitions for AIDS in children where HIV testing is not available).Centers for Disease Control and Prevention. 1994 revised classification systemfor human immunodeficiency virus infection in children less than 13 years ofage. Morbidity and mortality weekly report, 1994; 43 (No. RR-12): 1-10. (Casedefinition for AIDS in children where HIV testing is available).WHO case definitions for AIDS surveillance in adults and adolescents. Weeklyepidemiological record 1994, 69: 273-275.HIV-RELATED TUBERCULOSISCorbett EL,Watt CJ,Walker N, Maher D, Williams BG, Raviglione MC, Dye C.The growing burden of tuberculosis: global trends and interactions with theHIV epidemic. Archives of internal medicine, 2003, 163: 1009–1021.Raviglione MC, Harries AD, Msiska R, Wilkinson D, Nunn P. Tuberculosis andHIV: current status in Africa. AIDS, 1997, 11 (suppl B): S115 - S123.Ya Diul M, Maher D, Harries A. Tuberculosis case fatality rates in high HIVprevalence populations in sub-Saharan Africa. AIDS, 2001, 15: 143-152.World Health Organization. A strategic framework to decrease the burden ofTB/HIV. Geneva, 2002 (WHO/CDS/TB/2002.296;WHO/HIV_AIDS/2002.2).World Health Organization. Guidelines for collaborative TB and HIV programmeactivities. Geneva, 2003, (WHO/CDS/TB/2003.319;WHO/HIV/2003.01).40BACKGROUND INFORMATION ON TB AND HIV

AN EXPANDED FRAMEWORK FOR EFFECTIVETUBERCULOSIS CONTROL22.1 INTRODUCTIONWHO has declared that TB is a global emergency, because TB is out ofcontrol in many parts of the world.The following are the main reasonswhy TB is out of control:a) governments in many parts of the world have neglected the disease;b) inadequate TB control programmes have led to an increased burden ofdisease (inadequately treated TB patients live longer with chronic diseaseand infect other people) and the emergence of drug-resistant TB;c) high rates of population growth have contributed to an increasednumber of TB cases;d) the HIV epidemic has led to an enormous increase in the number ofTB cases, in places where HIV and TB are both common.WHO has expanded the framework for TB control in order to reflectexperience gained since the development of the original framework in1994.The expanded framework is relevant in all settings, including whereHIV is common. Successful TB control depends on health care workerstreating TB patients within this framework in a national TB programme(NTP). Full implementation of the DOTS strategy remains the priority.This means ensuring the accurate diagnosis and effective treatment of allTB patients.In addition TB and HIV/AIDS programmes must collaborate tocounteract the impact of HIV on TB.This depends on implementation ofthe DOTS strategy and other interventions. In addition to effective TBcase-finding and cure, these interventions include: measures to decreaseHIV transmission (e.g. promotion of condoms, treatment of sexuallytransmitted infections); highly active antiretroviral therapy (HAART);TBpreventive treatment; and antibiotic prophylaxis against HIV-relatedbacterial infections.2.2 COMPONENTS OF EXPANDED TB CONTROLFRAMEWORKThe expanded framework consists of the following:1. Goals of TB control.TB/HIV:A CLINICAL MANUAL41

2. Targets for TB control.3. TB control policy package.4. Key operations for DOTS implemantation.5. Indicators to measure NTP progress in TB control.2.2.1 Goals of TB controlThe goals of TB control are to reduce mortality, morbidity and diseasetransmission (while preventing drug resistance) until TB no longer posesa threat to public health.The aim is also to reduce human suffering andthe social and economic burden on families and communities as aconsequence of TB. In order to achieve this, it is necessary to ensureaccess to diagnosis, treatment and cure for each patient.2.2.2 Targets for TB control (cure and case detection)a) To cure 85% of the sputum smear-positive PTB cases detected.A national TB programme that achieves at least an 85% cure rate inpatients with sputum smear-positive PTB has the following impact on TB:i) TB prevalence,TB mortality and rate of TB transmission decreaserapidly;ii) TB incidence decreases gradually;iii) there is less drug resistance (which makes future treatment of TBeasier and more affordable).Achieving high cure rates is the highest priority.TB programmes withhigh cure rates rapidly reduce disease transmission.They are likely toattract the majority of existing cases in the community.b) To detect 70% of existing cases of sputum smear-positive PTB.It is important to expand case-finding only when the national TBprogramme has achieved a high cure rate.A national TB programme thathas a low cure rate makes the TB problem worse:i) there are more cases of sputum smear-positive PTB treatment failure;ii) transmission of drug resistance increases.A treatable epidemic becomes an untreatable epidemic.An effective NTP has a high cure rate and a low level of drug resistance.Provided that a high cure rate is achieved, increased case detection ofsputum smear-positive PTB cases will decrease TB transmission.42 AN EXPANDED FRAMEWORK FOR EFFECTIVE TB CONTROL

2.2.3 TB control policy package (the DOTS strategy)NTPs face new challenges.They need significant strengthening in orderto achieve the targets for TB control.2º General public health services need to increase their capacity tosustain and expand DOTS implementation. At the same time theymust maintain the quality of case detection and treatment.º Promoting a patient-centred approach and community involvement inTB care can improve both access to and utilization of health services.º Collaboration is essential between the public, private, and voluntarysectors to ensure accessible and quality-assured TB diagnosis andtreatment.º The increasing impact of HIV on the incidence of TB requires newapproaches and partnerships.º A high prevalence of drug-resistant TB requires two complementaryapproaches: NTPs need to cure existing multidrug-resistant (MDR) TBcases as well as prevent new cases (through the DOTS strategy).The expanded DOTS framework reinforces the five essential elementsof the DOTS strategy:a. Sustained political commitment to increase human andfinancial resources and make TB control a nationwide activityintegral to the national health system.b. Access to quality-assured TB sputum microscopy for casedetection among persons presenting with, or found throughscreening to have, symptoms of TB (most importantly prolongedcough). Special attention to case detection is necessary amongHIV-infected people and other high-risk groups, e.g. people ininstitutions.c. Standardized short-course chemotherapy (SCC) for allcases of TB under proper case-management conditionsincluding direct observation of treatment. Proper casemanagement conditions imply technically sound and sociallysupportive treatment services.TB/HIV:A CLINICAL MANUAL43

d. Uninterrupted supply of quality-assured drugs with reliabledrug procurement and distribution systems.e. Recording and reporting system enabling outcomeassessment of every patient and assessment of the overallprogramme performance.2.2.4 Key operations for DOTS implementationº Establish a national TB programme (NTP) with a central unit.º Prepare a programme development plan.º Prepare the NTP manual and make it available at district level.º Establish a recording and reporting system using standardizedmaterial allowing categorizaton of cases registered and cohort analysisfor treatment outcomes.º Plan and initiate a training programme covering all aspects of thepolicy package.º Establish a microscopy services network in close contact withprimary health care (PHC) services and subject to regular quality control.º Establish treatment services within the PHC system wheredirectly observed short-course chemotherapy is given priority andpatient education is provided.Treatment services should achieve totalgeographical and patient coverage.º Secure a regular supply of drugs and diagnostic material basedon previous case notification data.º Design a plan of supervision of the key operations at theintermediate and district level to be implemented from the start ofthe programme.º Undertake social mobilization through information, educationand communication activities, in order to mobilize and sustainsupport for TB control.º Involve all health care providers, e.g. private and voluntary healthcare providers, nongovernmental organizations (NGOs), religiousorganizations and employers.44 AN EXPANDED FRAMEWORK FOR EFFECTIVE TB CONTROL

º Undertake economic analysis and financial planning to ensurethat the NTP is on a sound financial footing.º Undertake operational research as an integral component ofDOTS implementation to improve NTP performance.22.2.5 Indicators to measure NTP progress in TB controlº National TB control policies, as set out in the NTP manual, consistentwith the DOTS strategy.º The number of administrative areas in the country that areimplementing the DOTS strategy.º The cure rate in new smear-positive cases.º The case detection rate.The WHO document, “An expanded DOTS framework for effectivetuberculosis control” (WHO/CDS/TB/2002.297), provides a full list ofindicators.2.3 DIRECTLY OBSERVED TREATMENTWhat is directly observed treatment?Patient adherence to treatment is necessary to ensure that thetreatment cures the patient. Patient adherence to SCC means thepatient takes every dose of the recommended treatment regimen. It maybe difficult for a patient to adhere to anti-TB treatment for 6 to 8months. It is difficult to predict which TB patients will adhere to selfadministeredtreatment. One certain way to ensure patient adherenceto treatment is direct observation of treatment. This means thatsomeone supports the patient during the course of treatment andwatches the patient swallow the tablets. The NTP coordinates thetraining of patient supporters and monitors their effectiveness inensuring treatment adherence.Directly observed treatment as close to the patient's home aspossibleTB patients are unlikely to adhere to treatment if they have far to go fortreatment. One of the aims of a TB programme is to organize TBservices so that patients have treatment as close to home as possible.ATB programme brings treatment to patients wherever they live. Many TBpatients live close to a health facility (e.g. health centre, district hospital).TB/HIV:A CLINICAL MANUAL45

For these patients, the treatment supporter who directly observestreatment could be one of the health staff in the health facility. Some TBpatients live far away from a health facility. For these patients, thesupervisor may be a trained local community member or a healthoutreach worker. Family members who provide health care support canalso be trained as TB treatment supporters. Some areas have HIV/AIDScommunity care schemes. With suitable training and supervision, theHIV/AIDS home care providers can support TB patients, includingdirectly observing treatment.Integration of TB treatment services with general health servicesIn the past, some TB programmes have relied on special TB hospitals andclinics, separate from the general health service.The problem with thatsystem is that many TB patients live far from a TB hospital or clinic. Onereason why TB is out of control in many countries is that TB patients donot have access to TB diagnosis and treatment services. A successfulNTP brings TB diagnosis and treatment services to the TB patients.Thisis why TB treatment services are integrated with existing general healthservices.2.4 TB/HIVTB and HIV are closely interlinked.TB is a leading cause of HIV-relatedmorbidity and mortality. HIV is the most important factor fuelling the TBepidemic in populations with a high HIV prevalence. The WHO globalstrategic framework to control TB/HIV represents a coordinatedresponse to the joint epidemics of TB and HIV. Collaboration betweenTB and HIV/AIDS programmes is crucial in supporting general healthservice providers. These providers need support in delivering the fullrange of HIV and TB prevention and care interventions. To counteractthe impact of HIV on TB, other interventions are required apart fromeffective TB case-finding and cure.These interventions includeº measures to decrease HIV transmission (e.g. promotion of condoms,treatment of sexually transmitted infections, voluntary counselling andHIV testing, safe intravenous drug use, reduction in the number ofsexual partners, prevention of mother-to-child HIV transmission, HIVscreening of blood for transfusion, and application of universal HIVprecautions by health care workers);º antiretroviral therapy (ART) (to improve or maintain immune functionin people living with HIV infection);º care for people living with HIV infection (e.g. treatment of HIV-relateddiseases, prevention of HIV-related infections,TB prevention, palliativecare and nutritional support).46AN EXPANDED FRAMEWORK FOR EFFECTIVE TB CONTROL

2.5 DOTS-PLUSHigh levels of multidrug-resistant TB (MDR-TB) in some areas threatenTB control efforts. MDR-TB is TB that is resistant to at least isoniazidand rifampicin. DOTS-Plus for MDR-TB is a comprehensive managementinitiative, built upon the five elements of the DOTS strategy. However,DOTS-Plus also takes into account specific issues, such as the use ofsecond-line anti-TB drugs.The goal of DOTS-Plus is to prevent furtherdevelopment and spread of MDR-TB. DOTS-Plus is not intended foruniversal application, and is not required in all settings. The aim ofimplementation of DOTS-Plus in selected areas with significant levels ofMDR-TB is to combat an emerging epidemic.The underlying principle isthat the first step in controlling MDR-TB is prevention by fullimplementation of DOTS. An effective DOTS-based TB controlprogramme is a prerequisite for implementation of DOTS-Plus.2SUGGESTIONS FOR FURTHER READINGInternational Union Against Tuberculosis and Lung Disease. Tuberculosis guidefor low income countries. Fifth edition. Paris, 2000.Maher D, van Gorkom JLC, Gondrie P, Raviglione MC. Community contributionto tuberculosis care in countries with high tuberculosis prevalence: past,present and future. International journal of tuberculosis and lung disease, 1999,3: 762–768.World Health Organization. Guidelines for the management of drug-resistantTuberculosis. Geneva, 1997, (WHO/TB/96.210 - Rev.1).World Health Organization. What is DOTS? A guide to understanding theWHO-recommended TB control strategy known as DOTS. Geneva, 1999,(WHO/CDS/CPC/TB/99.270).World Health Organization. Anti-tuberculosis drug resistance in the world. ReportNo.2. Prevalence and trends. Geneva, 2000 (WHO/CDS/TB/2000.278).World Health Organization. The WHO/IUATLD Global Project on anti-tuberculosisdrug resistance surveillance. Geneva, 2000.TB/HIV:A CLINICAL MANUAL47

World Health Organization. Guidelines for establishing DOTS-Plus pilot projectsfor the management of multidrug-resistant TB. Geneva, 2000(WHO/CDS/TB/2000.279).World Health Organisation. An expanded DOTS framework for effectivetuberculosis control. Geneva, 2002, (WHO/CDS/TB/2002.297).World Health Organization. A strategic framework to decrease the burden ofTB/HIV. Geneva, 2002, (WHO/CDS/TB/2002.296).World Health Organisation. Treatment of tuberculosis: guidelines for nationalprogrammes. Third edition. Geneva, 2003, (WHO/CDS/TB/2003.313).World Health Organization. Community contribution to TB care: practice andpolicy. Geneva, 2003, (WHO/CDS/TB/2003.312).World Health Organization. Guidelines for collaborative TB and HIV programmeactivities. Geneva, 2003, (WHO/CDS/TB/2003.319,WHO/HIV/2003.01).48AN EXPANDED FRAMEWORK FOR EFFECTIVE TB CONTROL

DIAGNOSIS OF PULMONARY TUBERCULOSISIN ADULTS33.1 DIAGNOSTIC APPROACHThe highest priority for TB control is the identification and cure ofinfectious cases, i.e. patients with sputum smear-positive PTB.Thereforeall patients (regardless of HIV status) with clinical features suggestive ofPTB must submit sputum for diagnostic sputum smear microscopy.Most TB suspects (people with symptoms or signs suggestive of TB) areambulatory. The diagnosis of PTB is therefore usually done on anoutpatient basis. Some TB suspects are severely ill and/or bed-bound andtherefore need investigation as inpatients.Clinical screening by assessment of symptoms identifies PTB suspectsamong patients attending health facilities. The most cost-effectivemethod of detecting TB cases among PTB suspects in high-prevalencecountries is by sputum smear microscopy.A suspect who has a positivesputum smear has sputum smear-positive PTB. The district TB officer(DTO) registers the TB patient, and treatment is started. In most casesof smear-positive PTB, a chest X-ray is unnecessary.Sometimes a patient may be negative on sputum smear microscopy butmay not improve on a broad-spectrum antibiotic. If you still suspect TB,reassess the patient and do a CXR. If the CXR is typical of PTB, registerthe patient with the DTO and start TB treatment. If doubtful about theCXR diagnosis of TB, e.g. if the CXR shows nonspecific pulmonaryinfiltrates, give the patient another course of antibiotics. If there is noclinical improvement, or if the cough disappears only to return shortlyafterwards, repeat sputum smear microscopy. If you still think the patientmay have TB despite, further negative sputum smears, again reassess thepatient and repeat the CXR.Then decide whether the diagnosis is TB ornot. In cases where diagnostic doubt persists, sputum culture may beuseful if suitable facilities are available.In populations with a high TB prevalence, the tuberculin skin test is oflittle value in the diagnosis of TB in adults.A positive tuberculin skin testdoes not by itself distinguish M. tuberculosis infection from TB disease.Previous exposure to environmental mycobacteria may also result in afalse-positive test result. Conversely, the tuberculin skin test result maybe negative, even when the patient has TB. Conditions often associatedwith a false-negative tuberculin skin test include HIV infection, severemalnutrition and miliary TB.TB/HIV:A CLINICAL MANUAL49

3.2 CLINICAL FEATURESSymptomsThe most important symptoms in the diagnosis of PTB are the following:º cough for more than 2 or 3 weeks;º sputum production;º weight loss.Over 90% of patients with sputum smear-positive PTB develop a coughsoon after disease onset. However, cough is not specific to PTB. Coughis common in smokers and in patients with acute upper or lowerrespiratory tract infection. Most acute respiratory infections resolvewithin 3 weeks.Therefore a patient with a cough for more than 2 or 3weeks is a PTB suspect and must submit sputum samples for diagnosticmicroscopy.Patients with PTB may also have other symptoms. These may berespiratory or constitutional (general or systemic).Respiratory: chest pain, haemoptysis, breathlessness.Constitutional: fever, night sweats, tiredness, loss of appetite,secondary amenorrhoea.Weight loss and fever are more common in HIV-positive PTB patientsthan in those who are HIV-negative. Conversely, cough and haemoptysisare less common in HIV-positive PTB patients than in those who areHIV-negative. This is probably because there is less cavitation,inflammation and endobronchial irritation in HIV-positive patients.Physical signsThe physical signs in patients with PTB are nonspecific.They do not helpto distinguish PTB from other chest diseases.There may be general signs,such as fever, tachycardia (fast pulse rate) and finger clubbing. Chest signs(heard through a stethoscope) may include crackles, wheezes, bronchialbreathing and amphoric breathing.There are often no abnormal signs inthe chest.PRACTICAL POINTAll PTB suspects must provide sputum samples for smearmicroscopy for TB case-detection.50DIAGNOSIS OF PULMONARY TB IN ADULTS

3.3 DIAGNOSTIC SPUTUM SMEAR MICROSCOPYCollection of sputum samplesA PTB suspect should submit three sputum samples for microscopy.Thechances of finding TB bacilli are greater with three samples than withtwo samples or one sample. Secretions build up in the airways overnight.So an early morning sputum sample is more likely to contain TB bacillithan one taken later in the day. It may be difficult for an outpatient toprovide three early morning sputum samples. Therefore in practice anout-patient usually provides sputum samples as follows:3day 1 sample 1 Patient provides an "on-the-spot" sample undersupervision when presenting to the health facility.Give the patient a sputum container to take homefor an early morning sample the following morning.day 2 sample 2 Patient brings an early morning sample.sample 3Patient provides another "on-the-spot" sampleunder supervision.Some patients cannot produce a sputum sample. A nurse orphysiotherapist may help them to give a good cough and bring up somesputum. Inpatients can follow the same method as outpatients.TerminologyMycobacteria are "acid- and alcohol-fast bacilli" (AAFB), often shortenedto "acid-fast bacilli" (AFB). The waxy coat of mycobacteria retains ananiline dye (e.g. carbol fuchsin) even after decolorization with acid andalcohol.Ziehl-Neelsen (Z-N) stainThis simple stain detects AFB.This is how to perform the Z-N stain:º Fix the smear on the slide.º Cover the fixed smear with carbol fuchsin for 3 minutes.º Heat, rinse with tapwater, and decolorize with acidalcoholfor 3–5 seconds.º Counterstain with methylene blue for 30 seconds.º Rinse again with tapwater.º Observe under the microscope (use the x100 oil immersion lensand x10 eyepiece lens).The bacilli appear as red, beaded rods, 2–4 µm long and 0.2–0.5 µmwide.TB/HIV:A CLINICAL MANUAL51

Fluorochrome stainUse of this stain to detect TB bacilli requires a special fluorescencemicroscope.The fluorochrome stain is phenolic auramine or auraminerhodamine.After acid-alcohol decolorization and a methylene bluecounterstain, the bacilli fluoresce bright yellow against a darkbackground.The advantage of this method is that smears can be scannedquickly under low magnification. It is important to check fluorochromestain-positive smears using the Z-N stain.Slide reportingThe number of bacilli seen in a smear reflects disease severity andpatient infectivity. Therefore it is important to record the number ofbacilli seen on each smear.The table below shows the standard methodof reporting using 1000 x magnification.Number of bacilliResult reportedno AFB per 100 oil immersion fields 01–9 AFB per 100 oil immersion fields scanty (or number AFB seen)10–99 AFB per 100 oil immersion fields + (1+)1–10 AFB per oil immersion field ++ (2+)> 10 AFB per oil immersion field +++ (3+)Laboratory technicians should examine all three sputum samples fromeach TB suspect. They must record the result of each sputum samplewith the laboratory reference number in the laboratory register and onthe sputum request form. Results as indicated above are made availableto the clinician who can then categorize the patient. Categorizingpatients as smear-positive or negative requires results from more thanone smear. A guide to classification of patients with pulmonarysymptoms is given below.Smear-positive Indeterminate Smear negativeAt least 2 smears Several possibilities, e.g. At least two smearsexamined and both º only one smear examined reported 0positive, i.e. reported (whatever the grading) (negative)1–9 per 100 fields º 3 smears examined but(scanty) or greater only one reported positiveIn either of thesesituations, either furthersputum smears or a CXRare required before apatient can be classified.52 DIAGNOSIS OF PULMONARY TB IN ADULTS

Sensitivity of sputum smear microscopySputum smear microscopy for tubercle bacilli is positive when there areat least 10000 organisms present per ml of sputum.3Sputum microscopy in HIV infectionSputum smear positivity rates in TB/HIV patients depend on the degreeof immunocompromise, as shown below.Degree ofimmunocompromisemildsevereLikelihood of positive sputum smearsimilar to HIV-negative patientdecreased(decreased inflammation in lungs)False-positive results of sputum smear microscopyA false-positive result means that the sputum smear result is positiveeven though the patient does not really have sputum smear-positivePTB. This may arise because of the following: red stain retained byscratches on the slide; accidental transfer of AFBs from a positive slideto a negative one; contamination of the slide or smear by environmentalmycobacteria; presence of various particles that are acid-fast (e.g. foodparticles, precipitates, other microorganisms).False-negative results of sputum smear microscopyA false-negative result means that the sputum smear result is negativeeven though the patient really does have sputum smear-positive PTB.This may arise because of problems in collecting, processing, orinterpreting sputum smears, or because of administrative errors.PRACTICAL POINTA sputum smear result may be unexpectedly negative (e.g.in a patient with upper lobe cavities on CXR).Think of thepossibility of a false-negative result and repeat the sputummicroscopy.Causes of false negative results of sputum smear microscopyType of problem Examplesputum collection patient provides inadequate sampleinappropriate sputum container usedsputum stored too long before smear microscopysputum processing faulty sampling of sputum for smearfaulty smear preparation and stainingsputum smear inadequate time spent examining smearinterpretation inadequate attention to smear (poor motivation)TB/HIV:A CLINICAL MANUAL53

administrative errorsmisidentification of patientincorrect labelling of samplemistakes in documentation3.4 DIFFERENTIAL DIAGNOSIS OF PULMONARY TBPRACTICAL POINTA PTB suspect with 3 negative sputum smears may not havePTB. Reassess the patient for conditions that may bemistaken for PTB.The table shows possible alternative diagnoses.Diagnosisbronchiectasisbronchial carcinoma(lung cancer)other infections, e.g.bacterial pneumonialung abscessPneumocystis cariniicongestive cardiac failureleft ventricular failureasthmachronic obstructiveairways diseasePointers to the correct diagnosiscoughing large amounts of purulentsputumrisk factor (smoking, older age,previous mine-work)usually shorter history, febrile, responseto antibioticcough with large amounts of purulentsputumabscess with fluid level on CXRoften dry, non-productive cough withprominent dyspnoeasymptoms of heart failure(dyspnoea, orthopnoea, paroxysmalnocturnal dyspnoea, haemoptysis, oedema,epigastric discomfort from hepaticcongestion)signs of heart failureintermittent symptoms, generalizedexpiratory wheeze;symptoms wake the patient at nightrisk factor (smoking), chronic symptoms,prominent dyspnoea, generalized wheeze,signs of right heart failure (e.g. ankle oedema)54DIAGNOSIS OF PULMONARY TB IN ADULTS

PRACTICAL POINTIf the patient is breathless, has continuing haemoptysis, andhas negative sputum smears, listen carefully for a lowpitched,rumbling, mid-diastolic murmur, indicating mitralstenosis with pulmonary oedema.33.5 CHEST X-RAY IN DIAGNOSISIndications for CXRPositive sputum smearThe first screening test for PTB suspects is sputum smear microscopy.In most cases of sputum smear-positive PTB a CXR is not necessary. Ina few cases, a CXR may be necessary; the indications are as follows:(a) suspected complications in a breathless patient, needing specifictreatment, e.g. pneumothorax, pericardial effusion or pleural effusion(note that a positive sputum smear is rare in pericardial effusion andpleural effusion);(b) frequent or severe haemoptysis (to exclude bronchiectasis oraspergilloma);(c) only 1 sputum smear positive out of 3 (in this case, an abnormalCXR is a necessary additional criterion for the diagnosis of sputumsmear-positive PTB).Negative sputum smearReassess patients who continue to cough despite a course of broadspectrumantibiotic, and who have had at least two (and preferablythree) negative sputum smears. If you still suspect TB despite negativesputum smears, the patient needs a CXR.3.6 RADIOGRAPHIC ABNORMALITIES SEEN INPULMONARY TBPRACTICAL POINTNo CXR pattern is absolutely typical of PTB, especially withunderlying HIV infection.The table below shows so-called "classical" and "atypical" CXR patterns.The classical pattern is more common in HIV-negative patients, and theatypical pattern in HIV-positive patients.TB/HIV:A CLINICAL MANUAL55

CLASSICAL PATTERNupper lobe infiltratesbilateral infiltratescavitationpulmonary fibrosis and shrinkageATYPICAL PATTERNinterstitial infiltrates (especiallylower zones)intrathoracic lymphadenopathyno cavitationno abnormalitiesPRACTICAL POINTCXR changes in TB/HIV patients reflect the degree ofimmunocompromise. In mild immunocompromise, theappearance is often classical (with cavitation and upper lobeinfiltrates). In severe immunocompromise, the appearanceis often atypical.3.7 DIFFERENTIAL DIAGNOSIS OF CHEST X-RAYFINDINGSThe CXR findings associated with PTB may be nonspecific. Diseasesother than PTB can cause both the "classical" and the "atypical" CXRfindings.PRACTICAL POINTThe vast majority of patients with cavitary PTB (over 90%)are sputum smear-positive.Therefore, a patient with cavitieson CXR and repeated negative sputum smears probably hasa disease other than PTB.The table shows the differential diagnosis of CXR findings oftenassociated with PTB.CXR findingcavitationDifferential diagnosisinfectionssome bacterial pneumoniasnocardiosismelioidosisparagonimiasis (lung fluke)lung abscesssome fungal infections56 DIAGNOSIS OF PULMONARY TB IN ADULTS

cavitationunilateral infiltrationbilateral infiltrationmediastinal lymphadenopathynon-infectious diseasebronchial carcinomaconnective tissue diseaseoccupational lung diseasepneumoniabronchial carcinomapneumoniaconnective tissue diseaseoccupational lung diseasesarcoidosislymphomabronchial carcinomasarcoidosis33.8 THE PLACE OF MYCOBACTERIAL CULTURE INTHE DIAGNOSIS OF TBLaboratory culture of M tuberculosisWhen M. tuberculosis is cultured from clinical specimens (e.g. sputum,lymph node aspirate, cerebrospinal fluid) this provides the gold standardfor the definitive diagnosis of TB. Tubercle bacilli that have grown inculture can also be tested in vitro for sensitivity to anti-TB drugs. Theusual culture medium is Löwenstein Jensen, although liquid culturemedia and automated systems (e.g. Bactec) can also be used in moresophisticated laboratories.Limitations of mycobacterial culture for diagnosisM. tuberculosis is a slow-growing organism, and it often takes between 6and 8 weeks before cultures become positive. Culture results maytherefore not be helpful in making a rapid individual diagnosis, althoughthey can be helpful retrospectively. There is also the need forconsiderable laboratory infrastructure and laboratory skills in order tosustain a mycobacterial culture facility. Most developing countries haveone or two mycobacterial reference centres where cultures and drugsensitivity analysis can be performed. However, most hospitals will nothave TB culture facilities readily available.3.9 SEPSIS AND CONCOMITANT TBSepsis can occur as a coinfection with TB. An inadequate clinicalresponse after treatment of sepsis, e.g. pneumonia, may be due to thepresence of concomitant HIV-related TB.TB/HIV:A CLINICAL MANUAL57

3.10 DISTINGUISHING OTHER HIV-RELATEDPULMONARY DISEASES FROM PULMONARY TBThis is a common, and often difficult, diagnostic problem. Severaldiseases in HIV-positive individuals may present in a similar way, withcough, fever, sometimes chest signs, and CXR shadowing. Pneumonia isthe most frequent and important differential diagnosis. Pneumonia canalso occur as a coinfection with TB. In each case, a careful clinicalassessment is needed. Send sputum samples for AFBs if the patient hashad cough for 3 weeks or more.Acute bacterial pneumoniaThis is common in HIV-positive patients. The shorter history usuallydifferentiates pneumonia from PTB. The most common pathogen isStreptococcus pneumoniae. Regardless of HIV status, acute bacterialpneumonia usually responds well to standard treatment with penicillin,cotrimoxazole or ampicillin.PRACTICAL POINTIf a patient with presumed pneumonia fails to respond to afull course of standard antibiotics, consider other pathogens,e.g. M. tuberculosis.Kaposi sarcoma (KS)The clinical recognition of KS is straightforward when there are typicallesions on the skin and mucous membranes.The diagnosis of pulmonaryor pleural KS is more difficult.The patient usually presents with cough,fever, haemoptysis and dyspnoea, and usually has KS lesions elsewhere.CXR shows a diffuse nodular infiltrate (with infiltrates spreading outfrom the hilar regions) or pleural effusion. The pleural fluid is usuallyblood-stained. Cytology may provide the diagnosis. It can be difficult torule out concurrent PTB.Pneumocystis carinii pneumonia (PCP)Adult PCP is less commonly seen in patients with AIDS in sub-SaharanAfrica than in developed countries.The patient usually presents with drycough and progressive dyspnoea.The table below shows the clinical andCXR features that help to distinguish PCP from PTB.58DIAGNOSIS OF PULMONARY TB IN ADULTS

Clinical and CXR features of PCP and TBTypical of PCP Typical of TBsymptoms dry cough productive coughsputum mucoid (if any) purulent sputumdyspnoeapleuritic chest painhaemoptysissigns may be normal signs of consolidationfine inspiratory crackles signs of pleural effusionCXR bilateral diffuse lobar consolidationinterstitial shadowing cavitationmay be normalpleural effusionintrathoraciclymphadenopathy3The definitive diagnosis of PCP rests on finding the cysts in inducedsputum, broncho-alveolar lavage or biopsy specimens. Theseinvestigations are often not possible in district hospitals. The diagnosistherefore depends on the clinical and CXR features, exclusion of TB andresponse to a trial of high-dose cotrimoxazole, combined withcorticosteroids if there is severe dyspnoea.Other conditionsOther uncommon conditions are cryptococcosis and nocardiosis.Theymay present in a similar way to TB. The diagnosis of pulmonarycryptococcosis rests on finding the fungal spores in sputum smears.Nocardiosis may be particularly difficult to differentiate from TB. TheCXR often shows upper lobe, cavitary infiltrates.The organism may alsobe weakly positive on acid-fast staining.Associated soft-tissue and brainabscesses raise clinical suspicion.The diagnosis rests on finding beadedand branching Gram-positive rods on sputum smear. In South-East Asia,penicilliosis (due to a fungus called Penicillium marneffei) and melioidosiscan present in a similar way to PTB and may be HIV-related.The same istrue for common fungal infections (paracoccidioidomycosis andhistoplasmosis) in the Americas.TB/HIV:A CLINICAL MANUAL59

SUGGESTIONS FOR FURTHER READINGCrofton J, Horne N, Miller F. Clinical tuberculosis, second edition.London, MacMillan Press Limited, 1999.Harries AD, Maher D, Nunn P. An approach to the problems of diagnosing andtreating adult smear-negative pulmonary tuberculosis in high-HIV-prevalencesettings in sub-Saharan Africa. Bulletin of the World Health Organization, 1998,76: 651–662.International Union Against Tubertculosis and Lung Disease. Technical guide.Sputum examination for tuberculosis by direct microscopy in low-income countries.Fifth edition. Paris, 2000.Toman K. Tuberculosis. Case finding and chemotherapy. Geneva,WHO, 1979.World Health Organization. Tuberculosis handbook. Geneva, 1998,(WHO/TB/98.253).60DIAGNOSIS OF PULMONARY TB IN ADULTS

DIAGNOSIS OF PULMONARY TUBERCULOSISIN CHILDREN44.1 EPIDEMIOLOGY OF CHILDHOOD TBThe source of transmission of TB to a child is usually an adult (often afamily member) with sputum smear-positive PTB. Cases of TB in childrenusually represent between 10% and 20% of all TB cases.The frequencyof childhood TB in a given population depends on the following: thenumber of infectious cases, the closeness of contact with an infectiouscase, the age of children when exposed to TB, and the age structure ofthe population. Children rarely have sputum smear-positive TB and so itis unlikely they are a powerful source of transmission.TB in children ismainly due to failure of TB control in adults. Failure of TB control inadults means failure to cure infectious cases (patients with sputumsmear-positive PTB). The highest priority in TB control is to cure theinfectious cases. However, it is still important to cure children with TB!Good treatment of TB in childhood will result in the following:a) improved well-being through decreased morbidity and mortality;b) improved credibility and reputation of the NTP; and c) less chance forchildren to have TB reactivation with cavitation in later life.PRACTICAL POINTA good TB control programme is the best way to prevent TBin children.ImmunizationIn many countries, newborns receive BCG immunization, and yetchildhood PTB still occurs.This shows that BCG is not fully effective inprotecting against PTB. BCG seems to give better protection againstdisseminated disease, such as miliary TB or TB meningitis, than it doesagainst PTB. The effectiveness of BCG against PTB is variable betweenregions, and the reasons for this are not completely understood. Oneproblem is likely to be the timing of the vaccination. In developingcountries where TB is common, children will often be exposed to TBearly in life and so immunization needs to be given as early as possible,i.e. soon after birth. However, the immune system of a newborn may betoo immature to be able to produce an effective immune reaction to theBCG. BCG has been more effective when given to school-aged children.However, in communities where TB is common, this would be too lateto protect against most disease. Other factors that reduce theTB/HIV:A CLINICAL MANUAL61

effectiveness of BCG immunization are malnutrition and severeinfections such as HIV or measles.Risk of infectionRisk of infection depends on extent of exposure to infectious dropletnuclei. An infant whose mother has sputum smear-positive PTB, forinstance, has a high chance of becoming infected. Being in very closecontact with the mother, he or she is likely to inhale a larger number ofinfectious droplets from the air than other household contacts. Thegreater the exposure to infection, the greater the likelihood of disease.Risk of progression of infection to diseaseThe chance of developing disease is greatest shortly after infection, andsteadily decreases as time goes by. Infants and young children under 5years of age have less-developed immune systems than school-agedchildren.They are therefore at particular risk (up to 20%) of developingdisease following infection. Many will present with disease within oneyear following infection, most within 2 years. For infants particularly, thetime-span between infection and disease may be quite short and thepresentation of PTB is as an acute rather than chronic pneumonia.Almostalways in those cases, the contact is the mother. The majority of HIVnegativechildren infected with M. tuberculosis do not develop TB diseasein childhood. In these healthy, asymptomatic, but TB-infected children, theonly evidence of infection may be a positive tuberculin skin test.PRACTICAL POINTThe suspicion of TB in an infant should lead to investigationof the mother for PTB. If there is no definite history of TB inthe mother, ask also about a history of chronic cough.An infected child can develop TB disease at any time.Various illnesses orstresses may trigger progression of infection to disease. The mostimportant trigger is weakening of immune resistance. This occurs withHIV infection, other infections (especially measles and whooping cough)and malnutrition.These conditions are also most common in infancy andearly childhood.4.2 HOW DOES TB IN CHILDREN DIFFER FROM TBIN ADULTS?The commonest age of presentation of childhood TB disease is between1 and 4 years. As already emphasized, young age is a risk factor forinfection, for progression from infection to disease, and for spread of62 DIAGNOSIS OF PULMONARY TB IN CHILDREN

disease to other parts of the body, i.e. dissemination. Most children withTB are not infectious to others.The commonest type of TB in children is smear-negative PTB. This isbecause cavitating TB is infrequent in children.The majority of childrenwith PTB are too young to provide a sputum specimen for smearmicroscopy.Therefore an alternative method of obtaining sputum, suchas gastric aspiration, is required. If alternative diagnostic methods are notavailable or routinely practised, the children are registered as having“smear-negative PTB”, even though a smear has not been done.The nextcommonest type is extrapulmonary TB. Common forms of EPTB inchildren include: miliary TB and TB meningitis (usually in children lessthan 3 years of age);TB lymphadenopathy (all ages);TB effusions (pleural,pericardial and peritoneal); and spinal TB (often school-aged children)(see Chapter 5). Smear-positive PTB is usually diagnosed in childrenolder than 6 years.The prevalence of PTB is normally low between 5 and12 years and then increases in adolescents. In adolescents, PTB isgenerally like adult PTB, e.g. often with cavitation.4PathogenesisTB disease in children is usually primary TB. Post-primary TB may occurin adults following reactivation of dormant TB bacilli acquired inchildhood. The age when a child is infected determines the pattern ofprimary disease. Pulmonary disease in young children is closely linked topathology of the mediastinal nodes. This is lymphobronchial TB, whichresults in a wide spectrum of segmental lesions.These lesions may alsobe found in adults, but are unusual. Adults usually develop TB in theapices of the upper or lower lobes.Young children (i.e. less than 5 yearsof age) are particularly susceptible to severe forms of disseminateddisease following primary infection. These severe forms include miliaryTB and extrapulmonary forms of TB, e.g. meningitis.PRACTICAL POINTMalnourished and HIV-infected children may develop severePTB at any age.4.3 APPROACH TO DIAGNOSIS OF TBThe diagnosis of PTB in children is difficult. If you find the diagnosis ofPTB in children easy, you are probably overdiagnosing. It is easy tooverdiagnose PTB, but also easy to miss the diagnosis and presume theTB/HIV:A CLINICAL MANUAL63

clinical presentation is due to malnutrition or AIDS. Carefully assess allthe evidence before making the diagnosis.The diagnosis of PTB is particularly difficult in children because, underthe age of 6–8 years, children with PTB rarely cough up sputum. Thereadily available usual test for adults and older children with PTB issputum smear microscopy. However, there is no such “gold standard”test for the majority of children with TB.Young children usually swallowtheir sputum. Gastric suction and laryngeal swabs are generally notuseful unless facilities are available for M. tuberculosis culture.This meansthat bacteriological confirmation is usually not possible.The diagnosis ofPTB in children is therefore nearly always presumptive.The approach to diagnosis of extrapulmonary TB in children is similar tothat described for adults and is outlined in Chapter 5. In some hospitals,helpful special diagnostic investigations may be available. These mayinclude microscopy of fluid (e.g. pleural fluid, cerebrospinal fluid, asciticfluid) and TB culture, specialized X-rays, biopsy and histology.Clinical assessmentThere are no specific features on clinical examination that can confirmthat the presenting illness is due to PTB. Respiratory symptoms anddisease are extremely common in childhood, particularly before 5 yearsof age. In most cases of suspected PTB, the child has been treated witha broad-spectrum antibiotic, with no clinical response. Always look forthree important clues to TB in children:(1) Contact with an adult or older child with smear-positive PTB.It is usually possible to identify the source of infection.This is mostoften the child’s mother or another female carer, such as an aunt,grandmother or older sister. They are the ones who spend mosttime with young children. Make sure you ask for a specific history ofillness in each household contact. For example, do not just ask “doesanyone in the home have TB?” but also “is anyone at home ill andwhat are the symptoms?” Remember that the contact may haveoccurred 6 months to 2 years ago. This is the usual time lapsebetween infection and developing symptoms of disease. Adult casesof PTB are occasionally diagnosed when a child presents withsuspected TB.(2) Failure to thrive or weight loss (growth faltering).This is a good indicator of chronic disease in children and TB may bethe cause. It is not specific and may also be due to poor nutrition,persistent or recurrent diarrhoea or HIV infection.64 DIAGNOSIS OF PULMONARY TB IN CHILDREN

(3) Respiratory symptoms such as cough lasting for more than threeweeks in a child who has received a course of broad-spectrumantibiotics.4PRACTICAL POINTAsk the mother of a child with suspected TB for the child's"road to health" card (growth card). If the card is available,look for growth faltering or weight loss.In the absence of these clues, TB is less likely. However, always take aclear history and examine the child carefully. There may be clues toother diagnoses, such as asthma or an inhaled foreign body. Note thenutritional state of the child and look for signs of HIV infection (seeChapter 7). Examine the chest.There may be unexpected findings, suchas consolidation or pleural effusion. A child with these abnormalitieswho does not look acutely unwell (e.g. no signs of respiratory distresssuch as tachypnoea) and has not recently had antibiotics is more likelyto have TB rather than the more common bacterial pneumonias. Finally,do not forget to examine the heart. Otherwise children with cardiacfailure due to congenital heart disease, rheumatic heart disease orcardiomyopathy may be misdiagnosed as having PTB.InvestigationsIf available, a tuberculin skin test should be done, as it may providesupportive evidence. A negative tuberculin test does not exclude TB.The tuberculin test is discussed in Section 4.5.CXR is a common investigation in suspected PTB or miliary TB. Themost consistent specific feature on CXR is nodal enlargement and thiswill be present in many children with PTB. Cavitation may be seen inolder children and adolescents, who will often be sputum smearpositive.Anormal CXR can be useful to exclude PTB or miliary TB in achild with suggestive symptoms, such as persistent fever, night sweatsand failure to thrive.A single CXR at the time of presentation of illnesshas limited value.A child presenting with persistent cough should receivea course of broad-spectrum antibiotics, with a follow-up CXR at leastone month later. As for clinical examination, marked abnormalities areoccasionally found on CXR in a child who does not look acutely unwell.This is suggestive of PTB.The usefulness of the tuberculin test and CXR are further reduced inmalnourished or HIV-infected children (see Section 4.5). This isTB/HIV:A CLINICAL MANUAL65

unfortunate as these are common conditions that the health workeroften needs to differentiate from TB. To add to the confusion, bothgroups are at particular risk for TB disease.Differential diagnosis of chronic respiratory symptomsOther conditions that present with chronic respiratory symptomsinclude:º pertussis (whooping cough)º asthmaº HIV infection (see section 4.8)º aspirated foreign bodyº bronchiectasisº cystic fibrosisº cardiac diseaseº severe gastro-oesophageal refluxº severe cerebral palsy4.4 SCORE SYSTEM FOR DIAGNOSIS OF TB INCHILDRENThere are a number of diagnostic score charts to improve diagnosis ofTB in children.These score charts have rarely been evaluated.The basisof a score system is the careful and systematic collection of diagnosticinformation. A score system is, in fact, not diagnostic but is rather auseful screening test that helps guide your clinical judgement. A scoreabove a certain threshold indicates a high likelihood of TB. Examples canbe found in Clinical tuberculosis (Crofton, Horne & Miller) or in the articleby van Beekhuizen in Tropical doctor (see “Suggestions for furtherreading” at the end of the chapter).Characteristic clinical features (e.g. spinal deformity, scrofula or painlessascites) supported by simple investigations often point to the diagnosisof various forms of extrapulmonary TB. These permit a confidentdiagnosis of TB, even if rarely confirmed microbiologically. However, thecommonest type is PTB and this is the most difficult to diagnose. Scorecharts are least useful for PTB because they are so nonspecific in regionswhere malnutrition and HIV are common. Features suggestive of TB (andcommonly used in score charts) include:º duration of illness greater than 4 weeks, particularly if the illness hasnot responded to other treatments, e.g. broad-spectrum antibioticsfor persistent cough;66 DIAGNOSIS OF PULMONARY TB IN CHILDREN

º evidence of wasting (i.e. under 60% of median weight-for-age),especially if there is a lack of weight gain in response to intensivenutritional support;º family history of sputum-positive PTB (this is very importantinformation);º significant or “positive” tuberculin test.4Some score charts use response to TB treatment as a factor supportinga diagnosis of TB.This does not mean that a TB treatment trial should beused for diagnostic purposes!4.5 TUBERCULIN SKIN TESTTuberculin is a purified protein derived from tubercle bacilli. Anothername for tuberculin is PPD (purified protein derivative). Followinginfection with M. tuberculosis, a person develops hypersensitivity totuberculin. Tuberculin injected into the skin of an infected personproduces a delayed local reaction after 24–48 hours. This reaction isquantified by measuring the diameter of skin induration (thickening) atthe site of the reaction. Various conditions can suppress this reaction.The reaction indicates hypersensitivity. In other words, the reactiononly shows that the person has at some time be infected with M.tuberculosis.PRACTICAL POINTA tuberculin test does not measure immunity. By itself, itdoes not indicate the presence or extent of TB disease; itonly indicates infection.The technical details about tuberculins and how to administer and reada tuberculin test are beyond the scope of this book. Clinical tuberculosis(Crofton, Horne & Miller) gives a good account.The standard amount oftuberculin used is 5 units, injected as 0.1 ml into the anterior surface ofthe forearm at the junction of the middle and upper thirds. It is veryimportant that the tuberculin is injected intradermally so that it is welllocalized. If correctly given, the injection should raise a small bump of 5mm or more in diameter, which disappears within 1–2 hours.This is noteasy in a vigorous and protesting child. Poor injection technique cancause a false-negative reaction.TB/HIV:A CLINICAL MANUAL67

Value of a negative tuberculin testA tuberculin test is not significant, or “negative”, when the diameter ofskin induration is less than 10 mm (or less than 5 mm in an HIV-infectedchild). This is regardless of whether the child has had BCG. A negativetuberculin skin test does not exclude TB.Thus, it is of no help in decidingthat someone does not have TB.The table below shows the conditionsthat can suppress a tuberculin skin test in a person with active TB.Conditions that may suppress the tuberculin skin testHIV infectionmalnutritionsevere bacterial infections, including TB itselfviral infections, e.g. measles, chickenpox, glandular fevercancerimmunosuppressive drugs, e.g. steroidsincorrect injection of PPDValue of a positive tuberculin skin testThe criterion for a significant or “positive” tuberculin test depends onwhether a child has previously had BCG vaccination or not. This isbecause a reaction to tuberculin is usual after a previous BCG, at leastfor several years.The reaction is usually weaker (diameter often less than10 mm) than the reaction to natural infection with M. tuberculosis. Atuberculin test is considered significant or positive when the diameter ofskin induration is 10 mm or more. However, if the child is HIV-infected,the tuberculin test is considered positive if the induration is 5 mm ormore. A positive tuberculin test is only one piece of evidence in favourof the diagnosis of TB. The younger the child and the greater thediameter of induration, the stronger is that one piece of evidence.4.6 THE DECISION TO START TB TREATMENT INCHILDRENThe decision to start TB treatment in a child is an active process, whichinvolves weighing up the clinical evidence and investigation findings,careful thought, and often a period of observation. For children withconfirmed TB or for whom there is a high likelihood of TB, there is noneed to hesitate about starting treatment. If the diagnostic evidence isweak and the child is older and not acutely ill, there is no need foranxiety or urgency about starting treatment.Wait and see! If, however,the child is very young and acutely ill it may be necessary to starttreatment on the basis of less robust evidence.68 DIAGNOSIS OF PULMONARY TB IN CHILDREN

In the past, some doctors have advocated a “treatment trial” with anti-TB drugs for purposes of diagnosis.The idea is that if the child respondsto the treatment, then the diagnosis is TB.There are some problems withthis approach:4a) some anti-TB drugs, such as rifampicin, kill other bacteria, soresponse to anti-TB drugs may be because the child has another(bacterial) infection;b) compliance with a "treatment trial" is often poor, because of the lackof certainty surrounding the decision to treat;c) there may be a tendency to jump too quickly to a "treatment trial"without the necessary careful and thoughtful approach to diagnosis;d) a hasty “treatment trial” may not leave enough time to givetreatment for other more common infections, such as bacterial oratypical pneumonia;e) once TB treatment is started, it should be completed.4.7 IMPACT OF HIV ON THE DIAGNOSIS OF TBIN CHILDRENHIV makes the diagnosis and management of TB in children even moredifficult than usual, for the following reasons:a) Several HIV-related diseases, including TB, may present in a similarway (see section 4.8 for differential diagnosis).b) The interpretation of tuberculin skin testing is less reliable. Animmunocompromised child may have a negative tuberculin skin testdespite having TB.c) In some countries HIV infection is very common in adults with TB.If there is a history of contact with an adult with smear-positive PTBand that adult is the child’s parent, then the child has an increasedchance of being HIV infected as well. In addition, the child with TB,even if not HIV-infected, may come from a household where one orboth parents have died. This situation makes compliance andcompletion of treatment more difficult.For these reasons and those mentioned above, many of the clinicalfeatures that are used to suggest a diagnosis of childhood TB are lessuseful in the presence of HIV infection.TB/HIV:A CLINICAL MANUAL69

Impact of HIV infection on the usefulness of features used todiagnose PTB in childrenDiagnostic featureChronic symptomsSmear-positive contact (if parent)Malnutrition or failure to thrivePositive tuberculin test“Characteristic” CXR abnormalitiesSatisfactory response to TB treatmentImpact of HIVless specificless specificless specificless sensitiveless specificless sensitive4.8 DIFFERENTIAL DIAGNOSIS OF PULMONARY TBIN HIV-INFECTED CHILDRENBacterial pneumoniaBacterial pneumonia is very common in all HIV-infected children andrecurrent bacterial pneumonia is a feature of children with AIDS. Thecommonest cause is Streptococcus pneumoniae and response totreatment is usually satisfactory. Other causes include Haemophilusinfluenzae, Salmonella, Staphylococcus aureus, Klebsiella pneumoniae andEscherichia coli.The presentation of PTB in infants can be acute, so PTBshould be considered when there is a poor clinical response to standardantibiotics and the mother has TB. Pneumonia due to Staphylococcus orKlebsiella may be a problem in HIV-infected children with chronic lungdisease.These bacteria can cause cystic changes and cavitation.Lymphocytic interstitial pneumonitis (LIP)LIP is a very common cause of lung disease in HIV-infected children over2 years of age. LIP may be difficult to differentiate from PTB or miliaryTB. Clinical features that are commonly associated with LIP includesymmetrical, generalized lymphadenopathy (painless and mobile),bilateral chronic non-tender parotid enlargement, and finger clubbing.Diagnosis is clinical as it can only be confirmed by lung biopsy. TypicalCXR findings are bilateral diffuse reticulonodular pattern and enlargedmediastinal/hilar lymph nodes. Note that the CXR abnormalities areoften unilateral with PTB. However, LIP presents with a broad spectrumof clinical and radiological features. Bacterial pneumonia is a commoncomplication and further confuses the CXR findings.BronchiectasisThis is usually a complication of LIP but may also complicate TB.A cough70 DIAGNOSIS OF PULMONARY TB IN CHILDREN

productive of copious purulent and sometimes blood-stained sputum,finger clubbing, and halitosis are typical features.Pulmonary Kaposi sarcomaKS can involve the lungs and causes diffuse lung infiltration and lymphnode enlargement. Patients may present with a large pleural effusionwhich is bloody on aspiration. Look for the typical KS lesions elsewhere:on the skin, palate or conjunctiva.4Pneumocystis carinii pneumoniaPCP is a common problem in HIV-infected children and usually presentsas an acute, severe pneumonia in infants less than 6 months of age.Compared with TB in infants, PCP is characterized by severe hypoxia.The commonest CXR abnormalities are diffuse interstitial infiltrationand hyperinflation. In developing countries, PCP is a very unlikelydiagnosis of persistent respiratory disease in children after infancy. Incountries where there is antenatal HIV screening and routinecotrimoxazole prophylaxis in HIV-infected infants, PCP is now unusual .OthersOther conditions to be considered in the differential diagnosis include:fungal pneumonia, e.g. due to Candida or cryptococcus, nocardiosis andpulmonary lymphoma.PRACTICAL POINTThe commonest HIV-related lung disease in children thatmay be confused with TB is LIP.4.9 MANAGEMENT OF CHILD CONTACTS OFINFECTIOUS ADULTSChildren with TB may present to health units when they are ill. However,most national TB control programmes also recommend active contacttracing of children who are household contacts of infectious adults. Inorder to be effective, this screening must be systematic. If you do nothave a systematic, organized process for child contact screening whereyou work, could you start one?The scheme below shows how to manage child contacts of infectiousadults (with sputum smear-positive PTB). Suspicion that a child contactis HIV-infected may arise because of the following: the child has clinicalTB/HIV:A CLINICAL MANUAL71

evidence of HIV infection; the parent (the infectious TB patient) isknown, or suspected, to be HIV-positive. If you suspect a child contact isHIV-infected, it is important to counsel the parents before HIV-testingthe child.How to identify and manage child contacts of infectious adultstarget group ofinfectious adultsadults with sputumsmear-positive PTBidentify allchildren at riskhousehold childcontactsselect childrenfor screeningall children < 5 yearschildren of any age with cough > 3 weeksscreeningprocesshistory and examinationtuberculin skin test and CXR (whereresources permit)outcome of TB TB TBscreening unlikely possible highly likelytreat forconfirmaction other possibilities diagnosisand re-evaluateisoniazidprophylaxisfor allchildren< 5 yearsregister andtreat for TBA child under 5 years of age living with a sputum smear-positive PTBpatient is at high risk of TB infection and developing TB disease, especiallyif HIV-positive. Tuberculin skin testing is not a reliable way of72 DIAGNOSIS OF PULMONARY TB IN CHILDREN

distinguishing TB-infected from non-TB-infected children and is oftennot available. The IUATLD therefore recommends isoniazid preventivetreatment for all child household contacts (under 5 years of age) ofsputum smear-positive PTB patients.The preventive treatment should bebased on the drug sensitivity profile of the likely source of infection,whenever this profile is available.4SUGGESTIONS FOR FURTHER READINGChaulet P et al. Childhood tuberculosis, still with us. Paris, International Children’sCentre, 1992.Crofton J, Horne N, Miller F. Clinical tuberculosis, second edition. London,MacMillan Press Limited, 1999.Donald PR, Fourie PB, Grange JM. Tuberculosis in childhood. Pretoria, JL vanSchaik, 1999.Graham SM, Coulter JBS, Gilks CF. Pulmonary disease in HIV-infected Africanchildren. International journal of tuberculosis and lung disease, 2001, 5: 12-23.Hesseling AC, Schaaf HS, Gie RP, Starke JR, Beyers N. A critical review ofdiagnostic approaches used in the diagnosis of childhood tuberculosis.International journal of tuberculosis and lung disease, 2002, 6: 1038-1045.International Union Against Tuberculosis and Lung Disease. Tuberculosis guidefor low income countries. 5 th edition, Frankfurt, pmi Verlagsgruppe, 2000.Miller FJW. Tuberculosis in children. New Delhi, Churchill-Livingstone, 1986.Mukadi YD, Wiktor SZ, Coulibaly I-M, et al. Impact of HIV infection on thedevelopment, clinical presentation, and outcome of tuberculosis amongchildren in Abidjan, Cote d’Ivoire. AIDS, 1997, 11: 1151-1158.TB/HIV:A CLINICAL MANUAL73

Osborne CM. The challenge of diagnosing childhood tuberculosis in adeveloping country. Archives of diseases in childhood, 1995, 72: 369-74.Palme IB, Gudetta B, Bruchfeld J, Muhe L, Giesecke J. Impact of humanimmunodeficiency virus 1 infection on clinical presentation, treatment outcomeand survival in a cohort of Ethiopian children with tuberculosis. The pediatricinfectious disease journal, 2002, 21: 1053-1061.Reider HL. Epidemiologic basis of tuberculosis control. Paris, International UnionAgainst Tuberculosis and Lung Disease, 1999.Schaaf HS, Beyers N, Gie RP, et al. Respiratory tuberculosis in childhood: thediagnostic value of clinical features and special investigations. The pediatricinfectious disease journal, 1995, 14: 189-194.Van Beekhuizen HJ.Tuberculosis score chart in children in Aitape, Papua NewGuinea. Tropical doctor, 1998, 28: 155-160.74DIAGNOSIS OF PULMONARY TB IN CHILDREN

DIAGNOSIS OF EXTRAPULMONARYTUBERCULOSIS IN ADULTS AND CHILDREN5Extrapulmonary TB (EPTB) can occur at any age.Young children and HIVpositiveadults are particularly susceptible. Up to 25% of TB cases maypresent with EPTB. Children of less than 2 years of age are at risk ofdisseminated disease causing miliary TB or TB meningitis.The commonforms of extrapulmonary TB associated with HIV are the following:lymphadenopathy, pleural effusion, pericardial disease, miliary TB, andmeningitis. Many patients with extrapulmonary TB also have coexistentpulmonary TB.PRACTICAL POINTIf a patient has extrapulmonary TB, look for pulmonary TB.If the patient has had a productive cough for more than 2 or3 weeks, send sputum samples for AFB. If testing AFBs thetest is negative, do a CXR.5.1 DIAGNOSTIC APPROACHDefinitive diagnosis of extrapulmonary TB is often difficult. Diagnosismay be presumptive, provided you can exclude other conditions.Patients usually present with constitutional features (fever, night sweats,weight loss) and local features related to the site of disease.These localfeatures are similar in adults and children. The degree of certainty ofdiagnosis depends on the availability of diagnostic tools, e.g. specializedX-rays, ultrasound, biopsy.5.2 TUBERCULOUS LYMPHADENOPATHYRegardless of HIV status, the lymph nodes most commonly involved arethe cervical nodes.The usual course of lymph node disease is as follows:firm, discrete fluctuant nodes skin breakdown, healing withnodes → matted together → abscesses, → scarringchronic sinusesPRACTICAL POINTIn severely immunocompromised patients, tuberculouslymphadenopathy may be acute and resemble acutepyogenic lymphadenitis.TB/HIV:A CLINICAL MANUAL75

In adults, the differential diagnosis of tuberculous lymphadenopathyincludes the following: persistent generalized lymphadenopathy (PGL),lymphoma, Kaposi sarcoma, carcinomatous metastases, sarcoid, and drugreactions (e.g. phenytoin).Lymphoid interstitial pneumonitis (LIP) is often associated with PGL inHIV-infected children. LIP may be confused with TB as chronicrespiratory symptoms are very common.The lymphadenopathy with LIPis characteristically generalized, symmetrical, mobile, non-tender, firmand non-fluctuant. Differential diagnoses of focal lymphadenopathy inchildren include bacterial or pyogenic adenitis and lymphoma (e.g.Burkitt lymphoma).Persistent generalized lymphadenopathy (PGL)PGL is a feature of HIV infection which develops in up to 50% of HIVinfectedindividuals. It is of no prognostic significance.There is no specifictreatment. The diagnostic criteria for PGL are as follows: lymph nodeslarger than1 cm in diameterin 2 or more extra-inguinal sitesfor 3 or more months.The nodes are non-tender, symmetrical, and often involve the posteriorcervical and epitrochlear nodes. PGL may slowly regress during thecourse of HIV infection and may disappear before the onset of AIDS. Inpopulations with a high HIV prevalence, PGL is the commonest cause oflymphadenopathy. In HIV-positive individuals PGL is a clinical diagnosis.Only investigate further if there are features of another disease. Thefeatures of lymph nodes that indicate a need for further investigation,including biopsy, are:º large (> 4 cm diameter) or rapidly growing lymph nodesº asymmetrical lymphadenopathyº tender/painful lymph nodes not associated with local infectionº matted/fluctuant lymph nodesº obvious constitutional features (e.g. fever, night sweats, weight loss)º hilar or mediastinal lymphadenopathy on CXR.76DIAGNOSIS OF EPTB IN ADULTS AND CHILDREN

Practical approach to investigation of lymphadenopathy(if clinical features suggest a cause of lymphadenopathy other than PGL).Procedure Test Result Diagnosis5look at material➝ caseation ➝ TBaspiratedneedle smear for ➝ AFB present ➝ TBaspirate AFBof lymphnode smear for ➝ malignant ➝ malignancycytology cells seen e.g. KS,lymphoma,carcinomaif no diagnosis after aspiratelook at cut ➝ caseation ➝ TBsurfacesmear from cut ➝ AFB seen ➝ TBsurface for AFBlymphnode fresh node ➝ positive ➝ TBbiopsy sent for TB cultureTB culturenode in ➝ granuloma ➝ TBformalinand AFBfor histologymalignant ➝ malignancycells➝Diagnosis of tuberculous lymphadenopathy is possible even withoutlaboratory facilities for histology or TB culture. Diagnostic sensitivity oftuberculous lymphadenopathy by aspirate and smear for AFB is 70%.Diagnostic sensitivity increases to 80% if you excise a lymph node, lookat the cut surface, and do a smear for AFB.The histological appearance of tuberculous lymph nodes from HIVpositivepatients depends on the degree of immunocompromise, asshown below.TB/HIV:A CLINICAL MANUAL77

Degree ofimmunocompromisemildsevereHistological appearance oflymph nodescaseating lesions with few or no AFBlittle cellular reaction with many AFB5.3 MILIARY (DISSEMINATED) TBMiliary TB results from widespread bloodborne dissemination of TBbacilli.This results from either a recent primary infection or the erosionof a tuberculous lesion into a blood vessel.Clinical featuresPatients present with constitutional features rather than respiratorysymptoms.They may have hepatosplenomegaly and choroidal tubercles(fundoscopy). Often the presentation is associated with fever ofunknown origin and wasting may be marked. Miliary TB is anunderdiagnosed cause of end-stage wasting in HIV-positive individuals.Ahigh index of suspicion is necessary.DiagnosisCXR shows diffuse, uniformly distributed, small miliary shadows."Miliary" means "like small millet seeds".The CXR can appear normal inadvanced cases because of severe immunosuppression and thereforeinability to mount an inflammatory response. Full blood count may showpancytopenia. Liver function tests may be abnormal. Bacteriologicalconfirmation (smears or mycobacterial culture) is sometimes possiblefrom sputum, cerebrospinal fluid, bone marrow, liver or blood.Differential diagnosisThe differential diagnosis includes the following: the syndrome of HIVwasting disease (sometimes referred to as “slim disease”), bacteraemia(including typhoid fever), disseminated carcinoma, disseminated infectionwith "atypical" mycobacteria, trypanosomiasis (in endemic regions) andconnective tissue diseases.The typical diffuse CXR abnormalities can be confused with those of LIPin children. The table below lists features that help to differentiatemiliary TB from LIP. However, there is clinical overlap as LIP presentswith a broad range of clinical and radiographic features, which varydepending on the stage of HIV disease.78DIAGNOSIS OF EPTB IN ADULTS AND CHILDREN

Clinical differentiation of miliary TB from LIP in childrenMiliary TB LIPClinical features:Respiratory symptoms -/+ +++Persistent fever ++ ++Wasting +++ -/+Generalized lymphadenopathy -/+ +++Parotid enlargement - ++Clubbing - +Hepatomegaly ++ ++5CXR features:Diffuse micronodular ++ +Diffuse reticular - ++Lymphadenopathy -/+ ++5.4 TUBERCULOUS SEROUS EFFUSIONS (PLEURAL,PERICARDIAL,ASCITES)Inflammatory tuberculous effusions may occur in any of the serouscavities of the body, i.e. pleural, pericardial or peritoneal cavities.They aremore common in HIV-positive than in HIV-negative adults, and alsooccur in school-aged children with or without HIV infection. Serouseffusions are often indicative of primary disease or reinfection.Approach to diagnosisThe presentation is usually with constitutional and local features.Microscopy of the aspirate from tuberculous serous effusions rarelyshows AFB because the fluid forms as an inflammatory reaction to TBlesions in the serous membrane. TB culture, even if available, is of noimmediate help. A culture result usually takes 4-6 weeks. The white cellcontent is variable,usually with predominant lymphocytes and monocytes.The aspirate is an exudate (i.e. protein content is more than 30 g/l).PRACTICAL POINTA biochemistry laboratory is not essential to diagnose anexudate. Simply leave the aspirate standing: if “spider clots”develop in the specimen, it is an exudate.TB/HIV:A CLINICAL MANUAL79

In populations in sub-Saharan Africa with high HIV prevalence,TB is thecommonest cause of an exudative serous effusion. The diagnosis isusually presumptive (i.e. without microbiological or histologicalconfirmation). It is important to exclude other causes of an exudate.PRACTICAL POINTInterpret with caution the laboratory result of proteinconcentration in any aspirated fluid. If there has been adelay in laboratory analysis, a protein clot may have formedin the sample.The laboratory result may then be falsely low.Tuberculous pleural effusionThe clinical and CXR diagnosis of a pleural effusion is straightforward.The typical clinical features are constitutional and local (chest pain;breathlessness; tracheal and mediastinal shift away from the side of theeffusion; decreased chest movement, dull percussion note and decreasedbreath sounds on the side of the effusion). CXR shows unilateral,uniform white opacity, often with a concave upper border. If available,ultrasound can confirm the presence of fluid in the pleural space in caseof doubt.Always perform diagnostic pleural aspiration if a patient has a pleuraleffusion. The fluid is usually straw-coloured. The white cell count isusually high (about 1000–2500 per mm 3 ) with predominantlymphocytes. Occasionally the fluid is blood-stained.The presence of puson aspiration indicates an empyema (purulent effusion).PRACTICAL POINTIn a hospital with limited facilities serving a population withhigh TB prevalence, patients with a unilateral exudativepleural effusion that has not responded to a full course ofantibiotics should be treated with anti-TB drugs.If facilities are available, closed pleural biopsy using an Abrams needle isuseful for histological diagnosis. Since the distribution of TB lesions in thepleura is patchy, the diagnostic yield of closed pleural biopsy is about75%. Multiple biopsies increase the diagnostic yield. A small open pleuralbiopsy increases the yield even further but is not usually necessary.Differential diagnosisThe differential diagnosis of an exudative pleural effusion includes80 DIAGNOSIS OF EPTB IN ADULTS AND CHILDREN

malignancy, post-pneumonic effusion, pulmonary embolism and amoebicliver abscess (extending on the right).Tuberculous empyemaThis usually arises when a tuberculous cavity in the lung ruptures intothe pleural space.The physical signs are those of a pleural effusion, butaspiration reveals thick white or yellow pus. If the pus is too thick toremove using a needle and syringe, use an intercostal drain. Send the pusto the laboratory for examination for TB and also for Gram stain andbacterial culture. If facilities are available, closed pleural biopsy is usefulfor histological diagnosis.5The main differential diagnosis is bacterial empyema, when the patient isusually more acutely ill and toxic. It may be possible to confirm bacterialempyema by Gram stain or culture of the aspirated pus.A succussion splash is a splashing sound heard with the stethoscopewhile shaking the patient's chest. A succussion splash indicates apyopneumothorax (pus and air in the pleural space). After CXRconfirmation, insert a chest drain with underwater seal.PRACTICAL POINTAlways test a patient with signs of a pleural effusion for asuccussion splash.Tuberculous pericardial effusionDiagnosisThe diagnosis usually rests on suggestive constitutional andcardiovascular features and investigation findings (ECG, CXR andechocardiography). It is important to exclude uraemia and Kaposisarcoma.Cardiovascular symptomsº chest painº shortness of breathº coughº dizziness and weakness (low cardiac output)º leg swellingº right hypochondrial pain (liver congestion)º abdominal swelling (ascites)TB/HIV:A CLINICAL MANUAL81

Cardiovascular signsº tachycardiaº low blood pressureº pulsus paradoxusº raised jugular venous pressure (JVP) with small amplitude "a" and "v"wavesº impalpable apex beatº quiet heart soundsº pericardial friction rubº signs of right-sided heart failure (e.g. hepatomegaly, ascites, oedema)PRACTICAL POINTThe signs may be subtle. Assess carefully any patient withoedema or ascites with the possibility of pericardial effusionin mind.CXRº large globular heartº clear lung fieldsº pleural fluidECGº tachycardiaº ST and T wave changesº low voltage QRS complexesº sometimes electrical alternans (alternating positive and negative Rwaves, reflecting a heart that moves with each beat within thepericardial fluid)Echocardiographyº pericardial fluidº strands crossing between visceral and parietal pericardiumPitfalls in diagnosis of pericardial effusionClinicians have misdiagnosed pericardial effusion as the following:º congestive cardiac failure;º hepatoma or amoebic liver abscess (enlarged liver);º bilateral pleural effusions.PericardiocentesisThis is only safe under the following conditions:a) echocardiography has confirmed a moderate to large pericardialeffusion;b) the operator is experienced.82DIAGNOSIS OF EPTB IN ADULTS AND CHILDREN

Therapeutic pericardiocentesis is necessary if there is cardiactamponade (acute life-threatening cardiac impairment).PRACTICAL POINTIn populations with high TB/HIV prevalence,TB is the mostlikely treatable cause of pericardial effusion. It may be saferfor the patient to start presumptive anti-TB treatment thanto undergo diagnostic pericardiocentesis.5Treatment with steroids and anti-TB drugs, without pericardiocentesis,usually results in satisfactory resolution of tuberculous pericardialeffusion.OutcomeA possible complication despite TB cure is the development ofpericardial constriction. Medical management of heart failure due topericardial constriction helps in some cases. A surgeon may weigh upthe possible benefit to the patient of pericardiectomy, set against theoperative risks.Differential diagnosisApart from TB, the differential diagnosis of pericardial effusion includesthe following:transudates: uraemia, heart failure, liver failure, hypothyroidism;exudates: malignancy, bacterial pericardial empyema, inflammatorydiseases.Tuberculous ascitesAscites results from peritoneal TB. Routes of spread of TB to theperitoneum include the following:a) from tuberculous mesenteric lymph nodes;b) from intestinal TB (pulmonary TB patients may develop intestinalulcers and fistulae as a result of swallowing infected sputum);c) bloodborne.Clinical featuresPatients present with constitutional features and ascites. Marked wastingis common in children. Signs of other causes of ascites such as nephroticsyndrome (peripheral and periorbital oedema) or portal hypertension(marked splenomegaly) are usually absent. There may be palpableabdominal masses (mesenteric lymph nodes). Adhesion of nodes toTB/HIV:A CLINICAL MANUAL83

owel may cause bowel obstruction. Fistulae may develop betweenbowel, bladder and abdominal wall.InvestigationsDo a CXR to look for associated PTB.Always do a diagnostic ascitic tap.The aspirated fluid is usually straw-coloured, but occasionally turbid orblood-stained.The fluid is an exudate, usually with more than 300 whitecells per mm 3 and predominantly lymphocytes. Ultrasound, if available,may show features consistent with TB, including enlarged mesenteric orretroperitoneal lymph nodes.PRACTICAL POINTAn ill, wasted patient with TB ascites may have a low serumalbumin concentration. In this case, the usual threshold of30 g/l albumin concentration for diagnosing an exudate istoo high. Instead, calculate the difference between thealbumin concentrations in serum and ascites. Aserum–ascites albumin difference of less than 11 g/l meansthat the ascites is an exudate.DiagnosisThe diagnosis is usually presumptive. Definitive diagnosis rests on aperitoneal biopsy, available in some hospitals. Blind percutaneous needlebiopsy of the peritoneum has a low pick-up rate and a high complicationrate. In experienced hands, laparoscopy under local anaesthetic has ahigh pick-up rate. Laparoscopy enables direct visualization and biopsy ofperitoneal TB lesions. Laparotomy will confirm the diagnosis in nearlyevery case but is too invasive for routine use.Differential diagnosisApart from TB, the differential diagnosis of ascites includes the following:transudates: heart failure, renal failure, nephrotic syndrome, chronicliver disease due to cirrhosis, hepatosplenic schistosomiasis,hypoproteinaemia;exudates: malignancy, other infections causing peritonitis.5.5 TUBERCULOUS MENINGITISRoutes of spread of TB to the meninges include the following:a) from rupture of a cerebral tuberculoma into the subarachnoid space;b) bloodborne.84DIAGNOSIS OF EPTB IN ADULTS AND CHILDREN

Clinical featuresThe patient may present with constitutional features and chronicmeningitis. There is gradual onset and progression of headache anddecreased consciousness. Examination often reveals neck stiffness and apositive Kernig's sign. Cranial nerve palsies result from exudate aroundthe base of the brain. Tuberculomas and vascular occlusion may causefocal neurological deficits and seizures. Obstructive hydrocephalus maydevelop. Spinal meningeal involvement causes paraplegia (spastic orflaccid).5DiagnosisThe diagnosis usually rests on clinical grounds and cerebrospinal fluid(CSF) examination. In most cases of clinically suspected TB meningitis,lumbar puncture is safe.PRACTICAL POINTLumbar puncture is hazardous if the patient has a focalneurological deficit (cerebral space-occupying lesion) or iffundoscopy shows papilloedema (raised intracranialpressure). In these circumstances, a CT brain scan is helpful,if available. Otherwise, it may be safer to start presumptivetreatment with anti-TB drugs rather than risk lumbarpuncture.The CSF opening pressure is high. The CSF may look clear oroccasionally cloudy.The white cell count is usually less than 500 per mm 3with predominantly lymphocytes (or early in the course of infection,predominantly polymorphs). Usually the protein level is high and theglucose low. CSF microscopy shows AFBs in a minority of cases. It ispossible to increase the diagnostic pick-up rate by the following:a) examine the deposit on centrifugation of a 10 ml CSF sample;b) examine the deposit for at least half an hour before reporting it asnegative;c) examine several CSF samples obtained over a few days.PRACTICAL POINTLumbar puncture is important for differentiating purulentfrom TB meningitis. Always exclude cryptococcal meningitisby CSF microscopy (India ink stain) and, if available, fungalculture.TB/HIV:A CLINICAL MANUAL85

Difficulties in interpreting CSF findingsSome of the CSF findings may be normal, especially in HIV-positivepatients. The percentages of HIV-positive TB meningitis patients withnormal CSF findings are as follows: glucose 15%, protein 40%, white cellcount 10%.Differential diagnosisThe table below shows the differential diagnosis of TB meningitis, withtypical CSF abnormalities.Differential diagnosis of tuberculous meningitisCSF abnormalitiesDisease White Protein Glucose Microscopycellstuberculous Elevated Increased Decreased AFBmeningitis L > PMN (in some cases)cryptococcal Elevated Increased Decreased Positive Indiameningitis* L > PMN ink stainingpartially Elevated Increased Decreased Bacteria on Gramtreatedstain (rarely)bacterialmeningitis*viral Elevated Increased Normalmeningitis L > PMN (low in mumpsor H. simplex)acute Elevated Increased Normalsyphilis L > PMNlate stage Elevated Increased Decreased Motiletrypanosomiasis L > PMNtrypanosomestumour Elevated Increased Decreased Cytology shows(carcinoma/ L > PMN malignant cellslymphoma)leptospirosis Elevated Increased Decreased LeptospiresL > PMNamoebic Elevated Increased Decreased Amoebaemeningitis L > PMNPMN = polymorphonuclear leukocytes; L = lymphocytes* common differential diagnosis86DIAGNOSIS OF EPTB IN ADULTS AND CHILDREN

5.6 OTHER FORMS OF EXTRAPULMONARY TBOther forms of extrapulmonary TB are less common. There is noinformation as to whether they occur any more frequently in HIVpositivethan in HIV-negative individuals. The table below shows theusual clinical features and diagnostic tests.5Site of disease Clinical features DiagnosisSpine Back pain Plain X-rayGibbusTissue biopsyPsoas abscessRadicular painSpinal cord compressionBone Chronic osteomyelitis Tissue biopsyPeripheral joints Usually monoarthritis Plain X-rayespecially hip or knee Synovial biopsyGastrointestinal Abdominal mass Barium X-rayDiarrhoeaLiver Right upper quadrant Ultrasound andpain and massbiopsyRenal and urinary Urinary frequency Sterile pyuriatract Dysuria Urine cultureHaematuriaIntravenousLoin pain/swelling pyelogramUltrasoundAdrenal gland Features of Plain X-rayhypoadrenalism (calcification)(hypotension,Ultrasoundlow serum sodium,normal/high potassium,raised urea, low glucose)Upper respiratory Hoarseness and stridor Usually complicationtract Pain in ear of pulmonary diseasePain on swallowingFemale genital tract Infertility Pelvic examinationPelvic inflammatory X-ray genital tractdiseaseUltrasound pelvisEctopic pregnancy Tissue biopsyMale genital tract Epididymitis Often evidence ofrenal/urinary tract TBTB/HIV:A CLINICAL MANUAL87

5.7 FURTHER INFORMATION ON SPINAL,GASTROINTESTINAL AND HEPATIC TBSpinal TBTB of the spine is important.The disastrous consequence for the patientof a missed diagnosis of thoracic or cervical spinal TB is paralysis. TBstarts in an intervertebral disc and spreads along the anterior andlongitudinal ligaments, before involving the adjacent vertebral bodies.Where TB is common, plain X-ray of the spine is usually diagnostic.Thetypical appearance is erosion of the anterior edges of the superior andinferior borders of adjacent vertebral bodies. The disc space isnarrowed. The sites most commonly involved are the lower thoracic,lumbar and lumbosacral areas.The main differential diagnoses are malignancy and pyogenic spinalinfections. Malignant deposits in the spine tend to erode the pedicles andspinal bodies, leaving the disc intact. Pyogenic infection tends to be moreacute than TB, with more severe pain.Gastrointestinal TBIleocaecal TB may present with constitutional features, chronicdiarrhoea, subacute obstruction, or a right iliac fossa mass. Diagnosisrests on barium examination of the small and large bowel, or oncolonoscopy, if available. The differential diagnosis includes ileocaecalCrohn disease, carcinoma of the caecum, appendix abscess, lymphoma,amoeboma and tubo-ovarian abscess.Hepatic TBMiliary TB may involve the liver. Hepatic TB can cause diagnosticconfusion. Solitary or multiple TB abscess formation can mimic amoebicliver abscess. Nodular hepatic TB can mimic hepatoma. In thesesituations, ultrasound examination is useful. Liver biopsy, available insome hospitals, is diagnostic.88 DIAGNOSIS OF EPTB IN ADULTS AND CHILDREN

SUGGESTIONS FOR FURTHER READINGCrofton J, Horne N, Miller F. Clinical tuberculosis. second edition. London,MacMillan Press Limited, 1999.5Donald PR, Fourie PB, Grange JM. Tuberculosis in childhood. Pretoria, JL vanSchaik, 1999.Harries AD, Maher D, Nunn P. An approach to the problems of diagnosing andtreating adult smear-negative pulmonary tuberculosis in high HIV prevalencesettings in sub-Saharan Africa. Bulletin of the World Health Organization, 1998,76, (6): 651-662.Maher D, Harries AD. Tuberculous pericardial effusion: a prospective clinicalstudy in a low-resource setting – Blantyre, Malawi. International Journal ofTuberculosis lung Disease, 1997, 1 (4): 358-364.Miller FJW. Tuberculosis in children. New Delhi, Churchill-Livingstone, 1986.Toman’s tuberculosis case detection, treatment and monitoring: questions andanswers. Edited by T Frieden, second edition. World Health Organization,Geneva, 2004. ISBN 92 4 154603 4. (WHO/HTM/TB/2004.334).TB/HIV:A CLINICAL MANUAL89

DIAGNOSIS OF HIV INFECTION IN ADULTSWITH TUBERCULOSIS66.1 CLINICAL RECOGNITION OF HIV INFECTION INTB PATIENTSIn many TB/HIV patients in sub-Saharan Africa, the only HIV-relatedillness present is TB. However, certain clinical features are morecommon in HIV-positive TB patients than in HIV-negative TB patients.The table below shows the clinical features that suggest possible HIVinfection.Clinical features suggestive of HIV coinfection in TB patientsPasthistorySymptomsSignsº sexually transmitted infection (STI)º herpes zoster (shingles), which often leaves a scarº recent or recurrent pneumoniaº severe bacterial infections(sinusitis, bacteraemia, pyomyositis)º recent treated TBº weight loss (> 10 kg or > 20% of original weight)º diarrhoea (> 1 month)º retrosternal pain on swallowing(suggests oesophageal candidiasis)º burning sensation of feet(peripheral sensory neuropathy)º scar of herpes zosterº pruritic (itchy) papular skin rashº Kaposi sarcomaº symmetrical generalized lymphadenopathyº oral candidiasisº angular cheilitisº oral hairy leukoplakiaº necrotizing gingivitisº giant aphthous ulcerationº persistent painful genital ulcerationPRACTICAL POINTAlways look in the mouth of any patient. Many mouthlesions are highly suggestive of HIV infection, and others arepathognomonic.TB/HIV:A CLINICAL MANUAL91

PRACTICAL POINTFull blood count (FBC) findings suggestive of HIV infectionare unexplained anaemia, leukopenia or thrombocytopenia.The definitive diagnosis of HIV infection rests on a positive HIV test.6.2 HIV TESTINGHIV infection is usually diagnosed through detection of antibodies to thevirus. Production of these antibodies usually begins 3–8 weeks afterinfection. The period following infection but before antibodies becomedetectable is known as the “window period”. Diagnosis of HIV infectionis also possible through detection of the virus (p24 antigen, nucleic-acidbased tests or culture).6.2.1 HIV antibody testsThe most widely available way of identifying HIV-infected individuals isthe detection of HIV antibodies in serum or plasma samples.The tablebelow shows the two main methods of testing for HIV antibodies.Serological tests are available that test for both HIV-1 and HIV-2. Thetechnical details of these tests are beyond the scope of this manual. HIVdiagnostic tests are extremely reliable, and are highly sensitive andspecific. The reliability of test results depends on proper samplecollection and testing. The staff taking the sample must label thespecimen bottle and the form accurately. High quality performance oftests by laboratory staff is crucial.Advantages and disadvantages of HIV antibody testsHIV testing Advantages DisadvantagesmethodEIA º less expensive than º some specialized(formerly known immunoblot laboratory equipmentas ELISA) º large numbers of sera necessarycan be tested daily º skilled technical staffº sensitive and specific º steady power supplyº a whole kit(90–100 samples)has to be used92 DIAGNOSIS OF HIV IN ADULTS WITH TB

Simple/rapid(e.g. rapidimmunobindingassay)º simple, rapidº less expensive thanimmunoblotº no specializedequipment necessaryº supplied as single-usetests so individualspecimens can be tested6EIAThe usual type of test for HIV antibodies is the enzyme immunoassay(EIA). EIAs are probably the most efficient tests for testing largenumbers of samples per day, as in large blood banks or for surveillancestudies.The cost per individual EIA is about US$ 0.75–1.75.Simple/rapid testsSeveral antibody tests can equal the performance of EIA and do notneed special equipment or highly trained staff. These tests areconsidered rapid if they take less than 10 minutes and simple if they takelonger.There are four types of assay: agglutination, comb/dipstick, flowthroughmembrane and lateral flow membrane. In most formats, theappearance of a clearly visible dot or line indicates a positive result. Manyof the tests have an internal control sample, which validates each testrun.Test kits are relatively expensive at US$ 1–2 per test.Tests not using plasma or serumTests are available that can use whole blood, dried blood spots, saliva orurine. They are much more user-friendly than those that requiretraditional blood sampling by venepuncture. The level of antibodies inthese specimens is much lower than in serum or plasma.While useful forsurveillance, a positive result needs to be confirmed for an individualdiagnosis.6.2.2 Tests to detect the virus itselfThe first assays capable of detecting free circulating HIV particles werethe HIV p24 antigen EIAs. Quantitative measurement of plasma HIVRNA (viral load) have now superseded these EIAs. Measurement of viralload is based on amplification of viral nucleic acids or of the probebindingsignal (e.g. branched DNA tests). Results are reported as copiesof virus per ml, and the new generation tests can detect 20–50 copiesper ml. Measurement of viral load is now standard in industrializedTB/HIV:A CLINICAL MANUAL93

countries for staging and monitoring response to antiretroviral therapy.However, several factors have limited their use so far in developingcountries. These include the expense of the complex equipmentnecessary and the need for rigorous laboratory conditions, qualitycontrol and highly trained staff.6.2.3 Objectives of HIV antibody testing in TB patientsThere are three possible main objectives in performing HIV antibodytests in TB patients:a) individual patient management (HIV testing in individual TB patients);b) surveillance (anonymous testing to monitor epidemiological trends);c) research (voluntary testing for epidemiological, clinical, or virologicalstudies).6.2.4 Strategy for HIV antibody testing in TB patients(which tests to use and when to use them)In general, WHO recommends different HIV testing strategies,depending on the objective of testing.The aim is to maximize accuracyand minimize cost.The table below shows the strategy appropriate foreach objective of testing.Objectives, strategies and interpretation of HIV testsObjective Testing strategy Interpretation ofresultIndividual Test sample with EIA 1st assay negative =patient or simple/rapid assay patient HIV negativemanagementor test to be repeated1st assay positive +2nd assay positive =patient HIV-positive1st assay positive and2nd assay negative ➝repeat both assaysResults remaindiscordant ➝repeat sample and testingSurveillance Test sample with EIA Assay negative =(in population or simple/rapid assay patient HIV-negativewith HIVprevalence Assay positive => 10%) patient HIV-positive94 DIAGNOSIS OF HIV IN ADULTS WITH TB

6.2.5 Diagnosis of HIV infection in individual TB patientsThe link between HIV and TB is well known to many members of thepublic. Patients with TB may therefore be well aware of the possibility ofHIV coinfection. It is important to offer counselling and voluntary HIVtesting, if available, to TB patients. Possible benefits include:a) patients may want the chance to know their HIV status;b) better diagnosis and management of other HIV-related illnesses;c) avoidance of drugs associated with a high risk of side-effects;d) increased condom use and decreased HIV transmission;e) possible use of chemoprophylaxis with cotrimoxazole to preventopportunistic infections and reduce mortality;f) possible use of ART for HIV;g) the opportunity to counsel patients and relatives about HIVinfection and about the prognosis;h) the opportunity to advise patients and relatives about measures toprevent further HIV transmission.6It is preferable to have same-day HIV testing using rapid test kits as thisminimizes the number of visits to counselling and testing centres. Theother important issue for clients is confidentiality.PRACTICAL POINTAnti-TB drug treatment is the same for HIV-positive andHIV-negative TB patients, with one exception: do not givethioacetazone to HIV-positive TB patients (increased risk ofsevere and sometimes fatal skin reactions).A policy of compulsory HIV testing of TB patients (even if this werelegal) would be counterproductive. This type of policy would have thefollowing results:a) patients would be deterred from seeking care;b) there would be decreased case-finding in at-risk groups;c) the credibility of health services would be reduced.6.3 HIV COUNSELLINGHIV voluntary counselling and testing (VCT) starts with counselling ofindividuals to enable them to make an informed choice about HIVtesting.This decision is entirely the choice of the individual, who must beassured that the process will be confidential. Confidential counselling isessential before and after HIV antibody testing. Individuals give explicitinformed consent to have the test. This means that they understandwhat the test involves and the implications of testing. The counsellorTB/HIV:A CLINICAL MANUAL95

provides support. Counselling is a dialogue between the individual andthe counsellor.CounsellorsWith suitable training, anyone who works with patients and families canbe a counsellor. Counsellors may be members of the community orhealth workers. For sustainability of VCT services, counsellors needsupport and supervision. Many health workers have had counsellingtraining. In the course of their duties they have the opportunity tocounsel patients for HIV testing. Doctors and other clinicians are oftenin a good position to counsel patients for HIV testing. This is becauseclinicians have already established a relationship with the patient, whousually trusts the clinician.Pretest counsellingThe aim is to enable people to make an informed decision to have thetest or not. People need to know what the test involves and what arethe implications of the result. Together the counsellor and the personconsidering being tested assess the person’s: a) likelihood of havingacquired HIV infection, b) knowledge about HIV, and c) ability to copewith a positive result.PRACTICAL POINTIn high HIV-prevalence regions, anyone with TB is in a highriskgroup for HIV.a) Assessment of risk º multiple sex partnersof having acquired º sex with commercial sex workersHIV infection º for men, sex with other menº nonsterile skin piercing, e.g. scarification,tattooingº previous blood transfusionº intravenous drug useº sexual partner/spouse of person at riskb) Assessment of º what does the test involve and mean?knowledge about HIV º how does HIV transmission occur?º what is high-risk behaviour?c) Assessment of º person's expected reaction to resultability to cope withresultº who will provide emotional support?º impact of a positive result on- relationships- social issues, e.g. employment- future health96DIAGNOSIS OF HIV IN ADULTS WITH TB

Post-test counsellingThe content of post-test counselling depends on the HIV test result.Theaims are to discuss the result, share information, provide support, andencourage future safe sexual behaviour. Always ensure confidentiality.Break the news openly and sympathetically. When someone has apositive HIV test result, common reactions at different times mayinclude shock, anger, guilt, grief and depression. People will needcontinuing support.6Issues for discussion when the HIV test result is negativeº If the person has recently indulged in high-risk behaviours, then he orshe could still be incubating HIV (i.e. the test could be in the "windowperiod").º Avoidance of unsafe sexual behaviour.º Promotion of healthy behaviour.Issues for discussion when the HIV test result is positiveº General health (good diet, balance of rest and exercise, avoidinginfections, when to seek advice about symptoms of other HIV-relatedillnesses).º Avoidance of preganancy.º Awareness of possible anti-TB drug side-effects.º A positive result is an entry point to medical care of HIV-relateddiseases, to chemoprophylaxis for opportunistic infections andpossibly to ART.º Safe sexual behaviour.º Avoidance of blood or organ donation.º The person's reaction to the test result.º Emotional and psychological support for the person.º How to tell friends, family and sexual partners.º Counselling of partner(s) if possible.º Referral to local community services and support groups, if available.º Social implications, e.g. employment, life assurance.TB/HIV:A CLINICAL MANUAL97

SUGGESTIONS FOR FURTHER READINGUNAIDS policy on HIV testing and counselling. Geneva, Joint UN Programme onHIV/AIDS, 1997.UNAIDS Technical Update. HIV testing methods. Joint UN Programme onHIV/AIDS, Geneva, 1997, UNAIDS Best Practice Collection.Joint UN Programme on HIV/AIDS, World Health Organization. Operationalcharacteristics of commercially available assays to determine antibodies to HIV-1and/or HIV-2 in human sera. Report 11. Geneva, 1999. WHO/BTS/99.1;UNAIDS/99.5.UNAIDS Technical Update.Voluntary counselling and testing (VCT). Geneva, 2000,Joint UN Programme on HIV/AIDS, Best Practice Collection.Volberding PA. HIV quantification: clinical applications. Lancet, 1996, 347: 71-73.World Health Organization. Revised recommendations for the selection anduse of HIV antibody tests. Weekly epidemiological record, 1997, 72: 81–83.World Health Organization.The importance of simple and rapid tests in HIVdiagnostics: WHO recommendations. Weekly epidemiological record, 1998, 73:321–328.World Health Organization. Increasing access to knowledge of HIV status:conclusions of a WHO consultation, 3–4 December 2001,WHO/HIV/2002.09.World Health Organization. Testing and counselling. Geneva, 2002http://www.who.int/hiv/topics/vct/testing (accessed 8 May 2003).98 DIAGNOSIS OF HIV IN ADULTS WITH TB

DIAGNOSIS OF HIV INFECTION IN CHILDRENWITH TUBERCULOSIS77.1 CLINICAL RECOGNITION OF HIV INFECTION INCHILDREN WITH TBHIV infection in children may show in many ways.The clinical signs areoften not specific for HIV infection. For example, weight loss, fever andcough are common in TB, with or without HIV infection. The clinicaldefinition of HIV infection is therefore difficult.PRACTICAL POINTParents provide important clues to possible HIV infection intheir children. Ask the parents about their health.Sometimes parents may reveal their own HIV status.WHO has developed a clinical staging system for HIV infection and HIVrelateddisease (see Chapter 1).The main uses are for prognosis and fordeciding when to start antiretroviral therapy.The features of paediatricHIV/AIDS are not very specific in developing countries where childhoodmalnutrition is common and TB is endemic. Severe malnutrition orwasting in a school-aged child or in a child from a well-nourished familyis unlikely to be due simply to poor intake. This should raise thesuspicion of underlying disease, e.g. HIV or TB or both.The table belowlists clinical signs suggestive of HIV infection. Many are more specificthan those in the WHO clinical staging system but are less sensitive. Inother words, the presence of a particular sign strongly suggests HIVinfection, but many children have HIV infection without that sign. Theinterpretation of clinical signs also depends on local patterns of disease.For example, splenomegaly is commonly caused by malaria in sub-Saharan Africa, where its specificity as a sign of HIV-related disease istherefore low.Clinical signs suggestive of HIV infection in childrenCommonfailure to thrive in a breastfed infant before 6 monthsof agerecurrent bacterial infectionsgeneralized symmetrical lymph node enlargementextensive oropharyngeal candidiasissuppurative otitis media in a breastfed infantgeneralized rash e.g. itchy papular rash, extensivemolluscum contagiosumTB/HIV:A CLINICAL MANUAL99

Lesscommonextensive fungal skin, nail and scalp infectionsbilateral non-tender parotid gland enlargementfinger clubbingenlarged non-tender liver with no apparent causesplenomegaly (in non-malarious areas)persistent severe anaemiarecurrent abscesses or deep tissue necrosisrecurrent herpes simplexKS lesionsshingles in more than one dermatomedevelopmental regressionacquired rectovaginal fistulaMany of these signs are strongly suggestive of HIV. However, noparticular sign is diagnostic and confirmation is necessary by HIV testing.7.2 HIV TESTINGThe usual HIV test is one that detects antibodies to HIV in the blood.Rarely, a single HIV test for an individual person may not be reliable.Theusual recommendation in diagnosing HIV infection is therefore toperform two tests. Both tests should be positive for a diagnosis of HIVinfection.A positive HIV antibody test is not a reliable indicator of HIV infectionin infants. During the pregnancy of a woman with HIV infection,antibodies to HIV cross the placenta.Therefore almost all children bornto HIV-positive mothers have HIV antibodies in their blood at birth.However, only about one-third of children born to HIV-infected mothersare infected. Initially, therefore, HIV antibody testing cannot distinguishuninfected from infected children. In uninfected children, these maternalantibodies usually become undetectable by 9 months of age, butoccasionally they remain detectable until 15 months. Most infectedchildren make their own antibodies, so the HIV antibody test will still bepositive after 15 months.PRACTICAL POINTIn children under 15 months of age, the diagnosis of HIVinfection rests on clinical features and a positive HIV test inthe mother.100 DIAGNOSIS OF HIV IN CHILDREN WITH TB

7.3 COUNSELLINGA child with suspected HIV generally means a family with suspected HIV.Counselling therefore has to take into consideration the mother and, ifpossible, the father. Until recently there have been few specific treatmentoptions to offer the child and family when a child tests HIV-positive.Thishas made raising the issue of testing difficult. However, the increasingavailability of antiretroviral treatment is likely to encourage HIV testing.Also, parents often want to know the cause of their child’s illness. SeeChapter 6 for the issues for discussion with adults with suspected HIV.7Pretest counsellingIt is important to counsel the mother before testing her child for HIV.Her consent is necessary before testing her blood (if the child is under18 months) or the child's blood (if the child is over 18 months) for HIV.If her child tests HIV-positive, then it is extremely likely that she is thesource of infection and is HIV-positive.Consider the implications for the mother when she hears that her childmay have HIV infection:º her child may have an incurable and fatal disease;º she herself may have HIV;º her husband may have HIV;º any future children may have HIV.Her decision to have a test or not is difficult. She will need time andsupport while she considers the advantages and disadvantages of a test.If she knows she is HIV-positive, the main advantage is that she can planfor the future. On the other hand, she may be fearful that her husbandwill beat her or leave her if she tells him that she is HIV-positive. She mayalso be concerned that if her child tests positive, the health workers willno longer provide good care for her child.PRACTICAL POINTThe mother may like to bring her husband for joint pretestcounselling. It is usually easier for a woman to tell herhusband she may be HIV-positive than to tell him afterwardsthat she is HIV-positive.Post-test counsellingChapter 6 lists the issues for discussion relevant to anyone who testsHIV-positive.There are other issues specific to a mother who tests HIV-TB/HIV:A CLINICAL MANUAL101

positive. These include the poor outlook for the child and the risk offuture babies being HIV-infected. About one-third of children born toHIV-positive women are also HIV-infected (in the absence ofinterventions to prevent mother-to-child transmission).When counselling women who are breastfeeding or who have deliveredrecently, it is important to discuss breastfeeding. There is risk of HIVtransmission by breastfeeding. However, in many low-income countries,breastfeeding is still a safer alternative to bottle-feeding. For example, achild whose mother is HIV-positive and who lives in an environmentwhere there is no clean water is probably at higher risk of dying fromdiarrhoea if bottle-fed than from AIDS if breastfed.It is also important to consider PCP prophylaxis with cotrimoxazole forinfants born to an HIV-infected mother. PCP is a very common cause ofdeath in HIV-infected infants especially before 6 months of age. Therecommended cotrimoxazole dosage for PCP prophylaxis is 150 mgTMP/750 mg SMX per m 2 /day given 3 times per week.Thus, appropriatedosage for infants 2–6 months (usually 3–6 kg) would be 40 mg TMP/200mg SMX once a day three times per week. If only cotrimoxazole tabletsare available, then give half a crushed tablet (80 mg TMP/400 mg SMX)on Monday,Wednesday and Friday.102 DIAGNOSIS OF HIV IN CHILDREN WITH TB

SUGGESTIONS FOR FURTHER READINGLepage P, Spira R, Kalibala S, et al. Care of human immunodeficiency virusinfectedchildren in developing countries. The pediatric infectious disease journal,1998, 17: 581–586.7Marum LH,Tindyebwa D, Gibb D. Care of children with HIV infection and AIDSin Africa. AIDS, 1997, 11 (Supplement B): S125-S134.Joint UN Programme on HIV/AIDS. Provisional WHO/UNAIDS Secretariatrecommendations on the use of cotrimoxazole prophylaxis in adults and childrenliving with HIV/AIDS in Africa. Geneva, 2000. (Available at http://www.unaids.org).Temmerman M, Ndinya-Achola J, Ambani J, Piot P.The right not to know HIVtestresults. Lancet, 1995, 345: 969–970.Joint United Nations Programme on HIV/AIDS, AIDS epidemic update:December 2002. Geneva.World Health Organization, Counselling for HIV/AIDS: a key to caring. Geneva,1995.World Health Organization, Scaling up antiretroviral therapy in resource-limitedsettings. Guidelines for a public health approach. Geneva, 2002 (includes a clinicalstaging system for HIV and HIV-related disease).TB/HIV:A CLINICAL MANUAL103

STANDARDIZED TUBERCULOSIS CASEDEFINITIONS AND TREATMENT CATEGORIES88.1 STANDARDIZED CASE DEFINITIONS8.1.1 IntroductionThe diagnosis of TB means that a patient has symptomatic disease dueto lesions caused by M. tuberculosis.What type of TB? It is important toanswer this question before starting treatment.A case definition tells usthe type of TB.We define TB cases in a standardized way.This means thatwhen we talk about a certain type of TB, we are all talking about thesame thing.A TB suspect is any person who presents with symptoms and signssuggestive of TB, in particular cough of long duration.A case of TB is a patient in whom TB has been bacteriologicallyconfirmed, or who has been diagnosed by a clinician.Note: any person given treatment for TB should be recorded.A definite TB case is a patient who is culture-positive for the M.tuberculosis complex. (In countries where culture is not routinelyavailable, a patient with two sputum smears positive for AFB is alsoconsidered a “definite case”.)8.1.2 Questions and answers about case definitionsWhy make case definitions? There are 2 purposes:a) to determine treatment;b) for recording and reporting (see Chapter 2).Why do case definitions determine treatment? There are 3reasons:a) to identify priority cases;b) to make the most cost-effective use of resources (by targetingresources on priority cases);c) to minimize side-effects for patients (by using the most intensiveregimens only for certain cases).What determines a case definition? There are 4 determinants:a) site of TB;TB/HIV:A CLINICAL MANUAL105

) result of sputum smear;c) previous TB treatment;d) severity of TB.PRACTICAL POINTAlways ask "new" TB patients if they have ever had TBtreatment before.The table below shows the determinants of the case definition and theirimportance.Determinant of case Importancedefinitionsite of TBrecording and reportingresult of sputum smearfor AFBsprevious TB treatmentseverity of TBº priority is to identify sputum smearpositivecases (since these are theinfectious cases)º in a good NTP, at least 50% of total caseswill be smear-positive PTBº recording and reporting (monitoring ofbacteriological cure is readily availableonly in this group)previously treated patients who are stillsputum smear-positive have a high risk ofdrug-resistant TB and so need a differentand more powerful regimenmost authorities recommend a lessintensive regimen for patients with noncavitary,smear-negative PTB (who areknown to be HIV-negative)8.1.3 Case definitions by site and result of sputum smearPulmonary TB – sputum smear-positive (PTB+)Two or more initial sputum smear examinations positive for AFBor1 sputum smear positive for AFB, and CXR abnormalities consistentwith active pulmonary TB as determined by a clinicianor1 sputum smear positive for AFB, which is also culture positive for M.tuberculosis106 STANDARDIZED TB CASE DEFINITIONS AND TREATMENT CATEGORIES

Pulmonary TB – sputum smear-negative (PTB-)A case of pulmonary TB that does not meet the above definition forsmear-positive TB.8In keeping with good clinical and public health practices, diagnosticcriteria should include:at least three sputum smears negative for AFBandno response to a course of broad-spectrum antibioticsandCXR abnormalities consistent with active TBanddecision by a clinician to treat with a full course of anti-TB treatmentExtrapulmonary TBTB of organs other than the lungs: e.g. pleura, lymph nodes, abdomen,genitourinary tract, skin, joints, bones, meninges. Diagnosis is based onone culture-positive specimen, or histological or strong clinical evidenceconsistent with active extrapulmonary TB, followed by a decision by aclinician to treat with a full course of anti-TB treatment. A patientdiagnosed with both pulmonary and extrapulmonary TB should beclassified as a case of pulmonary TB.PRACTICAL POINTThe following are forms of extrapulmonary TB:pleural effusion (the pleurae are outside the lungs);miliary (TB is widespread throughout the body and notlimited to the lungs).8.1.4 Category of TB patient for registration on diagnosisNewA patient who has definitely never taken anti-TB drugs or who has takenanti-TB drugs for less than one month.RelapseA TB patient who:a) previously received treatment and was declared cured or treatmentcompleted;andb) has once again developed bacteriologically positive (by smear orculture) TB.TB/HIV:A CLINICAL MANUAL107

Treatment after failureA patient who is started on a re-treatment regimen after having failedprevious treatment.Treatment after defaultA TB patient who returns to treatment, bacteriologically positive,following interruption of treatment for 2 months or more.Transfer inA TB patient who has been transferred from another TB register tocontinue treatment.OtherAll TB patients who do not fit the above definitions.This group includeschronic cases (TB patients who are sputum smear-positive at the end ofa re-treatment regimen).8.2 STANDARDIZED DIAGNOSTIC CATEGORIESBased on case definition, all TB patients (adults and children) fall into oneof four diagnostic categories for treatment. Patients are categorized inorder to match each diagnostic category with an effective treatmentregimen.The table below shows the patients belonging to each category.TB diagnosticcategoryCategory ICategory IICategory IIICategory IVPatientsº new sputum smear-positive PTBº new sputum smear-negative PTB withextensive parenchymal involvementº new cases of extrapulmonary TB (moresevere forms)º severely ill TB patients with concomitantHIV infectionº previously treated sputum smear-positivePTB: relapse, treatment after default,treatment after failureº new sputum smear-negative PTB withlimited parenchymal involvement andknown HIV-negativeº extrapulmonary TB (less severe forms)and known HIV-negativeº chronic and MDR-TB cases108 STANDARDIZED TB CASE DEFINITIONS AND TREATMENT CATEGORIES

The table below shows the severe and less severe forms ofextrapulmonary TB.Severe extrapulmonary TBmeningitismiliarypericarditisperitonitisbilateral or extensive pleural effusionspinalintestinalgenitourinaryLess severeextrapulmonary TBlymph nodepleural effusion (unilateral)bone (excluding spine)peripheral jointadrenal gland8ChildrenChildren often fall into Category III. PTB in children is almost always"smear-negative" (actually a smear is often not done, since childrenrarely cough up sputum).Young people infected during adolescence maydevelop primary TB. This usually presents as pleural effusion or smallparenchymal lesions in the lungs. In one series of adolescents withpleural effusion, without treatment about 25% went on to develop PTB.SUGGESTIONS FOR FURTHER READINGWorld Health Organization. Treatment of tuberculosis. Guidelines for nationalprogrammes. Third edition. Geneva, 2003 (WHO/CDS/TB/2003.313).International Union Against Tuberculosis and Lung Disease. Management oftuberculosis. A guide for low-income countries. Fifth edition. Paris, 2000.World Health Organization. Tuberculosis handbook. Geneva, 1998(WHO/TB/98.253).World Health Organization. International Union Against Tuberculosis and LungDisease, Royal Netherlands Tuberculosis Association. Revised internationaldefinitions in tuberculosis control. International journal of tuberculosis and lungdisease, 2001, 5 (3): 213–215.TB/HIV:A CLINICAL MANUAL109

MANAGEMENT OF PATIENTS WITHTUBERCULOSIS99.1 INTRODUCTIONAims of anti-TB drug treatment1. To cure the patient of TB.2. To prevent death from active TB or its late effects.3. To prevent TB relapse or recurrent disease.4. To prevent the development of drug resistance.5. To decrease TB transmission to others.PRACTICAL POINTProperly applied anti-TB drug treatment will achieve theseaims.Effective anti-TB drug treatment = properly applied short-coursechemotherapyWe have known for over 100 years that M. tuberculosis causes TB. Wehave had effective anti-TB drugs for nearly 50 years.Yet the world's TBproblem is now bigger than ever. Why? The problem is not the lack ofan effective treatment. Properly applied short-course chemotherapy(SCC) fulfils the above aims of anti-TB drug treatment.The problem isorganizational: how to apply SCC properly? The answer is a wellmanaged TB control programme. Chapter 2 describes the organizationalframework of an effective national TB programme (NTP).Standardized TB treatment regimensThere are many different possible anti-TB treatment regimens. WHOand the IUATLD recommend standardized TB treatment regimens.TheNTP in your country will recommend which regimens to use. Whenproperly applied, these standardized regimens fulfil the above aims ofanti-TB drug treatment. The regimens are affordable. The World Bankrecognises SCC as one of the most cost-effective of all healthinterventions.The Global Drug Facility (GDF) is a mechanism to ensureuninterrupted access to quality anti-TB drugs at low cost(http://stoptb.org/GDF).The first-line anti-TB drugsThe table below shows the first-line anti-TB drugs and their mode ofaction, potency, and recommended dose. The doses are the same foradults and children.TB/HIV:A CLINICAL MANUAL111

First-line Mode of Potency Recommended doseanti-TB drugs action (mg/kg of body weight)(abbreviation)daily intermittent(3 times a week)isoniazid (H) bactericidal high 5 10rifampicin (R) bactericidal high 10 10pyrazinamide (Z) bactericidal low 25 35streptomycin (S) bactericidal low 15 15ethambutol (E) bacteriostatic low 15 (30)thioacetazone (T) bacteriostatic low 2.5 not applicableThe available formulations and combinations of these drugs vary fromcountry to country. Follow the recommendations in your NTP manual.Intermittent useThioacetazone is the only essential anti-TB drug not effective whengiven intermittently. In any case, patients known or suspected to be HIVpositiveshould not receive thioacetazone. The efficacy of intermittentethambutol is not proven.ThioacetazoneSome countries still use thioacetazone (usually in combination withisoniazid in the continuation phase). WHO discourages the use ofthioacetazone because of the risk of severe toxicity, especially in HIVinfectedindividuals. Ethambutol should replace thioacetazone, especiallyin areas where HIV is common. It is becoming easier to mobilize theresources to replace it with ethambutol.The price of rifampicin is falling.Also, the GDF is now making low-cost, quality-assured anti-TB drugsavailable to more countries.Where thioacetazone is still in use, it is essential to warn patients aboutthe risk of severe skin reactions. Advise the patient to stopthioacetazone at once and report to a health unit if itching or a skinreaction occurs.9.2 MODES OF ACTION OF ANTI-TB DRUGSA population of TB bacilli in a TB patient consists of the following groups:a) metabolically active, continuously growing bacilli inside cavities;b) bacilli inside cells, e.g. macrophages;112 MANAGEMENT OF PATIENTS WITH TB

c) semidormant bacilli (persisters), which undergo occasional spurts ofmetabolic activity;d) dormant bacilli, which fade away and die on their own.9Different anti-TB drugs act against different groups of bacilli.PRACTICAL POINTAnti-TB drug treatment takes a long time because it isdifficult to kill the semidormant TB bacilli.Bactericidal drugsIsoniazid kills 90% of the total population of bacilli during the first fewdays of treatment. It is most effective against the metabolically active,continuously growing bacilli.Rifampicin can kill the semidormant bacilli that isoniazid cannot.Pyrazinamide kills bacilli in an acid environment inside cells, e.g.macrophages.Sterilizing actionThis means killing all the bacilli.The persisters are hardest to kill.The aimof killing all the bacilli is to prevent relapse. Rifampicin is the mosteffective sterilizing drug. Its effectiveness makes short-coursechemotherapy possible. Pyrazinamide is also a good sterilizing drug, sinceit kills the bacilli protected inside cells.Preventing drug resistanceA population of TB bacilli never previously exposed to anti-TB drugs willinclude a few naturally occurring drug-resistant mutant bacilli. Facedwith anti-TB drugs, these drug-resistant mutant bacilli will grow andreplace the drug-sensitive bacilli under the following circumstances:a) inadequate anti-TB drug combinations;b) inadequate application of anti-TB drug treatment.Isoniazid and rifampicin are most effective in preventing resistance toother drugs. Streptomycin and ethambutol are slightly less effective.9.3 TB TREATMENT REGIMENSTreatment regimens have an initial (intensive) phase and a continuationphase. The initial phase is designed for the rapid killing of activelyTB/HIV:A CLINICAL MANUAL113

growing bacilli and the killing of semidormant bacilli. This means ashorter duration of infectiousness. The continuation phase eliminatesbacilli that are still multiplying and reduces failures and relapses. Theprinciples of treatment are the same in all TB patients (adults andchildren).9.3.1 New casesInitial phase (2 months)During the initial phase, there is rapid killing of TB bacilli. Infectiouspatients become non-infectious within about 2 weeks. Patients improveand symptoms lessen.The vast majority of patients with sputum smearpositivePTB become sputum smear-negative within 2 months. Directlyobserved treatment (DOT) is essential in the initial phase to ensure thatthe patient takes every single dose.This protects rifampicin against thedevelopment of drug resistance. The risk of drug resistance is higherduring the early stages of anti-TB drug treatment when there are moreTB bacilli.Continuation phase (4-6 months)At the time of starting the continuation phase there are low numbers ofbacilli and hence less chance of selecting drug-resistant mutants. Thus,fewer drugs are necessary, but they are needed for a longer time inorder to eliminate the remaining TB bacilli. Killing the persisters preventsrelapse after completion of treatment. DOT is the ideal when the patientreceives rifampicin in the continuation phase. If local conditions do notallow DOT, the next best option is as close supervision as possible, forexample weekly supervision.The patient usually receives monthly drug supplies for self-administeredtreatment during a continuation phase that does not include rifampicin.9.3.2 Re-treatment casesThe initial phase lasts 3 months, with DOT.The continuation phase lasts5 months, with close supervision.9.3.3 Standard code for TB treatment regimensThere is a standard code for TB treatment regimens. Each anti-TB drughas an abbreviation (shown in the table on page 112). A regimenconsists of 2 phases.The number before a phase is the duration of thatphase in months. A number in subscript (e.g. 3 ) after a letter is the114 MANAGEMENT OF PATIENTS WITH TB

number of doses of that drug per week. If there is no number insubscript after a letter, then treatment with that drug is daily. Analternative drug (or drugs) appears as a letter (or letters) in brackets.9Examples2SHRZ/6HE. This is a common regimen.The initial phase is 2SHRZ. The duration of the phase is 2 months.Drug treatment is daily (no subscript number after the letters), withstreptomycin (S), isoniazid (H), rifampicin (R) and pyrazinamide (Z).The continuation phase is 6HE. The duration of the phase is 6months. Drug treatment is daily, with isoniazid (H) and ethambutol (E).2SHRZ/4H 3 R 3 . In some countries, resources are available to providerifampicin in the continuation phase as well as in the initial phase.The initial phase is 2SHRZ, the same as in the first example.The continuation phase is 4H 3 R 3 . The duration is 4 months, withisoniazid and rifampicin three times per week (subscript number 3 afterthe letters).9.3.4 Recommended treatment regimensThere are several possible regimens. The regimen recommendeddepends on the patients diagnostic category (see Chapter 8).The tablebelow shows possible alternative regimens for each diagnostic category.Follow the regimens recommended by the NTP in your country. Lookin your NTP manual.TB/HIV:A CLINICAL MANUAL115

Recommended treatment regimens for each diagnostic category(World Health Organization.Treatment of tuberculosis. Guidelines for nationalprogrammes.Third edition. Geneva, 2003) (WHO/CDS/TB/2003.313)TB treatment regimensTB TB patients Initial phase Continuationdiagnosticphasecategory(daily or 3 times (daily or 3 timesweekly) a weekly) aI New smear-positive 2HRZE b 4HRpatients.(orNew smear-negative 6HE daily c )pulmonary TB withextensive parenchymalinvolvement.Severe concomitantHIV disease orsevere forms ofextrapulmonary TB.II Previously treated 2 HRZES/1HRZE 5HREsputum smear-positivepulmonary TB:- relapse- treatment afterdefault- treatment failure d .III New smear-negative 2HRZE e 4HRpulmonary TB (other(orthan in Category I). 6HE daily c )Less severe forms ofextrapulmonary TB.IV Chronic and MDR-TB Specially designed individualizedcases (stillor standardized regimenssputum-positive are suggested for this categoryafter supervised (refer to the current WHOre-treatment) f . TB treatment guidelines, Chapter 5)a Direct observation of drug intake is required during the initial phase of treatment insmear-positive cases, and always in treatment including rifampicin.b Streptomycin may be used instead of ethambutol. In TB meningitis, ethambutol should bereplaced by streptomycin.c This regimen may be associated with a higher rate of treatment failure and relapsecompared with the 6-month regimen with rifampicin in the continuation phase (refer tothe current WHO TB treatment guidelines, section 4.8)d Whenever possible, drug sensitivity testing is recommended before prescribing Category IItreatment in failure cases. It is recommended that patients with proven MDR-TB useCategory IV regimens (refer to the current WHO TB treatment guidelines, Chapter 5).e Ethambutol may be omitted during the initial phase of treatment for patients with noncavitary,smear-negative pulmonary TB who are known to be HIV-negative, patients knownto be infected with fully drug-susceptible bacilli, and young children with primary TB.f Contacts of patients with culture-proven MDR-TB should be considered for early cultureand sensitivity testing.116 MANAGEMENT OF PATIENTS WITH TB

Some authorities recommend a 7 month continuation phase with dailyisoniazid and rifampicin (7HR) for Category 1 patients with particularforms of TB. These are TB meningitis, miliary TB and spinal TB withneurological signs.9Fixed-dose combination drugs (FDC) should be recommendedwherever they are available, especially for regimens containing rifampicinin the continuation phase or when direct observation is not fullyguaranteed.9.3.5 Use of streptomycin in areas of high HIV prevalenceº In populations with high TB/HIV prevalence, overcrowding is commonin TB wards.The staff workload is high, motivation may be poor andresources may be insufficient. This may result in inadequatesterilization of needles and syringes used for streptomycin injections.Without rigorous sterilization, there is a risk of transmission of HIVand other bloodborne pathogens between patients.º Streptomycin injections are very painful in wasted HIV-infected TBpatients.º Many NTPs now recommend the use of ethambutol in place ofstreptomycin.9.3.6 Use of TB drugs in childrenThe treatment regimens and drug dosages in mg/kg of body weight arethe same for children as for adults. Children usually tolerate TB drugsvery well and serious side-effects are unusual. Do not give thioacetazoneto HIV-infected children. Ethambutol is safe even in children too youngto report early visual side-effects provided that the recommended doseis not exceeded. Since TB drugs are often not available in syrup form,give children portions of tablets according to weight.Health service staff must identify a guardian responsible for the child’streatment.This is usually but not always the child’s mother. If a child hasHIV infection, often the parent is also sick. If the parent dies before thechild has completed treatment, this commonly causes some socialdislocation. For example, the family may send a child from the town tostay with other family members in a rural village.This may lead to poorcompliance and an adverse treatment outcome. Health service staffneed to be aware of a child’s family and social circumstances and arrangetransfer of TB treatment as necessary.TB/HIV:A CLINICAL MANUAL117

9.4 TB TREATMENT REGIMENS: QUESTIONS ANDANSWERSWhy use 4 drugs in the initial phase?* There is a high degree of initial resistance in some populations.* Use of a 3-drug regimen runs the risk of selecting drug-resistantmutants. This may happen especially in patients with high bacillaryloads, e.g. cavitary pulmonary TB, HIV-positive TB patients.* A 4-drug regimen decreases the risks of drug resistance, treatmentfailure, and relapse.Why use pyrazinamide only in the initial phase?* Pyrazinamide has its maximum sterilizing effect within the first 2months.* There is less benefit from longer use.Is a 4-month continuation phase possible?* A 4-month continuation phase is possible with rifampicin throughout(e.g. 2SHRZ/4HR). This is because isoniazid and rifampicin are bothpotent bactericidal drugs. In the usual 6 month continuation phase(6HE or 6HT), the only potent bactericidal drug is isoniazid.When should regimens containing rifampicin throughout beused?* Although the high cost of rifampicin has prevented some countriesfrom using these regimens, falling costs make them increasinglyaffordable.* Since rifampicin administration should be under direct observation,TBprogrammes need to mobilize the resources to ensure this.Why is it so important to prevent rifampicin resistance?* Rifampicin is the most effective anti-TB drug. It is unlikely that a newanti-TB drug will become widely available in the near future. Ifrifampicin resistance becomes widespread, TB will be effectivelyuntreatable.How do we prevent rifampicin resistance?* Acquired drug resistance develops for several reasons.These includepoorly performing TB control programmes, lack of supervision of anti-TB treatment, poor prescribing by clinicians, poor absorption in HIVpositivepatients, and the use of rifampicin alone. The best way toprevent rifampicin resistance is to strengthen NTPs and ensure DOTwhen and where possible. It is important to use methods of drug118 MANAGEMENT OF PATIENTS WITH TB

administration that avoid the danger of the use of rifampicin alone.These include the use whenever possible of FDC tablets and of anti-TB drugs supplied in blister packs.9What are the advantages of FDC tablets?* Dosage recommendations are more straightforward. Adjustment ofdosage according to patient weight is easier.Thus prescription errorsare likely to be less frequent.* There is a smaller number of tablets to ingest, which shouldencourage adherence to treatment.* Patients cannot be selective about which drugs they ingest. Thusmonotherapy is impossible and risk of drug resistance is reduced.When does multidrug-resistant (MDR) TB arise?* MDR-TB arises from failure to deliver anti-TB drug treatmentproperly.What is the treatment of MDR-TB?* MDR-TB treatment consists of second-line drugs, e.g. ethionamide,cycloserine, kanamycin, capreomycin and quinolones. These areunavailable in many countries with high TB prevalence and oftenprohibitively expensive.What should we do when faced with MDR-TB?* The cause of the problem is usually a poorly performing NTP. Theanswer is to spend time, effort and resources to improve the NTP. Insome countries, one or two specialist centres may have the expertiseand second-line drugs available to treat patients with MDR-TB.* NTPs are establishing “DOTS-Plus” pilot projects in areas whereMDR-TB is common.A global DOTS-Plus Working Group coordinatesthese pilot projects. DOTS-Plus aims to assess the feasibility and costeffectivenessof the use of second-line drugs within the DOTSstrategy. In negotiation with the Working Group, the pharmaceuticalindustry has agreed to provide second-line drugs at preferential pricesto DOTS-Plus pilot projects. Part of the Working Group is the GreenLight Committee.This assesses applications from TB programmes forinclusion among the projects supported by the Working Group. Youshould refer to the guidelines for establishing DOTS-Plus pilotprojects (see “Suggestions for further reading”).TB/HIV:A CLINICAL MANUAL119

9.5 USE OF ANTI-TB DRUGS IN SPECIAL SITUATIONSPregnancy* Streptomycin during pregnancy can cause permanent deafness in thebaby.* Do not give streptomycin in pregnancy. Use ethambutol instead.* Isoniazid, rifampicin, pyrazinamide and ethambutol are safe to use.* Second-line drugs such as fluoroquinolones, ethionamide andprotionamide are teratogenic, and should not be used.Breastfeeding women* All anti-TB drugs are compatible with breastfeeding.Renal failure* Rifampicin, isoniazid and pyrazinamide are safe and can be given innormal dosages. Patients with severe renal failure should receivepyridoxine with isoniazid to prevent peripheral neuropathy.* Ethionamide and protionamide are also safe.* The excretion of streptomycin is renal.The excretion of ethambutoland thioacetazone is partly renal.* Avoid streptomycin and ethambutol if there are alternatives.Otherwise give in reduced doses at less frequent intervals.* Do not give thioacetazone. The margin between the therapeuticand toxic dose is too narrow.* The safest regimen to give to patients in renal failure is 2HRZ/4HR.Liver disease* Most anti-TB drugs can cause liver damage and therefore care isneeded.* Do not give pyrazinamide because this is the mosthepatotoxic anti-TB drug.* Isoniazid and rifampicin plus one or two non-hepatotoxic drugs, suchas streptomycin and ethambutol, can be used for a total treatmentduration of eight months.* If the patient has severe liver damage, an alternative regimen isstreptomycin plus isoniazid plus ethambutol in the initial phasefollowed by isoniazid and ethambutol in the continuation phase witha total duration of 12 months.* Recommended regimens are 2SRHE/6HE or 2SHE/10HE.120 MANAGEMENT OF PATIENTS WITH TB

9.6 THE ROLE OF ADJUVANT STEROID TREATMENT:QUESTIONS AND ANSWERSWhat is adjuvant steroid treatment?Adjuvant steroid treatment is steroid treatment given in addition to anti-TB drug treatment. Studies in the pre-HIV era confirmed the benefit ofsteroids for TB meningitis and pleural and pericardial TB. Steroids arealso of benefit in HIV-positive patients with pericardial TB.9What are the indications for treatment with steroids?* TB meningitis (decreased consciousness, neurological defects, orspinal block).* TB pericarditis (with effusion or constriction).* TB pleural effusion (when large with severe symptoms).* Hypoadrenalism (TB of adrenal glands).* TB laryngitis (with life-threatening airway obstruction).* Severe hypersensitivity reactions to anti-TB drugs.* Renal tract TB (to prevent ureteric scarring).* Massive lymph node enlargement with pressure effects.What are the recommended treatment doses of prednisolone?Rifampicin is a potent inducer of hepatic enzymes that metabolizesteroids. The effective dose of prednisolone is therefore half theprescribed treatment dose given to the patient.The table below showssuggested treatment doses of prednisolone.IndicationPrednisolone treatment(dose for children in brackets)TB meningitis 60 mg (1–2 mg/kg) daily for weeks 1–4,then decrease over several weeksTB pericarditis 60 mg (1–2 mg/kg) daily for weeks 1–430 mg (0.5–1 mg/kg) daily for weeks 5–8, thendecrease over several weeksTB pleural effusion 30 mg (0.5–1 mg/kg) daily for 1–2 weeksIs steroid treatment safe in TB/HIV patients?Steroids are immunosuppressants. Steroids may further depressimmunity and increase risk of opportunistic infections in HIV-positivepatients. However, on balance,TB/HIV patients are still likely to benefitfrom the use of steroids for the above indications.TB/HIV:A CLINICAL MANUAL121

PRACTICAL POINTRecording treatment results in sputum smear-positive PTBpatients is vital to monitor patient cure and NTPeffectiveness (see Chapter 2).9.7 MONITORING OF TB PATIENTS DURINGTREATMENTIt is important to monitor all TB patients, adults and children, duringtreatment. This is in order to assess the progress of individual TBpatients and to evaluate NTP performance.Bacteriological monitoring is readily available only for patients withsputum smear-positive PTB. These are usually adults and sometimesolder children. Routine monitoring of treatment response by CXR isunnecessary and wasteful of resources.Clinical monitoring is the usual guide to treatment response for otherTB patients.These include adults with sputum smear-negative PTB andextrapulmonary TB and most children.9.7.1 Monitoring of patients with sputum smear-positive PTBWhen to monitor 8-month treatment 6-month treatmentregimenregimenAt time of diagnosis sputum smear sputum smearAt end of initial phase sputum smear sputum smearIn continuation phase sputum smear sputum smear(month 5) (month 5)During last month of sputum smear sputum smeartreatment (month 8) (month 6)Sputum smear at end of initial phaseThe vast majority of patients have a negative sputum smear at the endof the initial phase. If the sputum smear is still positive at the end of theinitial phase, continue initial phase treatment with the same 4 drugs for4 more weeks. If you check the sputum smear again at this point, it isunlikely still to be positive. Go on to the continuation phase (even if thesputum smear after the extra 4 weeks of initial phase treatment is stillpositive).122 MANAGEMENT OF PATIENTS WITH TB

Sputum smear in continuation phaseIn 8-month regimens, a positive sputum smear at 5 months (or any timeafter 5 months) means treatment failure. In 6-month regimens, a positivesputum smear at 5 months (or any time after 5 months) means treatmentfailure. A common cause of treatment failure is the failure of theprogramme to ensure patient adherence to treatment. The patient’streatment category changes to Category 2 and the re-treatment regimenstarts.9Sputum smear on completion of treatmentNegative sputum smears in the last month of treatment and on at leastone previous occasion mean bacteriological cure.9.7.2 Recording treatment outcomeSputum smear-positive PTB patientsAt the end of the treatment course in each individual patient, the districtTB officer (DTO) should record the treatment outcome as follows:Curepatient who is sputum smear-negative in thelast month of treatment and on at least oneprevious occasionTreatment completed patient who has completed treatment butdoes not meet the criteria to be classified asa cure or a failureTreatment failure patient who is sputum smear-positive at 5months or later during treatmentDiedpatient who dies for any reason during thecourse of treatmentDefaulted (treatment patient whose treatment was interrupted forinterrupted)Transferred out2 consecutive months or morepatient who has been transferred to anotherrecording and reporting unit and for whomthe treatment outcome is not known1. Treatment success is the sum of patients cured and those who havecompleted treatment.2. In countries where culture is the current practice, patients can beclassified as cure or failure on the basis of culture results.Sputum smear-negative PTB and extrapulmonary TB patientsFour of the above standard outcome indicators are applicable to adultsand children with smear-negative PTB or extrapulmonary TB. TheseTB/HIV:A CLINICAL MANUAL123

indicators are treatment completion, death, default and transfer out,which the DTO should record in the district TB register.Record as a treatment failure a patient who was initially smear-negativebefore starting treatment and became smear-positive after completingthe initial phase of treatment.9.7.3 Cohort analysis: questions and answersWhat is cohort analysis?A cohort is a group of patients diagnosed and registered for treatmentduring a specific time period (usually one quarter of the year). Forexample, all the sputum smear-positive PTB patients registered from 1January to 31 March in any year form the cohort for that quarter-year.Cohort analysis refers to the statistical breakdown of the cohortaccording to certain indicators. These indicators are the standardizedcase definitions and treatment categories (see Chapter 8) and thetreatment outcomes. New and previously treated patients form separatecohorts.Who performs cohort analysis and how often?Cohort analysis is a continuous process. The DTO performs cohortanalysis on TB patients registered in the district every quarter-year andat the end of every year.The regional TB officer performs cohort analysison all TB patients registered in the region. The NTP central unitperforms cohort analysis on all TB patients registered nationally.What is cohort analysis for?Cohort analysis is the key management tool used to evaluate theeffectiveness of NTP performance. It enables district and regional NTPstaff and the NTP directorate to identify districts with problems.Examples of problems identified include the following: low cure rate,high default rate, higher than expected proportions of sputum smearnegativePTB or extrapulmonary TB, lower than expected case detectionrate. Identification of problems enables the NTP to overcome them andimprove programme delivery.9.8 RESPONSE OF HIV-POSITIVE TB PATIENTS TOANTI-TB TREATMENTResponse in patients who complete treatmentPatients who complete treatment show the same clinical, radiographicand microbiological response to SCC whether HIV-positive or HIV-124 MANAGEMENT OF PATIENTS WITH TB

negative.The only exception is that on average weight gain is less in HIVpositivethan HIV-negative TB patients.Case-fatalityCase-fatality is the percentage of TB patients who die within a givenperiod (e.g. during treatment). HIV-positive TB patients have a muchhigher case-fatality during and after anti-TB treatment compared withHIV-negative patients. In sub-Saharan Africa, up to 30% of HIV-positivesmear-positive PTB patients die before the end of treatment. Evidence isalso accumulating that HIV-positive smear-negative PTB patients have aworse prognosis than those who have HIV-positive smear-positive PTB.Excess deaths in TB/HIV patients during and after treatment are partlydue to TB itself and partly due to other HIV-related problems. Theseinclude septicaemia, diarrhoea, pneumonia, anaemia, Kaposi sarcoma, andcryptococcal meningitis.9Case-fatality is lower in TB/HIV patients treated with SCC than with theold standard regimen (1SHT or SHE/11HT or HE).This is partly becauseSCC is a more effective anti-TB treatment. Also, as well as anti-TBactivity, rifampicin has broad-spectrum antimicrobial activity. This mayreduce deaths due to HIV-related bacterial infections during TBtreatment.Two studies suggest the importance of DOT in reducing deaths. Selfadministeredtreatment was associated with a higher mortality amongHIV-positive TB patients compared with DOT. This association remainedeven after controlling for all other factors in a multivariate analysis.Adjunctive treatments may be needed with anti-TB treatment to reducedeaths.Recurrence of TB after completion of anti-TB treatmentOld standard treatment (initial phase 1SHT or SHE; continuationphase 11HT or HE)The recurrence rate is higher in HIV-positive than in HIV-negative TBpatients. In one study of TB/HIV patients, there was an associationbetween recurrence and cutaneous reaction to thioacetazone.A severethioacetazone reaction necessitated interruption of treatment and achange to ethambutol. There are several possible explanations for thelink between increased risk of recurrence and thioacetazone reaction.These include treatment interruption, subsequent poor compliance,more advanced immunocompromise, and change to the combination ofisoniazid and ethambutol in the 11-month continuation phase.TB/HIV:A CLINICAL MANUAL125

SCCAmong TB patients who complete SCC, the recurrence rate may behigher in HIV-positive than in HIV-negative patients. Studies suggest twoways of reducing this higher recurrence rate, although they do notprolong survival. One way is to extend the duration of the treatmentregimen from 6 to 12 months. Another way is to give post-treatmentprophylaxis (for example with isoniazid). Further studies are neededbefore these treatments can be widely recommended. Studies are stillneeded to confirm the benefit, establish the optimum regimen (drugsand duration) and assess operational feasibility.Recurrence: relapse or reinfection?When TB recurs after previous cure, there are 2 possibilities:a) true relapse (reactivation of persisters not killed by anti-TB drugs);b) reinfection (due to re-exposure to another source of infection).The risk of re-infection depends on the intensity of exposure to TBtransmission.126 MANAGEMENT OF PATIENTS WITH TB

SUGGESTIONS FOR FURTHER READINGAlzeer AH, Fitzgerald JM. Corticosteroids and tuberculosis: risks and use asadjunct therapy. Tubercle and lung disease 1993; 74: 6–11.9Graham SM, Daley HM, Banerjee A, Salaniponi FM, Harries AD. Ethambutolusage in tuberculosis - time to reconsider? Archives of diseases in childhood,1998, 79: 274–278Horne NW. Modern drug treatment of tuberculosis. 7th edition. London, Chest,Heart and Stroke Association, 1990.Reider HL. Interventions for tuberculosis control and elimination.International Union Against Tuberculosis and Lung Disease, 2002.Paris,Stop TB Partnership. Global TB Drug Facility prospectus. Geneva, World HealthOrganization, 2001 (WHO/CDS/TB/2001.10a)World Health Organization. Tuberculosis handbook. Geneva, 1998(WHO/TB/98.253).World Health Organization. Guidelines for establishing DOTS-Plus pilot projectsfor the management of multidrug-resistant tuberculosis. Geneva, 2003(WHO/CDS/TB/2000.279).World Health Organization. Treatment of tuberculosis. Guidelines for nationalprogrammes. Third edition, Geneva, 2003 (WHO/CDS/TB/2003.313).World Health Organization, International Union Against Tuberculosis and LungDisease, Royal Netherlands Tuberculosis Association. Revised internationaldefinitions in tuberculosis control. International journal of tuberculosis and lungdisease, 2001, 5 (3): 213–215.Ya Diul M, Maher D, Harries A.Tuberculosis case fatality rates in high HIVprevalence populations in sub-Saharan Africa. AIDS, 2001, 15: 143–152.TB/HIV:A CLINICAL MANUAL127

SIDE-EFFECTS OF ANTI-TUBERCULOSIS DRUGSI010.1 INTRODUCTIONMost TB patients complete their treatment without any significant drugside-effects. However, a few patients do develop side-effects. So clinicalmonitoring of all TB patients for side-effects is important during TBtreatment. Routine laboratory monitoring is not necessary.Health personnel monitor patients for drug side-effects by:a) teaching patients and their family members how to recognisesymptoms of common side-effects, and to report if patients developsuch symptoms;b) asking specifically about these symptoms when they see all patientsat least monthly during treatment.10.2 PREVENTION OF SIDE-EFFECTSHealth personnel should be aware of the special situations that influencethe choice and dose of anti-TB drugs (see Chapter 9).It is possible to prevent the peripheral neuropathy caused by isoniazid.This neuropathy usually shows as a burning sensation of the feet. Itoccurs more commonly in HIV-positive individuals and in people whodrink alcohol. These patients should receive preventive treatment withpyridoxine 10 mg daily. Ideally, where possible, pyridoxine 10 mg dailyshould routinely accompany isoniazid.10.3 WHERE TO MANAGE DRUG REACTIONSReactionminor, e.g. gastrointestinal,joint painsmajor, e.g. jaundice,severe rashWhere to manage reactionoutpatient settingrefer to district or central hospital10.4 WHEN TO STOP ANTI-TB DRUGSWhen patients have minor drug side-effects, explain the situation, offersymptomatic treatment, and encourage them to continue treatment.TB/HIV:A CLINICAL MANUAL129

When a patient has a major reaction, stop the suspected responsibledrug(s) at once. A patient who develops one of the following reactionsmust never receive that drug again:Reactionsevere rash, agranulocytosishearing loss or disturbed balancevisual disturbance (poor visionand colour perception)renal failure, shock, orthrombocytopeniahepatitisDrug responsiblethioacetazonestreptomycinethambutolrifampicinpyrazinamide10.5 SIDE-EFFECTS OF ANTI-TB DRUGSDrug Common side-effects Rare side-effectsisoniazid º peripheral neuropathy convulsions, pellagra, jointº hepatitis if age > 40 pains, agranulocytosis, lupoidº sleepiness/lethargy reactions, skin rash, acutepsychosisrifampicin º gastrointestinal: acute renal failure, shock,anorexia, nausea, vomiting, thrombocytopenia, skin rash,abdominal pain "flu syndrome" (intermittentdoses), pseudomembranousº hepatitis colitis, pseudoadrenal crisis,º reduced effectiveness of osteomalacia, haemolyticoral contraceptive pillpyrazinamide º joint painsanaemiagastrointestinal symptoms,º hepatitis skin rash, sideroblasticanaemiastreptomycin º auditory and vestibular skin rashnerve damage (also tofetus)º renal damageethambutol º optic neuritis skin rash, joint pains,peripheral neuropathythiacetazone º skin rash, often withmucous membraneinvolvement andsometimes blisteringhepatitis,agranulocytosis130 SIDE-EFFECTS OF ANTI-TB DRUGS

PRACTICAL POINTRifampicin reduces the effectiveness of the oralcontraceptive pill. Advise women to use another form ofcontraception.I0PRACTICAL POINTWarn patients that rifampicin colours all body secretions(urine, tears, semen and sweat) red or orange.10.5.1 Side-effects of anti-TB drugs in HIV-positive TBpatientsAdverse drug reactions are more common in HIV-positive than in HIVnegativeTB patients. Risk of drug reaction increases with increasedimmunocompromise. Most reactions occur in the first 2 months oftreatment.Skin rashThis is the commonest reaction. Fever often precedes and accompaniesthe rash. Mucous membrane involvement is common. The usual drugresponsible is thioacetazone. Streptomycin and rifampicin aresometimes to blame. Severe skin reactions, which may be fatal, includeexfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermalnecrolysis.Other reactionsThe commonest reactions necessitating change in treatment includegastrointestinal disturbance and hepatitis.There may be an increased riskof rifampicin-associated anaphylactic shock and thrombocytopenia.TB/HIV:A CLINICAL MANUAL131

10.6 Symptom-based approach to management of drugside-effectsSide-effects Drug(s) probably ManagementresponsibleMinorContinue anti-TB drugsanorexia, nausea, rifampicin give tablets last thingabdominal painat nightjoint pains pyrazinamide give aspirin or nonsteroidalanti-inflammatory drugburning sensation isoniazid give pyridoxinein feet50–75 mg dailyorange/red urine rifampicin reassuranceMajorStop drug(s) responsibleskin itching/rash thioacetazone stop anti-TB drugs (see(streptomycin) below)deafness (no wax streptomycin stop streptomycin, giveon auroscopy)ethambutol insteaddizziness (vertigo streptomycin stop streptomycin, giveand nystagmus)ethambutol insteadjaundice (other most anti-TB drugs stop all anti-TB drugs untilcauses excluded)jaundice resolves(see below)vomiting and confusion most anti-TB drugs stop anti-TB drugs, urgent(suspected drug-inducedliver function testspre-icteric hepatitis)visual impairment ethambutol stop ethambutolgeneralized, including rifampicinstop rifampicinshock and purpura10.7 MANAGEMENT OF SKIN ITCHING AND RASHThe approach depends on whether the patient is receivingthioacetazone. In populations with a high TB/HIV prevalence,thioacetazone is the drug most likely to cause skin reactions.PRACTICAL POINTTry to determine if the skin reaction was present beforeanti-TB drugs were started, as many HIV-positive patientshave itchy skin lesions as a result of HIV infection.132 SIDE-EFFECTS OF ANTI-TB DRUGS

10.7.1 Treatment regimen includes thioacetazoneIf a patient starts to itch, and there is no other obvious cause (e.g.scabies), stop the anti-TB drugs at once. The itching may be a warningsign of severe skin reaction. Stopping thioacetazone at once may avert,or decrease the severity of, the skin reaction.I0Give the patient intravenous fluids if the skin reaction is severe andaccompanied by any of the following:a) exfoliative dermatitis or toxic epidermal necrolysis,b) mucous membrane involvement,c) hypotension.Many physicians give steroid treatment, although there is no firmevidence that this helps.A typical dose schedule consists of 60 mg dailyof oral prednisolone until there is some improvement. A gradualreduction in dose over the next few days depends on the patient'sresponse. Initially, if a patient is unable to swallow, give intravenoushydrocortisone 100–200 mg daily (instead of oral prednisolone).Patients with exfoliation should also receive antibiotics to safeguardagainst life-threatening infection of lesions. On recovery, restart anti-TBdrugs, replacing thioacetazone with ethambutol.PRACTICAL POINTNever give a patient thioacetazone again after anythioacetazone reaction.A severe reaction may mean stopping anti-TB treatment for 3–4 weeks.A severely ill TB patient may die without anti-TB treatment. In this case,give the patient 2 or more previously unused drugs until the reaction hasresolved.Then reintroduce the initial regimen (with ethambutol insteadof thioacetazone).10.7.2 Treatment regimen does not include thioacetazoneIf a patient starts to itch, exclude other obvious causes. Try treatmentwith antihistamines, continue anti-TB treatment and observe closely. Insome cases, the itching resolves. In other cases, a rash develops. In thiscase, stop the anti-TB drugs.Wait for the rash to resolve. If the reactionis severe, the patient may need supportive treatment as above.The problem now is to reintroduce TB treatment when it is not knownTB/HIV:A CLINICAL MANUAL133

which anti-TB drug was responsible for the reaction. The table belowshows the standard approach to reintroducing anti-TB drugs after a drugreaction.Reintroduction of anti-TB drugs following drug reactionLikelihood of Challenge dosescausing a reactionDrug Day 1 Day 2 Day 3Isoniazid least likely 50 mg 300 mg 300 mgRifampicin 75 mg 300 mg Full dosePyrazinamide 250 mg 1 gr Full doseEthambutol 100 mg 500 mg Full doseStreptomycin most likely 125 mg 500 mg Full doseIf possible, while a patient is underging drug challenge, give two anti-TBdrugs that the patient has not had before.The idea of drug challenge isto identify the drug responsible for the reaction. Drug challenge startswith the anti-TB drug least likely to be responsible for the reaction (i.e.isoniazid). Start with a small challenge dose. If a reaction occurs to asmall challenge dose, it will not be such a bad reaction as to a full dose.Gradually increase the dose over 3 days. Repeat the procedure, addingin one drug at a time. A reaction after a particular drug is addedidentifies that drug as the one responsible for the reaction.If the drug responsible for the reaction is pyrazinamide, ethambutol, orstreptomycin, resume anti-TB treatment without the offending drug. Ifpossible, replace it with another drug. It may be necessary to extend thetreatment regimen. Consider the start of the resumed regimen as a newstart of treatment. This prolongs the total time of TB treatment, butdecreases the risk of recurrence.PRACTICAL POINTRefer patients with severe drug reactions to a specialistcentre.10.8 DESENSITIZATIONRarely, patients develop hypersensitivity reactions to the two mostpotent anti-TB drugs, isoniazid and rifampicin. These drugs form thecornerstone of SCC. If an HIV-negative patient has had a reaction (but134 SIDE-EFFECTS OF ANTI-TB DRUGS

not a severe reaction) to isoniazid or rifampicin, it may be possible todesensitize the patient to the drug. However, desensitization in TB/HIVpatients needs very careful consideration because of the high risk ofserious toxicity.I0The following method may be used for desensitization. Startdesensitization with a tenth of the normal dose.Then increase the doseby a tenth of a normal dose each day, until the patient has the full doseon the tenth day. Once drug sensitization is over, give the drug as partof the usual treatment regimen. If possible, while carrying outdesensitization, give the patient two anti-TB drugs that he or she has nothad before.This is to avoid the risk of drug resistance developing duringdesensitization.10.9 MANAGEMENT OF HEPATITISMost anti-TB drugs can damage the liver. Isoniazid and pyrazinamide aremost commonly responsible. Ethambutol is rarely responsible. When apatient develops hepatitis during anti-TB treatment, the cause may bethe anti-TB treatment or something else. It is often difficult to find out.Try to rule out other possible causes before deciding that the hepatitisis drug-induced. Hepatitis presents with anorexia, jaundice and oftenliver enlargement.If you diagnose drug-induced hepatitis, stop the anti-TB drugs.Wait untilthe jaundice or hepatic symptoms have resolved and the liver enzymeshave returned to baseline. If liver enzymes cannot be measured, then itis advisable to wait two weeks after the jaundice has disappeared beforerecommencing anti-TB treatment.It is strange, but fortunate, that in most cases the patient can restart thesame anti-TB drugs without hepatitis returning.This can be done eithergradually or all at once (if the hepatitis was mild). If the hepatitis hasbeen life-threatening, it is probably safer to use the standard regimen ofstreptomycin, isoniazid and ethambutol.A severely ill TB patient may die without anti-TB drugs. In this case, treatthe patient with 2 of the least hepatotoxic drugs, streptomycin andethambutol. When the hepatitis resolves, restart usual anti-TBtreatment. In the face of extensive TB, the fluoroquinolones, especiallyofloxacin, can be considered in conjunction with streptomycin andethambutol as an interim non-hepatotoxic regimen.TB/HIV:A CLINICAL MANUAL135

SUGGESTIONS FOR FURTHER READINGCrofton J, Horne N, Miller F. Clinical tuberculosis. Second edition. MacMillanPress Limited, London, 1999.Horne NW. Modern drug treatment of tuberculosis. Seventh edition, London,The Chest, Heart and Stroke Association, 1990.Mitchell I, Wendon J, Fitt S, et al. Anti-tuberculosis therapy and acute liverfailure. Lancet, 1995, 345: 555–556.Reider HL. Interventions for tuberculosis control and elimination. Paris,International Union Against Tuberculosis and Lung Disease, 2002.136 SIDE-EFFECTS OF ANTI-TB DRUGS

ANTIRETROVIRAL THERAPY FOR THETREATMENT OF HIV INFECTION1I11.1 INTRODUCTIONRapid progress in developing antiretroviral therapy (ART) led in 1996 tothe introduction of highly active antiretroviral therapy (HAART). Thisrevolutionized the treatment of HIV infection. HAART is a combinationof at least three antiretroviral (ARV) drugs.As with anti-TB treatment, acombination of ARV drugs provides efficacy and decreases risk of drugresistance. HAART is the global standard of care in the treatment of HIVinfection. Although not a cure for HIV infection, HAART usually resultsin near-complete suppression of HIV replication. Treatment has to belifelong.ART results in dramatic reductions in morbidity and mortality in HIVinfectedpeople. There are several requirements for successful use ofART. These include considerable efforts to maintain adherence tolifelong treatment and to monitor response to treatment, drug toxicitiesand drug interactions.Although the benefits of ART are considerable, administration is noteasy. Many HIV-infected persons cannot tolerate the toxic effects of thedrugs.Adherence is difficult because of often large numbers of pills andcomplicated treatment regimens. Poor adherence to treatment leads tothe emergence of drug-resistant viral strains, which are very difficult totreat. Careful monitoring of patients is necessary to evaluate responseto treatment.HAART is the global standard of care. However, access is limited to veryfew HIV-infected people where the burden of HIV is greatest (in sub-Saharan Africa and Asia). WHO estimated that in 2002 there were 6million people in developing countries in need of ART. Of these, only230000 had access to ART (and half of those were in one country,Brazil). There are increasing international efforts to improve access toART in resource-limited settings. Drug costs (one of the major barriersto access in poor countries) are rapidly declining. Modification of drugpatent laws is under discussion to allow resource-poor countries toimport cheap generic versions of the drugs. Pilot schemes are underdevelopment to ensure proper and safe drug administration anddistribution at district level. The WHO Model List of Essential Drugsincludes eight ARV drugs. WHO has published guidelines for a publichealth approach to scaling up ART in resource-limited settings. TheseTB/HIV:A CLINICAL MANUAL137

developments will facilitate the achievement of the target to have 3million people in developing countries on ART by 2005.ART will become increasingly available in resource-poor countries.Clinicians treating TB patients need to be familiar with the principles andpractice of ART. This chapter therefore provides a brief guide to ART,including the specific treatment of HIV infection in TB/HIV patients.Youshould consult the suggestions for further reading for morecomprehensive guidance on ART. In this rapidly evolving field, you shouldalso consult national and international authorities for regularly updatedguidance. The WHO website is a useful source of up-to-date guidance(http://www.who.int/HIV).11.2 ANTIRETROVIRAL DRUGSARV drugs belong to two main classes:a) reverse transcriptase inhibitors (RTIs);b) protease inhibitors (PIs).RTIs are further divided into three groups:i) nucleoside reverse transcriptase inhibitors (NsRTIs);ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs);iii) nucleotide reverse transcriptase inhibitors (NtRTIs).The table shows the ARV drugs (abbreviation in brackets) approved forinclusion in WHO’s Model List of Essential Drugs (EDL) from April 2002.NsRTIs NNRTIs PIsZidovudine (AZT, ZDV) Nevirapine (NVP) Saquinavir (SQV)Didanosine (ddI) Efavirenz (EFV) Ritonavir (RTV)(as pharmacoenhancer)Stavudine (d4T)Indinavir (IDV)Lamivudine (3TC)Nelfinavir (NFV)Abacavir (ABC)Lopinavir/ritonavir (LPV/r)Examples of other drugs not included in the EDL are give below:NsRTIszalcitabine (ddC)NtRTItenofovir (TDF)NNRTIsdelavirdine (DLV)PIsamprenavir (APV)11.3 PRINCIPLES OF ARTARV drugs act by blocking the action of enzymes that are important for138 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

eplication and functioning of HIV. The drugs must be used instandardized combinations (usually three drugs together). Monotherapyis not recommended because of the inevitable development of drugresistance. However, for the specific indication of prevention of motherto-childtransmission of HIV infection, short course monotherapy is stillrecommended. Dual nucleoside therapy is also not recommendedbecause it does not reduce HIV-related mortality at a population level.1I11.4 PRINCIPLES OF A PUBLIC HEALTH APPROACHTO ARTWHO recommends a standardized approach to overall TB control anda standardized approach to TB treatment regimens. Similarly with HIV,WHO recommends a standardized approach to care, which includesstandardized ART regimens. Standardization and simplification of ARTregimens facilitate the effective implementation of HIV treatmentprogrammes. Effective implementation means maximized benefit forindividual patients with minimised risk of drug resistance. Althoughexperience with ART in resource-limited district settings is limited,countries are now scaling up ART. Further experience gained inproviding standardized first- and second-line regimens will inform futureWHO guidelines.PRACTICAL POINTFor effective and safe prescribing, consult guidelines forinformation on regimens, doses, side-effects and druginteractions. See “Scaling up antiretroviral therapy in resourcelimitedsettings”, Geneva,WHO, Revision 2003.The same public health principles underpin the approaches to TBtreatment and to ART. In both cases, success requires the following:political commitment; diagnosis and registration of patients; standardizeddrug treatment regimens under proper case management conditions;secure drug supply; programme monitoring and evaluation throughrecording and reporting of patients registered and their outcomes.11.5 INITIATION OF ARTThere is some controversy about the best time to start ART. Cliniciansin industrialized countries use plasma HIV RNA levels and CD4+ T-lymphocyte counts in guiding this decision. For example, a high viral load(i.e. above 30000 RNA copies/ml by RT-PCR) is an indication to startTB/HIV:A CLINICAL MANUAL139

ART.These expensive laboratory tests are used for staging HIV infectionand for monitoring therapy. WHO guidelines apply in resource-limitedsettings where these tests may not be available. Clinical stage (seeSection 1.2.7) is important as a criterion for starting ART.11.5.1 Adults and adolescents with documented HIV infectionRecommendations for initiating ARTCD4 testing available WHO stage 4 irrespective of CD4 cell countWHO stage1, 2 or 3 with CD4 cell countsless than 200/mm 3CD4 testingnot availableWHO stage 3 or 4 irrespective of totallymphocyte countWHO stage 2 with total lymphocytecount less than 1200/mm 3Contraindications to starting treatment include severe renal or hepaticinsufficiency, and concomitant incurable disease.11.5.2 Infants and childrenRecommendations for initiating ARTCD4 Age HIV Diagnostic Treatmenttesting testing recommendationIf CD4 < 18 Positive HIV º WHO Paediatric Stage 3testing months virological test 1 (AIDS), irrespective of CD4is cell percentage 2availableº WHO Paediatric Stage Idisease (asymptomatic) orStage 2 disease with CD4percentage < 20% 3HIV virological º WHO Paediatric Stage 3testing not available disease (AIDS) with CD4 cellbut infant HIV- percentage < 20%seropositive orborn to knownHIV-infected mother(Note: HIV antibodytest must berepeated at age 18months to obtaindefinitive diagnosisof HIV infection)140 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

18 HIV antibody º WHO Paediatric Stage 3months seropositive disease (AIDS) irrespectiveof CD4 cell percentage 2º WHO Paediatric Stage I(asymptomatic) orStage 2 disease, with CD4percentage 18 HIV antibody º WHO Paediatric Stage 3 2months seropositive1I1 HIV DNA PCR or HIV RNA or immune complex dissociated p24 antigen assays, or HIV culture.2 Initiation of ARV can also be considered for children who have advanced WHO Paediatric StageII disease including e.g. severe recurrent or persistent oral candidiasis outside the neonatalperiod, weight loss, fevers, or recurrent severe bacterial infections, irrespective of CD4 count.3 The rate of decline in CD4 percentage (if measurement available) should be factored into thedecision-making.4 Many of the clinical symptoms in the WHO Paediatric Stage II and III disease classification arenot specific for HIV infection and significantly overlap those seen in children without HIVinfection in resource-limited settings; thus, in the absence of virological testing and CD4 cell assayavailability, HIV-exposed infants

Drug Dose 1Nucleoside RTIs (NsRTIs)Zidovudine (ZDV)300 mg twice dailyStavudine (d4T)40 mg twice daily(30 mg twice daily if < 60 kg)Lamivudine (3TC)150 mg twice dailyDidanosine (ddI)400 mg once daily(250 mg once daily if < 60 kg)Abacavir (ABC)300 mg twice dailyNucleotide RTI (NtRTIs)Tenofovir (TDF)300 mg once dailyNon-nucleoside RTIs (NNRTIs)Efavirenz (EFZ)600 mg once dailyNevirapine (NVP)200 mg once daily for 14 days, then200 mg twice dailyProtease inhibitors (PIs)Nelfinavir (NFV)1250 mg twice dailyIndinavir/ritonavir (IDV/r) 800 mg/100 mg twice daily 2,4Lopinavir/ritonavir (LPV/r) 400 mg/100 mg twice daily(533 mg/133 mg twice daily whencombined with EFZ or NVP)Saquinavir/ritonavir (SQV/r) 1000 mg/100 mg twice daily 3,41 These dosages are in common clinical use.The dosages in this table were selected on thebasis of the best available clinical evidence, and dosages that can be given on a once ortwice daily basis were preferred in order to enhance adherence to therapy.The doses listedare those for individuals with normal renal and hepatic function. Product-specificinformation should be consulted for dose adjustments that may be indicated with renal orhepatic dysfunction or for potential drug interactions with other HIV and non-HIVmedications.2 This dosage regimen is in common clinical use. Other IDV/r dosage regimens that rangefrom 800 mg/200 mg twice daily to 400 mg/100 mg twice daily are also in clinical usage.3 Both the hard-gel and soft-gel capsule formulations can be used when SQV is combinedwith RTV.4 Dosage adjustment when combined with an NNRTI is indicated but a formalrecommendation cannot be made at this time. One consideration is to increase the RTVcomponent to 200 mg wice daily when EFZ or NVP is used concomitantly. More druginteraction data are needed.11.6.2 ChildrenThe following table indicates the recommended doses of ARV drugs forchildren.142 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

Name of drug Formulations Pharmacokinetic Age (weight), dose* Other commentsdata available and dose frequencyNucleoside reverse transcriptase inhibitors (NsRTIs)Zidovudine Syrup: 10 mg/ml All ages < 4 weeks: 4 mg/kg Large volume of syrup not(ZDV) twice daily well tolerated in older childrenCapsules: 100 mg;250 mg 4 weeks to 13 years: 180 Needs storage in glass jars andmg/m 2 twice daily is light-sensitiveTablet: 300 mg Maximum dose:>13 yrs: 300 mg Can give with foodtwice dailyDoses of 600 mg/m 2 twice dailyrequired for HIV encephalopathyDo not use with d4T(antagonistic antiretroviral effect)Lamivudine Oral solution: All ages < 30 days: 2 mg/kg Well tolerated(3TC) 10 mg/ml twice dailyCan give with foodTablet: 150 mg >30 days and < 60 kg:4 mg/kg twice daily Store solution at roomtemperature (use within oneMaximum dose: month of opening)> 60 kg: 150 mgtwice daily Tablet can be washed, mixed witha small amount of water or food,and taken immediately1ITB/HIV:A CLINICAL MANUAL143

Fixed-dose No liquid Adolescents Maximum dose: Tablet should not be splitcombination of available and adults > 13 years or > 60 kg: Tablet can be washed, mixed withZDV plus 3TC 1 tablet twice daily a small amount of water or food,Tablet: 300 mg and taken immediatelyZDV plus For children 13 years or > 60 kg:100 mg; 150 mg; 200 mg twice daily200 mg or 400 mg once dailyEnteric-coated Enteric-coated beadlets in capsulesbeadlets in capsules: can be opened and sprinkled on125 mg; 200 mg; small amount of food250 mg; 400 mgStavudine Oral solution: All ages < 30 kg: 1 mg/kg Large volume of solution(d4T) 1 mg/ml twice dailyCapsules: 15 mg, 30 to 60 kg: 30 mg Keep solution refrigerated;20 mg, 30 mg, twice daily stable for 30 days; must shake well40 mg144 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

Stavudine Maximum dose: Needs to be stored in glass bottles(d4T) > 60 kg: 40 mg(continued) twice daily Capsules opened up and mixedwith small amount of food arewell tolerated (stable in solutionfor 24 hours if kept refrigerated)Do not use with AZT(antagonistic antiretroviral effect)Abacavir Oral solution: Over age 3 < 16 years or < 37.5 kg: Syrup well tolerated or can(ABC) 20 mg/ml months 8 mg/kg twice daily crush tabletTablet: 300 mg Can give with foodMaximum dose:> 16 years or > 37.5 kg: MUST WARN PARENTS ABOUT300 mg twice daily HYPERSENSITIVITY REACTION.ABC should be stopped permanentlyif hypersensitivity reactionFixed-dose No liquid available Adolescents Maximum dose: Tablet cannot be split.combination of and adults > 40 kg: 1 tablet MUST WARN PARENTS ABOUTZDV plus 3TC twice daily HYPERSENSITIVITY REACTION.plus ABC Tablet: Trizavir should be stopped(trizavir) ZDV 300 mg permanently if hypersensitivityplus 3TC 150 mg reactionplus ABC 300 mg For children

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)Nevirapine Oral suspension: All ages 15 to 30 days: 5 mg/kg If rifampicin coadministration,(NVP) 10 mg/ml once daily for 2 weeks, then avoid useTablet: 200 mg 120 mg/m 2 twice dailyfor 2 weeks, then200 mg/m 2 twice daily Store suspension at roomtemperature; must shake well> 30 days to 13 yrs:120 mg/m 2 once daily Can give with foodfor 2 weeks, then120–200 mg/m 2 twice daily MUST WARN PARENTS ABOUTRASH. Do not escalate dose ifMaximum dose: rash occurs (if mild/moderate> 13 years: 200 mg once rash, hold drug; when rash cleared,daily for first 2 weeks, then restart dosing from beginning of200 mg/ twice daily dose escalation; if severe rash,discontinue drug)Drug interactionsEfavirenz Syrup: 30 mg/ml Only for children Capsule (liquid) dose for Capsules may be opened and(EFZ) (note: syrup over 3 years > 3 years: added to food but have veryrequires higher 10 to 15 kg: 200 mg peppery taste; however, can mixdoses than (270 mg = 9 ml) once daily with sweet foods or jam tocapsules, see disguise tastedosing chart) 15 to 20 kg: 250 mgCapsules: 50 mg, (300 mg = 10 ml) once daily Can give with food (but avoid100 mg, 200 mg 20 to 25 kg: 300 mg after high-fat meals which increase(360 mg = 12 ml) once daily absorption by 50%).146 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

Efavirenz 25 to 33 kg: 350 mg(EFZ) (450 mg = 15 ml) once daily Best given at bedtime, especially(continued) first 2 weeks, to reduce central33 to 40 kg: 400 mg nervous system side-effects.(510 mg = 17 ml) once dailyDrug interactionsMaximum dose:>40 kg: 600 mg once dailyProtease inhibitors (PIs)Nelfinavir Powder for oral All ages 1 year to < 13 years: 55 to milk, formula, pudding, etc. – do(50 mg per for very high doses 65 mg/kg twice daily not use acidic food or juice1.25 ml scoop) in infants < 1 yr (increases bitter taste)Maximum dose:Tablet: 250 mg >13 yrs: 1250 mg Because of difficulties with use of(tablets can be twice daily powder, crushed tabletshalved; can be preferred (even for infants) ifcrushed and appropriate dose can be givenadded to foodor dissolved Powder and tablets can be storedin water) at room temperature1ITB/HIV:A CLINICAL MANUAL147

Nelfinavir Take with food(NFV)(continued) Drug interactions (less thanritonavir-containing proteaseinhibitors)Lopinavir/ Oral solution: 6 months of age > 6 months to 13 years: Preferably oral solution andritonavir 80 mg/ml lopinavir or older 225 mg/m 2 LPV/57.5 mg/m 2 capsules should be refrigerated;(LPV/r) plus 20 mg/ml ritonavir twice daily however, can store at roomritonavir temperature up to 25°Cor weight-based dosing: (77°F) for 2 monthsCapsules: 7–15 kg: 12 mg/kg LPV133.3 mg lopinavir 3 mg/kg ritonavir twice daily Liquid formulation has low volumeplus 33.3 mg but bitter tasteritonavir 15–40 kg: 10 mg/kglopinavir 2–5 mg/kg ritonavir Capsules largetwice dailyShould be taken with foodMaximum dose:> 40 kg: 400 mg LPV/100 mg Drug interactionsritonavir (3 capsules or 5 ml)twice daily* Body surface area calculation (m 2 ): square root of (height in cm multiplied by weight in kg divided by 3600)148 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

11.7 CHOICE OF ART REGIMENWHO recommends standardized and simplified ART regimens insupport of effective large-scale ART programmes. Countries shouldselect a single first-line, and a limited number of second-line, regimensfor large-scale use. This clinical manual provides guidance onrecommended first-line regimens. The WHO guidelines Scaling upantiretroviral therapy in resource-limited settings provide full details,including guidance on second-line regimens.The results of clinical studiesand of surveillance for drug resistance should inform policies forrecommended first-line and second-line regimens.1I11.7.1 AdultsRecommended combination regimens without a PITwo NsRTIs (e.g. zidovudine/lamivudine) + one NNRTI (eithernevirapine or efavirenz)orthree NsRTIs (including abacavir), e.g. zidovudine/lamivudine/abacavirAlternative NsRTI combinations (not in preferred order):zidovudine + didanosinestavudine + lamivudine or didanosineZidovudine and stavudine should not be used together because of theirmutually antagonistic effect. Didanosine and zalcitabine may lead toadditive neurotoxicity and should not be combined.Recommended combination regimens containing a PITwo NsRTIs + one PI, e.g. zidovudine/lamivudine/indinavirThese are effective regimens. However, there are some disadvantages,such as complex dosing schedules, drug interactions with rifampicin, andconcern over long-term toxicity of PIs.TB/HIV:A CLINICAL MANUAL149

Recommended first-line ARV combination regimens in adults andadolescents with documented HIV infectionRegimen* Pregnancy Major toxicitiesConsiderationsZDV/3TC/EFZ or Substitute NVP for EFZ ZDV-related anaemiaZDV/3TC/NVP in pregnant women or EFZ-associated CNSwomen for whom effective symptomscontraception cannot beassuredPossible teratogenicityof EFZNVP-associatedhepatotoxicity andsevere rashZDV/3TC/ABC ABC safety data limited ZDV-related anaemiaABC hypersensitivityZDV/3TC/ PI** LPV safety data limited ZDV-related anaemiaor ZDV/3TC/NFV NFV: most supportivesafety dataNFV-associated diarrhoeaIDV-relatednephrolithiasisPI-related metabolicside-effects*ZDV/3TC is listed as the initial recommendation for dual NsRTIcomponent based on efficacy, toxicity, clinical experience and availabilityof fixed-dose formulation. Other dual NsRTI components can besubstituted including d4T/3TC, d4T/ddI and ZDV/ddI depending uponcountry-specific preferences. ZDV/d4T should never be used togetherbecause of proven antagonism.** PIs include IDV, LPV, and SQV.11.7.2 ChildrenThere have been a limited number of studies of ART in children. Theysuggest that many different ARV regimens result in broadly similarimprovements in surrogate markers. Most ARVs available for adults arealso available for children in specific formulations, including dosagesbased on either body surface area or weight. First-line treatmentoptions for children include ZDV/3TC plus either a non-nucleoside(NVP or EFZ) or ABC. Children under the age of 3 years should notreceive EFZ because of lack of appropriate dosing information. Inchildren over three years, EFZ is the NNRTI of choice when startingART before completion of rifampicin-containing anti-TB therapy.150 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

Recommended first-line ARV combination regimens for children 1RegimenCommentsZDV/3TC 2 plus ABC Preferred if child receiving concomitantanti-TB therapyZDV/3TC 2 plus NNRTI NNRTI choice:º if < 3 years or < 10 kg, NVPº if >3 years or >10 kg, NVP or EFVI11 Country-specific considerations and preferences should determine which regimen or regimens tomake available.2 The greatest clinical experience is with ZDV/3TC, which is therefore the first choice dual NsRTIregimen. Other dual NsRTI components can be substituted, including ZDV/ddI, d4T/3TC,d4T/ddI, and ddI/3TC. ZDV/d4T should never be used because of proven antagonism.11.8 MONITORING THE EFFICACY OF ARTEfficacy is monitored by:clinical improvementº gain in body weight,º decrease in occurrence and severity of HIV-related diseases(infections and malignancies),increase in total lymphocyte count,improvement in biological markers of HIV (when available)º CD4+ T-lymphocyte counts,º plasma HIV RNA levels.11.9 ADVERSE EFFECTSAll ARV drugs have class-specific adverse effects.º NsRTIs: fatty changes in the liverlactic acidosislipodystrophy syndrome with prolonged useº PIs: lipodystrophy syndromeelevated serum cholesterol and triglycerideselevated blood glucosebleeding episodes in patients with haemophiliaº NNRTIs: skin rashabnormal liver enzymes/hepatitisTB/HIV:A CLINICAL MANUAL151

Lactic acidosis is due to toxicity of NsRTIs on cellular mitochondria. Ifunrecognized, it is potentially fatal. If patients develop pronouncedfatigue, nausea, vomiting and abdominal pain, lactic acidosis should beconsidered.Lipodystrophy syndrome has distinctive features.There is peripheral fatloss around the face, limbs and buttocks. Fat accumulates centrallyaround the abdomen and breasts and over the back of the neck (socalled“buffalo hump”). Often associated with lipodystrophy are raisedblood levels of cholesterol, triglycerides and glucose.Other specific drug side-effects include:NsRTIszidovudinedidanosinezalcitabinestavudinelamivudineabacavirNNRTIsnevirapineefavirenzdelavirdinePIssaquinavirritonavirindinavirnelfinaviramprenavirlopinavir/ritonavirnausea, headache, fatigue, muscle pains, myopathy,anaemia, agranulocytosis,nausea, diarrhoea, neuropathy, pancreatitisneuropathy, pancreatitis, oral ulcersneuropathy, pancreatitisnausea, headache, fatigue, muscle pains, anaemia,agranulocytosis,nausea, fatigue, sleep disturbance, hypersensitivityreactionrash, hepatitisneuropsychiatric disturbancesheadachesnausea, diarrhoeanausea, diarrhoea, weakness, skin sensitivity,abnormal taste, perioral numbnessnausea, abdominal pain, headache, kidney stonesdiarrhoea, nausea, skin rashnausea, vomiting, diarrhoea, abnormal taste, mooddisorder, perioral numbnessabdominal pain, diarrhoea, fatigue, headache,nausea, vomiting, pancreatitisMonitoring the safety of ART and tolerance depends on clinicalassessment and laboratory tests. Laboratory tests includemeasurements of full blood count, liver enzymes, serum amylase(pancreatitis), glucose, triglycerides and creatine phosphokinase(myopathy). Different ART regimens require different laboratory tests.152 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

11.10 INTERACTIONS BETWEEN ARV DRUGS ANDDRUGS USED TO PREVENT OR TREATOPPORTUNISTIC INFECTIONS1IThere are many interactions between ARV and other drugs. Twoexamples of common interactions are between: i) zidovudine andcotrimoxazole; and ii) PIs and ketoconazole or fluconazole.º Trimethoprim-sulfamethoxazole can give additive haematologicaltoxicity when given with zidovudine.º Antifungal drugs such as ketoconazole and fluconazole may inhibit themetabolism of PIs.This may result in increased serum levels of PI andincreased risk of toxicity.11.11 ANTIRETROVIRAL DRUGS AND TB TREATMENT11.11.1 Drug interactionsRifampicin stimulates the activity of the cytochrome P450 liver enzymesystem, which metabolizes PIs and NNRTIs.This can lead to decreasedblood levels of PIs and NNRTIs. PIs and NNRTIs can also enhance orinhibit this same enzyme system, and lead to altered blood levels ofrifampicin. The potential drug interactions may result in ineffectivenessof ARV drugs, ineffective treatment of TB or an increased risk of drugtoxicity.Isoniazid can cause peripheral neuropathy. The NsRTIs (didanosine,zalcitabine and stavudine) may also cause peripheral neuropathy.There isa potential added toxicity if isoniazid is added. Isoniazid also has atheoretical interaction with abacavir.11.11.2 Treating TB and HIV togetherIn patients with HIV-related TB, the priority is to treat TB, especiallysmear-positive PTB (on account of the need to stop TB transmission).However, patients with HIV-related TB can have ART and anti-TBtreatment at the same time, if managed carefully. Careful evaluation isnecessary in judging when to start ART. In the case, for example, of apatient with a high risk of death during the period of TB treatment (i.e.disseminated TB and/or CD4 count

infection, who does not appear to be at high risk of dying, it may be saferto defer ART until the initial phase of TB treatment has been completed.This decreases the risk of immune reconstitution syndrome and avoids therisk of drug interaction between rifampicin and a PI.11.11.3 Immune reconstitution syndromeOccasionally, patients with HIV-related TB may experience a temporaryexacerbation of symptoms, signs or radiographic manifestations of TBafter beginning anti-TB treatment. This paradoxical reaction in HIVinfectedpatients with TB is thought to be a result of immunereconstitution.This occurs as a result of the simultaneous administrationof ART and anti-TB drugs. Symptoms and signs may include high fever,lymphadenopathy, expanding central nervous system lesions andworsening of CXR findings. A thorough evaluation is necessary toexclude other causes, particularly TB treatment failure, before diagnosinga paradoxical reaction. For severe paradoxical reactions, prednisone(1–2 mg/kg for 1–2 weeks, then gradually decreasing doses) may help,although there is no evidence for this.11.11.4 Options for ART in patients with TBPossible options for ART in patients with TB include the following:º Defer ART until completion of TB treatment.º Defer ART until the completion of the initial phase of TB treatmentand then use ethambutol and isoniazid in the continuation phase.º Treat TB with a rifampicin-containing regimen and use efavirenz + twoNsRTIs.154 ANTIRETROVIRAL THERAPY FOR THE TREATMENT OF HIV INFECTION

SUGGESTIONS FOR FURTHER READINGBartlett JG, Gallant JE. Medical management of HIV infection. Baltimore, MD, JohnsHopkins University School of Medicine, 2000–2001.1ICarr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet, 2000,356: 1423–1430.Harrington M, Carpenter CCJ. World AIDS Series: Hit HIV-1 hard, but onlywhen necessary. Lancet, 2000, 355: 2147–2152.Pozniak AL, Miller R, Ormerod LP. The treatment of tuberculosis in HIVinfectedpersons. AIDS, 1999; 13: 435–445.World Health Organization. Scaling up antiretroviral therapy in resource-limitedsettings: treatment guidelines for a public health approach. 2003 revision. Geneva,(www.who.int/hiv).Harries AD, Nyangulu DS, Hargreaves NJ, Kaluwa O, Salaniponi FM. Preventingantiretroviral anarchy in sub-Saharan Africa. Lancet, 2001, 358: 410-14.Harries AD, Hargreaves NJ, Chimzizi R, Salaniponi FM. Highly activeantiretroviral therapy and tuberculosis control in Africa: synergies and potential.Bulletin of the World Health Organization, 2002, 80: 464–469.TB/HIV:A CLINICAL MANUAL155

TREATMENT AND PREVENTION OF OTHERHIV-RELATED DISEASES IN TB/HIV PATIENTSI212. 1 INTRODUCTIONWhether or not TB/HIV patients have access to ART, they may have, orwill develop, other HIV-related diseases.This chapter is a brief guide totheir management at district hospital level.At the end of the chapter isa guide to prevention of HIV-related diseases. Therapies in bold areavailable in most district hospitals.The WHO publications, Guidelines forthe clinical management of HIV Infection for adults and for children andManagement of sexually transmitted infections, give a fuller account.Clinicians should always check drug dosages.12.2 CLINICAL SPECTRUM OF HIV-RELATED DISEASEIn general, pathogens may be high-grade or low-grade. High-gradepathogens may be pathogenic in healthy individuals with normal immunestatus. Low-grade pathogens are usually pathogenic in persons withimmunodeficiency. The pathogens that cause disease and the type ofclinical disease they cause depend on the degree of progression of HIVinfection and the associated extent of immunosuppression. High-gradepathogens (e.g. the pneumococcus, non-typhoid salmonellae and M.tuberculosis) can cause disease at any stage in the course of HIV infection.Low-grade pathogens (e.g. candida, Cryptococcus neoformans, toxoplasma,cytomegalovirus, Pneumocystis carinii and atypical mycobacteria) causedisease in the more advanced stages. Disseminated infections becomeincreasingly common in advanced stages of HIV infection with moresevere imunosuppression. The WHO clinical staging system for HIVinfection and disease reflects these features. Diseases caused by lowgradepathogens and disseminated infections characterize stage 4 inadults and adolescents and stage 3 in children. Infections caused by thehigh-grade pathogens tend to be easier to diagnose and treat than thosecaused by the low-grade pathogens.The spectrum of disease in HIV-positive persons varies among regions.Dominating the picture in sub-Saharan Africa are the high-gradepathogens (bacterial and mycobacterial) such as the pneumococcus,non-typhoid salmonellae and M. tuberculosis, which are endemic, highlyassociated with poverty, and intensely transmitted in overcrowdedunsanitary environments.TB has become a leading cause of death amongpeople with HIV infection, accounting for up to a third of AIDS deathsTB/HIV:A CLINICAL MANUAL157

worldwide. There has also been recent recognition of the associationbetween HIV infection and increased frequency of clinical malaria. In thisregion, some low-grade opportunistic pathogens are important(particularly cryptococcus and toxoplasma), but those that dominate thepicture in the industrialized countries, such as Pneumocystis carinii andatypical mycobacteria, are relatively rare. Although the spectrum ofdisease in HIV-positive persons has not been as fully characterized inother regions, a similar pattern is likely to be seen throughout thedeveloping world.Nearly 90% of all HIV-positive persons live in developing countries inAfrica and South-East Asia.Thus, worldwide, the main burden of diseasein HIV-infected individuals arises from a limited number of commoninfectious agents, namely M. tuberculosis, pneumococcus and non-typhoidsalmonellae. Diagnosis of these infections is usually possible at healthcentres or district hospitals.They are generally amenable to treatmentwith cheap, affordable and effective antimicrobials. For example, a courseof TB treatment may cost as little as US$10 in some countries (althoughmore in sub-Saharan Africa). Thus diagnosis and treatment of commonHIV-related diseases due to high-grade pathogens are feasible andaffordable. There is a need to strengthen the ability of general healthcare providers to diagnose and treat these diseases. This has thepotential to dramatically decrease their contribution to HIV-relatedmorbidity and mortality.WHO has developed an essential drugs list forthe treatment of common HIV-related diseases. In many parts of theworld the treatments for a variety of HIV-related infections (includingherpes simplex virus, cytomegalovirus and atypical mycobacteria) andcancers (including Kaposi sarcoma and non-Hodgkin lymphoma) aremore expensive and not yet widely available.12.3 SEXUALLY TRANSMITTED INFECTIONSA person who has unsafe sex is at risk of several sexually transmittedinfections (STIs). So a patient with one STI is at increased risk of havinganother STI. HIV is usually sexually transmitted. STIs other than HIV arecommon in TB/HIV patients. This section gives a brief account of thedrug treatment of STIs. When you treat a patient with STI, alsoremember patient education, counselling, condom provision and partnermanagement.12.3.1 Syndromic managementAccurate STI diagnosis is often not feasible. WHO has developed a158 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

syndromic management approach based on the recognition ofconsistent groups of symptoms and signs (syndromes). The treatmentrecommended for each syndrome cures the majority of infectionsresponsible for causing the syndrome. The table below shows therecommended plans of treatment for the common STI-associatedsyndromes where laboratory investigations are not available.I2SyndromeMenurethral dischargeWomencervicitisvaginal dischargeMen and womengenital ulcersPlan of treatmenttreat for gonorrhoea and chlamydiatreat for uncomplicated gonorrhoea andchlamydiatreat for vaginitis (candidiasis andTrichomonas vaginalis/bacterial vaginosis)treat for cervicitis (in high gonorrhoea andchlamydia prevalence settings)treat for syphilis and chancroid (andherpes in high HSV-2 prevalence settings)inguinal bubo- with ulcers treat for syphilis and chancroid- without ulcers treat for lymphogranuloma venereum12.3.2 Treatment regimens for common STIsThe table below shows treatment regimens for the common STIs.Do not use ciprofloxacin or tetracyclines in pregnancy. Avoidtetracyclines in childhood.STIgonorrhoea(uncomplicated)Treatment regimenciprofloxacin 500 mg orally as a single dose ORceftriaxone 250 mg by i.m. injection as a singledose ORcefixime 400 mg orally as a single dose ORspectinomycin 2 g by i.m. injection as a singledose ORtrimethoprim 80mg/sulfamethoxazole400 mg (TMP-SMX)10 tablets orally as a single dose ORgentamicin 240 mg by i.m. injection as a singledoseTB/HIV:A CLINICAL MANUAL159

chlamydia doxycycline 100 mg orally twice daily for 7days ORtetracycline 500 mg orally 4 times daily for 7days ORerythromycin 500 mg orally 4 times daily for 7daysprimary syphilis benzathine penicillin G 2.4 million IU, by i.m.(chancre) injection at a single session (often split into 2doses at separate sites) ORprocaine penicillin G 1.2 million IU by i.m.injection daily for 10 consecutive daysOR (if allergic to penicillin)tetracycline 500 mg orally 4 times daily for 15days ORdoxycycline 100 mg orally twice daily for 15days ORerythromycin 500 mg orally 4 times daily for15 dayschancroid erythromycin 500 mg orally 3times daily for 7days ORciprofloxacin 500mg orally twice daily for 3 daysORceftriaxone 250 mg by i.m. injection as a singledose ORazithromycin 1 g orally as a single dose ORTMP-SMX 2 tablets orally twice daily for 7dayslymphogranuloma doxycycline 100 mg orally twice daily for 14venereumdays ORtetracycline 500 mg orally 4 times daily for 14days ORerythromycin 500 mg orally daily for 14 daysORsulfadiazine 1 g orally 4 times daily for 14 dayscandidiasisnystatin 100000IU intravaginally once daily for14 days ORmiconazole or clotrimazole 200mg intravaginallyonce daily for 3 days ORclotrimazole 500 mg intravaginally as a singledoseTrichomonas metronidazole 2 g orally as a single dose ORvaginalismetronidazole 400–500mg orally twice dailyfor 7 daysbacterialvaginosismetronidazole 2g orally as a single dose ORmetronidazole 400-500mg orally 2x daily for7 days160 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

12.4 SKIN AND MOUTH PROBLEMSThe diagnosis of these HIV-related skin and mouth problems usuallyrests on characteristic clinical features.The tables below show diagnosesand treatments.I2Skin problemsº Virus infectionsInfection Local treatment Drug treatmentAdults ChildrenHerpes Local lesion care Acyclovir orally 5 times/dailysimplex (oral (i.e. regular cleaning until healedand genital) and avoiding secondary 200 mg 2 years 200 mgVaricella Local lesion care Analgesiazoster (i.e. regular cleaning Acyclovirand avoiding secondary 800 mg orally 20 mg/kgbacterial infection) 5 times/daily (max. 800 mg)for at least 4 times/daily7 days for 5 daysAnal/genital Topical 20%warts (human podophyllin 1-2papilloma times per weekvirus) until healedTrichloracetic acidCryotherapyMolluscum Leave the lesionscontagiosum alone OR prick eachlesion with a needleor sharpened orangestick and touchwith phenol.Trichloracetic acidCryotherapyTB/HIV:A CLINICAL MANUAL161

º Fungal infectionsInfection Local treatment Drug treatmentAdults ChildrenTinea Whitfield's In resistant cases griseofulvin(pedis/ ointment orcorporis/ Castellani's paintcruri) Topical antifungals 500 mg 10 mg/kg orally1% clotrimazole orally daily in divided doses2% miconazole twice daily or as a single doseCandidiasis 1% aqueous gentianviolet or nystatinointment twice dailyuntil lesions areclearedTopical antifungalsCutaneousSystemic antifungal therapycryptococcosis/histoplasmosisº Bacterial infectionsInfection Local treatment Drug treatmentAdults ChildrenImpetigo,Penicillin V orally 4 timesfurunculosisdaily for 1–2 weeks500 mg Up to 1 year 62.5 mg,1–5 years 125 mg,6–12 years 250 mgOR flucloxacillin orally 4times daily for 1–2 weeks500 mg < 2 years quarteradult dose2–10 years halfadult doseOR Erythromycin orally 4x daily for 1 - 2 weeks500 mg < 2 years125 mg2-8 years 250 mg> 8 years250–500 mg162 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

Pyomyositis Surgical drainage Plus antibiotics (as forimpetigo)BacillaryErythromycin orally 4 timesangiomatosisdaily for 8 weeks(due to 500 mg < 2 years125 mgBartonella2–8 years 250 mghenselae)> 8 years(lesions may250–500 mgresembleDoxycycline orally twice aKaposiday for 8 weeksSarcoma 100 mg Not to be given–definitive (Not to be to children < 12diagnosis by given to yearsbiopsy)pregnantor breastfeedingwomen)I2º OtherCondition Local treatment Drug treatmentAdults ChildrenPruritus Calamine lotionwithout skin AntihistamineslesionsPapular Calamine lotion Antihistaminesfolliculitis Topical antifungals Metronidazole twice a day(pruritic with 1% for 7–14 dayspapular hydrocortisone 250 mg 7.5 mg/kg everydermatosis; Strong topical 8 hourseosinophilic corticosteroidsfolliculitisSeborrhoeic Antifungal shampoos If severe, ketoconazole orallydermatitis OR topical antifungalswith steroids ORtopical 1% 200 mg 3 mg/kg dailyhydrocortisone twice dailyStrong topicalcorticosteroidsTB/HIV:A CLINICAL MANUAL163

Ichthyosis(dry scalyskin)PsoriasisEmollients (e.g.aqueous cream)Conventionalantipsoriasistreatment, e.g. coaltar in salicylateointment twice dailyScabies Topical benzyl Ivermectin 200 µg/kgbenzoate 25% as a single dose with topicalTopical lindane lotion drugsKaposi Local lesion care. Chemotherapysarcoma Radiotherapyº Mouth problemsCondition Local treatment Drug treatmentAdults ChildrenOral Topical antifungals In resistant cases oralcandidiasis such as amphotericin ketoconazole for 14 dayslozenges, nystatin 200 mg 3 mg/kg dailypastilles/pessaries: twice dailynystatin drops 100000 As an alternative in resistantunits 3 times daily OR cases (except in children under 1nystatin pessaries one year) fluconazole for 14 daysevery 4 hours OR 100 mg 2 mg/kgnystatin tabs 500000 daily dailyunits 4 times daily. Ifnystatin not available, usegentian violet 0.25–0.5%In all cases treat for 7–14days. Recurrence iscommon withoutprophylaxis.Hairy No treatmentleukoplakiaAngular Topical antifungalscheilitis e.g. 1% clotrimazole164 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

Gingivitis/ Metronidazole orally for 7dentaldaysabscesses400 mg 3 7.5 mg/kgtimes daily every 8 hoursAND/OR penicillin V for 7days500 mg 4 Up to 1 yeartimes 62.5 mgdaily 1–5 years 125 mg,6–12 years 250 mgAphthous Mouth rinses with Oral prednisoloneulcers steroid and tetracycline Oral acyclovirTopical corticosteroids (Oral thalidomide 200 mg dailyin refractory cases)I212.5 RESPIRATORY PROBLEMS12.5.1 Respiratory problems in adultsSome TB/HIV patients fail to improve, or even deteriorate, during anti-TB treatment. They continue to have, or develop new, respiratoryproblems, e.g. cough, breathlessness, chest pain. First check that theyhave taken their anti-TB drugs.Then consider the following possibilities.Original diagnosissputum smear-negative PTBsputum smear-positive PTBPossibilitiesincorrect diagnosis e.g. otherpathogens, heart failure, chronicobstructive airways diseasepatient not adherent to anti-TBtreatment;drug-resistant TB;superimposed infection withother pathogens.The flow chart shows the management approach in HIV-positive PTBpatients who fail to respond or deteriorate while on anti-TB treatment.TB/HIV:A CLINICAL MANUAL165

sputuminductionusing 3–5%hypertonicsaline maybe helpfulpatient fails to respond,or deteriorates, on TB treatmenttake sputum sampleand do CXRsputum testCXR resultsmear forAFBTBcultureGram stainand cultureforbacterialpathogensdiffuseinterstitialshadowing(sputumAFBnegative)new cavities(sputumAFBnegative)positiveafter 5monthstreatmentfailuredrugresistancebacterialpneumoniaPneumocystiscariniipneumoniaNocardiasuspectedre-treatmentregimenrefer tospecialistcentreantibiotics(see below)TMP-SMX 4 tablets 4 timesdaily for 3 weeks thenprophylaxis 2 tablets dailyThe table below shows the main bacterial pathogens responsible forsuperimposed pneumonia in smear-positive PTB patients and thetreatment.PathogenStreptococcus pneumoniaeHaemophilus influenzaeStaphylococcus aureusGram-negative bacilliTreatmentpenicillin or TMP-SMXamoxycillin or TMP-SMXflucloxacillin or chloramphenicolchloramphenicol (and gentamicinif necessary)166TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

12.5.2 Respiratory problems in childrenHIV-infected children with TB are also more susceptible to otherrespiratory diseases and more likely to die despite TB treatment. Animportant reason for a poor response to TB treatment is that the childdoes not have PTB. The difficulties in diagnosing PTB in children meanthat it may be confused with other causes of HIV-related lung disease(see Chapter 4). Most children who receive treatment for PTB aresmear-negative cases. If they do not improve on TB treatment, considerother diagnoses, e.g. LIP or cardiac disease. In all cases, consider poortreatment adherence as a cause of poor treatment response.I2Mixed respiratory infections are a particular feature of HIV-infectedchildren. It is common for children with TB to develop bacterialpneumonia as a complication. The main bacterial pathogens are thoselisted above. Treatment should follow Integrated Management ofChildhood Illness (IMCI) guidelines. If the child has severe pneumonia,admit to hospital and give chloramphenicol 25 mg/kg intramuscularly orintravenously three times a day (and oxygen if necessary). If the childdoes not improve within 48 hours, switch to gentamicin 7.5 mg/kg IMonce a day and cloxacillin 50 mg/kg IM or IV every 6 hours.HIV-infected children with presumed TB may have lymphocyticinterstitial pneumonitis (LIP) either as an alternative diagnosis oroccasionally as a mixed infection. LIP is also often complicated by acutebacterial pneumonia. Clinical features that suggest LIP are generalizedsymmetrical lymphadenopathy, non-tender parotid enlargement andfinger clubbing. Typical CXR features are a bilateral reticulonodularinterstitial pattern and adenopathy. If the child with LIP has persistentrespiratory distress, then give prednisolone 1–2 mg/kg daily for 2–4weeks and then reduce gradually over 2 weeks.12.6 GASTROINTESTINAL PROBLEMS12.6.1 DysphagiaThere are various HIV-related causes of oesophageal inflammation.Theypresent in a similar way with pain on swallowing. Oesophagealcandidiasis is the commonest HIV-related cause of dysphagia. Thediagnosis of other causes needs endoscopy, biopsy and a goodlaboratory.Where there are no facilities for investigation of a known HIV-positivepatient with dysphagia, treat empirically with an oral antifungal agent.TB/HIV:A CLINICAL MANUAL167

Where available, barium swallow shows characteristic appearances offine mucosal ulceration. Upper gastrointestinal endoscopy shows whiteplaques and biopsy allows confirmation.The table below shows the treatment of the causes of dysphagia.Cause of dysphagiaCandidal oesophagitisHerpes simplexCytomegalovirusUlcers of unknowncauseTreatmentAdultsChildrenNystatin 4 times daily for 1–14 days500000 units 100000 units(OR Nystatinpessaries 100,000units every4 hours)Ketoconazole for 7–14 days200 mg twice daily 3 mg/kg dailyOR fluconazole for 7–14 days100 mg once daily Not recommendedunder one year1–2mg/kg dailyProphylaxis with nystatin pastilles ORfluconazole for lifeAcyclovir800 mg orally five 20 mg/kg (max. 800 mg)times daily for 4 times daily for 5 days7–10 days.Treatment usually not available (intravenousganciclovir or foscarnet) on account ofexpense.Prednisolone for 2 weeks, then slowlytaper to zero40 mg daily12.6.2 Diarrhoea in adultsIntroductionEpisodes of acute diarrhoea, recurrent diarrhoea or chronic diarrhoeaare very common, affecting up to 60% of HIV-positive individuals at sometime in their illness. Common accompanying features include nausea,vomiting, abdominal cramps, flatulence, weight loss and dehydration.RehydrationAlways assess the state of hydration of any patient with diarrhoea. Most168 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

patients with mild to moderate dehydration should receive oralrehydration solution. A few patients, with severe dehydration, needintravenous fluids.I2InvestigationWhere facilities are available, send multiple stool samples formicroscopy and culture. With appropriate stains it is possible onmicroscopy to diagnose the following pathogens: Cryptosporidium,Isospora belli, Microsporidia. Stool culture can permit the diagnosis ofSalmonella, Shigella, and Clostridium difficile.TreatmentIn most cases, the cause is not known. So treatment in these cases isempirical. Some cases (probably due to Isospora belli) respond totreatment with trimethoprim-sulfamethoxazole (TMP-SMX). Othercases (probably due to Microsporidia) respond to treatment withmetronidazole or albendazole.Sometimes you do find a specific cause of diarrhoea. Many of thetreatable causative pathogens are common in unsanitary environments.The table shows specific causes with the appropriate treatment.DiagnosisBacterial infectionsSalmonellaShigellaTreatmenttrimethoprim 80 mg/sulfamethoxazole400 mg (TMP-SMX) 2 tablets twicedaily for 7 days ORchloramphenicol 500 mg 4 times dailyfor 7 days.ciprofloxacin 500 mg twice daily for 7 daystrimethoprim 80 mg/sulfamethoxazole400 mg (TMP-SMX) 2 tablets twicedaily for 7 days ORnalidixic acid 1g 4 times daily for 7 daysciprofloxacin 500 mg twice daily for 3–7 daysCampylobacter jejuni erythromycin 500 mg 4 times daily for 7daysciprofloxacin 500 mg twice daily for 3–7 daysClostridium difficileProtozoal infectionsCryptosporidiummetronidazole 400 mg 3 times daily for7–14 daysvancomycin 250 mg twice daily for 7–14 dayssymptomatic treatment onlyparamomycin (efficacy is marginal)TB/HIV:A CLINICAL MANUAL169

Isospora bellitrimethoprim 80 mg/sulfamethoxazole400mg (TMP-SMX) 2 tablets twice dailyfor 7–14 daysMicrosporidiametronidazole 400 mg 3 times daily for(Enterocytozoon 7 daysbieneusi or albendazole 800 mg twice daily for 4Septata intestinalis) weeksGiardia lamblia metronidazole 2 gr daily for 3 daystinidazole 2 gr as a single doseEntamoeba histolytica metronidazole 800 mg 3 times daily for7 days,then diloxanide furoate 500 mg 3 times dailyfor 10 daysor tetracycline 500 mg 4 times daily for10 daysCyclospora cayetanensis trimethoprim 80 mg/sulfamethoxazole400 mg (TMP-SMX) 2 tablets twicedaily for 3–7 daysPersistent diarrhoeaGive symptomatic treatment if diarrhoea persists, the cause is notknown, and there is no response to TMP-SMX then metronidazole thenalbendazole. Antidiarrhoeal agents for symptomatic treatment includecodeine and loperamide but these should be avoided in children.12.6.3 Diarrhoea in childrenAcute diarrhoeaManagement of acute watery diarrhoea in HIV-infected children issimilar to that in HIV-uninfected children with an emphasis onprevention of dehydration or rehydration of the dehydrated child. Stateof hydration is more difficult to assess if the patient is severelymalnourished and rehydration needs to be more careful.Do not restrict intake of food but rather advise small frequent meals ofnutritious food. If the child is breastfed, then this should be continued.Restricting the intake of food increases the chance of the childdeveloping persistent diarrhoea.DysenteryIf a child has dysentery, i.e. acute bloody diarrhoea usually with fever andabdominal pain, treat with an antibiotic for 5 days.Antibiotic choice willdepend on local sensitivity patterns for Shigella. This might be TMP170 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

4 mg/SMX 20 mg twice daily, nalidixic acid 15 mg/kg 4 times a day orciprofloxacin 10–15 mg/kg twice a day for 5 days.Persistent diarrhoeaThis is diarrhoea that lasts for two weeks or longer. Occasionally it isdue to gut parasites such as Entamoeba histolytica or Giardia lamblia. If so,give oral metronidazole 10 mg/kg, 3 times a day for 5 days. The mostimportant aspect of management (and the most neglected) is nutritionalrehabilitation. Micronutrients such as zinc, vitamin A and folic acid areimportant and should be given. Feeds should be more frequent thanusual and should contain adequate calories and protein. Milk-based oregg-based diets are useful.Yoghurt is also effective.I212.7 NEUROLOGICAL PROBLEMS IN ADULTSA wide variety of neurological problems may occur in TB/HIV patients.The common presentations are the following:1) acute confusion,2) chronic behaviour change,3) persistent headache,4) difficulty in walking,5) poor vision,6) burning sensation in the feet.Neurological problems are often thought to be difficult to diagnose. Infact, they are no more difficult to diagnose than other problems,provided that you take time and care. You have to take time andcare to obtain a detailed history and perform a proper neurologicalexamination. It is usually necessary to obtain some, if not all, of thehistory from the patient's relatives or friends. Some simple district-levellaboratory tests on blood and cerebrospinal fluid (CSF) are oftenhelpful.12.7.1 Acute confusionThe differential diagnosis when a TB/HIV patient becomes acutelyconfused includes the following:a) acute superimposed infection, e.g. septicaemia, meningitis, malaria;b) hypoxaemia, e.g. pneumothorax, pneumonia, heart failure, anaemia;c) metabolic disturbance, e.g. secondary to diarrhoea, hypoadrenalism;d) adverse drug reaction, e.g. acute confusion may be the first sign ofdrug-induced acute fulminant liver failure (a useful test, if available, isthe prothrombin time).TB/HIV:A CLINICAL MANUAL171

Always check a blood film for malaria. Do a lumbar puncture if thepatient has meningism and it is safe to do a lumbar puncture. Otherinvestigations depend on the laboratory facilities available and clinicalclues to the diagnosis.12.7.2 Chronic behaviour changeChronic behaviour change, i.e. over a period of month is usually due toAIDS dementia or progressive multifocal leukoencephalopathy. Theseare untreatable, unless there is access to ART. Since the diagnoses areclinical, you must rule out other treatable possibilities. Send blood forsyphilis serology and (in endemic areas) microscopy for trypanosomes.If lumbar puncture is safe, send CSF to the laboratory to excludechronic meningitis (e.g. cryptococcal,TB).12.7.3 Persistent headacheThe flow chart below shows the management approach to the TB/HIVpatient with headache.The following features may accompany headache:reduced level of consciousness, confusion, convulsions.172 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

Flow chart showing management approach for persistent headacheexclude a local cause,e.g. sinusitisdental abscesspersistentheadhachebloodtestsmalaria parasitessyphilis serologyfilm for trypanosomes(in endemic areas)I2clinical assessmentevidence of space-occupyinglesion (e.g. papilloedema,focal neurological defect)clinical diagnosis ofspace-occupying lesion(treatable causesare pyogenic, Toxoplasma,or Nocardia brain abscess)empirical treatment:dexamethasone 4 mg 3 times dailyANDchloramphenicol 1g 4 times daily(pyogenic brain abscess)ANDsulfadoxine 500 mg- pyrimethamine 25 mg (S-P)2 tablets 2 times daily for 6 weeks(cerebral toxoplasmosisor nocardiasis)Maintenance S-P 1 tablet weeklyusually untreatable causes:fungal brain abscess,cerebral lymphoma,cerebral Kaposi sarcoma.N.B. definitive diagnosisof cerebral space-occupyinglesions is usually notpossible without CT brainscan and sophisticatedlaboratory investigations.meningismclinical diagnosis of suspectedsubacute/chronic meningitislumbar puncture (if safe)CSF investigations:white cell count and differentialprotein and glucose concentrationsstains (Gram, ZN, India ink)culture for bacteria and fungicytology (if available)Cryptococcus(positive Indiaink stain orculture)antifungaldrugs ifavailableacutebacterialmeningitise.g.Pneumococcus(identifiedon Gramstain orculture)chloramphenicol1g 4 x dailyfor 7-14 daysmalignancy(positivecytology)It is possible, but rare, for TB meningitis to develop after a TB patient hasalready started anti-TB treatment. For example, a cerebral tuberculomacould rupture into the subarachnoid space releasing TB bacilli not yetkilled by anti-TB drugs. A commonly recommended treatment regimenfor TB meningitis is as follows: 2SHRZ/7HR.TB/HIV:A CLINICAL MANUAL173

It is unlikely, but possible, that a patient already on TB treatment coulddevelop acute bacterial meningitis. The diagnosis rests on CSFexamination.Cryptococcal meningitisThe outcome is fatal without treatment and often very poor withtreatment. In many countries the drugs for treating cryptococcalmeningitis are expensive, and are not often available in routine settings.The treatment for many patients is therefore symptomatic withanalgesia and sedation. Patients who can afford specific antifungal drugtreatment should receive fluconazole 400 mg daily initially for 10 weeks.Alternative regimens are i) intravenous amphotericin B (0.5 mg/kg perday) for 14 days followed by fluconazole 400 mg daily for 8 weeks orii) intravenous amphotericin B (0.5 mg/kg per day) for 14 days followedby intraconazole 400 mg daily for 8 weeks. Lifelong maintenancetreatment with fluconazole 200 mg daily is then necessary to preventrelapse.12.7.4 Difficulty in walkingSpinal TB may cause difficulty in walking. So first make sure (by clinicalexamination and spine X-ray) that the patient does not also have spinal TB.The cause of difficulty walking in a TB/HIV patient may be HIV-related(spinal cord myelopathy and occasionally peripheral neuropathy) orunrelated to HIV. A patient with difficulty walking and HIV myelopathyusually has a spastic paraparesis. It is only possible to make this diagnosisby excluding the causes of spinal cord disease unrelated to HIV.The tablebelow shows the main causes of spinal cord disease unrelated to HIV,and the diagnostic tests. In HIV-related peripheral neuropathy, sensorydisturbance tends to predominate over motor weakness.Cause of spinal cord diseasecervical spondylosisprolapsed intervertebral discepidural abscesstreatable tumours(neurofibroma, meningioma)schistosomiasisneurosyphilissubacute combineddegeneration of the cordDiagnostic testscervical spine X-ray, myelographymyelographymyelographymyelographyidentification of eggs in stool, urine,or rectal snipsmyelographysyphilis serology, CSF findingsanaemia with raised MCV, low serumvitamin B12 level174TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

Spinal cord schistosomiasis is difficult to diagnose, but schistosomiasis iseasy to treat. If a patient with a spinal cord problem lives in an areaendemic for schistosomiasis, give empirical treatment with a single doseof praziquantel (40 mg/kg) while pursuing further management.I212.7.5 Poor visionPRACTICAL POINTIf a patient receiving ethambutol develops difficulty seeingclearly, or has problems perceiving colours, stopethambutol.Cytomegalovirus retinitis can cause poor vision but is rare in AfricanAIDS patients. The diagnosis rests on the characteristic appearance onfundoscopy of a necrotizing retinitis with perivascular haemorrhages andexudates. The treatment with ganciclovir or foscarnet is prohibitivelyexpensive in many countries.12.7.6 Burning sensation in the feetHIV may cause a peripheral neuropathy, often worse when a TB patientstarts isoniazid.The main symptom is a painful burning sensation in thefeet. The signs include distal weakness and atrophy with absent anklejerks.PreventionIf resources allow, all TB patients should receive pyridoxine 10 mg dailyas prophylaxis against isoniazid neuropathy. Otherwise reservepyridoxine prophylaxis for HIV-positive TB patients and TB patients whodrink alcohol.TreatmentTreat patients with established isoniazid neuropathy with pyridoxine50–75 mg daily. Amitryptiline (25–75 mg at night), phenytoin (100–300mg at night), or carbamazepine (100–200 mg twice daily) may relievesymptoms in HIV neuropathy.12.8 NEUROLOGICAL PROBLEMS COMMON INCHILDRENDevelopmental delay or even developmental regression are the mostcommon neurological problems. Developmental delay is common in anychild who is chronically ill and malnourished, both common in HIVinfectedchildren with TB. HIV can also infect the brain.This may lead toTB/HIV:A CLINICAL MANUAL175

a variety of neurological problems including developmental regression,behaviour change, confusion and seizure disorders.Much of the same applies for children as for adults (see above). It isimportant to consider other diagnoses such as cerebral malaria ormeningitis. Cryptococcal meningitis does occur in HIV-infected childrenbut bacterial meningitis is more common. Occasionally very wasted HIVinfectedchildren have an acute psychotic reaction with confusion,aggressive behaviour and hallucinations one to two weeks after startingTB treatment. It is likely that this is due to isoniazid and treatment is towithhold isoniazid and give pyridoxine.The condition usually settles overa week and then isoniazid can be reintroduced.12.9 FEVER12.9.1 Approach to managementFever usually settles within 2–3 weeks of starting anti-TB treatment.Further fever may signal a drug reaction or a disseminated infection.Thetable below shows the approach to management of further or persistentfever.Features accompanying Likely cause Actionfeverrash drug reaction Stop anti-TB drugsweight loss disseminated Examine patientprogressive anaemia infection Investigations:or pancytopeniaº blood film for malariaº blood film fortrypanosomesº blood culturesº consider lumbarpunctureConsider empiricaltreatment for malaria–if no responsestart antibiotics forsuspected septicaemia12.9.2 Disseminated infectionDisseminated infection carries a high mortality.The table below showsthe wide variety of pathogens that can cause disseminated infection inTB/HIV patients.176 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

Pathogens causing disseminated infection in TB/HIV patientsBacteria Mycobacteria Viruses OthersNon-typhoidal M. tuberculosis Cytomegalovirus CryptococcusSalmonellaStreptococcus M. avium complex Histoplasmapneumonia (MAC)PseudomonasLeishmaniaaeruginosaStaphylococcusPenicilliumaureusmarneffeiOtherGram-negativebacteriaI2Bacterial septicaemiaNon-typhoidal Salmonella such as S. typhimurium or S. enteritidis andPneumococcus are the commonest identified causes of septicaemia inHIV-positive adults and children in sub-Saharan Africa. Many strains of S.typhimurium are resistant to several antibiotics. If you suspectsepticaemia, treat the patient with chloramphenicol or ampicillinand gentamicin.Disseminated M. avium complex (MAC)MAC is less frequent in AIDS patients in sub-Saharan Africa thanelsewhere. Diagnostic facilities and treatment (e.g. clarithromycin +ethambutol + rifabutin) are generally not available in district hospitalsand many central hospitals.12.10 OTHER HIV-RELATED PROBLEMSTumoursKaposi sarcoma (KS)KS can affect many parts of the body, but usually the skin and mouth, andsometimes the lung and pleura, gastrointestinal tract, and pericardium.The clinical appearance is usually distinctive.There is often oedema withKS on the face and legs. Diagnostic confusion can arise with keloids,leprosy, sarcoidosis, melanoma and bacillary angiomatosis due toBertonella henselae. In case of doubt, particularly with bacillaryangiomatosis which is treatable with erythromycin or doxycycline (seeTB/HIV:A CLINICAL MANUAL177

section 12.4 on skin problems), a biopsy is diagnostic. Histology showstypical proliferation of spindle cells and small blood vessels.In a TB/HIV patient with KS, development of a pleural effusion orprogressive lung infiltrations during anti-TB treatment is probably due to KS.Many countries have limited resources for treating KS. Treatment isoften unsatisfactory. Nonsteroidal anti-inflammatory drugs (NSAIDs)may help relieve pain. Cytotoxic chemotherapy (e.g. vincristine) andradiotherapy may be available in some central hospitals but treatmentresponse is unsatisfactory.LymphomaAIDS patients are at increased risk of developing atypical aggressivelymphomas. Prognosis is poor even with cytotoxic chemotherapy.AnaemiaAnaemia in TB/HIV patients may be due to any of the following:TB, HIVinducedmarrow suppression, concurrent infections, drug side-effects.Treatment is supportive: iron and folic acid; blood transfusion if essential.In malaria-endemic regions, check a blood film for malaria parasites.ThrombocytopeniaThe main causes are HIV-induced autoimmune thrombocytopenia anddrug side-effects. High-dose steroids may help if there is bleeding andthe platelet count is low (less than 20 x 10 9 per litre).Renal diseaseHIV-related nephropathy causes nephrotic syndrome and progressiverenal damage. There is no specific treatment. Treat urinary tractinfections in the usual way.Congestive cardiomyopathyConsider HIV-related congestive cardiomyopathy in the differentialdiagnosis of heart failure.Treat heart failure in the usual way.ArthropathyPyrazinamide often causes joint pains but rarely arthritis. HIV-relatedarthropathy usually affects small joints. NSAIDs may help relieve pain.HypoadrenalismCytomegalovirus can cause necrotizing adrenalitis. This is difficult to178 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

distinguish from TB of the adrenal glands or pseudoadrenal crisis(rifampicin).Treatment is with steroid supplements.Soft-tissue infections, e.g. pyomyositis, and sinusitisThese are common in HIV-positive patients. They are diagnosed andtreated in the usual way.I212.11 PREVENTION OF HIV-RELATED OPPORTUNISTICINFECTIONS12.11.1 General measuresThere are some general measures that may help in reducing exposureto selected pathogens in HIV-positive patients.PathogenPneumocystis cariniiiToxoplasma gondiiCryptosporidiumHistoplasma capsulatumSuggested interventionAvoid close contact with patients whohave known Pneumocystis cariniipneumoniaAvoid eating undercooked red meatAvoid exposure to catsAvoid drinking ground water (difficult forrural communities)Avoid young household petsIn endemic areas avoid caves (bats) orcleaning chicken coops12.11.2 ImmunizationsKilled or inactivated vaccines pose no danger to immunosuppressedindividuals.AdultsIn general, adult HIV-positive patients should not receive live bacteria orlive virus vaccines (e.g. oral poliovirus, measles, varicella, mumps andyellow fever vaccines). It is often recommended that pneumococcal,hepatitis B and influenza vaccines be given to HIV-positive persons.However, this is rarely done in resource-poor countries within thepublic health sector because of cost.Also, a study in Uganda showed nobenefit to using a 23-valent pneumococccal polysaccharide vaccine inHIV-1 infected adults.TB/HIV:A CLINICAL MANUAL179

ChildrenIn children with known or suspected asymptomatic HIV infection, all EPIvaccines should be given (see section 14.4).12.11.3 Primary chemoprophylaxis in adultsIndustrialized countriesThe table shows the opportunistic infections, the indications and thedrug regimens commonly recommended for primary prophylaxis inindustrialized countries. Primary prophylaxis refers to preventing a firstepisode of disease in an HIV-positive individual. Primary prophylaxis isnot routinely recommended against herpes viruses (herpes simplex,varicellazoster and cytomegalovirus) or fungi.Primary prophylaxis recommended in industrialized countriesPathogen Indications Drug regimen (First Choice)Pneumocystis CD4+ lymphocyte trimethoprim 80 mg/carinii count < 200/mm 3 sulfamethoxazole 400 mghistory of oral (TMP-SMX) 2 tablets dailycandidiasisunexplained weightlossAIDS-defining event(e.g.TB)fever of unknownoriginToxoplasma CD4+ lymphocyte trimethoprim 80 mg/gondii count < 100/mm 3 sulfamethoxazole 400 mg(TMP-SMX) 2 tablets dailyM. avium complex CD4+ lymphocyte azithromycin 1200 mg once(MAC) count < 50/mm 3 per weekORclarithromycin 500 mg twiceper daySub-Saharan AfricaMost hospitals in sub-Saharan Africa do not currently have facilities forCD4+-lymphocyte counts. Infection with MAC is rare. UNAIDS hasmade provisional recommendations that adults and children living withHIV/AIDS in Africa should receive TMP-SMX as part of a minimumpackage of care. UNAIDS has based these recommendations on180 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

evidence from industrialized countries and studies carried out in Côted’Ivoire on both HIV-positive TB patients and symptomatic HIV-positivepatients without TB.TMP-SMX may prevent several secondary bacterial(S. pneumoniae, S. typhimurium), parasitic (Toxoplasma gondii, Isospora belli,malaria) and fungal (Pneumocystis carinii) infections.I2The following HIV-positive adults should receive TMP-SMX in a dose oftwo tablets daily:º all persons with symptomatic HIV infection;º asymptomatic persons with CD4+ lymphocyte count < 500/mm 3;º pregnant women after the first trimester.12.11.4 Primary chemoprophylaxis in childrenTMP-SMX should be offered to all HIV-exposed infants from six weeksof age, using the following criteria:º any child born to an HIV-infected woman irrespective of whether thewoman received ART in pregnancy;º any child who is identified as HIV-infected within the first year of lifeby PCR (polymerase chain reaction), HIV serology or by a clinicaldiagnosis of HIV infection (according to WHO or national guidelines)º children older than 15 months who have had a Pneumocystis cariniievent, have symptomatic HIV infection, an AIDS-defining illness or aCD4+ lymphocyte percentage less than 15%.The dose should be 150 mg TMP/750 mg SMX per m 2 three times perweek. Cotrimoxazole syrup may not be available: for an infant of 6weeks, give half of a cotrimoxazole tablet (trimethoprim 80mg/sulfamethoxazole 400 mg) daily on Monday,Wednesday and Friday.These are preliminary recommendations, that recognize the need formore research to determine cost-effectiveness in different settings,optimal timing of the start of therapy, duration of prophylaxis andaffordable alternatives.12.11.5 Secondary chemoprophylaxis in adultsSeveral severe or life-threatening opportunistic infections in HIVpositivepatients have high recurrence rates after initial successfultreatment. Lifelong secondary prophylaxis is generally recommended.The table below shows recommended drug regimens for secondarychemoprophylaxis in adults.TB/HIV:A CLINICAL MANUAL181

PathogenPneumocystis cariniiDrug regimen (first choice)trimethoprim 80 mg/sulfamethoxazole400 mg (TMP-SMX) 2 tablets dailyToxoplasma gondii sulfadiazine 500 mg 4 times daily +pyrimethamine 25 mg dailyORtrimethoprim 80 mg/sulfamethoxazole400 mg (TMP-SMX) 2 tablets dailyM avium complex Clarithroymicin 500 mg twice daily +ethambutol 15mg/kg once dailyORazithromycin 500 mg once daily + ethambutol15 mg/kg once dailyCryptococcusfluconazole 200 mg once dailyneoformansHistoplasma capsulatum itraconazole 200 mg twice dailyCytomegalovirus ganciclovirSalmonella species ciprofloxacin 500 mg twice daily for(not S. typhi) 6–8 monthsbacteraemia182 TREATMENT AND PREVENTION OF OTHER HIV-RELATED DISEASES IN TB/HIV PATIENTS

SUGGESTIONS FOR FURTHER READINGBartlett JG , Gallant JE. Medical management of HIV infection. Baltimore, MD,Johns Hopkins University School of Medicine, 2000-2001.I2French N, Nakiyingi J, Carpenter LM, et al. 23-valent pneumococcalpolysaccharide vaccine in HIV-1 infected Ugandan adults: double-blind,randomised and placebo controlled trial. Lancet, 2000, 355: 2106–2111.World Health Organization. Improving child health. IMCI: the integrated approach.Rev.2. Geneva (WHO/CHD/97.12) (www.who.int/child-adolescent-health) 1997.Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients withhuman immunodeficiency virus infection. New England journal of medicine2000, 342: 1416–1429.World Health Organization. Management of the child with a serious infection orsevere malnutrition. Guidelines for care at the first-referral level in developingcountries. Geneva, 2000 (WHO/FCH/CAH/00.1).Provisional WHO/UNAIDS secretariat recommendations on the use ofcotrimoxazole prophylaxis in adults and children living with HIV/AIDS in Africa.Geneva, 2000, WHO/UNAIDS.Wiktor SZ, Sassan-Morokro M, Grant AD, et al. Efficacy of trimethoprimsulphamethoxazoleprophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d’Ivoire: a randomisedcontrolled trial. Lancet, 1999, 353: 1469–1475.World Health Organization. Guidelines for the clinical management of HIV infectionin adults. Geneva, 1991.World Health Organization. Guidelines for the clinical management of HIV infectionin children. Geneva, 1993.World Health Organization. AIDS in Africa: a manual for physicians. Geneva, 1992.World Health Organization. Guidelines for the management of sexually transmittedinfections. Geneva, 2003.World Health Organization. Improving child health. IMCI: the integrated approach.Geneva, 1997 (WHO/CHD/97.12 Rev. 2)TB/HIV:A CLINICAL MANUAL183

COORDINATED CARE IN DIFFERENT SETTINGSI313.1 INTRODUCTIONTB/HIV patients may receive care in different settings. These settingsinclude the patient's home, local health centre, district hospital, andtertiary referral hospital. Coordination of care in different settingspromotes continuity of care for the patient. NTP staff and general healthservice staff need to be aware that many HIV-positive TB patientsdevelop other HIV-related illnesses during anti-TB treatment. Deliveringinterventions to reduce the frequency of opportunistic infections (e.g.cotrimoxazole prophylaxis, ART) requires effective collaboration withHIV/AIDS programmes.TB/HIV patients sometimes know that they are HIV-positive and lateron develop TB. More often, they only find out that they are HIV-positiveafter developing TB. In either case, the TB control programme needs tocollaborate closely with other services providing support and care forHIV-positive individuals.The clinician treating TB/HIV patients is in a keyposition to refer patients to appropriate services.13.2 THE EXPANDED SCOPE OF A NEW APPROACHTO DECREASE THE BURDEN OF TB/HIVSince HIV fuels the TB epidemic, HIV programmes and TB programmesshare mutual concerns. Prevention of HIV should be a priority for TBcontrol; TB care and prevention should be priority concerns ofHIV/AIDS programmes. Until recently, the efforts to control TB in HIVinfectedpeople have mainly focused on implementing the DOTSstrategy for TB control.Through the identification and cure of infectiousTB cases, the strategy aims at interrupting the transmission of M.tuberculosis infection.The expanded scope of a new approach to TB control in populationswith high HIV prevalence comprises interventions against TB andinterventions against HIV (and therefore indirectly against TB).Interventions against TB include intensified case-finding, cure and TBpreventive therapy. Interventions against HIV (and therefore indirectlyagainst TB) include condom promotion, STI treatment or prophylaxis,and ART. Previously TB programmes and HIV/AIDS programmes largelypursued separate courses. However, they need to collaborate in areas ofTB/HIV:A CLINICAL MANUAL185

mutual concern in their support to general health service providers.Anintegrated system of HIV/AIDS and TB care uses available health serviceproviders to ensure continuity of care for TB/HIV patients.13.3 REFERRAL TO LOCAL HIV/AIDS CARE SERVICESOne of the important features of a successful NTP is integration of TBcontrol activities with the general health services (see Chapter 2).Thismeans that at the district and primary health care levels, the generalhealth service staff manage TB patients according to NTP guidelines.NTP staff provide support.General health service staff and NTP staff need to know what localHIV/AIDS services are available for HIV-positive patients.The Ministry ofHealth may run a system for accreditation of the range of local providersof HIV/AIDS services. They include the government, nongovernmentalorganizations (NGOs), community organizations, private practitionersand employer health services. Often it is possible to refer patientsdirectly to these providers of HIV/AIDS services.Some TB/HIV patients choose not to accept referral to HIV/AIDSservices. It is important to respect patients' wishes and confidentiality. Inmany districts there is a district coordinator for HIV/AIDS. District NTPstaff liaison with the district coordinator for HIV/AIDS promotes theeasy referral of TB/HIV patients to HIV/AIDS services.In many towns and cities there are now HIV counselling and voluntarytesting centres. Some of the people attending these centres may have TB.A study in Kampala, Uganda, showed that 6% of people attending theHIV counselling and voluntary testing centre had undiagnosed TB. NTPcollaboration with these centres is important. Staff in the centres shouldask clients about chronic cough and refer TB suspects to the NTP forsputum microscopy.13.4 BENEFITS OF SUPPORT FROM LOCAL HIV/AIDSCARE SERVICESThe HIV/AIDS care services available vary from place to place. Theyinclude HIV/AIDS care groups within the general health services,HIV/AIDS community support groups and HIV/AIDS home careschemes. TB/HIV patients may gain the following benefits from thesupport of local HIV/AIDS services:186 COORDINATED CARE IN DIFERENT SETTINGS

º access to voluntary counselling and HIV testing;º knowledge about safer sexual behaviour and use of condoms;º preventive therapy for HIV-related opportunistic infections;º (e.g. trimethoprim-sulfamethoxazole,TMP-SMX);º early identification and treatment of any new infections, includingsexually transmitted infections;º symptomatic treatment in end-stage disease;º emotional support;º support for the family;º possible access to ART.I313.5 A FRAMEWORK FOR HIV/AIDS CARE THATINCORPORATES INTERVENTIONS TO ADDRESS TBClose collaboration is necessary between different health serviceproviders at the different levels of the health care system. This willfacilitate the referral of patients along the “continuum of care”.13.5.1 Home and community careLocal responses involve people in their homes, neighbourhoods andcommunity organizations. They take responsibility for addressingHIV/AIDS as a shared community concern. Community interventions tosupport PLWH should include supporting TB patients to completetreatment. Some PLWH regard TB as an ominous sign of AIDS.A moreoptimistic view of the development of TB is as an opportunity to seekhelp for a treatable condition.The prospect is of an increased healthy lifeexpectancy. Targeted information, education and communicationinterventions can encourage the more optimistic view.General health services staff can refer patients directly to HIV/AIDScare services. Community care means providing the patient with accessto care as close to home as possible. Some HIV/AIDS care servicesprovide home care for AIDS patients.The home care provider may be ahealth care worker or community volunteer. See WHO’s AIDS home carehandbook for more information.Home care alone is not enough for a TB/HIV patient.TB patients needto continue to receive their anti-TB treatment, directly observed by atrained and supervised home care provider.This training and supervisionrequires collaboration between the HIV/AIDS home care scheme andthe NTP.Also, the HIV/AIDS home care provider can recognize problemswith anti-TB treatment and refer patients as necessary to the NTP.TB/HIV:A CLINICAL MANUAL187

13.5.2 Primary carePrimary care measures for detecting and treating common HIV-relateddiseases should include diagnosis and treatment of infectious (sputumsmear-positive pulmonary) TB. Primary care staff need to detect TBcases among persons presenting with, or found through screening tohave, symptoms of TB.The most important symptom is prolonged cough.Detection of infectious TB cases requires access to quality-assured TBsputum microscopy. Special attention to case detection is necessary incongregate settings (e.g. prisons, health care facilities) and among peopleattending VCT centres.There are two preventive treatments that should be available at primarycare level for the prevention of common HIV-related diseases. Isoniazidis effective as preventive treatment of TB. Cotrimoxazole may preventcommon bacterial infections.Health care workers and HIV-infected patients are often exposed to therisk of TB in health facilities. Health services have a responsibility toimplement measures to decrease nosocomial risk of TB in healthfacilities. They also need to protect health care workers fromoccupational exposure to HIV.Information for communicable disease surveillance passes from primarycare level to those responsible at district level.This includes reporting ofTB cases and recording of TB treatment outcomes. Systems ofsurveillance of HIV-related diseases other than TB are currently lackingor poorly developed at all levels of care. TB surveillance can be astarting-point for the development of these systems.An effective NTP ensures integration of TB diagnosis and treatmentactivities with general health service provider activities (see Chapter 2).So primary health care staff are in a good position to identify and treatcommon HIV-related problems during or after anti-TB treatment. Goodcommunication between general health service staff and HIV/AIDS careworkers is important for continuity of care of TB/HIV patients.The IMCI strategy, developed by WHO, provides management guidelinesfor sick children. In outpatient settings, the aim of the strategy is toimprove diagnosis and treatment of childhood illnesses. In the homesetting, IMCI has several aims.These include promoting appropriate careseekingbehaviour, improved nutrition and preventive care, and ensuringthe child receives the care prescribed.188 COORDINATED CARE IN DIFERENT SETTINGS

13.5.3 Secondary careMeasures applicable at secondary care level are additional to thoseapplicable at the primary care level. Measures for detecting and treatingcommon HIV-related diseases should include diagnosis and treatment ofsputum smear-negative pulmonary TB and extrapulmonary TB. Diagnosisusually requires investigations often available only at secondary level, e.g.X-ray and biopsy.I3Primary health care staff can manage many HIV-related problems inhealth centres and dispensaries. Sometimes TB/HIV patients developproblems requiring investigations and treatment unavailable at primaryhealth care level.Then they need to be referred to the district hospital,either to the outpatient department or for admission. After treatment,often the district level staff can refer the patient back to the primarycare or community level. Good channels of communication promotecontinuity of care.The IMCI strategy includes management guidelines (see Suggestions forFurther Reading) for district level care of children with HIV-relatedproblems.13.5.4 Tertiary careMeasures applicable at tertiary care level are additional to thoseapplicable at the secondary care level. They include diagnosis andtreatment of complications of common HIV-related diseases. Specialistmanagement of complicated forms of TB (e.g. peritoneal and pericardialTB) is often available only at the tertiary level.District level staff sometimes are faced with difficult problems ofdiagnosis or treatment. The patient may benefit from transfer to atertiary referral hospital. It is usually wise to obtain advice on thetelephone before transferring the patient. This is to ensure that thespecialist agrees that the patient is likely to benefit from the referral.The table below shows HIV/AIDS and TB care integrated at differentlevels of the health care system.Availability of interventions depends onwhether a country is low-, middle- or high-income.TB/HIV:A CLINICAL MANUAL189

Level of care Low-income Middle-income High-incomeHome and Information As per low- income As per middlecommunityand education level income levelCondoms plus plusBreastfeeding a) terminal care a) terminal careadvice with health with advancedPalliative care professional technologySupport groups inputb) domiciliaryb) formula feeds for treatment of HIVinfantnutritional related diseasessupplementationPrimary care VCT for HIV As per low-income As per middle-(health centre) Prevention of levelincome levelHIV plus plus clinical andtransmission a) antiretroviral laboratoryDetection and drugs for prevention monitoring oftreatment of of mother-to-child HIV progressioncommon HIV- transmissionrelated diseases b) prevention of(e.g. TB) fungal infectionsPrevention ofcommon HIVrelateddiseasesPain reliefIntensified TBcase-findingDiseasesurveillance(e.g. TB)Decreasednosocomialtransmissionandprotection ofhealth workers190 COORDINATED CARE IN DIFERENT SETTINGS

Secondary care As for primary As per low- income As per middle-(district care level level plus income levelhospital) plus disease surveillance plusa) safe blood of less common a) diagnosis andb) terminal HIV-related treatment ofin-patient care diseasesuncomplicatedc) possible HIV-relatedaccess to ARTillnessb) access to ARTc) post-exposureprophylaxisI313.6 THE PRIVATE SECTORThe private sector includes private medical practitioners and traditionalhealers. Many patients choose to go to one or both.13.6.1 Private medical practitionersIdeally there should be close collaboration between privatepractitioners and the NTP. This can result in improved management ofTB patients according to NTP guidelines. Private practitioners serve thecommunity and can guarantee their TB patients good care by followingNTP guidelines. Private practitioners can register TB patients with theNTP and share continued management. Private practitioners do nothave to give up their patients entirely to the NTP. Some TB/HIV patientsprefer to go to a private practitioner for reasons of confidentiality. In acountry where the NTP is very good, many patients will prefer the NTPto a private practitioner. More countries are now introducing schemesfor training and accreditation of private practitioners as TB andHIV/AIDS care providers.13.6.2 Traditional practitionersTB is a difficult disease for traditional practitioners. Many do notunderstand it, do not know how to cure it, and do not have theappropriate drugs. General health services can collaborate withtraditional practitioners. For example, traditional practitioners canrecognize TB suspects and refer them.Traditional healers often have animportant role in supporting PLWH when they are ill.TB/HIV:A CLINICAL MANUAL191

13.7 OPERATIONAL RESEARCH AIMED ATIMPROVING INTEGRATED TB AND HIV/AIDSPREVENTION AND CARETB and HIV programmes need to collaborate in implementing theinterventions set out in the above framework (see section 13.5). Theycomprise HIV interventions relevant to TB control and TB interventionsrelevant to HIV/AIDS care.TB and HIV programmes need to mainstreamthese interventions as part of their routine activities. Operationalresearch is necessary to improve the delivery of integrated TB andHIV/AIDS prevention and care.13.7.1 Promoting voluntary counselling and testing (VCT)for HIV as an entry point to better TB careThere are several benefits of promoting VCT for HIV (see Chapter 6).One potential benefit is improved access to various HIV prevention andcare activities, including TB interventions. The ProTEST initiative,coordinated by WHO, is one of several operational research initiativeson integrated HIV/AIDS and TB care.This initiative aims to promote HIVvoluntary testing as a key to a more coherent response to TB in settingswith high HIV prevalence.The name “ProTEST” reflects the promotionof voluntary HIV testing, as an entry point for access to HIV and TBprevention and care. The initiative supports district-level experience inseveral field sites.These sites are combining efforts against HIV and TBto reduce the combined TB/HIV burden. Local experience will informthe development of a district-based model for the integrated delivery ofhealth care services. Integrated delivery involves all service providers,e.g. government, NGOs, community and the private sector. The resultsfrom the field sites will inform the development of policy guidelines forscaling up the model, if shown to be effective and affordable.13.7.2 The Practical Approach to Lung Health (PAL)Strengthened general health services are also crucial to ensure that HIVinfectedpersons have access to care for common HIV-related diseases.These include the respiratory diseases that constitute a large part of theburden of HIV-related disease. The use of a syndromic approach mayimprove the care of patients with common respiratory problems bygeneral health service providers.The Practical Approach to Lung Health(PAL) represents WHO’s contribution to promoting this approach bydeveloping guidelines and algorithms.192 COORDINATED CARE IN DIFERENT SETTINGS

SUGGESTIONS FOR FURTHER READINGGilks C, Floyd K, Haran D, Kemp J, Squire B, Wilkinson D. Care and support forpeople with HIV/AIDS in resource-poor settings. London, UK Department forInternational Development, 1998 (Health and Population Occasional Paper).I3Godfrey-Faussett P, Maher D, Mukadi YD, Nunn P, Perriens J, Raviglione M. Howcan HIV voluntary testing contribute to a more coherent response totuberculosis in high HIV prevalence settings? Bulletin of the World HealthOrganization, 2002, 80: 939-945.World Health Organization. Provision of HIV/AIDS care in resource-constrainedsettings. Report of a meeting. Geneva, 1994.World Health Organization. A strategic framework to decrease the burden ofTB/HIV. Geneva, 2002 (WHO/CDS/TB/2002.296).World Health Organization. Improving child health. IMCI: the integrated approach.Rev.2. Geneva, 1997 (WHO/CHD/97.12) (www.who.int/child-adolescenthealth).World Health Organization. Management of the child with a serious infection orsevere malnutrition. Guidelines for care at the first-referral level in developingcountries. Geneva, 2000 (WHO/FCH/CAH/00.1).World Health Organization. Guidelines for collaborative TB and HIV programmeactivities. Geneva, 2003 (WHO/CDS/TB/2003.319;WHO/HIV/2003.01).World Health Organization. AIDS home care handbook. Geneva, 1993.World Health Organization. Report of the first international review meeting.Practical Approach to Lung Health Strategy, 4–6 September 2002, Rabat, Marocco.Geneva, 2003 (WHO/CDS/TB/2003.324).World Health Organization. Community contribution to TB care: practice andpolicy. Geneva, 2003 (WHO/CDS/TB/2003.312).TB/HIV:A CLINICAL MANUAL193

PREVENTION OF TUBERCULOSIS INHIV-INFECTED INDIVIDUALSI414.1 INTRODUCTIONFrom the public health point of view, the best way to prevent TB is toprovide effective treatment to people with infectious TB.This interruptsthe chain of transmission. Good treatment programmes are the bestprevention programmes. HIV-infected individuals are particularlysusceptible to infection with M. tuberculosis and the development of TB.What are the ways of protecting HIV-infected individuals from exposureto TB in health care settings? What is the role of BCG? HIV-infectedindividuals who are already infected with M. tuberculosis have a high riskof developing active TB. Can we do anything to decrease this risk? Thischapter addresses these questions.14.2 PROTECTION OF HIV-POSITIVE PERSONSAGAINST EXPOSURE TO TBHIV-positive patients and staff in health units face daily exposure to TB.The risk of exposure is greatest in adult medical wards and TB wardswhere there are many PTB cases. Often the wards are crowded andbadly ventilated.We do not yet know the size of this risk.Training of health care workers about the importance of infectioncontrol measures should assist in the implementation of controlactivities. Prompt diagnosis and treatment of patients with sputumsmear-positive PTB helps to reduce exposure to TB. Prompt outpatientdiagnosis and treatment of PTB patients avoids hospital admission.Thisis an advantage in decreasing exposure to TB in hospital wards. In someNTPs there is a move away from an inpatient intensive phase towardsoutpatient management.Known HIV-positive health workers should not work with PTB patients.They should therefore not work in TB wards or adult medical wards.14.2.1 Environmental controlGood ventilation helps reduce TB transmission indoors. Sunlight is asource of ultraviolet light, which can kill TB bacilli. So, ideally, wardsshould have large windows. Laboratories that process sputum specimensfor AFB should follow published guidelines to minimize TB transmissionto laboratory workers.TB/HIV:A CLINICAL MANUAL195

PRACTICAL POINTIn wards, outpatient clinics, sputum collection rooms,microbiology laboratories, surgical and autopsy suites, keepthe doors closed and the windows open.14.2.2 Face-masksA face-mask decreases the risk that the person wearing the mask caninfect other people. So a TB suspect or a TB patient, if possible, shouldwear a mask when moving from one part of a hospital to another. Healthworkers often wear a mask for protection against TB, e.g. when workingon the TB ward. In fact, a mask is generally not very good at protectingthe person wearing the mask from inhaling other people's infectiousdroplets. The exception is when the health worker is supervising acough-inducing procedure, e.g. bronchoscopy or sputum induction usingnebulized hypertonic saline. HEPA (high efficiency particulate air) filtermasks can prevent the inhalation of very small droplet nuclei. However,HEPA masks have certain drawbacks. They are very expensive, have tobe fitted correctly to be effective, and need to be changed regularly.14.2.3 Patient educationHealth workers should teach TB suspects and TB patients simplemeasures to decrease the risk of transmitting TB.These include coveringthe mouth with the hand when coughing, and using sputum pots withlids. When examining TB patients or suspects, ask them to turn theirhead away, to avoid coughing directly at the health worker.14.2.4 Pulmonary TB suspectsIn the majority of cases, PTB suspects attend as outpatients for thediagnosis of TB. In some cases it is necessary to admit PTB suspects tohospital. If possible admit them to a separate ward from other patients.There are often no facilities to separate PTB suspects from otherpatients. At least try to keep PTB suspects in a part of the ward awayfrom other patients. Staff should also encourage PTB suspects to spenddaylight hours outside the ward if the weather is good. Sputum forsmear examination should be collected as rapidly as possible. Thelaboratory should process and examine sputum smears rapidly andefficiently. Hospitals should ensure a minimum of delay in deliveringsmear examination results back to the wards.Adults accompanying smallchildren with possible TB may also themselves have TB and be thesource of the child’s disease.196 PREVENTION OF TB IN HIV-INFECTED INDIVIDUALS

14.2.5 Patients with sputum smear-positive pulmonary TBIdeally, sputum smear-positive PTB patients should start anti-TBtreatment as soon as the smear results are known. In many NTPs,sputum smear-positive PTB patients spend at least part, and often all, ofthe intensive phase of anti-TB treatment in hospital. Isolation of thesepatients in TB wards helps reduce the risk of TB exposure to otherpatients. Do not admit a patient to the TB ward until you have made thediagnosis of TB.TB suspects with HIV infection and high susceptibility toTB should avoid exposure to TB.They may turn out not to have TB.I414.2.6 Patients with multidrug-resistant TB (MDR-TB)In many cases it is impossible to predict or to detect MDR-TB, and inmany countries this information never becomes available. Howeverpatients with known MDR-TB require special management at a referralcentre.These patients may have prolonged periods of infectiousness. Itis therefore necessary to minimize the possibility of contact with otherpatients who do not have TB or do not have MDR-TB.They should bein a separate area or facility, preferably in well-ventilated individualpatient rooms. If this is not feasible, then it is necessary to establish award or an area of a ward for MDR-TB.PRACTICAL POINTPatients with MDR-TB must be separated from patientswho have HIV infection. In many countries, outbreaks ofMDR-TB have spread very rapidly on wards for AIDSpatients.14.3 ROLE OF BCG IN PREVENTING TB INHIV-INFECTED INDIVIDUALS14.3.1 BackgroundBCG (Bacille Calmette-Guerin) is a live attenuated vaccine derivedoriginally from M. bovis.The route of injection is intradermal.The usualdose is 0.05 ml in neonates and infants under the age of 3 months, and0.1 ml in older children. In countries with high TB prevalence, WHOrecommends a policy of routine BCG immunization for all neonates.The benefit of BCG is in protecting young children against disseminatedand severe TB, e.g. TB meningitis and miliary TB. BCG has little or noeffect in reducing the number of adult cases of PTB.TB/HIV:A CLINICAL MANUAL197

14.3.2 BCG protection against TB in HIV-infected childrenIt is not known if HIV infection reduces the protection conferred byBCG against TB in children.There is some evidence that conversion toa positive tuberculin test after BCG is less frequent in HIV-infectedchildren.The significance of this finding for protection against TB is notclear.14.3.3 BCG safety in HIV-infected childrenThere have been a few case reports of local complications anddisseminated BCG infection after BCG immunization of HIV-infectedchildren. However, prospective studies comparing BCG immunization inHIV-infected and uninfected infants showed no difference in risk ofcomplications. So, in the vast majority of cases, BCG immunization issafe.14.3.4 WHO recommended policy on BCG and HIVWHO recommended policy depends on the TB prevalence in a country,as shown below. In a country with high TB prevalence, the possiblebenefits of BCG immunization outweigh the possible disadvantages.Country TB prevalencehighlowWHO recommended policyBCG for all children (according tostandard programme) except childrenwith symptoms of HIV disease/AIDSDo not give BCG immunization toHIV-infected childrenLow prevalence of TB is defined asa) average annual notification rate of smear-positive PTB for the past 3years equal to or less than 5/100000,b) average annual notification rate of TB meningitis in children under 5years for the past five years less than one case per million, andc) average annual risk of tuberculous infection 0.1% or less.198 PREVENTION OF TB IN HIV-INFECTED INDIVIDUALS

14.4 THE ROLE OF THE EXPANDED PROGRAMME ONIMMUNIZATION (EPI)BCG is not the only immunization in the EPI that may help to protect achild against TB. Measles and whooping cough lower a child's resistanceto TB. So whenever you treat a child for TB, check his or herimmunization record. If the child has not received scheduledimmunisations, encourage the mother to bring him or her forimmunizations, once symptoms of TB have resolved. WHO hascollaborated with UNICEF in establishing guidelines for immunization.The recommendation is that individuals with known or suspectedasymptomatic HIV infection should receive all EPI vaccines, accordingto national schedules.I414.5 PREVENTIVE TREATMENTPreventive TB treatment refers to decreasing the risk of a first orrecurrent episode of TB. A first episode of TB may occur in someoneexposed to infection or with latent infection.A recurrent episode of TBoccurs in someone who has previously had TB.a) Aimed at decreasing the risk of a first episode of TBPeople at high risk of developing TB may benefit from preventivetreatment, as an intervention currently for individual benefit rather thanas a public health measure to control TB. For example, WHO has formany years recommended isoniazid preventive treatment (IPT) forchildren who are household contacts of infectious index cases of TB, andwho, after screening, are found not to have TB.WHO and UNAIDS recommend IPT for 6 months for tuberculinpositiveHIV-infected individuals who do not have TB. However, evenwhere tuberculin testing is not feasible, IPT may still be valuable in HIVinfectedindividuals at high risk of TB. Among PLWH, IPT is likely toprovide protection against the risk of developing TB through twomechanisms. Firstly, by decreasing the risk of progression of recentinfection, and secondly, by decreasing the risk of reactivation of latent M.tuberculosis infection. In populations with high TB prevalence, theduration of benefit following completion of a 6-month course of IPT islimited (up to 2.5 years).This is probably due to continued exposure toM. tuberculosis infection. The duration of protection depends on theduration of preventive treatment.TB/HIV:A CLINICAL MANUAL199

) Aimed at decreasing risk of a recurrent episode of TBAmong TB patients who complete SCC, the recurrence rate is higher inHIV-positive than in HIV-negative TB patients. Post-treatmentprophylaxis (for example with isoniazid) can decrease the risk of TBrecurrence in HIV-infected individuals, although it does not prolongsurvival. Further studies are needed to confirm the benefit, establish theoptimum regimen (drugs and duration), and assess operational feasibility,before treatment aimed at decreasing risk of TB recurrence can berecommended.14.5.1 Target groups for preventive treatmentA 6-month course of preventive treatment with daily isoniazid (5 mg/kg)is effective in preventing progression of M. tuberculosis infection todisease. However, preventive treatment for all individuals infected withM. tuberculosis is not a recommended TB control strategy. It is notfeasible to try to identify all individuals infected with M. tuberculosis.TBdisease develops in only 10% of these individuals. So it is not costeffectiveto identify and treat all infected individuals in order to preventdisease in 10%. However, it is possible to identify certain groups at highrisk of progressing from M. tuberculosis infection to TB disease. It may becost-effective to target preventive treatment at these high-risk groups.Young children are at special risk, especially if they are HIV-infected. HIVinfection, in children and in adults, is a potent cause of progression of M.tuberculosis infection to TB disease (see Chapter 1).Infants of mothers with PTBA breastfeeding infant has a high risk of infection from a mother withPTB, and a high risk of developing TB. The infant should receive 6months' isoniazid treatment, followed by BCG immunisation. Analternative policy is to give 3 months' isoniazid, then perform atuberculin skin test. If the skin test is negative, stop the isoniazid and giveBCG. If the skin test is positive, continue another 3 months' isoniazid,then stop isoniazid and give BCG.Children under 5 years of ageIt is important to screen child household contacts of adults with sputumsmear-positive PTB (see Chapter 4). Screening identifies those childrenunder 5 years of age without symptoms. Give these children 6 months'isoniazid preventive treatment. Children under 5 years of age withsymptoms need to be investigated for TB. If investigations show TB, thechild should receive anti-TB treatment. If investigations do not show TB,the child should receive isoniazid preventive treatment.200 PREVENTION OF TB IN HIV-INFECTED INDIVIDUALS

HIV-infected individualsControlled clinical studies have shown that IPT reduces the risk of TBdisease in HIV-positive individuals also infected with M. tuberculosis.Theevidence of M. tuberculosis infection is a positive tuberculin skin test. InHIV-positive individuals, an extra benefit of a reduced risk of TB may bea reduced rate of progression of HIV infection.I414.5.2 Role of isoniazid preventive treatment in HIV-positiveindividualsThe theoretical benefits of IPT are attractive. The table shows thepotential disadvantages and necessary precautions.Potential disadvantage Necessary precautionrisk of drug toxicitydo not give to people with chronic(especially liver damage) disease or who regularly drinkexcessive amounts of alcoholemergence of drug resistance in all cases exclude TB disease by(if the patient has undetected CXR,TB disease and not just in patients with cough of 3 weeks'M. tuberculosis infection) duration or more, do sputummicroscopydiversion of resources from funding must be from sources otherNTP activitiesthan NTP (e.g.AIDS controlprogramme, voluntary sector)or extra funding sources for theNTP must be found14.5.3 WHO/UNAIDS recommendations on preventivetherapy against TB in HIV-positive personsServices needed before setting up a preventive therapy serviceBefore a preventive therapy service is considered, the followingprerequisites should be in place:º adequate capacity for HIV counselling,which should include IEC about TB;º sufficient trained health care staff;º linkage between HIV care and TB control services;º good TB control programme with high cure rates and combineddefault/failure rates at the end of treatment of less than 10%.Recommendations for a preventive therapy serviceº Preventive therapy against TB should be part of a package of care forpeople living with HIV/AIDS.º Preventive therapy should be used only in settings where it is possibleTB/HIV:A CLINICAL MANUAL201

to exclude active TB and to ensure appropriate monitoring andfollow-up.º Information about TB and preventive therapy should be made availableto HIV-positive people.º Preventive therapy should be provided from within settings thatinclude voluntary counselling and testing (VCT) services for HIV.º The priority for TB control programmes continues to be thedetection and cure of infectious TB cases.º Procurement and supply of anti-TB drugs must be regulated bynational authorities in order to prevent the development ofdrugresistance.Steps in the delivery of preventive therapyThose who have a positive HIV test should receive:counselling on TBscreening for active TBAsk whether persons have a cough:those with a cough should be screened for TB;those with no cough should have a CXR;if the CXR is normal proceed to next steptargeting those most Preventive therapy is recommended forlikely to benefittuberculin-positive HIV-positive personswho do not have active TB.Sometimes it is not possible to performtuberculin testing. In these circumstances,HIV-positive persons may still be consideredfor preventive therapy if they area) living in high TB prevalence areasb) health care workersc) household contacts of TB patientsd) prisonerse) minersprovision of preventive Isoniazid is the recommended drug -therapy to thosewithout active TBmonitor for adherenceand toxicityevaluation of outcome5 mg/kg (max. 300mg) given as a daily,self-administered therapy for 6 months.Individuals are seen monthly and receiveone month’s supply of drugs at each visitThose who interrupt therapy should befollowed up.The aim is to provide at least 6 months oftherapy during a one-year periodStop isoniazid in those who developsymptoms and signs of active TB orhepatitis.Regularly assess the effectiveness ofpreventive therapy (attendance, adherence,toxicity, withdrawals, completion of therapy)202PREVENTION OF TB IN HIV-INFECTED INDIVIDUALS

ConclusionsIPT is not an alternative to the DOTS strategy for controlling TB.However, there are many opportunities for providing IPT to peopleliving with HIV which could prevent many cases of active TB. Systemsneed to be developed to greatly increase the accessibility of preventivetherapy to people living with HIV in settings of high TB prevalence. Atthe same time it is crucial to avoid compromising NTP quality.I4TB/HIV:A CLINICAL MANUAL203

SUGGESTIONS FOR FURTHER READINGHarries AD, Maher D, Nunn P. Practical and affordable measures for theprotection of health care workers from tuberculosis in low-income countries.Bulletin of the World Health Organization, 1997, 75: 477–489.Reider HL. Interventions for tuberculosis control and elimination. Paris,International Union Against Tuberculosis and Lung Disease, 2002.World Health Organization. Childhood tuberculosis and BCG vaccination. BCG -gateway to EPI. Geneva, 1989.World Health Organization. Global Programme for Vaccines and Immunization.Immunization Policy. Geneva, 1995.World Health Organization. Guidelines for the management of drug-resistanttuberculosis. Geneva, 1996 (WHO/TB/96.210, Rev.1).World Health Organization. Preventive therapy against tuberculosis in peopleliving with HIV. Weekly epidemiological record, 1999, 74: 385–400.World Health Organization. Guidelines for the prevention of tuberculosis in healthcare facilities in resource-limited settings. Geneva, 1999 (WHO/TB/99.269).204 PREVENTION OF TB IN HIV-INFECTED INDIVIDUALS

INDEXAbscesslung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 56tuberculous lymphadenopathy . . . . . . . . . . . . . . . . . . . . .75Acid-fast bacilli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23, 51Adrenal gland TB . . . . . . . . . . . . . . . . . . . . . . . . .27, 87, 109, 121, 178AIDSWHO case definition . . . . . . . . . . . . . . . . . . . . . . . .35, 36Anal/genital warts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161Anaemia . . . . . . . . . . . . . . . . . . . . . . . . . .92, 100, 130, 152, 174, 176Angular cheilitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .91Antiretroviral therapy . . . . . . . . . . . . . . . . . . . . . . . . . .94, 95, 97, 137Anti-TB drugs (see also essential TB drugs) . . . . . . . . . . . . . .111-120modes of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112Aphthous ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .165Ascites, tuberculous . . . . . . . . . . . . . . . . . . . . . . . . . . . . .66, 79, 83, 84Aspergilloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 65, 66Bacterial pneumonia . . . . . . . . . . . . . . . . . . . . . .54, 56, 58, 65, 70, 166Bacterial vaginosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159BCGHIV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .198infants of mothers with TB . . . . . . . . . . . . . . . . . . . . . . .200WHO policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .197-199Biopsydiagnostic approach to extrapulmonary TB . . . . . . . . . . .75lymph node . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75-78peritoneal TB . . . . . . . . . . . . . . . . . . . . . . . . . . . .79, 83, 84pleural . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79-81Blood spread of tubercle bacilli . . . . . . . . . . .25, 38, 39, 63, 78, 84, 107Bone TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27, 87, 107, 109Breathlessness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50, 80, 165Bronchial carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 57Bronchiectasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 55, 66, 70Candidiasis . . . . . . . . . . . . . .33-36, 91, 99, 141, 157, 159,160, 162, 164Capreomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119Caseation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77Case definitions of TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .105-107Case-finding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42, 95, 185Cavitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26, 50, 63, 70Cerebrospinal fluid . . . . . . . . . . . . . . . . . . . . . . . . .64,85-86, 171-174Cervicitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Chancroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159, 160Chest pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50, 59, 80, 81, 165CXR . .26,38,49,54-57,59,65,70-72,106,107,122,154,167,201,202TB/HIV:A CLINICAL MANUAL205

Childrenapproach to TB diagnosis . . . . . . . . . . . . . . . . . . . . . . . . .63BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .197clinical recognition of HIV infection . . . . . . . . . . . . . . . . .99contacts of infectious adults . . . . . . . . . . . . . . . . . . . . . . .71counselling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101differential diagnosis of pulmonary TB . . . . . . . . . . . . . . .66Expanded Programme on Immunization . . . . . . . . . . . . .199HIV-related TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39HIV testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100impact of HIV infection on TB diagnosis . . . . . . . . . . . . . .69preventive treatment . . . . . . . . . . . . . . . . .72, 197, 199-202score system for TB diagnosis . . . . . . . . . . . . . . . . . . . . .66side-effects of anti-TB drugs . . . . . . . . . . . . . . . . . . . . . .129"treatment trial" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69tuberculin testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67Chlamydia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159-160Chronic behaviour change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .172Chronic obstructive airways disease . . . . . . . . . . . . . . . . . . . . .54, 165Clostridium difficile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169Code for TB treatment regimens . . . . . . . . . . . . . . . . . . . . . .114-115Cohort analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44, 124Congestive cardiac failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 82Conjunctivitis, phlyctenular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26Connective tissue disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57Continuation phase of treatment . . . . . . . . . . . . . . . . . . . . . .114-118Cough . . .23,35,36,43,49,50,55,58,59,62,64,70,105,109,165,186,196Cryptococcal meningitis . . . . . . . . . . . . . . . . . . . . .32, 35, 85, 173, 174Cryptosporidium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169, 179Culture, sputum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49Cure, definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123Cycloserine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119Cytomegalovirus . . . . . . . . . . . . . . . . . . . . .33, 157, 158, 168, 177, 182Dactylitis, tuberculous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26Default, definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123Desensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134-135Diarrhoea . . . . . . . . . . . . . . .32-36, 87, 88, 91, 102, 125, 152, 168-171Difficulty walking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .174-175Disseminated (miliary) TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .167, 168Directly Observed Therapy (DOT) . . . . . . . . . . . . . . . . . . . . . . .45, 46District level care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .188Dormant TB bacilli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23, 63, 113Drug resistance . . . . . . . . . . . . . . . .38, 42, 47, 111, 113, 114, 118, 119Drug side-effects (TB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .129Education of patients to prevent TB transmission . . . . . . . . . . . . .196Environmental control measures to prevent TB transmission .195-196206 INDEX

Erythema nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26Essential anti-TB drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .111-117Ethambutol . . . . . . . . . . . . . . . . .112, 113, 120, 125, 126,130-132, 154Ethionamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119,120Extrapulmonary TB . . . . . . . . . . . . .34, 75, 107-109, 116, 121-124, 189Failure of treatment . . . . . . . . . . . . . . . . . .42, 108, 116, 118, 122, 123Face masks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .196Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .176-177Fluorochrome stain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52Flow chartsidentification and management of child contacts . . . . . . .72investigation of lymphadenopathy . . . . . . . . . . . . . . . . . . .77management of HIV-positive TB patients who failto respond or deteriorate while on anti-TB treatmentmanagement approach for persistent headache . . . . . . .173Gastric suction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64Gastrointestinal TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88Genital tract TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27,87Genital ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28,159-160Gibbus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87Gingivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .91, 165Gonorrhoea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Hairy leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33, 91Haemophilus influenzae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70, 166Haemoptysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50, 54, 55, 58, 59Hepatic TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88-87Hepatitis . . . . . . . . . . . . . . . . . . . . .129, 130, 132, 135, 151, 152, 202Herpes simplex . . . . . . . . . . . . . . . . . . . . . . . . .35, 100, 159, 161, 180Herpes zoster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32,33,35,91HIVbackground information . . . . . . . . . . . . . . . . . . . . . . . . . .27epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28, 36HIV-related TB, basic facts . . . . . . . . . . . . . . . . . . . . . . . .36immunopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . .30natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31prevention of transmission in health units . . . . . . . .29, 188Hypoadrenalism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87, 178Hypersensitivity reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26, 121Immunization (see also BCG and Expanded Programme onImmunization) . . . . . . . . . . . . . . . . . . . . . . . . . . . .25, 61, 179, 197-199Impetigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .162Inguinal bubo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Initial phase of treatment . . . . . . . . . . . . . . . . .120, 122, 113-118, 154Integrated HIV/AIDS and TB care . . . . . . . . . . . . . . . . . . . . . .187-191Isoniazid . . . . . .47, 72, 112-118, 129-130, 132, 134-135, 175, 199-203Isospora belli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169-170, 181Kanamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119TB/HIV:A CLINICAL MANUAL207

Kaposi sarcoma . . . . . . . . . .32, 34, 35, 58, 71, 76, 81, 91, 164, 177-178Laryngeal swabs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64Lymph nodesapproach to investigation of lymphadenopathy . . . . . . . . .77biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76, 77features of lymph nodes which indicatefurther investigation . . . . . . . . . . . . . . . . . . . . . . . . . . .76histological appearance . . . . . . . . . . . . . . . . . . . . . . . .77, 78persistent generalized lymphadenopathy . . . . .31, 33, 34, 76tuberculous lymphadenopathy . . . . . . . . . . . . . . . . . . . . .75Lymphocytic interstitial pneumonitis . . . . . . . . . . . . . . . . . . . .70, 167Lymphogranuloma venereum . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Lymphoma . . . . . . . . . . . . . . . . . . .34, 57, 71, 76, 86, 88, 158, 173, 178Malnutrition, children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36, 62-68Meningitis, cryptococcal . . . . . . . . . . . . . . .32, 35, 85, 86,173, 174, 177Meningitis,tuberculous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84-86differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86subacute/chronic meningitis . . . . . . . . . . . . . . . . . . .85, 173Microsporidia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169, 170Miliary TB . . . . . . . . . . . .39, 49, 61, 63, 65, 70, 75, 78, 79, 88, 117, 197Molluscum contagiosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .99, 161Multidrug-resistant TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47, 119Mycobacterium africanum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23Mycobacterium avium complex . . . . . . . . . . . . . . . . . . . . . . . . .177, 180Mycobacterium bovis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23Mycobacterium tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23National TB Programme . . . . . . . . . . . . . . . . . . . . . . . .41, 42, 44, 111Neurosyphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .173Nocardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .166, 173Occupational lung disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57PAL (Practical Approach to Lung health) . . . . . . . . . . . . . . . . . . . .192Papular folliculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .163Pathogenesis of TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25Pericarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26,109,121Pericardial effusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55,81,82,83Pleural effusion,tuberculous . .26, 27, 38, 55, 59, 64, 71, 75, 80, 107, 109, 121Pneumocystis carinii pneumonia . . . . . . . . . . . . . . . . . . . .33, 58, 71, 166Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55, 81Post-primary TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26, 63Prednisolone (see also steroid treatment) . . . . . . . .121, 133, 165, 167Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . .87, 100, 120, 150, 159, 181Prevention of TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .195BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .197environmental control measures . . . . . . . . . . . . . . .195-196Primary complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25-26Private medical practitioners . . . . . . . . . . . . . . . . . . . . . . . . . . . . .191208 INDEX

Pulmonary TBadults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49,75CXRs in diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49,50diagnostic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49diagnostic sputum smear microscopy . . . . . . . . . . . . . . . .51differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54differential diagnosis of CXR findings . . . . . . . . . . . . . . . .56differential diagnosis in HIV-infected children . . . . . . . . . .70distinguishing other HIV-related pulmonary diseases . . . .58patterns of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .164Pyogenic brain abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .173Pyomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33, 91, 163, 179Pyrazinamide . . . . . . . . . . . . . . . . . . . . . . .112-116, 120, 130, 132, 178Pyridoxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120, 132, 175Rehydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .168-170Relapse . . . . . . . . . . . . . . . . . . . . . . . . . .107,108,111, 113, 116, 118Renal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120, 178Renal and urinary tract TB . . . . . . . . . . . . . . . . . . . . . . . . . . . .87,126Re-treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .114, 116Rifampicin . . . . . . . . . . . . . . . . . . . .47, 69, 112-120, 125, 132, 153, 154Road to health card . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57Scabies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .133, 164Second-line drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119Sexually transmitted infections . . . . . . . .28, 41, 46, 157, 158, 185, 187Salmonella . . . . . . . . . . . . . . . . . . . . . . .34, 70, 157, 158, 169, 177, 182Schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84, 174Shigella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169, 170Short-course chemotherapy . . . . . . . . . . . . . . . . . . . .43, 44, 111, 113Skin TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27Source of TB infection . . . . . . . . . . . . . . . . . . . . . . . . . . .23, 61, 64, 73Spastic paraparesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .174Spinal block, in tuberculous meningitis . . . . . . . . . . . . . . . . . . . . . .121Spinal cord disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .174Spinal TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63, 88, 117, 174Sputum smear microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51-54children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64Staphylococcus aureus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70, 166Steroid treatment, adjuvant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121Streptococcus pneumoniae . . . . . . . . . . . . . . . . . . . . . . . . . . .58, 70, 166Streptomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112-120, 130-132Syphilisprimary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159, 160meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86TB/HIV:A CLINICAL MANUAL209

Target groups for preventive treatment . . . . . . . . . . . . . . . . . . . . .200Targets for TB control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42Thioacetazone . . . . . . . . . . . . . . .95, 112, 117, 118, 125, 131, 132, 133Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92, 178Tinea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .162Toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33, 173Traditional practitioners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .191Transfer out, definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123Treatment of TB (see also anti-TB drugs)default, definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123failure, definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123modes of action of anti-TB drugs . . . . . . . . . . . . . . . . . .112monitoring of patients during treatment . . . . . . . . . . . .122National TB Programmes . . . . . . . . . . . . . . . . . . . . .41, 186recommended treatment regimens . . . . . . . . . . . . .113-117recording treatment outcome . . . . . . . . . . . . . . . . . . . .123recurrence . . . . . . . . . . . . . . . . . . . . . . . .107-108, 125, 200response to treatment . . . . . . . . . . . . . . . . . . . . . . . . . .123special situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120standardized diagnostic categories . . . . . . . . . . . . . . . . .108steroid treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121treatment regimens of anti-TB drugs . . . . . . . . . . .113-119Trichomonas vaginalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Tubercle bacilli . . . . . . . . . . . . . . . . . . . . . .23, 25, 26, 38, 51-54, 57, 67Tuberculin skin test . . . . . . . . . . . . . .24-26, 49, 62, 65, 67, 72, 198-202Tuberculosis (see also individual headings)basic facts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41diagnosis in adults . . . . . . . . . . . . . . . . . . . . . . . . . . . .49, 75diagnosis in children . . . . . . . . . . . . . . . . . . . . . . . . . .61, 75HIV-related, basic facts . . . . . . . . . . . . . . . . . . . . . . . . . . .36pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25, 63prevention in HIV-infected individuals . . . . . . . . . . . . . .195TB suspect . . . . . . . . . . . . . . . . . . . . . . . . . .49-54, 105, 186treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .111Urethral discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Vaginal discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Vaginitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159Voluntary HIV testing centres . . . . . . . . . . . . . . . . . . . . . . . . . .95, 186Walking difficulty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .174Weight loss . . . . . . . . . . . . . .32-36, 50, 64, 65, 75, 76, 91, 99, 168, 176Ziehl-Neelsen stain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51210 INDEX

Stop TB DepartmentDepartment of HIV/AIDSDepartment of Child and Adolescent Healthand DevelopmentWORLD HEALTH ORGANIZATIONFor further information about tuberculosis orother communicable diseases, please contactInformation Resource CentreCommunicable DiseasesWORLD HEALTH ORGANIZATIONCH 1211 Geneva 27, Switzerlande-mail: cdsdoc@who.int - fax +41 22 791 4285You can also visit our website athttp://www.who.int/gtb