Drug Resistance in Tuberculosis and Its Public Health Management ...

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnDrug Resistance in Tuberculosisand Its Public Health Management1Dr. Paul NunnTB Operations and Coordination (TBC)WHO Stop TB DepartmentGeneva, SwitzerlandContentsDefinitionsRationale for addressing drug resistanceThe size and distribution of the drug resistance epidemicGlobal strategies, plans and implementationNational planning and implementationObstaclesConclusionsPolicy background2DefinitionsMono-drug resistance• Resistance to any one anti-TB drugPoly-drug resistance• Resistance to more than one anti-TB drug,but not to those that define multi-drug resistanceMulti-drug resistance(MDR-TB)Extensive drug resistance(XDR-TB)• Resistance to isoniazid and rifampicin,the main drugs of the first-line regimen• MDR-TB plus resistance to any fluoroquinoloneand any one of the injectable second-line agents,amikacin, capreomycin and kanamycin"Total" drug resistance• No technical definition, as of May 20123The screen versions of these slides have full details of copyright and acknowledgements1

4Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnRationale for concern about MDR-TB,and worse forms of resistanceMDR-TB is:• Much more difficult and expensive to treat than susceptible TB• Represents "catastrophic expenditure" for any family affected• Highly lethal in HIV populations (80-98% case fatality reported)• Countries generally have very low capacity to respond• MDR strains already replacing susceptible ones –especially in Eastern Europe• 3.6% of all TB, but rising in many countries• Minsk, Belarus – 35% in new patients, 76% in previously treated*• Yet, political will is difficult to generate*Skrahina A et al., Europ Resp J. 2012, 39(6): 1425-1431As drug resistance increases,treatment success rates fall –and mortality increases2.6 million smear +ve cases –2009 cohortDrug susceptible TBTreatment success 87%, Mortality 4%2008 cohorts816 – 4,383 casesMDR-TBTreatment success 22 – 74%Mortality 5 - 20%52008 cohorts19 – 345 casesData from WHO; Global Tuberculosis Control 2011XDR-TBTreatment success 5 - 44%Mortality 21 - 90%Managing a severe epidemic of resistance6The screen versions of these slides have full details of copyright and acknowledgements2

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnDistribution of proportion of MDRamong previously treated TB cases, 1994-2010• The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoeveron the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities,or concerning the delimitation of its frontiers or boundaries10• Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2011. All rights reservedEstimated MDR-TB incidence rates, 2009(new and previously treated)Selected countriesof the former Soviet Union:Estonia: 7 / 100,000Kazakhstan: 57 / 100,000Russia: 27 / 100,000Tajikistan: 59 / 100,000African countries with estimatedMDR-TB incidence rates ≥ 15;MDR-TB cases per 100,000population:Botswana: 27 / 100,000Mozambique: 16 / 100,000Namibia: 17 / 100,000Rwanda: 16 / 100,000South Africa: 26 / 100,000Swaziland: 23 / 100,000Zimbabwe: 19 / 100,00011India: 8 / 100,000China: 7 / 100,000MDR-TBcasesemergingannually,per 100,000population13 top settings with highest % of MDR-TBamong new cases, 2001-2010Minsk, Belarus (2010)35.312The screen versions of these slides have full details of copyright and acknowledgements4

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnTime trends in TB (incidence/100,000 population, log scale)and MDR-TB (proportion of all TB)1000100____ TB____ MDR -TB0.3% per yearBotswana1019.4% per year11996 1998 2000 2002 2004 2006 2008100Tomsk Oblast, Russia____ TB ____ MDR-TB2.4% per year____ TB ____ MDR-TB10100-6.7% per yearEstonia1-2.4% per year101999 2001 2003 2005 2007 2009113-5.1% per year1998 2000 2002 2004 2006 2008Countries that had reportedat least one XDR-TB case by end March 2011% XDR in MDR 9.4%(95% CI: 7.4-11.6)Argentina Bhutan France Japan Namibia Republic of Korea ThailandArmenia Cambodia Georgia Kazakhstan Nepal Republic of Moldova TogoAustralia Canada Germany Kenya Netherlands Romania TunisiaAustria Chile Greece Kyrgyzstan Norway Russian Federation UkraineAzerbaijan China India Latvia Pakistan Slovenia United Arab EmiratesBangladesh Colombia Indonesia Lesotho Peru South Africa United KingdomBelgium Czech Republic Iran (Islamic Lithuania Philippines Spain United States of AmericaRep. of)Botswana Ecuador Ireland Mexico Poland Swaziland UzbekistanBrazil Egypt Israel Mozambique Portugal Sweden Viet NamBurkina Faso Estonia Italy Myanmar Qatar TajikistanThe boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on thepart of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerningthe delimitation of its frontiers or boundaries; Dotted lines on maps represent approximate border lines for whichthere may not yet be full agreement.; © WHO 2011. All rights reserved14Global strategies, plans and implementation15The screen versions of these slides have full details of copyright and acknowledgements5

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnStrategic challengesin the control of MDR and XDR-TB16• Political/Funding• Financial barriers to patients• Engaging all care providers• Optimizing management and care• Addressing laboratory crisis• Ensuring access to quality-assured drugs• Controlling availability of anti-TB drugs• Prioritizing infection control• Addressing health workforce crisis• Improving surveillance systems• Investing in research and developmentIndicators for PMDTIndicators 2009 Baseline 2015 Target% previously treated cases tested for MDR-TB 7% 100%% new bact. +ve cases tested for MDR-TB 7% 20%No. countries with >1 C lab per 5m population 18 36% confirmed cases of MDR-TB enrolled on Rxby WHO standards36% 100%No. confirmed cases of MDR-TB enrolled on Rxby WHO standards11,000 270,000Treatment success rate among MDR-TB cases 60% >75%17Funding increasing,but lower than set out in global plan18 Source: WHO Global Tuberculosis Control Report 2011The screen versions of these slides have full details of copyright and acknowledgements6

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnMDR-TB cases notified,projected and global targets –reporting improving, but notificationstill far from targetNumber of patients (thousands)Projected enrolmentsGlobal plan targetsNon-GLCGLC19 Source: WHO Global Tuberculosis Control Report 2011120001000080006000MDR-TB treatment enrolment targets 2011in 27 HBC• GPSTB target for 27 HBC = 112,000• 27 HBC plan target = 44,200• Projected enrolment in 27 HBC pre 2011 = 30,000• Estimated global enrolment = 18,00040002000020DST coverage in 2010: diagnostic capacityand/or data transmission issues?21GPSTB 2015 targets: 20% of new & 100% of retreatment cases to have DSTThe screen versions of these slides have full details of copyright and acknowledgements7

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnMore countries reporting outcomesof patients on second-line treatment, but…% success was only 53% for patients startedon treatment in 2008 (2015 target is 75% or more)22Source: WHO Global Tuberculosis Control Report 2011National level planning and implementation23Guidance for country level planning for MDR-TBmanagement programmes24The screen versions of these slides have full details of copyright and acknowledgements8

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnWhy is planning for MDR-TBtreatment programmes important?• MDR-TB treatment is difficult, complex, time-consumingand expensive – much more so than drug sensitive TB• Provision of reliable treatment to hundreds of patientsfor ~2 years on a national scale requires enormouscoordination of multiple players – and is thus a majorplanning exercise25http://www.path.org/publications/detail.php?i=1678Essential principles of care for MDR-TBstrengthen basic TB controlPolitical commitment to implement objectives of the responsewith adequate budget to startMicrobiological diagnosis (culture, drug susceptibility test by a qualityassuredlaboratory) and monitoring of response to treatmentCollaboration with HIV programmePatient-centred approach for direct observation of treatmenton out-patient or hospitalised basisCare under proper infection control conditions26Quality assured second-line anti-TB drugs, meeting at leastWHO-GMP standardsRecording and reporting for monitoring and evaluationEssential elements in planning the strengtheningof basic TB control through MDR-TB managementEstimate burdenMeasure diagnostic capacity in place and define gapsDecide models of care (hospitalisation, outpatient)Ensure infection control measures in place and define gapsEnsure social support networkPlan drug procurement – second-line anti-TB drugs and those for adverse effectsSet up recording and reporting systemEnsure workforce in place and define gapsSet up staff development and trainingWrite national guidelines and manual of operationsConsider operational research agendaBudget and financing27The screen versions of these slides have full details of copyright and acknowledgements9

28Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnSpecific recommendations from 2011Guidelines for Programmatic Managementof Drug Resistant TB (PMDT)• Rapid drug susceptibility testing (DST)of isoniazid and rifampicin or of rifampicin aloneis suggested over conventional testingor no testing at the time of diagnosis of TB• The use of sputum smear microscopy and culturerather than sputum smear microscopy aloneis recommended for the monitoring of patientswith MDR-TB during treatment• In the treatment of patients with MDR-TB:– A later generation Fluoroquinolone should be used– Ethionamide (or prothionamide) should be usedSpecific recommendations (2)• In the treatment of patients with MDR-TB it is advised thatfour second-line anti-tuberculosis drugs likely to be effective(including a parenteral agent), as well as pyrazinamide,should be included in the intensive phase• Regimens should also include either cycloserine or PAS(p-aminosalicylic acid) if cycloserine cannot be used29Specific recommendations (3)• In the treatment of patients with MDR-TB,an intensive phase of 8 months’ duration is advised• A total treatment duration of at least 20 monthsin patients without any previous MDR-TB treatment30The screen versions of these slides have full details of copyright and acknowledgements10

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnSpecific recommendations (4)• Antiretroviral therapy is advised for all patientswith HIV and drug-resistant TB requiring second-lineanti-tuberculosis drugs, irrespective of CD4 cell-count,as early as possible (within the first 8 weeks)following initiation of anti-tuberculosis treatment• Patients with MDR-TB should be treatedusing mainly ambulatory care rather thanmodels of care based principally on hospitalisation31Research gapsThe 2011 update revealed important gaps in knowledge, including:• A lack evidence from randomized controlled trialsfor best treatment regimens and treatment duration• Lack of evidence for optimal drug regimens for treating patientswith isoniazid resistance, with XDR-TB and with non-MDR-TBpolydrug-resistance• Very limited information about:• Treatment of paediatric MDR-TB• Identification of the most effective chemoprophylaxisfor contacts of MDR-TB cases• Therapy for symptomatic relief from adverse reactions32Obstacles to MDR-TB management33The screen versions of these slides have full details of copyright and acknowledgements11

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul NunnWhy are so few cases of MDR-TBdiagnosed and treated?Insufficient national political commitment and ownership• National plans far below targets in Global Plan and WHA resolution 62.15Second-line drug costs remain exorbitant, at around $3000 per course• Funds increased from US$ 0.2b in 2006 to US$ 0.7b in 2011, but still US$ 0.2b short of needInsufficient links between diagnosis and treatmentUncertainty around the future of the Global Fund,which has been vital to progress34Countries nevertheless are moving and better planning is needed35Conclusions1. Management of MDR-TB is in the interestsof the public health – it saves lives2. Provision of care for people with MDR-TBis insufficient and increasing too slowly3. Greater national-level political commitmentis the most urgent need4. Reduction in the costs of second-line drugsis the next most important5. Guidance is available from the global levelfor most aspects of MDR-TB management6. If you feel there are any gaps please contactWHO Stop TB Department - glc@who.intPolicy background36The screen versions of these slides have full details of copyright and acknowledgements12

37Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul Nunn• Planning:– MDR-TB planning toolkit (http://www.path.org/publications/detail.php?i=1678)– MDR/XDR-TB assessment and monitoring tool (http://www.path.org/publications/detail.php?i=1678)– Planning and budgeting tool for TB control(http://www.who.int/tb/publications/factsheet_pbtool_mar10.pdf)• ImplementingManagement of MDR-TB diagnosis,treatment and care– PMDT Guidelineshttp://www.who.int/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/index.htl– Guidance on ethics of tuberculosis prevention, care and controlttp://whqlibdoc.who.int/publications/2010/9789241500531_eng.pdf– Information note: Management of MDR-TB http://www.who.int/tb/dots/mdr.pdf– Note on pharmacovigilance http://www.who.int/tb/challenges/pharmacovigilance_interimadvice_rd10.pdf– Drug quantification tool http://www.who.int/tb/challenges/mdr/greenlightcommittee/en/index.html– GDF procurement manual http://whqlibdoc.who.int/hq/2008/WHO_HTM_STB_2008.51.pdf– Guidelines for surveillance of drug resistance in tuberculosis and (M/XDR-TB): 2010– Global report on surveillance and response:http://www.who.int/tb/publications/mdr_surveillance/en/index.html– Companion manual to the PMDT guidelines (to be published 2012)• Monitoring– Minimum indicatorhttp://www.who.int/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/index.html– Electronic recording and reporting– http://www.who.int/tb/publications/electronic_recording_reporting/en/index.html– How to monitor PMDT (Handbook for consultant) – (to be published 2012)• EvaluatingManagement of MDR-TB diagnosis,treatment and care (2)– Global tuberculosis control report (http://www.who.int/tb/country/en/)– MDR-TB data/country profile: http://www.who.int/tb/country/data/profiles/en/index.html– WHO Annual MDR-TB progress report (to be published yearly up to 2015)– http://www.who.int/tb/publications/2011/mdr_report_2011/en/index.html38Acknowledgements• Chris Dye• Dennis Falzon• Katherine Floyd• Philippe Glaziou• Tauhid Islam• Ernesto Jaramillo• Eva Nathanson• Glenn Thomas• Matteo Zignol39The screen versions of these slides have full details of copyright and acknowledgements13

Drug Resistance in Tuberculosisand Its Public Health ManagementDr. Paul Nunn40The screen versions of these slides have full details of copyright and acknowledgements14