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Mycobacteria in the tropics

Mycobacteria in the tropics. April 2018 UBC tropical medicine rounds. Recent case from clinic Cosmetic surgery in China …. Cosmetic surgery in China …. Mycobacteria - microbiology. Acid fast bacilli Lipid rich cell wall Mycolic acid Grow slowly (divide every 20 hours – 20 days).

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Mycobacteria in the tropics

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  1. Mycobacteria in the tropics April 2018 UBC tropical medicine rounds

  2. Recent case from clinicCosmetic surgery in China…

  3. Cosmetic surgery in China…

  4. Mycobacteria - microbiology • Acid fast bacilli • Lipid rich cell wall • Mycolic acid • Grow slowly (divide every 20 hours – 20 days)

  5. Mycobacteria in the tropicsOverview • M. TB complex • M. tuberculosis • M. bovis • M. bovis BCG • Non-TB mycobacteria • M. avium • M. ulcerans • M. leprae

  6. World TB day was Mach 24 • Koch discovery of TB bacteria 1882 • 1 per 1,000 • 1 in 7 deaths • 1st RCT was streptomycin for TBM • Single leading infectious disease cause of death worldwide

  7. TB! • About 1 million more deaths from TB than from HIV…

  8. TB • Epidemiology… • How many cases per year? • How many deaths? • What percent occur in children? • More men then women? • What % of all cases are HIV positive?

  9. Global Burden of TB

  10. Case fatality among new TB cases

  11. Find, Treat, and Prevent LTBI (2 billion) Uninfected (5 billion) Active TB (10 million) Death (1.7 million)

  12. Undiagnosed TB • 40% of all cases!

  13. Gene Xpert MTB-RIF

  14. 6648 adults with suspected TB, 6 countries Xpert detected: - 98% of smear positive cases - 77% of smear negative cases Faster time to treatment start for sm-/c+ - 56 days prior to Xpert - 5 days with use of Xpert Less untreated patients with sm-/c+ -dropouts reduced from 39%  14% Lancet 2011; 377: 1495–1505

  15. Xpert Ultra • Xpert Ultra had higher sensitivity than Xpert • Overall: 88%  vs 83% • Smear-negative: 63% vs 46% • HIV co-infected: 90% vs 77%

  16. Urine Lipoarabinomannan (LAM)Urine POC lateral flow assay • LAM: • Major component of mycobacterial cell wall • Very immunogenic • Cost of test = $3

  17. Chaisson, CROI 2018

  18. Unrecognized TB Autopsy findings in KwaZulu-Natal • 240 adult inpatients who died in hospital underwent limited autopsies • 94% HIV positive, medical and surgical floor • 50% had positive TB cultures on autopsy • 50% were already on TB rx  58% still culture positive • 50% were not on TB rx  48% culture positive • “Unrecognized TB” = 25% of all in-hospital deaths Cohen et al. PLoS Med 2010

  19. Undiagnosed TB cases Chaisson, CROI 2018

  20. Unrecognized M. TB bacteremia among patients with fever • Prospective study of mycobacterial blood cultures for 344 consecutive hospitalized adults with fever • Lilongwe (Malawi) and Bangkok (Thailand) • 74% HIV infected • 10% had MTB bacteremia • In 55% (16 patients) it was “unrecognized” • (not accompanied by additional diagnostic test to suggest TB; sputum smear or chest x-ray) Lancet 1999; 354: 1159–63

  21. TB presenting as severe sepsis • Prospective observational study in 2 hospitals in Uganda

  22. TB as severe sepsis • Retrospective observational study of 8, 670 patients admitted to ICU (Canada, US, Saudi) • 53 patients had TB (1% of all culture positive cases) • 5,419 had other bacterial infections • 2, 651 culture-negative • TB patients had higher mortality • 79.2% TB vs. 49.7% bacterial • Mortality was higher in patients who had delays in start of TB treatment (>24hours) • 95.2% mortality in patients with delay (>24hours) • 45.5% mortality in patients with early treatment Chest2013; 144(2):474–482

  23. Routine symptom screening misses cases…. • Exit interviews of patients leaving primary health clinics • Study staff tested sputum from 779 participants not tested by clinic staff. • 39 (5.0%) tested positive for TB; 3 had MDR-TB • 15/39 (38.5%) were never screened • 24/39 (61.5%) were screened but not tested by clinic staff. • 70% of TB cases were missed by primary health clinics

  24. Screening HH contacts…Universal vs Symptom screening… TUTT… Martinson CROI 2018

  25. 1992 MDR-TB in New York City 1992, TB was on the rise and 20% of cases were MDR-TB….

  26. WHO declares TB a global emergency 1992 MDR-TB in New York City 1992, TB was on the rise and 20% of cases were MDR-TB….

  27. WHO declares TB a global emergency TB identified as #1 infectious killer 1992 MDR-TB in New York City 1992, TB was on the rise and 20% of cases were MDR-TB….

  28. $1 billion invested in NYC - Health care resources - MDR-TB treatment 1992 MDR-TB in New York City….

  29. “In developing countries, people with MDR-TB usually die, because effective treatment is often impossible in poor countries.” - WHO 1996 Photo: James Nachtwey For the rest of the world, The MDR-TB death sentence as a public health policy…

  30. “MDR-TB is too expensive to treat in poor countries; it detracts attention and resources from treating drug-susceptible disease.” - WHO 1997 Photo: James Nachtwey For the rest of the world, The MDR-TB death sentence as a public health policy…

  31. Enter the Human Rights Response… Isn’t there a moral imperative to treat? Why are the medications so expensive? Why is it a zero-sum calculation? What will happen if we don’t treat people with a lethal airborne infectious disease?

  32. Cost of MDR-TB medications decreased - $35,000 in 1997  $1,500 in 2000 World Health Assembly 2009 “universal access to diagnosis and treatment of MDR and XDR-TB by 2015”

  33. Very slow scale up of treatment for MDR-TB 480,000 MDR-TB cases ★ Number of patients with MDR-TB on treatment Year

  34. MDR-TB treatment outcomes Only 50% success - similar to placebo…

  35. MDR-TB treatment • Standard WHO regimen, ≥ 20 months…. • 8 Km + Lfx + Eto + Cs + Z / 12 Lfx + Eto + Cs + Z • 9-month, Bangladesh/STREAM • 4 Km + Mx + Pto + INH + Clo + EMB + Z / 5 Mx + Clo E + Z

  36. STREAM study • Evaluated the 9-month MDR-TB regimen • Interim data • 300 patients • Successful outcome: • 78% short-course • 80% standardized course

  37. “New” drugs • Bedaquiline • Delamanid and Pretomanid • Linezolid and Sutezolid • Surrogate end-points • EBA, TTP, 2-month SCC

  38. endTB trial Chaisson, CROI 2018

  39. NiX trial

  40. Modelling impact of better treatments for active TB and better use of treatment for LTBI… Abu-Raddad et al PNAS 2009

  41. TEMPRANO trial

  42. Very slow scale up of IPT

  43. Better evidence for IGRA

  44. Improved TST

  45. Improved treatment for LTBI Once weekly dosing x 12 weeks

  46. BRIEF TB (1HP) • 3,000 HIV-infected • Positive TST, IGRA or live in high burden region • Median CD4 count 400 • 50% on ARVs (NNRTI) • TST: 20% positive, 70% negative, 10% not ddone • Randomized • 9H (9 months INH) • 1HP (1 month Rifapentine+INH) • Followed for 3 years…. Chaisson CROI 2018

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