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TB – Yesterday, Today and Tomorrow. Jerrold J. Ellner MD Boston University Sept 2013.

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TB – Yesterday, Today and Tomorrow


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    1. TB – Yesterday, Today and Tomorrow Jerrold J. Ellner MD Boston University Sept 2013

    2. “If the number of victims that a disease claims is the measure of its significance, then all diseases, particularly the most dreaded infectious diseases such as bubonic plague, Asiatic cholera, etc., must rank far behind tuberculosis.” - Robert Koch, 1882

    3. Short History of TB • 1882 – Koch discovers tubercle bacillus* • 1907 – von Pirquet adapts Koch’s tuberculin as diagnostic test • 1919 – Calmette & Guerin produce BCG vaccine • 1943 – Schatz and Waksman discover streptomycin* • 1948 – BMRC trial of streptomycin vs. bedrest • 1952 – development of INH • 1966 – development of rifampicin • 1978 – ‘short-course’ TB treatment (6 months) • 1990s- DOTS strategy

    4. Global TB 2010 • 8.8 million new cases – 1.1 HIV • 1.5 million deaths – 0.35 HIV • 0.65 MDR – 10% XDR = 3.4% new; 20% retreatment cases WHO Reports. 2011

    5. TB Cases

    6. Natural History of TB Re-expos 50% 5% (40%) Re-expos 5% (2-10%/y) Lancet Inf Dis 2008;8:601-11

    7. DIAGNOSIS OF ACTIVE TB TB diagnostics, 1882 TB diagnostics, 2010

    8. AFB (acid fast bacilli) smear AFB (shown in red) are tubercle bacilli

    9. 70 60 50 40 30 20 10 0 Proportion of Patients with Pulmonary TB with Positive AFB Smears AFB positivity in TB patients HIV uninf Early HIV Late HIV Similar for “classic” RUL infiltrate

    10. MGIT LJ PCR FM ZN 1+ 2+ 3+ 4+ 101 102 103 104 105 106 107 E-MTD sensitivity >95% smear (+); 75-90% smear (-) Amplicor sensitivity >95% smear (+); 60-70% smear (-) MMWR Jan 16, 2009

    11. NEJM. – published on-line Sept 1, 2010

    12. Xpert – MTB-RIF • One sample – 98% smear pos, 73% smear neg • Three samples – 100% smear pos, 90% smear neg • Specificity - 99% • Sensitivity MDR-TB – 97%

    13. GeneXpert rolled out as first-line diagnostic for TB in South Africa - 31 March 2011 "If a minister can do it, it can’t be that hard," said South African Health Minister Aaron Moatsoaledi, Demonstrating GeneXpert test for TB

    14. GeneXpert Xpert MTB/RIF 5 20 80 Samples per shift 500-1000

    15. IGRA v TST • Mtb specific antigens (ESAT-6, CFP-10, TB 7-7) • Higher specificity, correlation with exposure, less cross-reactivity BCG, non tuberculosis mycobacteria • One visit dx • TST not quality controlled application, reading

    16. TST v IGRA • Variable cut-point, risk stratification • Strong epi basis • Standard definitions, TST conversion, boosting • ? Less variability near cutpoint • Preferable for annual screening • Less expensive

    17. Diagnosis LTBI • TST first: if negative IGRA: immunocompromised, high risk, ?active TB if positive IGRA: BCG vaccinated, ?NTM

    18. Nature Rev Micro. 2009

    19. 393 Trancripts TB v LTBI v HC Nature. 2010

    20. Estimated HIV-TB Co-infection Prevalence, 2000 Rate per 100 000 < 5 5 - 9.9 10 - 99 100 - 999 1000 - 4999 5000 or more No estimate From presentation made by: Paul Nunn, WHO, Geneva, Durban 2002

    21. Accuracy of Determine TB-LAM, by CD4 96.6 98.3 63.9 % Sensitivity 69% for CD4 <50 Sensitivity 53% for CD4 50-100

    22. Rapid Dx TB-HIV AFB Smear Neg PTB • Xpert sens 62% • LAM sens 45% • LAM plus/then Xpert sens 79%

    23. Optimal timing of antiretroviral therapy in adults with untreated HIV-infection and new TB ART started within 2 weeks of TB tx improves survival in PTB patients with Adv. immunosupression; increased risk of IRIS

    24. Why is TB treatment duration so long?

    25. Hypothetical Model of TB Chemotherapy anatomic/metabolic populns of bacilli cavitary TB D. Mitchison A: rapidly multiplying, INH>RIF>EMB B: slowly multiplying, PZA>RIF>INH C: sporadically multiplying, RIF>INH A # bacilli B C 1 2 3 4 5 6 # months of therapy

    26. Drug-susceptible TB: strategies for shortening duration of treatment required for cure • Optimize the use of the drugs • in the regimen (RIF) • RIF at higher dose • RPT instead of RIF • Replace EMB (low potency) • with a more active drug (e.g. FQ) EMB PZA RIF RIF INH INH 1 2 3 4 5 6 Treatment month

    27. Bedaquiline (‘Sirturo’, from Johnson & Johnson) Addition of bedaquiline (vs. placebo) to a 5-drug MDR-TB regimen resulted in: • Faster culture conversion • Higher sputum culture conversion rate at 24 weeks (78.8% vs. 57.6%) • Prevention of acquired resistance to other background drugs

    28. From Johnson & Johnson

    29. LINEZOLID in XDR-TB: Kaplan–Meier Curves for Culture Conversion According to Time since Randomization. NEJM. 2012 Lee M et al. N Engl J Med 2012;367:1508-1518.