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CLINICAL SCIENCE

Prevalence of hepatitis B co-infection and response to antiretroviral therapy among HIV-infected patients in Tanzania

Hawkins, Claudiaa,b; Christian, Beatriceb; Ye, Jitaoc; Nagu, Tumainid; Aris, Ericb,d; Chalamilla, Guerinob,c; Spiegelman, Donnac; Mugusi, Ferdinandd; Mehta, Saurabhe; Fawzi, Wafaieb,c

Author Information

aNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA

bManagement and Development for Health (MDH), Dar es Salaam, Tanzania

cHarvard School of Public Health, Boston, Massachusetts, USA

dMuhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

eDivision of Nutritional Sciences, Cornell University, Ithaca, New York, USA.

Correspondence to Claudia Hawkins, MD, MPH, DTM&H, Division of Infectious Diseases, Northwestern University, 645 N. Michigan, Suite 900, Chicago, IL 60611, USA. Tel: +1 312 695 4993; fax: +1 312 695 5088; e-mail: [email protected]

Received 6 August, 2012

Revised 6 November, 2012

Accepted 16 November, 2012

doi: 10.1097/QAD.0b013e32835cb9c8
  • Free

Abstract

Introduction

Chronic hepatitis B (HBV) co-infection is common in HIV-infected individuals in sub-Saharan Africa (SSA) [1,2]. HIV significantly modifies the course of HBV, resulting in a higher risk of HBV-associated liver diseases including cirrhosis, end-stage liver disease, and hepatocellular carcinoma [3,4]. In industrialized countries, liver disease is now a leading cause of morbidity and mortality in HIV-infected individuals with chronic HBV and hepatitis C virus (HCV) co-infection [5], with the greatest risk observed among those with HBV [6]. Although much is known about the effect of HIV on HBV, the effect of HBV on HIV and antiretroviral treatment (ART) responses is less clear. Whereas some studies have observed impaired immunological, virologic, and clinical outcomes with ART in HIV/HBV co-infected compared to HIV mono-infected patients [2,7,8], others have shown no differences in these outcomes between the two patient groups [9,10].

In SSA there are very few studies of HIV/HBV co-infection and ART outcomes where the highest burden of both HIV and HBV exists and where ART is now widely available. In this study, we assessed the prevalence of HBV co-infection in a cohort of HIV-infected adults enrolled in an HIV Care and Treatment program, in Dar es Salaam, Tanzania. We compared immunologic and clinical outcomes in response to ART in HIV mono-infected and HIV/HBV co-infected individuals to test the hypotheses that the co-infection results in a higher risk of mortality and liver enzyme elevation (hepatotoxicity) and delayed immunologic recovery. In addition, we examined the extent to which ART regimens modified the effect of HBV on these outcomes.

Methods

Study design, site, and population

The observational study was conducted at the Management and Development for Health, (MDH) President's Emergency Plan For AIDS Relief (PEPFAR) – supported HIV Care and Treatment Program in Dar es Salaam, Tanzania. This program was established in 2004 and provides financial, laboratory, and technical support to HIV Care and Treatment Centers, and integrated Prevention of Mother-to-Child Transmission (PMTCT) and HIV/tuberculosis (TB) facilities in the Dar es Salaam region. The population of Dar es Salaam is approximately 3.2 million with an HIV prevalence of 9.3%. All HIV-infected adult patients who were enrolled at one of 18 supported ART Care and Treatment Clinics (CTCs) and initiated on ART between November 2004 and September 2011 and who were tested for hepatitis B surface antigen (HBsAg) at least once, were considered eligible for this study. Other criteria for inclusion in the analysis were age above 15 years, not pregnant at the time of ART initiation, and no prior use of ART. HCV antibody testing was performed in 47.4 and 46.2% of HIV and HIV/HBV patients, respectively. The prevalence of HCV antibody seropositivity was very low [104/16 460 (0.63%) in HIV mono-infected and 4/1079 (0.37%) in HIV/HBV co-infected patients]; therefore these patients were not excluded from the study. Patients were recruited for participation and enrolled in MDH-supported CTCs following written informed consent which was subject to ethical reviews by the Muhimbili University of Health and Allied Sciences and Harvard School of Public Health Institutional Review Boards.

Clinical and laboratory procedures

Clinical care of all HIV-infected patients at MDH supported HIV CTCs follows National Tanzanian and WHO guidelines [11,12]. HIV-infected patients are examined monthly by a physician, undergo adherence and nutrition counseling, and receive ART refills. Laboratory tests including hemoglobin (Hgb), CD4+ T-cell count, and chemistries [alanine transaminase (ALT), creatinine and lipid panel] are performed every 6 months. According to national guidelines, viral load testing is not performed routinely [9]. Hepatitis B (HBsAg) and C status (HCV antibody) is recommended at enrollment and determined using a rapid DIMA device strip. A comprehensive patient tracking system is in place to maximize patient retention. ART and co-trimoxazole are provided free of charge by the Tanzanian government. During the study period, standard first-line ART regimens included stavudine or zidovudine, lamivudine (3TC), and efavirenz (EFV) or nevirapine (NVP). In 2008, tenofovir (TDF), 3TC or emtricitabine (FTC) and EFV or NVP was recommended as a preferred alternative first-line regimen for patients with HIV/HBV coinfection. Recommended second-line regimens until 2008 included the combination of abacavir + 3TC and lopinavir/ritonavir (LPV/r) or saquinavir/ritonavir. In 2008, the preferred second-line regimen became TDF + 3TC or FTC + LPV/r. During the study enrollment period, no patients experienced treatment interruptions owing to drug shortages.

Data collection and management

Patient demographic, clinical, laboratory, and therapeutic data are collected by physicians and nurses on standard case report forms and National Care and Treatment Center forms (CTC 2) which are completed at enrollment and at each follow-up visit. Data reviewers are stationed at each clinic to ensure adequacy and completeness of data recording by the healthcare workers. Data collected is then entered into a secure computerized database designed solely for the purpose of data collection and analysis. Unique patient identifiers are used. The database is updated daily by dedicated data entry clerks trained to use a prospective data collection instrument. Weekly quality assurance checks of the database are performed by the data management team to ensure data accuracy. Data collected for this analysis includes baseline demographics, age, weight, height, BMI, WHO stage, history of current TB, ART regimen at initiation and follow-up, ART duration, date of loss to follow-up or death. Laboratory data collected at baseline and follow-up included Hgb (g/dl), CD4+ cell count/μl, ALT (IU/l). The upper limit of normal (ULN) for ALT is 40 IU/l.

Outcomes and definitions

The primary outcome of interest was all cause mortality. Secondary outcomes included hepatotoxicity, defined as greater than 40 IU/l, above 3 × ULN (120 IU/l) and above 5 × ULN (>200 IU/l) [13,14], and immunologic response which was assessed as the change of CD4+ cell count from baseline to the end of the study or patient death. Deaths were either recorded after notification by family members, friends, or by the patient tracking team. If the date of death was unknown but the patient was known to have died, the date of the last encounter with the patients was used as the day of death. For patients who did not die, follow-up ended on 30 September 2011.

Statistical analysis

Baseline characteristics of HIV/HBV and HIV-infected patients were compared using the Wilcoxon rank-sum test for continuous variables and the χ2 test for categorical variables. We examined the relationship of HBV co-infection in HIV-infected patients with the risk of mortality and hepatotoxicity using Cox proportional hazards models [15]. All available plausible clinical, anthropometric, and demographic known or suspected risk factors for mortality or heptatotoxicity were considered as possible confounders of the relationships with hepatitis and included in the multivariate models if they were significant at a P-value of less than 0.20 in univariate models. The missing indicator method was used for covariates with missing values in multivariate analyses [16]. Risk of death was calculated from time of ART initiation to date of death or date of last visit or whichever happened first. Generalized estimating equations [17] were used to assess the change in CD4+ cell count over time between HIV and HIV/HBV patients using stepwise restricted cubic splines to account for nonlinearity in the trajectories [18,19]. In these models, the CD4+ cell count trajectory was modeled as a function of time from ART initiation, hepatitis status, and the interaction between these two. The criterion for significance for all analyses was a two-sided P-value of less than 0.05. All statistical analyses were performed with the statistical software package SAS release 9.1 (SAS Institute Inc., Cary, North Carolina, USA).

Results

Baseline status

Antiretroviral therapy was given to 47 006 HIV-infected adults during the study period. After excluding patients who were pregnant, had previous ART use, or had not been tested for HBV, 17 539 patients were included in the analyses. HIV patients who were tested for HBV were more likely to be male (35 vs. 33%; P < 0.01), have lower median CD4+ cell counts (115 vs. 117 cells/μl; P = 0.03), and higher median ALT levels (21.1 vs. 20.0 IU/l; P < 0.01) than patients who were not tested for HBV. However, HIV patients tested for HBV were less likely to be on a NVP-containing regimen (43 vs. 50%; P < 0.01) or receiving current anti-TB medications (10 vs. 40%; P < 0.01). They were also older {37 years [interquartile range (IQR) 21–44] vs. 36 years (IQR 31–43); P < 0.01} and had higher BMIs (20.1 vs. 20.0; P = 0.01) than the patients not tested for HBV.

The prevalence of HBV in the study cohort was 6.2% (1079/17 539). HIV/HBV patients were more likely to be male (50 vs. 34%; P < 0.01), younger [median age 36 years (IQR 31–41) vs. 37 years (IQR 31–44); P < 0.01], have significantly lower median CD4+ cell counts (101 vs. 116 cells/μl; P < 0.01), and BMIs (19.8 vs. 20.1; P < 0.01), and significantly higher median ALT (26.5 vs. 21 IU/l; P < 0.01) and ALT greater than 40 IU/l (29 vs. 16%; P < 0.01) at ART initiation compared to HIV patients. A higher proportion of HIV/HBV patients reported current alcohol consumption compared to HIV patients; however, the difference was not statistically significant (Table 1).

T1-8
Table 1:
Baseline characteristics of HIV-infected patients co-infected with HBV at ART initiation (N = 17 539).

Clinical and immunologic outcomes

Median follow-up time on ART was 18.6 (IQR 4.9–29.5) and 18.2 (IQR 4.2–27.2) months in HIV and HIV/HBV patients, respectively. The incidence of overall mortality in HIV and HIV/HBV patients was 6.16 deaths per 100 person-years and 7.74 deaths per 100 person-years, respectively. Over two-thirds of all deaths occurred within the first 6 months in each of the patient groups (Fig. 1). In multivariate analyses, mortality was higher in HIV/HBV than HIV patients; however, the finding did not quite reach statistical significance [hazard ratio 1.18 [95% confidence interval (CI) 0.98–1.42, P = 0.07] (Table 2). Mean CD4+ cell count changes/μl at 6 [71 (SD 5.9) vs. 77 (SD 1.5); P = 0.46] and 12 months [143 (SD 7.6) vs. 158 (SD 2.1); P = 0.05] were lower in HIV/HBV patients compared to HIV patients; at 12 months the finding was of borderline significance. When comparing the overall CD4+ cell count response between the two patient groups, HIV/HBV patients had significantly lower CD4+ counts throughout the period of recovery compared to HIV patients (P < 0.01; Fig. 2). During follow-up, 129 patients with known HBV status experienced at least one episode of ALT greater than 200 IU/l [110/16 426 HIV patients (0.6%) and 19/1071 HIV/HBV patients (1.8%)]. The corresponding incidence rate was 0.43 per 100 person-years (95% CI 0.33–0.53) in HIV patients and 1.16 per 100 person-years (95% CI 0.52–1.80) in HIV/HBV patients. A total of 322 of 16 303 (2.0%) and 40 of 1053 (3.8%) HIV and HIV/HBV patients developed an ALT greater than 120, respectively, with corresponding incidence rates of 1.29 per 100 person-years (95% CI 1.12–1.46) in HIV patients and 2.49 per 100 person-years (95% CI 1.55–3.43) in HIV/HBV patients. In multivariate analyses, there was a significantly higher risk of ALT above 200 IU/l [hazard ratio 2.30 (95% CI 1.39–3.81), P < 0.01] and ALT above 120 IU/l [hazard ratio 1.76 (95% CI 1.26–2.46), P < 0.01] after ART initiation in HIV/HBV patients compared to HIV patients, and a trend towards a higher risk of ALT above 40 IU/l [hazard ratio 1.17 (95% CI 1.00–1.36), P = 0.05] (Table 2, Fig. 3a, b). In both patient groups, over 75% of hepatotoxic events occurred within the first 12 months; the timing of ALT elevations (occurring < or > 12 weeks after ART initiation) at all ALT cut-offs did not significantly differ between HIV/HBV and HIV patients. The effect of HBV on hepatotoxic and mortality outcomes was unchanged after adjusting for HCV status (where known) in the multivariate models.

F1-8
Fig. 1:
Cumulative risk of mortality by HBV status.HBV, hepatitis B virus.
T2-8
Table 2:
Mortality and hepatotoxicity for HIV-infected patients co-infected with HBV.
F2-8
Fig. 2:
CD4+ cell count (cells/μl) trajectory by HBV status (P < 0.01).HBV, hepatitis B virus.
F3-8
Fig. 3:
Cumulative risk of hepatotoxicity by HBV status.(a) Cumulative risk of hepatotoxicity (ALT >200 IU/l) by HBV status. (b) Cumulative risk of hepatotoxicity (ALT >120 IU/l) by HBV status. ALT, alanine transaminase; HBV, hepatitis B virus.

To account for the possibility that nonadherence was biasing the results, sensitivity analyses were conducted examining mortality and hepatotoxicity among study patients just during the time since ART initiation that they remained adherent to care (that is consistently coming to clinic to collect ART refills within 35 days of consecutive clinic visits following ART initiation). The risk of mortality [hazard ratio 1.21 (95% CI 1.0–1.46), P = 0.04] and hepatotoxicity [ALT >120 IU/l hazard ratio 1.82 (95% CI 1.30–2.54), P < 0.01; ALT >200 IU/l hazard ratio 2.40 (95% CI 1.45–3.97), P < 0.01] remained higher in HIV/HBV compared to HIV patients than in the full study population although the mortality effect was now significant.

Effect of hepatitis B virus status on antiretroviral treatment outcomes by treatment regimen

When we examined immunologic, hepatotoxic, and mortality outcomes stratified by whether or not the patient had TDF (in addition to 3TC or FTC) in their antiretroviral regimen (i.e. two vs. one HBV active drug), we observed a significantly higher risk of mortality in HIV/HBV co-infected patients compared to HIV patients on ART that did not contain TDF [hazard ratio 1.28 (95% CI 1.02–1.61), P < 0.03], whereas there was no difference in the risk of mortality observed in HIV/HBV co-infected patients compared to HIV patients on TDF-containing ART [HR 0.70 (95% CI 0.34–1.44), P < 0.33]; the interaction, however, was not statistically significant (P = 0.30). The association between HBV status and hepatotoxic and immunologic outcomes was not modified by ART regimen (TDF-containing vs. non-TDF containing); interaction P-values greater than 0.05.

Discussion

In this large, urban Tanzanian HIV cohort we observed a relatively high prevalence of HBV similar to that reported in other cohorts in Tanzania and neighboring SSA countries [1]. HIV/HBV co-infection was associated with significantly lower CD4+ cell counts during the period of immune restoration, an almost 20% higher risk of mortality, and significantly increased risk of moderate-to-severe hepatotoxicity after ART initiation. Thus, we found that HBV impacts HIV treatment outcomes in our program population.

Our study is the first to demonstrate a significant impact of HBV on long-term immunologic response. Although several other studies have shown a significant association between HIV/HBV co-infection and low CD4+ cell counts prior to ART initiation [9,10,20–22], differences in subsequent immunologic recovery between HIV and HIV/HBV patients have not been observed. A limitation of these other studies is that they had significantly fewer HIV/HBV co-infected patients and were likely underpowered to detect a difference in CD4+ cell count response during follow-up of the magnitude we did in our study. Our findings support a potential immunosuppressive effect of HBV, which is thought to be due to HBV mediated destruction of CD4+ cells through T-cell activation or splenic sequestration resulting from advanced liver disease [20]. The exact mechanisms, however, are unknown. In two recent studies from Nigeria and Ghana, lower pretreatment CD4+ cell counts in HIV/HBV co-infected patients were found to be significantly associated with high HBV DNA levels and HBeAg seropositivity, suggesting the degree of HBV viral activity plays an important role [20,23]. Our findings of an association between HBV status and immunosuppression are highly relevant to the long-term management of HIV/HBV co-infected individuals. Lower CD4+ cell counts are strongly associated with higher HIV-related morbidity and mortality [24] and, in patients with HBV, a higher risk of liver-related mortality, cirrhosis, and hepatocellular carcinoma [25–27]. Thus HIV/HBV co-infected individuals clearly need to be monitored more closely for such complications in this setting.

Consistent with most other studies of viral co-infection in SSA and other settings, a significantly higher risk of moderate-to-severe hepatotoxicity was observed in our cohort of HIV/HBV patients compared with those with HIV [13,28–30]. Overall, the risk of hepatotoxicity was very low. Notably, only 16 of 130 (12%) HIV/HBV patients who died had an ALT greater than 120 at the time of death, suggesting hepatotoxic events did not significantly contribute to mortality (data not shown). Causes of transaminase elevations in HIV/HBV co-infected individuals after ART initiation include the direct toxic effect of antiretrovirals and other hepatotoxic medications (particularly TB therapies), or ‘flares’ related to the discontinuation of an HBV-active drug, the development of resistance, or immune reconstitution [31]. In a study from South Africa, grade III and IV hepatotoxic events in HIV/HBV co-infected individuals were found to be associated with high HBV DNA levels and most occurred after the first 12 weeks of ART leading the authors to conclude that development of HBV resistance or immune reconstitution was the most likely cause of these events [10]. In this study, over 75% of hepatotoxic events in HIV/HBV patients occurred within the first 12 months suggesting direct ART toxicity and immune reconstitution rather than the development of resistance were more likely. Further examining the correlation between transaminase elevations and HBV disease activity markers (HBV DNA and HBeAg status) would be useful to determine the cause of hepatotoxic events in this study. In addition the impact of these hepatotoxic events if any, on liver disease progression needs to be assessed.

We observed an almost 20% higher risk of mortality in HIV/HBV compared to HIV mono-infected individuals, an important finding despite only attaining borderline significance. Notably, mortality was high in both patient groups, particularly early after ART initiation. In SSA, other studies have observed a similar risk between HIV/HBV co-infected and HIV mono-infected patients [8,20,32]. This is in contrast to studies from the US and Europe where there is a significantly higher risk of mortality in HIV/HBV co-infected compared to HIV mono-infected populations, predominantly due to the rise in non-AIDS defining deaths in patients surviving longer on ART [7,33]. A more detailed analysis of causes of death is needed to determine whether similar rises in non-AIDS-defining causes of mortality in HIV/HBV co-infected individuals, are occurring in SSA as ART rollout continues. The individual findings of a significantly higher mortality in HIV/HBV compared to HIV patients on antiretroviral regimens not containing TDF and similar risk of mortality among HIV/HBV compared to HIV patients on regimens that did contain TDF are notable even though p value for interaction was not significant. In several SSA countries including Tanzania, the use of stavudine is now being phased out in favor of TDF in first-line regimens. TDF (in addition to 3TC or FTC) is preferred in HIV/HBV co-infected patients based on studies from US and other developed countries that have observed improved virologic recovery and lower rates of resistance in patients with HBV on both TDF and 3TC or FTC compared to 3TC alone [34,35]. Longer follow-up is needed to confirm whether mortality is also improved among HIV/HBV co-infected patients on TDF as suggested by our data and the underlying mechanisms involved.

Our study has a number of strengths which adds to the robustness of our findings, notably the large number of HIV/HBV-infected patients in our cohort, the relatively homogenous, urban population, and long duration of follow-up on ART. In other studies of HBV co-infection in SSA, the endpoint of mortality has rarely been examined, and we are the first to examine the effect of HBV on mortality by ART regimen, adding important new findings in this area. A number of limitations should be highlighted including, foremost, the lack of laboratory data on HBV DNA and HBeAg, both of which would have helped to provide additional insight into the relationship between HBV disease activity and hepatotoxic and mortality outcomes [10,36]. Of note, in a recent study from South Africa, the risk of hepatotoxicity was increased only among HBV patients with the highest DNA levels suggesting that the effect of HBV on hepatoxicity is not due to HBsAg alone [10]. In this study, no confirmatory testing of HBsAg was performed to confirm chronic HBV; however, since HBV is mostly acquired during childhood in SSA, it is unlikely that acute HBV was acquired recently in any of the patients. Antibodies to hepatitis delta (HDV) were also not measured; co-infection with HDV has been shown to significantly increase the risk of liver decompensation and mortality among patients with HBV [37]. HIV RNA levels were not routinely measured and thus virologic outcomes were not presented. Although mortality was included as an endpoint, specific causes of death were not examined which may have helped further elicit trends in non-AIDS-defining vs. AIDS-defining deaths as ART access improves. We can also not rule out selection bias which may have occurred when determining which patients were tested for HBV however, in most cases the decision to test for HBV was based on the availability of laboratory reagents. In addition, the differences in baseline characteristics between those tested for HBV and those not tested for HBV were minimal. Finally, information on possible confounders such as use of hepatotoxic agents (i.e. herbal agents) was not obtained which could have influenced the study outcomes. However, we were able to extensively control for other important confounders that have not been examined in other studies including ART regimen and TB treatment history both of which have been found to influence mortality and hepatotoxic outcomes in other studies [13,38].

In conclusion, HBV co-infection was observed to significantly impact ART outcomes in this large Tanzanian HIV cohort. The complex relationship between HBV, host immune response and its effect on long-term outcomes in HIV/HBV co-infected individuals requires further investigation. In addition, longer follow-up is needed to confirm the potential benefits of TDF in ART for HIV/HBV co-infected patients in SSA.

Acknowledgements

The authors thank Management and Development for Health (MDH), Dar es Salaam City, Kinondoni, Ilala, Temeke Municipal Councils, Muhimbili University of Health and Allied Sciences (MUHAS), Harvard School of Public Health (HSPH), and the Ministry of Health and Social Welfare for the guidance and collaboration in implementing a national HIV Care and Treatment program in Dar es Salaam, Tanzania.

This program is supported by the US President's Emergency Plan for AIDS Relief (PEPFAR) through the HSPH and by the Ministry of Health and Social Welfare, Tanzania. We thank all the patients and staff of the MDH-supported care and treatment sites who have contributed to these findings.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

antiretrovirals; chronic hepatitis B; HIV

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