Global Tuberculosis Report -- 2012.pdf

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cal trial sites and building laboratory and pharmacologyresearch capacity; efforts are coordinated with otherclinical trial networks to optimize efforts to develop newcombination regimens. The Critical Path to New TB DrugRegimens initiative, whose goal is to accelerate the developmentof novel regimens that will shorten TB treatment,is also an important example of a global effort to ensurethat the necessary trials can be implemented. 18.3 New vaccines to prevent TBThe BCG (Bacille-Calmette-Guérin) vaccine for the preventionof TB is almost 100 years old. The vaccine protectsagainst severe forms of TB in children (TB meningitis andmiliary TB), but its efficacy in preventing pulmonary TBin adults is highly variable. BCG is not recommendedfor use in infants known to be infected with HIV, dueto the risk of disseminated BCG disease. Historic opportunitiesfor developing new TB vaccines arose duringthe 1990s, following the development of techniques forgenetic manipulation of mycobacteria and completion ofthe genome sequence of M. tuberculosis.Two different approaches are being used to developTB vaccines for prevention of TB. 2 The first approach isto develop vaccines that would do better than BCG andreplace it – such as an improved version of BCG or anew attenuated live M. tuberculosis vaccine. The secondapproach is to develop a “prime-boost” strategy in whichBCG continues to be given to neonates (as now), since itprevents TB in infants and children, and give the newvaccine as a “booster” dose at a later stage. Alternatively,the new vaccine would be delivered to infants alongsideother vaccines at 3–9 months of age and as a separatebooster in young adults. The vaccine candidates currentlyunder development could be used to prevent either infection(pre-exposure), or to prevent primary progression todisease or reactivation of latent TB (post-exposure). Workis also being carried out to develop vaccines that couldbe used as immunotherapeutic agents, i.e. to improveresponsiveness to chemotherapy.The status of the pipeline for new vaccines in July 2012is shown in Figure 8.3. Of the 12 vaccine candidates inclinical trials, 11 are for prevention of TB and one is animmunotherapeutic vaccine.MVA85A is an attenuated vaccinia-vectored vaccinecandidate designed as a booster vaccine for infants, adolescentsand adults. Among existing vaccine candidatesfor TB prevention, it is the one that is most advanced interms of clinical testing. The first Phase IIb trial of thisvaccine was conducted in South Africa from 2009 to2011, with 2797 infants enrolled. Results are expected inearly 2013, and will provide the first efficacy data of aBOX 8.3Testing the new drug regimen PaMZ(NC-001): progress by mid-2012Novel anti-TB drug regimens could transform therapy byshortening and simplifying the treatment of both drugsensitiveand drug-resistant TB with the same oral regimen.Novel regimens for treatment of MDR-TB have the potential tobe much less expensive than currently recommended therapies(since they include fewer drugs and treatment duration isshorter), fostering expansion of treatment globally.NC-001 – also known as New Combination 1 – is a trial of anovel TB regimen that includes the drug candidate PA-824combined with moxifl oxacin and the standard fi rst-line anti-TB drug, pyrazinamide (PaMZ). The trial is being conductedin partnership with and sponsored by the TB Alliance. Theregimen has been tested for early bactericidal activity againstpulmonary TB over a 2-week period, with encouraging results. 1The regimen had bactericidal activity at least comparableto a standard regimen of isoniazid (H), rifampicin (R),pyrazinamide (Z) and ethambutol (E). This study also validateda new approach to the development of new anti-TB drugregimens, which has the potential to reduce the time requiredto complete clinical trials from decades to years. Research onNC001 has also included testing of some novel combinationsof two drugs that may form the “core” of future regimens, thusinforming other clinical trials being planned during the next 18months and beyond.The testing of the PaMZ regimen advanced to a 2-month trial(called NC-002) in March 2012. In this trial, carried out inBrazil, South Africa and the United Republic of Tanzania, PaMZis being tested for patients with drug-sensitive TB and patientswith drug-resistant TB who are sensitive to the drugs includedin the new regimen. The NC-002 trial is a landmark trial: it isthe fi rst to simultaneously investigate treatment of both drugsensitiveand drug-resistant disease using the same regimen.Results are expected in the third quarter of 2013.1Diacon AH et al. 14-day bactericidal activity of PA-824, bedaquiline,pyrazinamide, and moxifl oxacin combinations: a randomised trial.Lancet, 2012;380(9846):986-93.1http://www.c-path.org/CPTR.cfm2Kaufmann SHE, Hussey G, Lambert PH. New vaccines fortuberculosis. Lancet, 2010, 375:2110–2119.GLOBAL TUBERCULOSIS REPORT 2012 87
FIGURE 8.3 The development pipeline for new vaccines, July 2012Phase I Phase II Phase IIbPhase IIIAdAg85AMcMaster UniversityP B PIHybrid-I+CAF01with Statens SerumInstitute (SSI),Tuberculosis VaccineInitiative (TBVI)P B PIH56+IC31Statens Serum Institute(SSI), Aeras, IntercellP B PIHyvac 4/AERAS-404+IC31with Statens SerumInstitute (SSI), SanofiPasteur, Aeras, IntercellBID93Infectious DiseaseResearch Institute(IDRI), AerasB PI itM72+AS01GlaxoSmithKline (GSK),AerasB PIVPM 1002Max Planck, VakzineProjekt Mgmt,Tuberculosis VaccineInitiative (TBVI)P BHybrid-1+IC31Statens Serum Institute(SSI), TuberculosisVaccine Initiative(TBVI), European andDeveloping CountriesClinical Trials (EDCTP),IntercellP B PIRUTIArchivel Farma, S.L.B PI itMVA85A/AERAS-485Oxford-EmergentTuberculosis Consortium(OETC), AerasB PI itAERAS-402/Crucell Ad35Crucell, AerasBMw [M. indicus pranii(MIP)]Department ofBiotechnology (India),M/s. CadilaitP Prime B Boost PI Post-infection it ImmunotherapyTB Vaccine Types Viral-vectored: MVA85A, AERAS-402, AdAg85AProtein/adjuvant: M72, Hybrid-1, Hyvac 4, H56, ID93rBCG: VPM 1002Killed WC or Extract: Mw, RUTISource: Stop TB Partnership Working Group on New VaccinesBOX 8.4Tuberculosis vaccines: a strategic blueprintResearch into TB vaccines is at a pivotal moment as focus shifts from the discovery of novel approaches and moving new vaccinecandidates from the laboratory to early clinical trials to building on the progress that has already been made. This includes learning fromthe effi cacy of vaccine candidates in clinical development, establishing much-needed markers and correlates of immune protection thatwill help to identify the next generation of vaccine candidates, and laying the groundwork for the licensure and distribution of new TBvaccines.In March 2012, the Stop TB Partnership’s Working Group on New TB Vaccines published Tuberculosis vaccines: a strategic blueprint. Thischarts the future course of TB vaccine research and is intended as guidance for researchers, regulators, advocates, donors, policy anddecision-makers, among other stakeholders. The blueprint outlines the major scientifi c challenges and priorities, critical activities andcrucial questions that need to be addressed to develop life-saving TB vaccines in fi ve key priority areas:■ Creativity in research and discovery. The major question to be answered is why certain individuals infected with M. tuberculosis areresistant to TB disease.■ Correlates of immunity and biomarkers for TB vaccines. Here, the focus is on identifying correlates of immunity for TB vaccines.■ Clinical trials: harmonization and cooperation. The main question to be addressed is whether TB vaccines can effectively reduce thetransmission of M. tuberculosis.■ Rational selection of TB vaccine candidates. This priority area tackles the challenge of having all developers of vaccines agree tostandardized criteria for the selection and development of novel TB vaccines.■ The critical need for advocacy, community acceptance and funding. Here, the emphasis is on innovative approaches to mobilizingfunding for TB vaccines.The blueprint is designed to initiate a renewed, intensifi ed and well-integrated international effort to develop TB vaccines that will have asignifi cant impact on global TB control.The complete blueprint, including relevant opinion editorials, is available at http://www.stoptb.org/wg/new_vaccines/88 GLOBAL TUBERCULOSIS REPORT 2012
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GLOBALTUBERCULOSISREPORT2012
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ContentsAbbreviationsivAcknowledgem
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AcknowledgementsThis report on glob
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WHO Western Pacific RegionShalala A
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Executive SummaryThe World Health O
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CHAPTER 1IntroductionBOX 1.1Basic f
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TABLE 1.1 Targets for the scale-up
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TABLE 1.2 Reporting of data in the
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BOX 2.1Uncertainty in estimates of
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TABLE 2.2 Estimated burden of disea
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FIGURE 2.5 Estimated TB incidence r
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FIGURE B2.2.1Reporting of notificat
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FIGURE 2.8Estimated TB incidence ra
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FIGURE 2.11 Countries (in blue) for
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FIGURE 2.12 Trends in estimated TB
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● producing and widely disseminat
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FIGURE 2.16 Progress in global cove
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BOX 2.6Efforts by the Task Force to
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CHAPTER 3TB case notificationsand t
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BOX 3.1 1Definitions of TB casesDef
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TABLE 3.3 Contribution of public-pr
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BOX 3.4Integrating community-based
Page 46 and 47: TABLE 3.4 Estimates of the case det
Page 48 and 49: TABLE 3.5 Treatment success for new
Page 50 and 51: CHAPTER 4Drug-resistant TBKEY FACTS
Page 52 and 53: FIGURE 4.2 Percentage of new TB cas
Page 54 and 55: BOX 4.1Frequencies of resistance to
Page 56 and 57: FIGURE 4.6 Number of MDR-TB cases e
Page 58 and 59: FIGURE 4.7Notified cases of MDR-TB
Page 60 and 61: egimens globally, providing more su
Page 62 and 63: 5.1 Funding for TB care and control
Page 64 and 65: TABLE 5.2 NTP budgets, available fu
Page 66 and 67: FIGURE 5.5Trends in domestic and do
Page 68 and 69: FIGURE 5.6Domestic funding as a per
Page 70 and 71: FIGURE 5.8Cost per TB patient succe
Page 72 and 73: FIGURE 5.10 Total cost and unit cos
Page 74 and 75: ● The 14 countries not included i
Page 76 and 77: on public health by an external Exp
Page 78 and 79: evised as a result of the introduct
Page 80 and 81: TABLE 6.2 Incorporation of WHO poli
Page 82 and 83: FIGURE 6.3The Supranational Referen
Page 84 and 85: of TB disease by 65%, irrespective
Page 86 and 87: FIGURE 7.3Percentage of TB patients
Page 88 and 89: BOX 7.1Accelerating progress in pro
Page 90 and 91: TABLE 7.2 Assumptions used to estim
Page 92 and 93: FIGURE 8.1 The development pipeline
Page 94 and 95: sputum specimens and TB isolates fr
Page 98: new TB vaccine candidate. A Phase I
Page 102 and 103: This annex explains the methods tha
Page 104 and 105: 2011. On average, 15 data points we
Page 106 and 107: may suffer from biases. These biase
Page 108 and 109: TABLE A1.3Parameter estimates used
Page 110 and 111: 5. Estimates of TB prevalence, 1990
Page 112: the Republic of Moldova, Romania, t
Page 116 and 117: AFGHANISTANPopulation 2011 32 milli
Page 118 and 119: BRAZILPopulation 2011 197 millionHI
Page 120 and 121: CHINAPopulation 2011 1 348 millionH
Page 122 and 123: ETHIOPIAPopulation 2011 85 millionH
Page 124 and 125: INDONESIAPopulation 2011 242 millio
Page 126 and 127: MOZAMBIQUEPopulation 2011 24 millio
Page 128 and 129: NIGERIAPopulation 2011 162 millionH
Page 130 and 131: PHILIPPINESPopulation 2011 95 milli
Page 132 and 133: SOUTH AFRICAPopulation 2011 50 mill
Page 134 and 135: UGANDAPopulation 2011 35 millionHIG
Page 136 and 137: VIET NAMPopulation 2011 89 millionH
Page 138: ANNEX 3Regional profiles
Page 141 and 142: WHO REGION OF THE AMERICASPopulatio
Page 143 and 144: WHO EUROPEAN REGIONPopulation 2011
Page 145 and 146: WHO WESTERN PACIFIC REGIONPopulatio
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SUMMARY BY WHO REGIONTable A4.1 Est
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MORTALITY (EXCLUDING HIV) PREVALENC
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NEW AND RELAPSENOTIFICATION RATE aY
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-% OF TB PATIENTS WITHKNOWN HIV STA
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AFRICAN REGIONTable A4.1 Estimates
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INCIDENCE (INCLUDING HIV) INCIDENCE
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NEW AND RELAPSENOTIFICATION RATE aY
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NEW AND RELAPSENOTIFICATION RATE a1
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TREATMENT SUCCESS (%) a1995-2010YEA
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YEARTOTALCONFIRMEDCASES OFMDR-TB aE
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MALEYEAR 0-14 15-24 25-34 35-44 45-
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REGION OF THE AMERICASTable A4.1 Es
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% OF COHORTTREATMENT SUCCESS (%) a1
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MALEFEMALEYEAR 0-14 15-24 25-34 35-
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EASTERN MEDITERRANEAN REGIONTable A
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EUROPEAN REGIONTable A4.1 Estimates
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SOUTH-EAST ASIA REGIONTable A4.1 Es
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SMEAR LABS % OF SMEARPER 100K LABS
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Estimates of mortality, prevalence
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YEARPOPULATION(MILLIONS)MORTALITY (
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YEARPOPULATION(MILLIONS)INCIDENCE (
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YEARPOPULATION(MILLIONS)INCIDENCE (
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SMEAR LABS % OF SMEARPER 100K LABS
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