1. CCEB 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. CCEB 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. CCEB 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. CCEB 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. CCEB 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. CCEB 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. CCEB 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. CCEB 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. CCEB 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. CCEB Baseline Characteristics by HIV Status Characteristic HIV+ N=40 HIV- N=30 P-value Median Age (years, IQR)39 (30-45)33 (24-59)0.4 Sex, n (%) Male Female 29 (73) 11 (28) 22 (73) 8 (27) >0.5 TB Treatment History, n (%) Any 1 st line therapy Any 2 nd line (plus 1 st line) Unknown 29 (73) 7 (18) 4 (10) 23 (77) 3 (10) 4 (13) >0.5 Resistant Drugs at Baseline (median, IQR)5 (4-5)5 (5-5)>0.5 Number Active Drugs (median, IQR)4 (4-4) >0.5

11. CCEB 1 st Line Anti-TB Drug Resistance by HIV Status Drug n (%) HIV+ N=40 HIV- N=30 P-value Ethambutol Yes No Unknown 24 (60) 16 (40) 0 (0) 23 (77) 7 (23) 0 (0) 0.14 Streptomycin Yes No Unknown 25 (63) 13 (33) 2 (5) 19 (63) 9 (30) 2 (7) >0.5

12. CCEB 2 nd Line Anti-TB Drug Resistance by HIV Status Drug n (%) HIV+ N=40 HIV- N=30 P-value Kanamycin Yes No Unknown 1 (3) 18 (45) 21 (53) 3 (10) 12 (40) 15 (50) 0.4 Ofloxacin Yes No Unknown 2 (5) 16 (40) 22 (55) 3 (10) 10 (33) 17 (57) >0.5 Ethionamide Yes No Unknown 7 (18) 12 (30) 21 (53) 6 (20) 9 (30) 15 (50) >0.5

13. CCEB Anti-TB Drugs Used by HIV Status Drug, n (%)HIV+ (n=40)HIV- (n=30)P value Ethambutol12 (30%)8 (27%)>0.5 Pyrazinamide38 (95%)29 (97%)>0.5 Ciprofloxacin37 (93%)27 (90%)>0.5 Ofloxacin0 (0%)1 (3%)0.4 Moxifloxacin2 (5%)3 (10%)0.4 Streptomycin2 (5 %)1 (3%)>0.5 Amikacin35 (88%)20 (83%)>0.5 Capreomycin2 (5%)3 (10%)0.4 Cycloserine27 (67%)20 (67%)>0.5 Terizidone0 (0%)1 (3%)0.4 PAS2 (5%)3 (10%)0.4 Amox/Clav2 (5%)6 (20%)0.05 Clarithromycin3 (8%)1 (3%)0.5

14. CCEB 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. CCEB 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. CCEB 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. CCEB

18. Toxicity Type of toxicity HIV positive n (%) HIV negative n (%) P-value Neuropathy16 (40)3 (10)p<0.01 Nephropathy10 (25)2 (7)p=0.04 Ototoxicity21 (53)21 (70)p=0.14 Neuro- psychiatric 3 (8)3 (10)p>0.5

19. CCEB 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

20. CCEB 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

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

22. CCEB Acknowledgements Univ of Pennsylvania –Chawanga Modongo –Lephata Molopisi –Craig Newcomb –Elizabeth Lowenthal –Andrew Steinhoff –Rob Roy MacGregor –Harvey Friedman –Gregory Bisson Botswana NTP –Tore Steen, Howard Moffet Botswana TB Reference Lab –Koobiditse Radisowa –Valentina Anisimova CDC-Atlanta –Victoria Gammino CDC-Botswana –Robert Makombe Funding Support: –NIH T32AI055435 –Penn CFAR NIH P30AI045008