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Impact of HIV on Early MDR-TB Treatment Outcomes in Botswana

Impact of HIV on Early MDR-TB Treatment Outcomes in Botswana. Jeffrey Hafkin MD. Botswana- UPenn Partnership Center for Clinical Epidemiology and Biostatistics Infectious Disease Division, Department of Medicine University of Pennsylvania School of Medicine.

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Impact of HIV on Early MDR-TB Treatment Outcomes in Botswana

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  1. Impact of HIV on Early MDR-TB Treatment Outcomes in Botswana Jeffrey Hafkin MD Botswana-UPenn Partnership Center for Clinical Epidemiology and Biostatistics Infectious Disease Division, Department of Medicine University of Pennsylvania School of Medicine

  2. Background: MDR-TB and HIV-infection • In the pre-HAART era,MDR-TB with HIV infection had worse treatment response and higher mortality compared to HIV-uninfected MDR-TB • Few studies of MDR-TB outcomes in HIV+ with access to HAART, particularly in sub-Saharan Africa Seung et al. PloS One 2009 Brust et al. PloS One 2011

  3. Background: Epidemiology of HIV and TB in Botswana • Prevalence of HIV infection = 25% (UNAIDS 2009) • Incidence of TB disease = 503 cases per 100,000 population (WHO 2010) • Prevalence of MDR-TB during 1995-2008: • 0.2% to 3.4% (treatment naïve) • 6.1% to 13.1% (treatment experienced) • Start of HAART roll-out in Botswana in 2003 Nelson et al. Lancet 2005 WHO. M/XDR-TB: 2010 global report on surveillance and response

  4. Study Design • Cohort study • MDR-TB patients receiving individualized, integrated, ambulatory care at a two public clinics in Botswana • Exposure • HIV infection (two parallel HIV ELISA assays) • Outcome • Sputum culture conversion (two consecutive negative sputum cultures at least one month apart)

  5. Endpoints • Primary: • Time to initial sputum culture clearance after starting MDR-TB treatment • Proportion of patients converting sputum cultures • Secondary: • Proportion of patients with ototoxicity, peripheral neuropathy, and renal toxicity

  6. Data Collection • Subject population: • All confirmed MDR-TB patients who were started on anti-MDR-TB treatment prior to September 2008 • Excluded from analysis if no quantifiable culture follow up time after start of treatment

  7. Statistical Analysis • Unadjusted Analysis: • Time to culture conversion by HIV status • Log rank test and Kaplan-Meier curves • Proportion of patients with sputum culture conversion by HIV status • Chi-Square test • Adjusted Analysis: • Cox proportional hazard models controlling for age, sex, number of active anti-TB agents and TB treatment history

  8. Baseline Characteristics • 74 patients with culture-confirmed MDR-TB were identified • 4 were excluded • no quantifiable culture f/u time after start of treatment • 70 had complete data for analysis • 40 (57%) HIV-infected • 30 (43%) HIV-uninfected

  9. HIV-Related Characteristics • Baseline CD4+ count = 158 (IQR 88-347)  3m f/u CD4+ count = 262 (IQR 129-382) • 28 (69%) on HAART prior to start of MDR-TB treatment and 36 (90%) during treatment • Most regimens consisted of 2NRTI + NNRTI • 19 (53%) zidovudine/lamivudine • 8 (22%) stavudine/lamivudine • 8 (22%) tenofovir/lamivudine • 4 (11%) abacavir/lamivudine

  10. Baseline Characteristics by HIV Status

  11. 1st Line Anti-TB Drug Resistance by HIV Status

  12. 2nd Line Anti-TB Drug Resistance by HIV Status

  13. Anti-TB Drugs Used by HIV Status

  14. Follow-up • Median on treatment follow up time: • 82 days (IQR 52-133) • Median duration aminoglycoside: • 8 mos (no difference by HIV status, p=0.48) • Sputum culture conversion: • Overall: 59 of 70 (84%) • HIV-infected: 34 of 40 (85%) • HIV-uninfected: 25 of 30 (83%) (p>0.5)

  15. Follow-up • 4 patients died following enrollment: • 2 following sputum culture conversion (both HIV-infected) • 2 prior to culture conversion (both HIV-uninfected) • 2 patients identified with XDR TB during follow-up (one HIV+, one HIV-) • No patients defaulted from care during the study period

  16. Time to Sputum Culture Conversion • Median time to sputum culture conversion: • 78 days (IQR 42-186) for HIV-infected • 95 days (IQR 70-133) for HIV-uninfected • (log rank p >0.5) • Unadjusted HR = 0.9 (95% CI: 0.5 to 1.5) • Adjusted HR = 0.8 (95% CI: 0.4 to 1.4) • adjusting for age, gender, TB treatment history, and number of active agents

  17. Toxicity

  18. Limitations • Sample size • Generalizability: • Botswana vs. Sub-Saharan Africa • Selection bias: • Specialist care in a referral center • Missing culture/DST data • Misclassification bias: • Characterization of toxicity • Unmeasured confounding

  19. Conclusions • HIV infection did not impact time to culture conversion in cohort of adults with MDR-TB from Botswana • Suggests that in resource-limited settings with broad access to ART and individualized MDR-TB care, short term microbiologic outcomes may be comparable in HIV-infected and uninfected patients

  20. Conclusions • Furthermore, high rates of drug toxicity overall and more likely to be associated with co-infection

  21. Acknowledgements • Univ of Pennsylvania • ChawangaModongo • LephataMolopisi • Craig Newcomb • Elizabeth Lowenthal • Andrew Steinhoff • Rob Roy MacGregor • Harvey Friedman • Gregory Bisson • Botswana NTP • Tore Steen, Howard Moffet • Botswana TB Reference Lab • KoobiditseRadisowa • ValentinaAnisimova • CDC-Atlanta • Victoria Gammino • CDC-Botswana • Robert Makombe • Funding Support: • NIH T32AI055435 • Penn CFAR NIH P30AI045008

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