pepfar hepatitis b co-infection and response to antiretroviral therapy among hiv-infected patients...

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 TogetherPresented in part as an Oral presentation at the 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, Feb 16-19th, 2010

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

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

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

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

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.

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

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)

Results: study population

HIV HIV/HBV p-valueOverall 16460 1079

Age (years) 37 (31-44) 36 (31-41) 0.008

Male sex, % 34 50 <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

BMI 20.1 (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, % 16 29 <0.0001

Values are median (interquartile) or percentages* variables for which >5% of data missing

Results: study populationHIV HIV/HBV p-value

Overall 16460 1079WHO Stage

I, % II, % III, % IV, %

6165820

5165326

<0.0001

Current TB treatment, %

17.3 10 0.04

*Current alcohol intake, %

3.25 6.60 0.09

*ART contains tenofovir,%

3.1 17.0 0.27

ART duration, mon 18.6 (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

Results: Risk of mortalityHIV HIV/HBV p-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)

1.00 1.28 (1.07, 1.53) 0.007

Adjusted* HR (95% CI)

1.00 1.18 (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

Results: cumulative incidence of all cause mortality

Results: mean changes in CD4+ cell count from baseline

Month Group Mean (SEM) of change

p-value (adjusted)*

6HIV 77 (1.5)

0.46HIV/HBV 71 (5.9)

12HIV 158 (2.1)

0.05HIV/HBV 143 (7.6)*adjusted for gender, age, WHO HIV Disease Stage, hemoglobin level (g/dL), BMI (kg/m2)

Results: overall CD4+ cell count response

p<0.01

HIV HIV/HBV p-value

Number with ALT>120/PY

322/24639 40/1507

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) 1.00 1.99 (1.43, 2.77) <0.001

Adjusted* HR (95% CI) 1.00 1.76 (1.26, 2.46) 0.0009

Number with ALT>200/PY

110/25,246 19/1589

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) 1.00 2.70 (1.66, 4.40) <0.001

Adjusted* HR (95% CI) 1.00 2.30 (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

Results: Cumulative incidence of moderate-severe hepatotoxicity

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

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

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)

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 HealthThe speaker has no conflicts of interest to declare.

Results: risk of mortality by ARV regimen (contains TDF vs. not)

* Note, ALL regimens contained LAM

Outcome ARV regimen Events

/Number at risk

MultivariateInteraction p

value TDF/HBV

statusHR for HBV status p-value

MortalityIncluded

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

pepfar hepatitis b co-infection and response to antiretroviral therapy among hiv-infected patients...

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