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:: FIG. 8.2 The global development pipeline for new anti-TB drugs, August 2016 a Discovery Preclinical development Clinical development Lead optimization Early stage development Good Laboratory Practice toxicity Phase I Phase II Phase III Cyclopeptides Diarylquinolines DprE Inhibitors InhA Inhibitor, Ureas Macrolides, Azaindoles Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Ruthenium(II)Complexes Spectinamides Translocase-1 Inhibitors, Clp, Mmp13, Oxazolidinones, Pyrimidines DprE1, Aryl Sulfonamides, PKS13, Squaramides TBI-166 CPZEN-45* SQ609* 1599* BTZ-043* TBA-7371* GSK-070* Q203* PBTZ169* Sutezolid (PNU- 100480) Linezolid EBA c High Dose Rifampicin for DS-TB Bedaquiline (TMC207)– Pretomanid (PA-824)–Pyolive greenrazinamide Regimen Levofloxacin with OBR b for MDR-TB Rifapentine–Moxifloxacin for Drug Sensitive TB Delamanid (OPC-67683) with OBR b for MDR-TB Pretomanid- Moxifloxacin- Pyrazinamide Regimen (STAND) Bedaquiline–Pretomanid– Linezolid NiX-TB Regimen Bedaquiline–STREAM MDR-TB Trial Stage 2 with oral OBR b (9 mo) or OBR b with injectables (6 mo) Bedaquiline–Linezolid with OBR for MDR-TB (NExT Trial) Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, imidazopyridine amide. * New chemical class a Details for projects listed can be found at http://www.newtbdrugs.org/pipeline.php and ongoing projects without a lead compound series identified can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php b OBR = Optimized Background Regimen c EBA = Early Bactericidal Activity Source: Working Group on New TB Drugs, 2016 – www.newtbdrugs.org Pretomanid Pretomanid is a nitroimidazole developed by the Global Alliance for TB drug development (TB Alliance). It is currently being tested as part of three potential combination regimens for the treatment of both drug-susceptible and drug-resistant TB (further details in Section 8.2.2). Q203 Q203 is a new compound of the imidazopyridine class developed by Qurient. It blocks the growth of TB bacilli by targeting the respiratory cytochrome bc1 complex, inhibiting the synthesis and homeostasis of adenosine triphosphate (ATP). 1 Different levels of a single dose are being tested in a Phase I trial. Sutelozid Sutezolid (PNU-100480) is an oxazolidinone and an analogue of linezolid. Results from a study of early bactericidal activity presented in 2012 showed that this compound led to a significant reduction in counts of colony-forming units compared with the baseline level following 14 days of treatment. In August 2016, however, there was no further information available to WHO about its subsequent development. 1 Pethe K, Bifani P, Jang J, Kang S, Park S, Ahn S et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat. Med. 2013;19(9):1157–1160. 8.2.2 Approved or repurposed drugs Rifapentine Investigation of the potential effectiveness of rifapentine in the treatment of drug-susceptible TB has continued, based on the encouraging results from TB Trial Consortium (TBTC) Studies 29 and 29X. TBTC Study 31/A5349 is investigating the possibility of shortening treatment of drug-susceptible pulmonary TB to 4 months by using rifapentine, with or without moxifloxacin. Recruitment started in January 2016. Rifampicin A recent 2-month study testing the safety of high doses of rifampicin together with standard treatment for drugsusceptible TB showed no significant increase in adverse events at doses of 10 mg/kg, 15 mg/kg and 20 mg/kg. 2 8.2.3 New regimens for the treatment of drugsusceptible or drug-resistant TB Besides individual compounds, new combinations of drugs are being tested in several Phase II or Phase III trials. The TB Alliance is investigating the efficacy, safety and tolerability of pretomanid in combination with moxifloxacin and pyrazinamide (PaMZ). Following the encour- 2 Jindani A, Borgulya G, de Patino IW, Gonzales T, de Fernandes RA, Shrestha B et al. A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis. Int. J. Tuberc. Lung Dis. 2016;20(6):832–838. GLOBAL <strong>TUBERCULOSIS</strong> REPORT 2016 :: 127
aging results of the 2-month NC-002 Phase IIb trial, 1 the STAND trial was launched in February 2015. This is a Phase III trial of the safety and efficacy of Pa(100 mg)MZ for 4 months, Pa(200 mg)MZ for 4 months and Pa(200 mg) MZ for 6 months in patients with drug-susceptible TB; and of Pa(200 mg)MZ for 6 months in patients with drugresistant TB. In late 2015, enrolment was temporarily suspended due to three deaths related to high liver toxicity. Subsequently, the TB Alliance has been working with regulatory authorities and the trial’s data safety and monitoring committee to determine whether to restart enrolment, and if so, when to do so. A Phase IIb trial (NC-005) to test all-oral combination regimens started in October 2014. The regimens being tested are bedaquiline (at two different doses), pretomanid and pyrazinamide for patients with drug-susceptible TB, and the same drugs in combination with moxifloxacin for patients with MDR-TB. Enrolment was completed towards the end of 2015, and results are expected in late 2016. The NiX-TB trial is being implemented by the TB Alliance in South Africa. It is investigating the safety and efficacy of a 6-month combination of bedaquiline, pretomanid and linezolid in patients with extensively drug-resistant TB (XDR-TB). The primary end-point is the incidence of bacteriologic failure (relapse or clinical failure) 6 months after completion of treatment, with long-term follow-up for 24 months after the end of treatment. Alongside this trial, the efficacy of escalating doses of linezolid in patients with drug-susceptible TB over a period of 2 weeks is also being investigated. Results will inform adjustments to the dosing of linezolid in the NiX-TB trial as well as other regimens that include linezolid. The endTB and TB-PRACTECAL trials are scheduled to start around the end of 2016. The former is a Phase III trial funded by UNITAID, and implemented by Partners in Health and Médecins Sans Frontières (MSF). It will compare several regimens for treatment of MDR-TB or XDR- TB with the current WHO standard of care. The regimens being tested contain bedaquiline or delamanid (or both), moxifloxacin or levofloxacin, and pyrazinamide plus linezolid or clofazimine (or both), in various combinations. The TB-PRACTECAL trial is a Phase II/III adaptive trial to evaluate the safety and efficacy of 6-month regimens that contain bedaquiline, pretomanid and linezolid, with or without moxifloxacin or clofazimine, for the treatment of adults with MDR-TB or XDR-TB. The trial is funded by MSF and will be conducted in Belarus, Uzbekistan, and potentially in countries in southern Africa. The NeXT study is an open label trial of a 6–9 month injection-free regimen containing bedaquiline, ethionamide or high-dose isoniazid, linezolid, levofloxacin, and pyrazinamide, compared with the WHO-recommended 1 Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a Phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet. 2015;385(9979):1738–1747. 12-month shorter regimen for MDR-TB treatment. Recruitment started in South Africa in 2016. 8.2.4 Treatment of latent TB infection Several studies evaluating shorter regimens for LTBI are being implemented, particularly for prevention of LTBI in people living with HIV. ACTG A5279 is evaluating the safety and effectiveness of ultra-short-course rifapentine or isoniazid (or both) for the prevention of active TB in HIV-positive people with LTBI. Rifapentine (at a dosage based on weight) in combination with 300 mg of isoniazid for 1 month is being compared with 300 mg of isoniazid for 9 months. Results are expected in the last quarter of 2017. The “Weekly High dose Isoniazid and rifapentine (P) Periodic Prophylaxis for TB” trial, known as WHIP3 TB, is due to start by the end of 2016. It will evaluate a 3-month regimen of high dose rifapentine plus isoniazid for people living with HIV, administered either as a single round or given annually. It will be implemented in South Africa, Mozambique and Ethiopia, in two parts. Part A will compare a single round of weekly high dose rifapentine plus isoniazid for three months (3HP) to six months of daily isoniazid (6H); Part B will compare periodic 3HP (p3HP) to a single round of 3HP. Two trials to investigate drugs or regimens for the prevention of TB in contacts of MDR-TB patients are being implemented or are planned. The V-QUIN MDR study is assessing 6 months of daily levofloxacin for household contacts of patients with MDR-TB. It is being conducted in Viet Nam and recruitment started in March 2016. The TB- CHAMP study is a multicentre trial to evaluate the efficacy of levofloxacin in children aged 0–5 years who are household contacts of MDR-TB cases. It is due to start in South Africa in October 2016. 8.3 New vaccines to prevent TB Both the slow decline in TB incidence globally and the persistent threat of MDR-TB highlight the critical need for new TB vaccines that are more effective than the Bacille- Calmette-Guérin (BCG) vaccine in preventing TB. The status of the pipeline for new vaccines in August 2016 is shown in Fig. 8.3. The pipeline includes recombinant BCGs, whole-cell derived vaccines, recombinant viral-vectored platforms, protein and adjuvant combinations, and mycobacterial extracts. These vaccines aim either to prevent infection (pre-exposure) or to prevent primary progression to disease or reactivation of LTBI (post-exposure). Further details are provided below. 8.3.1 Phase II and Phase III clinical trials There are currently eight vaccines in Phase II or Phase III trials. M72/AS01E M72/AS01E is made by GlaxoSmithKline (GSK) and is a recombinant fusion protein of the M. tuberculosis antigens 128 :: GLOBAL <strong>TUBERCULOSIS</strong> REPORT 2016
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GLOBAL REPORT TUBERCULOSIS 2016
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WHO Library Cataloguing-in-Publicat
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:: Abbreviations aDSM AE AIDS ART A
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The principal source of financial s
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Zhumagali Ismailov, Sarah Jackson,
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:: Executive Summary Background The
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TB prevention services South Africa
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Chapter 1 :: Introduction Tuberculo
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:: Box 2.1 The Sustainable Developm
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:: Box 2.3 The End TB Strategy at a
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:: TABLE 2.1 Top 10 indicators (not
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TABLE 2.2 :: The three TB high-burd
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Chapter 3 :: TB disease burden :: K
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:: Box 3.1 The WHO Global Task Forc
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:: Box 3.2 Updates to estimates of
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:: Box 3.3 Updated and interim esti
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:: FIG. 3.1 Strengthening national
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:: TABLE 3.2 Estimated epidemiologi
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:: FIG. 3.3 Estimated TB incidence
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:: FIG. 3.5 Global trends in the es
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:: FIG. 3.8 Trends in estimated TB
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:: FIG. 3.10a Top causes of death w
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:: FIG. 3.14 Trends in estimated TB
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:: FIG. 3.16 Data sources available
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:: TABLE 3.5 Estimated incidence of
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:: FIG. 3.20 Estimated incidence of
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:: FIG. 3.22 Global progress in imp
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:: TABLE 3.6 Number of TB cases fou
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:: TABLE 3.7 HIV-negative and HIV-p
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:: FIG. 3.29a The prevalence:notifi
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:: FIG. 3.31b The average CFR by st
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SIM and SINAN case-based databases,
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Prompt and accurate diagnosis of tu
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:: FIG. 4.2 New and relapse TB case
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:: FIG. 4.5 Percentage of new and r
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:: FIG. 4.8 Global numbers of notif
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:: TABLE 4.4 National guidance in p
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:: FIG. 4.9 Percentage of bacteriol
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:: FIG. 4.12 Number of MDR/RR-TB ca
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:: FIG. 4.14 Case notification rate
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:: FIG. 4.16a The ten countries wit
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:: Box 4.5 Community contributions
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:: FIG. 4.18 Estimated ART treatmen
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Page 90 and 91: :: FIG. 4.22 Treatment outcomes for
Page 92 and 93: :: Box 4.6 Active TB drug-safety mo
Page 94 and 95: Prevention of new infections of Myc
Page 96 and 97: :: TABLE 5.2 TB preventive treatmen
Page 98 and 99: :: TABLE 5.3 Provision of TB preven
Page 100 and 101: :: FIG. 5.5 Coverage of BCG vaccina
Page 102 and 103: This chapter aims to provide a tube
Page 104 and 105: :: FIG. 6.2 Government spending on
Page 106 and 107: :: Box 6.1 Implications for TB of e
Page 108 and 109: :: Box 6.2 Innovations in engaging
Page 110 and 111: :: Box 6.4 Reforming systems to exp
Page 112 and 113: :: TABLE 6.1 TB patient social supp
Page 114 and 115: :: FIG. 6.5 Surveys of costs faced
Page 116 and 117: :: TABLE 6.3 Status of selected SDG
Page 118 and 119: Continue current trend (base case s
Page 120 and 121: can provide insights into progress
Page 122 and 123: lion, most (US$ 4.4 billion, 67%) i
Page 124 and 125: :: Box 3.2 Updates to estimates of
Page 126 and 127: :: FIG. 7.5 Funding for NTP budgets
Page 128 and 129: :: Box 7.2 International donor fund
Page 130 and 131: :: FIG. 7.6 Reported funding gaps f
Page 132 and 133: :: Box 7.3 Methods used to estimate
Page 134 and 135: :: Box 8.1 WHO’s Global Action Fr
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Page 140 and 141: :: FIG. 8.3 The development pipelin
Page 142: Annex 1 Access to the WHO global TB
Page 145 and 146: A data dictionary that defines each
Page 147: Annex 2 Country profiles :: FOR 30
Page 150 and 151: Bangladesh population 2015 :: 161 m
Page 152 and 153: China population 2015 :: 1 376 mill
Page 154 and 155: Democratic Republic of the Congo po
Page 156 and 157: India population 2015 :: 1 311 mill
Page 158 and 159: Kenya population 2015 :: 46 million
Page 160 and 161: Myanmar population 2015 :: 54 milli
Page 162 and 163: Pakistan population 2015 :: 189 mil
Page 164 and 165: Russian Federation population 2015
Page 166 and 167: Thailand population 2015 :: 68 mill
Page 168: Viet Nam population 2015 :: 93 mill
Page 171 and 172: Central African Republic population
Page 173 and 174: Lesotho population 2015 :: 2.1 mill
Page 175 and 176: Namibia population 2015 :: 2.5 mill
Page 177 and 178: Sierra Leone population 2015 :: 6.5
Page 179 and 180: Zimbabwe population 2015 :: 16 mill
Page 182 and 183: WHO African Region WHO MEMBER STATE
Page 184 and 185: WHO Eastern Mediterranean Region WH
Page 186 and 187: WHO South-East Asia Region WHO MEMB
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Annex 4 TB burden estimates, notifi
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:: TABLE A4.1 TB incidence estimate
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:: TABLE A4.1 Table TB incidence A4
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:: Table TABLE A4.2 A4.2 Estimates
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Table :: TABLE A4.2 A4.2 Estimates
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:: TABLE A4.3 Measured percentage o
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:: TABLE A4.3 Measured Table A4.3 p
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:: TABLE A4.4 TB case notifications
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:: TABLE A4.4 TB case notifications
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:: TABLE A4.5 Treatment outcomes by
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:: TABLE A4.5 Treatment outcomes by
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ISBN 9 789241 565394 Ending TB by 2
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