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"What Will It Take To Control TB?" Richard Chaisson, MD

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Dr. Richard Chaisson, Professor of Medicine, Epidemiology and International Health and Director of the Center for Tuberculosis Research at the Johns Hopkins University in Baltimore was the keynote …

Dr. Richard Chaisson, Professor of Medicine, Epidemiology and International Health and Director of the Center for Tuberculosis Research at the Johns Hopkins University in Baltimore was the keynote Jan. 19 as part of the Washington Global Health Discovery Series. His talk was on ""What Will It Take To Control TB?"

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  • 1. What Can Be Done to Control Tuberculosis? Richard E. Chaisson, MD Center for Tuberculosis Research Johns Hopkins University
  • 2. A History of TB Control: Mission Accomplished? • 1882 – Koch discovers the tubercle bacillus* • 1907 – von Pirquet adapts Koch’s tuberculin • 1919 – Calmette and Guerin produce BCG vaccine • 1943 – Schatz and Waksman discover streptomycin* • 1948 – BMRC trial of streptomycin vs bed rest • 1952 – Development of INH • 1966 – Development of rifampin • 1978 – Short-course TB therapy  6 months *Awarded Nobel Prize
  • 3. Federal Funding for Tuberculosis Research and Control, 1962 - 1990 BR Bloom and CJL Murray, Science 1992;257:1055-64
  • 4. Reported Tuberculosis Cases in the United States, 1953 - 1999 80000 Number of cases (log scale) 40000 20000 1950 1960 1970 1980 1990 2000 Year of notification Centers for Disease Control and Prevention Reported Tuberculosis in the United States, 1999
  • 5. Estimated Global Incidence of Tuberculosis, 1990 - 2005 140 Cases per 135 100,000 130 125 120 1990 1995 2000 2005 WHO 2007
  • 6. WHO Estimates of Global Burden of Tuberculosis as of December 31, 2008 Estimated Estimated number of number of cases deaths All forms of TB 9.4 million 1.3 million* MDR-TB 511,000 ~150,000 XDR-TB 50,000 30,000 *excludes 500,000 HIV-TB deaths
  • 7. TB Incidence in Africa, 1990 and 2005 Chaisson and Martinson, N Engl J Med 2008;358:1089
  • 8. XDR TB outbreak in Tugela Ferry, South Africa Survival of XDR TB Patients at the Church of Scotland Hospital (N=53) 1.1 1.0 .9 .8 Proportion Surviving .7 .6 .5 .4 .3 .2 .1 0.0 -.1 0 30 60 90 120 150 180 210 240 Days since Sputum Collected Gandhi et al., Lancet 2006; 368:1575-80
  • 9. TB in HIV+ Patients at Chris Hani Baragwanath Hospital, Soweto, South Africa – TB admissions 2005-2008: • 6500-6800 per year • 18-20 new cases per day – 85% HIV+ – >90% fully drug susceptible – Inpatient mortality = 18% • ~1200 deaths per year from drug-susceptible TB Edgington et al., Int J Tuberc Lung Dis 2006;10:1018; ML Wong, pers. comm.; Martinson et al., AIDS. 2007;21:2043 Shah et al., JAIDS 2009, epub
  • 10. Tools to Control of Tuberculosis What went wrong? • Failure to apply tools broadly – Weaknesses in health systems • Inadequacies of existing tools – Smear detection of cases ~50% – Adherence to regimens is very poor – BCG vaccine does not prevent adult TB • Changing epidemiological situation – HIV epidemic and other co-morbidities – MDR • Lack of understanding of best epidemiologic approaches
  • 11. An Epidemiological Model of Tuberculosis in the United States INFECTED Step 1 CASES Infected Step 4 Cases Step 2 Step 3 UNINFECTED Ferebee, SH. Natl Tuberc Assoc Bull 1967;53:4
  • 12. An Epidemiological Model of Tuberculosis in the United States INFECTED Interventions to control TB Step 1 Find and treat cases: Steps 2 and 4 Treat latent TB: Steps 1 and 3 Vaccinate susceptible: Step 2 CASES Step 4 Step 2 Step 3 UNINFECTED Ferebee, SH. Natl Tuberc Assoc Bull 1967;53:4
  • 13. The Kolin Study of Tuberculosis Control with Mass Case Finding and Treatment Mass case finding Type 1960 1961 1962 1963 1964 New Cases 46 132 61 88 47 Relapses 29 25 18 13 16 Chronic 29 40 17 11 8 Other 26 26 42 14 20 Total 150 233 138 126 91 Rates per 100,000 Population “It is concluded from the study that in developed countries priority should be given to adequate treatment of all persons with active tuberculosis, and to early diagnosis in persons consulting physicians and in the high-risk populations.” Styblo et al., Bull WHO 1967;37:819-74
  • 14. World Health Organization Strategies for Tuberculosis Control, 1974 – present • Passive case detection and treatment – DOTS targets added in 1991 • 70% case detection, 85% cure rate • BCG vaccination of all children at birth • Isoniazid preventive therapy for young children exposed to smear-positive cases (PPD+)
  • 15. Epidemiologic Basis for TB Control Key Considerations for Strategies • Where are the seedbeds of tuberculosis? – Who has latent TB infection? – Who amongst these is most likely to develop disease? • Who has active TB and how can they be reached? – What proportion of cases are detected, and when? – Is treatment effective in controlling spread? • Where is TB transmission occurring, and how can it be curtailed? – Who are the contacts of cases who become infected? – What measures can be taken to reduce transmission? • What can be done to reduce susceptibility? – Vaccination – Antiretrovirals – Control of co-morbidities, e.g., diabetes
  • 16. The Origin of TB Cases: Prevalence of Risk Factors in Patients with Culture-Confirmed Pulmonary TB in Baltimore Characteristic No. (Total = 139) % Foreign born 12 9% HIV Infection 31 24% IDU 28 20% Diabetes 18 14% Renal Failure 12 9% Recent Cancer 8 6% Steroid Use 7 6% Oursler et al., CID 2002;34:729-9
  • 17. TB Incidence and Prevalence of Diabetes, 2010 and 2030 Dooley and Chaisson, Lancet Infect Dis, 2009; 9: 737–46
  • 18. Smoking and incident TB in HIV-infected adults in Soweto, South Africa Pack Pack years Incidence IRR years Incidence IRR 6.5 6.7 <1 REF Never REF (5.9-7.4) (6.0-7.6) 9.0 1.36 7.8 1.15 1-5 Past (6.8-11.7) (1.01-1.82) (5.8-1.2) (0.9-1.55) 12.8 1.95 10.7 1.59 >5 Current (9.7-16.7) (1.44-2.60) (8.4-13.4) (1.21-2.05) Martinson et al CROI 2008
  • 19. Biomedical Tools and Public Health Control of infectious diseases requires: - effective biomedical tools (diagnostics, drugs and vaccines) and - effective public health strategies for applying and utilizing the tools at the population level to reduce disease burden
  • 20. Current Tools for Controlling TB Target Available tools Diagnostics Sputum smear, culture, x-rays, (molecular assays) Drugs Isoniazid, rifampin, PZA, ethambutol, 2nd line drugs Vaccine BCG (>10 strains)
  • 21. Current Strategies for Controlling TB • Passive case finding (DOTS) – Relying on sputum smear (~50% sensitivity) – No drug susceptibility testing – Most cases not diagnosed or effectively treated • INH preventive therapy – Rarely used outside US and Europe • BCG Vaccination – Most widely used vaccine, but not effective • Infection control – Little attention has been paid to controlling transmission
  • 22. A Platform for Controlling Global Tuberculosis • FIND the TB that is there – Passive case detection is not sufficient • TREAT the TB that is found – Treatment success is unacceptably low – Treatment for M/XDR is abysmal – New drugs and treatment strategies urgently needed • Prevent the TB that hasn’t occurred yet – Preventive therapy essential for high risk populations – Infection (transmission) control critical – Control susceptibility (antiretrovirals, diabetes control) – New vaccine essential
  • 23. FIND TB • Identify TB suspects – Symptomatic screening in health facilities – Campaigns to identify prevalent cases • Community-based active case finding • Evaluate TB suspects – Better use of existing technologies – New technologies
  • 24. Estimated TB case detection rates in 2008, by WHO region 90 78 78 Case detection rate (%) 80 70 70 65 57 60 47 50 40 30 20 10 0 a a R pe fic as ic si EM ic ro ci fr A er Pa A Eu st m Ea rn A te th es u So W WHO 2009 EMR = Eastern Mediterranean Region
  • 25. Routine detection of TB in HIV-infected patients in Vietnam and Thailand Diagnosis N detected/N Percent Any TB 147//1060 14% Pulmonary only 61/147 42% Extrapulmonary only 21/147 14% Both 65/147 44% Pulmonary Cases Smear + 47/126 37% Liquid culture + 124/126 98% Lymph node aspirates Smear + 16/52 31% Culture + 34/82 42% Monkongdee et al., AJRCCM 2009, epub
  • 26. Outside the HIV Clinic: Prevalence of Active TB with Case Finding in HIV-Infected Populations Setting Time Prevalence of Active TB Population Studied Period in Population HIV+ Women in HIV MTCT Soweto 2001 13% OF TST+ Program South 3% overall (N=438) Africa Patients in HIV Home Care Phnom 2001 9% of patients Program (N=441) Penh Adults in HIV VCT Program Cape 2000-1 8% of HIV+ (N=5000) Town Adult residents of an urban Cite Soleil 1991-2 6% of HIV+ shantytown Haiti 2% of HIV– (N=10,900) Nachega 2003; Kimerling 2002; Coetzee 2005; Desourmeaux 1996
  • 27. Should we consider campaigns to detect prevalent, untreated TB cases?
  • 28. Impact of mass radiography on TB case detection, incidence and survival • 1945-1948 – USPHS screened 6 million people in 21 communities with CXR – 85-90% of cases unknown to local health depts. – TB mortality decreased significantly • 1950’s – USPHS used mass x-ray on ships, trains, airplanes and dog sleds to screen Alaskan natives – Tuberculosis mortality declined • 665/100,000 in 1950 • 116/100,000 in 1957 Golub et al., Active case finding of tuberculosis: historical perspective and future prospects. IJTLD 2005;9:1183
  • 29. Rocinha favela, Rio de Janeiro
  • 30. A cluster-randomized trial of door-to-door active case finding for TB in Rio de Janeiro (14 clusters, 58,587 residents) Analysis Time Household Pamphlet Rate ratio Case Finding Only (95% CI) TB incidence TB incidence Intervention only 9.34/1000 py 6.04/1000 py 1.55 (1.10, 1.99) Intervention plus 5.16/1000 py 4.93/1000 py 1.05 (0.56, 1.54) 60 days Post-intervention Pre-intervention Rate ratio TB incidence TB incidence (95% CI) Entire Study 4.5/1000 py 3.4/1000 py 1.3 (0.97, 1.77) Miller et al., IJTLD in press
  • 31. Availability of culture and drug susceptibility testing in TB/HIV high-burden countries Country Culture Drug Susceptibility Testing N of Labs N per 5 million N of Labs N per 10 million South Africa 15 1.5 10 2.1 Nigeria 2 0.1 1 0.1 Ethiopia 1 0.1 1 0.1 DR Congo 1 0.1 1 0.2 Kenya 5 0.7 1 0.3 Tanzania 3 0.4 1 0.2 Uganda 3 0.5 2 0.6 Zimbabwe 1 0.4 1 0.7 Mozambique 1 0.2 1 0.5 Cambodia 3 1.0 1 0.7 WHO Global TB Report, 2009
  • 32. New TB Diagnostic Tools • LED fluorescent microscopy • Liquid culture (e.g. MGIT) • Capilia TB – Rapid strip test that detects a TB-specific antigen from culture • Molecular assays (e.g. Cepheid GeneXpert, Hain GenoType MTBDRplus) – Rapid detection of TB and drug-resistance
  • 33. Impact of Improving Case Finding and Treatment on Tuberculosis Control: A Mathematical Model 1000 TB Incidence, per 100,000 900 800 700 600 0.0% 500 -1.0% -0.3% 400 -2.1% -1.5% 300 -0.3% -2.8% -1.8% 200 -0.7% -3.4% -2.5% -1.0% 100 -11.2% -2.9% -1.4% -0.8% -0.7% -4.2% 0 -0.6% -4.6% -3.3% 0 20 40 60 80 100 Year/Case Detection Rate (%) Increase CDR to 70% immediately, then hold Hold CDR constant constant Increase CDR by 1%/year 22 High burden countries Increase CDR by 2%/year Dowdy and Chaisson, Bull WHO 2009: 87:296–304
  • 34. TREAT TB • Assure treatment completion for all patients • Prevent the emergence of drug resistance • Manage co-morbidities – HIV, diabetes, ESRD, IDU • New drugs to improve therapy – M/XDR TB treatment – Treatment-shortening regimens
  • 35. Rocinha Family Health Program Community Health Worker Team
  • 36. Results of DOTS: Health Center-Based versus Community-Based using CHWs DOTS at Health Center DOTS CHWs N= 565 N=331 Non-slum Patients Slum Patients Slum Patients Cure, all cases 272/355 (77%) 165/210 (78%) 288/331 (87%) Cure, new cases 236/289 (82%) 138/164 (84%) 230/261 (88%) Cure, new smear + 106/134 (79%) 82/98 (84%) 135/153 (88%) cases Cure, retreatment 36/66 (55%) 27/46 (59%) 58/70 (83%) cases Abandoned 39/355 (11%) 27/210 (13%) 16/331 (5%) Cavalcante et al., Int J TB Lung Dis 2007;11:544-9
  • 37. New Drugs for TB • Fluoroquinolones – Moxifloxacin • Rifapentine • TMC 207 (ATP synthase inhibitor) – In Phase 2 trials for MDR TB in Africa • Nitroimidazopyrans – PA-824 – OPC-67683 • Phase 2 trial for MDR TB beginning in January 2008 • Diamines (SQ-109) – Phase 1 studies complete, awaiting Phase 2 • Oxazolidinones • >12 other new compounds in development
  • 38. Moxifloxacin vs. Ethambutol as 4th Drug in Initial Phase of TB Therapy: Culture Conversion by Week MOX EMB 100 0.02 0.14 80 0.30 0.01 0.01 % Culture 60 0.0001 Negative 40 0.001 0.04 20 0 0 1 2 3 4 5 6 7 8 Week of Treatment Conde et al., Lancet 2009; 373:1183-9
  • 39. Bactericidal activity of daily regimens in mice 8 R10H25Z150 RIF10 INH PZA 7 Log10 CFU per lung R10M100Z150 RIF10 MOX PZA 6 2 logs P10M100Z150 RPT10 MOX PZA 5 4 3 4 2 logs 1 0 0 2 4 6 8 10 12 14 16 Weeks Rosenthal et al., PLoS Medicine 2007;4(12):e344
  • 40. TMC 207 for MDR TB Culture conversion at 2 months 8.7% culture negative 47.5% culture p = 0.003 negative Diacon et al., N Engl J Med 2009;360:2397
  • 41. PREVENT TB • TB preventive therapy for high-risk individuals without active TB • Contact evaluation and treatment • Prevention of nosocomial transmission
  • 42. Isoniazid Preventive Therapy: The (George) Comstock Lode
  • 43. TB Rates in the 6 Years After 1-year of Treatment with INH or Placebo in the Bethel Trial 16 14 TB per 1,000 PY 12 10 Placebo 8 INH 6 4 2 0 1 2 3 4 5 6 Year After Randomization Cumulative reduction 5.1%  2.1% = 60% GW Comstock, Ferebee SH, Hammes LM.. Am Rev Respir Dis 1967;95:935-43.
  • 44. Efficacy of IPT in HIV+ Adults: Risk of TB • 11 randomised trials with 8,130 HIV+ participants  overall reduction in TB = 36%, reduction PPD+ = 62% Relative Risk (Fixed) 95% CI 1.0 Reference 0.64 TB incidence 0.95 Death Woldehanna and Volmink, Cochrane Review 2006
  • 45. TB screening, treatment and IPT 2002-2008 By 2008, 1 out of 4 estimated HIV positive TB patients were identified and put on TB treatment 1200.0 59 2002 1000.0 2003 2004 Thousands of patients 2005 800.0 2006 71 2007 600.0 2008 400.0 44 14 77 63 200.0 84 58 17 28 59 7 63 3 72 28 3 26 10 25 42 0.0 Screened for TB Diagnosed with TB IPT Data for 2008 is preliminary and does not include data from European region
  • 46. Infection Control?
  • 47. New paradigms • What can be done now to control TB in communities with high burdens of TB? • How can multiple interventions be combined to yield maximal effects?
  • 48. CREA E Mission To organize, implement and evaluate novel public health strategies to reduce tuberculosis incidence in populations with high rates of HIV and TB co-infection. Funded by the Bill and Melinda Gates Foundation
  • 49. The CREATE Portfolio of Population-Level Studies Study Intervention Design (N) Mass TB preventive Cluster randomized therapy for S.A. gold trial miners (~60,000) Intensified TB case Community finding, contact randomized trial evaluations in Zambia (~1.2 million) and S.A. Preventive therapy and Phased ARVs for HIV patients implementation trial in Rio de Janeiro (15,000)
  • 50. Prevalence of INH resistance after receiving IPT vs. controls without IPT 7/58 (12.1%) First episodes 12/200 (6.0%) 32/270 (11.8%) 1/13 (7.7%) Retreatment episodes 14/75 (18.7%) van Halsema, IAS 2009
  • 51. ZAMSTAR • 24 communities in South Africa and Zambia • Designed to reduce TB prevalence through – improved TB case finding by increased access to TB diagnostics for symptomatic persons – Household interventions for families of TB patients, which include HIV testing and treatment, TB screening, and IPT for contacts of TB cases PIs: P. Godfrey-Faussett, H. Ayles, N. Beyers
  • 52. ZAMSTAR Preliminary Results • Baseline population surveys – TB prevalence 900/100,000 in Zambia and 2,200/100,000 in South Africa! • Enhanced Case Finding – 15-26% of all TB cases in intervention communities detected by ECF • Household evaluations – >2-5% of households have secondary TB case – ~50% contacts HIV tested • HIV prevalence high - ~50% • >50% HIV+ started on ART
  • 53. The THRio Study: A Clinic - Randomized Trial of INH Preventive Therapy in HIV+ Patients • 29 HIV clinics randomized to time that IPT program initiated • TB rates compared pre- and post- intervention 29 4 Control Clinic 3 Follow-up 2 Intervention 1 1 2 3 4 5 30 36 42 Month
  • 54. TB Rates by ART and INH Treatment Status, 2003-2005 Exposure Person- TB Incidence Rate Percent category Years Cases (per 100 PYs) Reduction No Rx 3,865 155 4.01 (3.40-4.69) - ART only 11,627 221 1.90 (1.66-2.17) 52% IPT only 395 5 1.27 (0.41-2.95) 68% Both 1,253 10 0.80 (0.38-1.47) 80% Total 17,140 391 2.28 (2.06-2.52) Golub et al., AIDS 2007;21:1441-8
  • 55. Tools and Strategies for Reducing the Global Burden of TB • Improved diagnostics ( case finding) – Better tests – Campaigns to find prevalent cases • Improved therapy ( treatment completion) – Shorter duration regimens to assure adherence – New drugs for MDR/XDR TB • Prevention – INH preventive therapy – Reduction of susceptibility (ART, diabetes, smoking) – Effective vaccine • Combination of approaches essential
  • 56. Lessons from Tuberculosis Control for Communicable Disease Control • Good biomedical tools are essential but not sufficient for disease control • Understanding the epidemiology and dynamics of the disease is essential for targeting interventions • Trials of control that measure population level impacts are important • It ain’t over till it’s over!
  • 57. With thanks to… Jonathan Golub Neil Martinson Ann Miller Peter Godfrey-Faussett Solange Cavalcante Gavin Churchyard Betina Durovni Liz Corbett Jacques Grosset Eric Nuermberger Larry Moulton The CREATE Team Marcus Conde Generous funders - BMGF David Dowdy NIH, CDC, FDA
  • 58. Thank you

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