1. PEPFAR Hepatitis B co-infection and Response to Antiretroviral Therapy among HIV-infected Patients in Tanzania Oral abstract # MOAB0101 C. Hawkins, B. Christian, J. Ye, T. Nagu, E. Aris, G. Chalamilla, D. Spiegelman, F, Mugusi, S. Mehta, W. Fawzi AIDS 2012 - Turning the Tide Together Presented in part as an Oral presentation at the 17 th Conference on Retroviruses and Opportunistic Infections, San Francisco, Feb 16-19 th, 2010

2. Introduction Approximately 6-20% of HIV-infected individuals co-infected with chronic Hepatitis B (HBV) in Sub-Saharan Africa (SSA) HIV/HBV co-infection associated with – Decreased spontaneous clearance of HBsAg and HBeAg – Faster progression to cirrhosis and hepatocellular carcinoma – Higher liver-related mortality

3. Introduction The effect of HIV/HBV co-infection on antiretroviral treatment responses is unclear: – Impaired virologic, clinical and immunologic outcomes (Sheng et al. 2004, Hoffman et al. 2009) – Minimal or no impact of HBV co-infection on ART responses (Hoffman et al. 2008, Konopnicki D et al. 2005, Lincoln et al. 2003) Very few studies of HIV/HBV co-infection in SSA where both HIV and HBV highly endemic

4. Objectives Assess the prevalence of HBV in cohort of HIV- infected adults in urban Tanzania Compare immunologic and clinical outcomes after ART initiation between HIV mono- infected (HIV) and HIV/HBV co-infected (HIV/HBV) individuals

5. Methods Cohort study of adult HIV-infected patients in the Management and Development for Health (MDH) PEPFAR- supported HIV Care and Treatment Program, Tanzania 18 sites in Dar es Salaam with patients followed in care from November 2004-September 2011

6. Methods All patients receive HIV Care and Treatment per National Tanzanian and WHO guidelines Standard first-line ART – d4T or AZT + 3TC + EFV or NVP – TDF +3TC or FTC+ EFV or NVP preferred for HIV/HBV (2008) Comprehensive electronic database captures detailed information on clinical diagnoses, antiretroviral therapy, CD4+ cell counts, alanine aminotransferase (ALT), hemoglobin (Hgb), HBsAg, HCV antibody.

7. Methods Inclusions: – HBsAg + – Age>15 – ART naïve – Not pregnant at ART initiation Exclusions: – Co-infection with HBV and chronic HCV* (HCV Ab +) – HBV status unknown * HCV antibody testing was not performed in 53% of study participants

8. Methods: analysis Changes in CD4+ cell count over time generalized estimating equations and robust regression Incidence of mortality and liver enzyme elevation (hepatotoxicity)* events/100 person-years Cox proportional hazards models to examine HBV co-infection in HIV-infected patients in relationship to mortality and hepatotoxicity outcomes * Hepatotoxicity defined as ALT >40 U/l, >3X ULN (120 U/l) and >5X ULN (>200 U/l)

9. Results: study population HIVHIV/HBVp-value Overall164601079 Age (years)37 (31-44)36 (31-41)0.008 Male sex, %3450<0.0001 *CD4 (cells/μL)116 (47-190)101 (41-179)0.003 *Hemoglobin (g/dl) 10.2 (8.8-11.5)10.4 (8.8-12.0)0.006 BMI20.1 (17.9-22.9)19.8 (17.9-22.2)0.007 ALT ( IU/L)21 (14.6-32)26.5 (17.2-42)<0.0001 ALT ( IU/L) > 40, %1629<0.0001 Values are median (interquartile) or percentages * variables for which >5% of data missing

10. Results: study population HIVHIV/HBVp-value Overall164601079 WHO Stage I, % II, % III, % IV, % 6 16 58 20 5 16 53 26 <0.0001 Current TB treatment, % 17.3100.04 *Current alcohol intake, % 3.256.600.09 *ART contains tenofovir,% 3.117.00.27 ART duration, mon18.6 (4.9-29.5)18.2 (4.2-27.2)0.08 Values are median (interquartile) or percentages *variables for which >5% of data missing

11. Results: Risk of mortality HIVHIV/HBVp-value Number of deaths/PY 1572/25,494 130/1635 Incidence rate (event/100 PY) 6.16 (95% CI 5.79, 6.53) 7.74 (95% CI 6.16, 9,33) Unadjusted HR (95% CI) 1.001.28 (1.07, 1.53)0.007 Adjusted* HR (95% CI) 1.001.18 (0.98, 1.42)0.07 *covariates -gender, age, WHO HIV Disease Stage, hemoglobin level (g/dL), CD4+ cell count (cells/μL), ALT greater than 200 IU/L, BMI (kg/m2), current TB, all at year of initiation as well as year of ARV initiation

12. Results: Risk of mortality HIVHIV/HBVp-value Number of deaths/PY 1572/25,494 130/1635 Incidence rate (event/100 PY) 6.16 (95% CI 5.79, 6.53) 7.74 (95% CI 6.16, 9,33) Unadjusted HR (95% CI) 1.001.28 (1.07, 1.53)0.007 Adjusted* HR (95% CI) 1.001.18 (0.98, 1.42)0.07 *covariates -gender, age, WHO HIV Disease Stage, hemoglobin level (g/dL), CD4+ cell count (cells/μL), ALT greater than 200 IU/L, BMI (kg/m2), current TB, all at year of initiation as well as year of ARV initiation

13. Results: cumulative incidence of all cause mortality

15. Results: mean changes in CD4+ cell count from baseline MonthGroup Mean (SEM) of change p-value (adjusted)* 6 HIV 77 (1.5) 0.46 HIV/HBV 71 (5.9) 12 HIV 158 (2.1) 0.05 HIV/HBV 143 (7.6) *adjusted for gender, age, WHO HIV Disease Stage, hemoglobin level (g/dL), BMI (kg/m2)

16. Results: overall CD4+ cell count response p<0.01

17. HIVHIV/HBVp-value Number with ALT>120/PY 322/2463940/1507 Incidence rate (event/100 PY) 1.29, (95% CI 1.12-1.46 )2.49, (95% CI 1.55-3.43 ) Unadjusted HR (95% CI)1.001.99 (1.43, 2.77)<0.001 Adjusted* HR (95% CI)1.001.76 (1.26, 2.46)0.0009 Number with ALT>200/PY 110/25,24619/1589 Incidence rate (event/100 PY) 0.43, (95% CI 0.33-0.53)1.16, (95% CI 0.52-1.80) Unadjusted HR (95% CI)1.002.70 (1.66, 4.40)<0.001 Adjusted* HR (95% CI)1.002.30 (1.39, 3.81)0.001 Results: Risk of hepatotoxicity Patients with the event at baseline were excluded * adjusted for gender, age, WHO HIV Disease Stage, Hemoglobin level (g/dL), CD4+ cell count (cells/μL), BMI (kg/m2), current TB, NVP use, all at year of initiation, as well as year of ARV initiation

18. HIVHIV/HBVp-value Number with ALT>120/PY 322/2463940/1507 Incidence rate (event/100 PY) 1.29, (95% CI 1.12-1.46 )2.49, (95% CI 1.55-3.43 ) Unadjusted HR (95% CI)1.001.99 (1.43, 2.77)<0.001 Adjusted* HR (95% CI)1.001.76 (1.26, 2.46)0.0009 Number with ALT>200/PY 110/25,24619/1589 Incidence rate (event/100 PY) 0.43, (95% CI 0.33-0.53)1.16, (95% CI 0.52-1.80) Unadjusted HR (95% CI)1.002.70 (1.66, 4.40)<0.001 Adjusted* HR (95% CI)1.002.30 (1.39, 3.81)0.001 Results: Risk of hepatotoxicity Patients with the event at baseline were excluded * adjusted for gender, age, WHO HIV Disease Stage, Hemoglobin level (g/dL), CD4+ cell count (cells/μL), BMI (kg/m2), current TB, NVP use, all at year of initiation, as well as year of ARV initiation

19. Results: Cumulative incidence of moderate-severe hepatotoxicity

20. Strengths and limitations Large cohort in SSA examining the effect of HBV on HIV treatment outcomes Long duration of follow up, comprehensive data on important confounders (TB therapy, alcohol), death Lack of HBV serologic and virologic data (HBeAg, HBV DNA) HIV virologic endpoints not assessed Specific causes of death not examined

21. Conclusions Prevalence of HIV/HBV co-infection (6.2%) in this Tanzanian cohort relatively high Antiretroviral treatment outcomes are impacted by the presence of HBV Lower CD4+ counts throughout immune restoration almost 20% higher* risk of mortality higher risk of moderate-severe hepatotoxicity *p=0.07

22. Further study Causes of death –do our results suggest a shift towards more non-AIDS related mortality in SSA? Mechanisms involved in HBV and HIV-related immune-suppression and any effect on long-term morbidity and mortality? Etiology of hepatotoxic events and effect (if any) on long-term liver disease progression The impact of long-term suppressive HBV therapy on these outcomes with agents that are more durable than lamivudine (such as tenofovir)

23. Acknowledgements Co-authors and MDH Management All study participants HSPH Data managers Wafaie Fawzi (HSPH), Chloe Thio (JHI), Robert Murphy (NU) This research was supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through HRSA under the terms of grant number U51HA02522 through the Harvard School of Public Health The speaker has no conflicts of interest to declare.

24. Results: risk of mortality by ARV regimen (contains TDF vs. not) * Note, ALL regimens contained LAM Outcome ARV regimen Events /Number at risk Multivariate Interaction p value TDF/HBV status HR for HBV status p-value Mortality Included TDF 59/573 0.70 (0.34, 1.44) 0.33 0.30 Did not include TDF 1244/14031 1.28 (1.02, 1.61) 0.03