HIV and Drug-Resistant TB Reflections from rural Tugela Ferry

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1 HIV and Drug-Resistant TB Reflections from rural Tugela Ferry Neel R. Gandhi, MD Tugela Ferry Care & Research Collaboration (TF CARES) Albert Einstein College of Medicine 3 March 2010

2 HIV & Drug-Resistant TB Epidemic Rise of Drug-resistant TB cases in Africa confirms convergence of HIV & drug-resistant TB epidemics MDR TB caseload in Botswana has risen consecutively over past decade Explosive MDR and XDR TB epidemics seen in South Africa over past 5 years MDR TB prevalence now exceeds 25 cases per 100,000 population in certain areas

3 Convergence of HIV & MDR/XDR TB Why is the convergence of these epidemics concerning? Usual public health implications: drug-resistant TB is more costly, complex & difficult to treat Two factors especially worse with HIV co-infection: Worse outcomes: dramatically greater mortality Potential for explosive spread due to primary transmission

4 HIV-associated XDR TB 2006: 53 XDR TB cases in South Africa 52 of 53 (98%) died median survival 16 days All HIV-infected, if status known Transmission of XDR TB likely 51% never previously received TB treatment 85% with genetically similar TB strains

5 Local Outbreak vs Epidemic Unclear if data represented an isolated outbreak Or first signs of a broader epidemic : MDR TB prevalence low: 2-4%

6 Tugela Ferry June 2005

7 Tugela Ferry December 2005

8 Tugela Ferry June 2006

9 Tugela Ferry December 2006

10 Tugela Ferry March 2007

11 Drug-resistant TB cases: KwaZulu-Natal K. Wallengren et al., submitted for publication

12 Drug-resistant TB cases: KwaZulu-Natal 2,645 MDR TB cases 26 cases per 100,000 K. Wallengren et al., submitted for publication

13 Drug-resistant TB cases: KwaZulu-Natal 2,645 MDR TB cases 26 cases per 100, MDR TB cases in US in 2007 K. Wallengren et al., submitted for publication

14 Rise of MDR TB in 1990s Numerous outbreaks in congregate settings Primarily among HIV co-infected patients Characterized by high and rapid mortality HIV co-infection Mortality Survival (median) Florida 93% 72% 7 weeks New York 95% 77% 4 weeks Argentina 98% 79% 4 weeks New York 91% 83% 4 weeks New York 100% 89% 16 weeks Italy 98% 95% 6-8 weeks Spain 100% 98% 7 weeks Wells C et al. CID 2007;196:S86-107

15 Mortality in HIV-Associated XDR TB Proportion Surviving N = days Days since Sputum Collected Gandhi et al. Lancet 2006

16 HIV-Associated MDR & XDR TB in S Africa MDR TB (n = 272) 0.25 XDR TB (n = 382) days SURV1YR Survival in days STRATA: TYPE=MDR Censored TYPE=MDR TYPE=XDR Censored TYPE=XDR 60 days Gandhi et al AJRCCM 2010

17 HIV-Associated MDR & XDR TB in S Africa HIV co-infection 90% Median CD4: 87 cells/mm 0.50 MDR TB HIV co-infection 98% Median CD4: 66 cells/mm XDR TB days SURV1YR Survival in days STRATA: TYPE=MDR Censored TYPE=MDR TYPE=XDR Censored TYPE=XDR 60 days Gandhi et al AJRCCM 2010

18 Survival by Degree of Resistance Survival 0.50 HR group HRE, HRS, HRES group 0.25 HROKm, HREOKm, HRSOKm HRESOKm group SURVIVAL Survival in days STRATA: RESSTCAT=HR Censored RESSTCAT=HR RESSTCAT=HRCK, HRECK, HRSCK Censored RESSTCAT=HRCK, HRECK, HRSCK RESSTCAT=HRE, HRS, HRES Censored RESSTCAT=HRE, HRS, HRES RESSTCAT=HRESCK Censored RESSTCAT=HRESCK Gandhi et al AJRCCM 2010

19 Survival by Degree of Resistance Survival 0.50 HR group HRE, HRS, HRES group 0.25 HROKm, HREOKm, HRSOKm HRESOKm group days SURVIVAL Survival in days STRATA: RESSTCAT=HR Censored RESSTCAT=HR RESSTCAT=HRCK, HRECK, HRSCK Censored RESSTCAT=HRCK, HRECK, HRSCK RESSTCAT=HRE, HRS, HRES Censored RESSTCAT=HRE, HRS, HRES RESSTCAT=HRESCK Censored RESSTCAT=HRESCK Gandhi et al AJRCCM 2010

20 DST Results of XDR TB : % 80% Percentage 60% 40% 20% 4-drug: HROflKm 5-drug: HREOflKm, HRSOflKm 6-drug: HRESOflKm 0% Jul-Dec 05 Jan-Jun 06 Jul-Dec 06 Jan-Jun 07 Months Moll A, et al. 38th Union World Conference on Lung Health, Cape Town, 2007

21 Drug Resistance Pattern of XDR TB Isolates from Tugela Ferry, % 80% Percentage 60% 40% 4-drug: HROflKm 5-drug: HREOflKm, HRSOflKm 6-drug: HRESOflKm 20% 0% Jul-Dec 05 Jan-Jun 06 Jul-Dec 06 Jan-Jun 07 Study Months

22 DST Among XDR TB Cases All XDR TB isolates resistant to at least 6 drugs: H, R, E, S, OFL, KAN 2 (11%) 6-drug resistance only 6-drug + CAP + ETHIO resistance 13 (68%) 4 (21%) 6-drug + CAP resistance 8-drug resistance

23 Survival by Degree of Resistance Survival 0.50 HR group HRE, HRS, HRES group 0.25 HROKm, HREOKm, HRSOKm HRESOKm group SURVIVAL Survival in days STRATA: RESSTCAT=HR Censored RESSTCAT=HR RESSTCAT=HRCK, HRECK, HRSCK Censored RESSTCAT=HRCK, HRECK, HRSCK RESSTCAT=HRE, HRS, HRES Censored RESSTCAT=HRE, HRS, HRES RESSTCAT=HRESCK Censored RESSTCAT=HRESCK Gandhi et al AJRCCM 2010

24 Predictors of Mortality: HIV & MDR/XDR TB Adjusted Hazard Ratio p CD4 Count: <50 cells/mm cells/mm >200 cells/mm3 ref ref ARVs before MDR/XDR TB diagnosis Extrapulmonary TB Admission within last year Smear Positive

25 Mortality in HIV & MDR/XDR TB In absence of HIV, favorable treatment outcomes possible in low and middle income countries With HIV co-infection, however, drug-resistant TB takes on a different and more aggressive course Nearly two decades of experience demonstrating rapid and high mortality Majority die within 6-8 weeks, before diagnosis can be made by conventional culture and DST Thus, majority die before treatment with secondline TB drugs can be initiated

26 What do we need to do?

27 Comprehensive Response Prevention Strengthen TB DOTS program to curb creation of drug resistance Create & Implement comprehensive infection control program to prevent transmission of drug-resistance Diagnosis Develop and implement rapid diagnostic assays to reduce time to diagnosis from 6-8 weeks to 1-10 days Use intensified case finding to find patients at earlier stages of disease

28 Comprehensive Response cont d Treatment Decentralize to reduce referral delay, increase capacity and improve treatment completion rates Use SLDs empirically in HIV-infected patients suspected of MDR or XDR TB Integrate antiretroviral therapy into MDR/XDR TB treatment programs to facilitate early and widespread use

29 Implications Rise of MDR/XDR TB epidemics in Africa, and HIV epidemic in Eastern Europe, suggest that we are just at the beginning of this catastrophic convergence Significant efforts are needed to understand the implications of these dual diseases and to develop the tools to address them effectively Implementation of infection control programs Availability of rapid diagnostics at district level Better understanding of concurrent use of SLDs and ART

30 Acknowledgements Tugela Ferry Care & Research Collaboration: Tony Moll, Jerry Friedland, Sarita Shah, Claudio Marra, James Brust, Sheela Shenoi, Jason Andrews, Sanjay Basu, Francois Eksteen, Theo van de Merwe, Eugene Meyer, Palav Babaria, Michelle Scott, Krisda Chaiyachati, Willem Sturm, Umesh Lalloo, Prashini Moodley, Jessica Richardson, Laurie Andrews, Darren Weissman, Romualde Montreuil Funding: Doris Duke Charitable Foundation, PEPFAR, Howard Hughes Medical Institute, Irene Diamond Fund Tugela Ferry: TB DOTS & HIV Staff, Home Based Care Program Nelson R. Mandela School of Medicine: Leora Sewnarian Inkosi Albert Luthuli Hospital Microbiology Lab KZN Department of Health: Bruce Margot Italian Cooperation: Venanzio Vella & Claudio Marra Patients and families who participated in these studies