An estimated 4–5 million patients are coinfected with HIV and chronic hepatitis C virus (HCV) worldwide.1 In the United States and other developed countries, the majority of studies have found no significant long-term impact of HCV on HIV virologic, immunologic, or clinical outcomes. Overall mortality rates have been shown to be similar in HIV/HCV-coinfected and HIV-monoinfected patients, although HIV-HCV patients are at higher risk of liver-related mortality specifically.2,3
The prevalence of HCV in HIV-infected individuals in sub-Saharan Africa ranges between 0% and 22%.4 The effect of HCV on HIV outcomes in these settings, however, is not well known. Competing risks, such as exposure to liver carcinogens, hepatotoxic therapies, including the antiretrovirals, nevirapine (NVP) and stavudine (d4T), and more advanced HIV immunosuppression in sub-Saharan Africa may put HIV/HCV-coinfected patients at higher risk of adverse outcomes compared with coinfected populations in the United States. In addition, HCV-specific antiviral therapies are rarely available in these settings.
In this evaluation, we studied participants enrolled at one of the largest President’s Emergency Plan for AIDS Relief (PEPFAR)–supported HIV care and treatment sites in Nigeria, the Jos University Teaching Hospital (JUTH), to determine whether chronic HCV infection impacts HIV disease or the early response to antiretroviral therapy (ART) in previous antiretroviral-naive patients.
The Harvard/AIDS Prevention Initiative in Nigeria PEPFAR program provides ART to eligible HIV-infected patients in Nigeria since June 2004. Eligibility criteria for ART include WHO stage IV, World Health Organization (WHO) stage III with CD4 <350 cells per cubic millimeter, or WHO stage I or II with CD4 ≤200 cells per cubic millimeter. Patients are assessed by physicians monthly and receive free ART and prophylaxis or treatment of opportunistic infections. Every 6 months, they receive immunologic and virologic monitoring. Standard first-line ART regimens include d4T or zidovudine, lamivudine, and efavirenz or NVP. More recently, Truvada (tenofovir and emtricitabine) has been recommended as a first-line alternative nucleoside reverse transcriptase inhibitor combination in Nigeria. Patients were recruited for participation and enrolled in the ART program after written informed consent. For this study, we included participants who initiated ART between October 2004 and June 2006, were HIV antibody positive, had a known HCV status, were hepatitis B surface antigen negative, and had a minimum of 6 months of follow-up on ART. This study was approved by the Institutional Review Boards at the JUTH, Harvard School of Public Health, and Johns Hopkins University.
HCV antibody was tested with a third-generation enzyme immunoassay assay (DIA PRO Diagnostic Bioprobes, Milan, Italy) at the time of inclusion into the PEPFAR program. HCV RNA was quantified retrospectively on serum specimens stored at −80°C using the COBAS Amplicor HCV Monitor test, which has a lower limit of detection of 42 IU/mL (v2.0; Roche Diagnostics GmbH, Mannheim, Germany). Hepatitis B surface antigen was determined by enzyme immunoassay assay (Sysmex, Kobe, Japan). HIV RNA was determined using the Roche COBAS Amplicor HIV-1 Monitor Test (Roche Diagnostics GmbH) with a lower limit of detection of 400 copies per milliliter. CD4+ T-cell count was determined via flow cytometry (Partec GmbH, Munster, Germany). Hepatotoxicity was defined as alanine aminotransferase (ALT) values (Sysmex, Kobe, Japan) that were at least 5-fold more than the normal range for the JUTH laboratory (upper limit of normal ALT = 41 IU/mL). All laboratory tests were performed according to the respective manufacturer specifications.
A participant was classified as HIV/HCV coinfected if they had evidence of chronic HCV infection, which was defined as a positive HCV antibody and detectable HCV RNA. All other participants were considered HIV monoinfected. The HIV-monoinfected group included participants who were HCV antibody positive with an undetectable HCV RNA because they were presumed to either have a past infection with spontaneous clearance or a false-positive HCV antibody.5,6 For these analyses, data up to 12 months were evaluated. For patients with >12 months of follow-up, data were censored at month 12.
Univariate methods were used to compare demographic and baseline clinical characteristics and virologic, immunologic, and hepatotoxic outcomes at weeks 24 and 48 between the HIV/HCV-coinfected and HIV-monoinfected groups; patients with elevated ALT at baseline were excluded for the hepatotoxic outcome evaluations at weeks 24 and 48. Baseline ALT was included in multivariate models as a continuous variable. The Pearson χ2 test or Fisher exact test was used for categorical variables, as relevant, and the Wilcoxon test for continuous variables. Variables with a P value of ≤ 0.20 were selected for inclusion into logistic regression modeling, which was conducted to further evaluate factors potentially related to hepatotoxicity. Cox-proportional hazards models were also generated using these data. All analyses were conducted using Stata version 10.1 (College Station, TX).
One thousand four hundred thirty-one HIV-infected participants were included in this study; of whom, 1352 (94%) were HIV-monoinfected (183 HCV antibody positive with undetectable HCV RNA; 1169 HCV antibody negative), whereas 79 (6%) were HIV/HCV coinfected (Table 1). The HIV/HCV-coinfected group was significantly older than the HIV-monoinfected group (median: 39 vs. 34 years, respectively; P < 0.001). The gender distribution was similar between the 2 groups. The median CD4+ T-cell count was 134 cells per cubic millimeter, and there were no statistically significant differences between the 2 groups (115 cells/mm3 for HIV/HCV coinfected and 135 cells/mm3 for HIV monoinfected, respectively; P = 0.43). Likewise, baseline HIV RNA levels were similar between groups (4.9 log copies/mL for HIV/HCV coinfected and 4.8 log copies/mL for HIV monoinfected, respectively; P = 0.12). HIV/HCV-coinfected patients had a significantly higher median baseline ALT than HIV-monoinfected patients (27.3 vs. 19.1 U/mL; P = 0.008). Overall, 0.21% of the participants had an ALT >5× upper limit of normal at baseline; there were no statistically significant differences in the proportion of patients with elevated baseline ALT between HIV/HCV-coinfected and HIV-monoinfected patients (0% vs. 0.23%, P = 1.00). There were no significant differences in ART regimen by HCV status.
Hepatitis C and ART Response
The proportion of HIV/HCV-coinfected and HIV-monoinfected patients achieving an undetectable HIV RNA did not differ at either 24 (65% vs. 70%, P = 0.40) or 48 weeks (55% vs. 61%, P = 0.30) (Table 2). In addition, there were no significant differences in the median CD4+ T-cell count increase between HIV/HCV-coinfected and HIV-monoinfected patients at either 24 (90 vs. 88 cells/mm3, respectively; P = 0.41) or 48 weeks (111 and 129 cells/mm3, respectively; P = 0.32). Overall, the proportion of HIV/HCV subjects who developed hepatotoxicity was small at 24 weeks (6.35%) and declined further to 2.82% at 48 weeks.
In logistic regression modelling, after adjusting for age, d4T use, and sex, HIV/HCV coinfection [adjusted odds ratio (aOR) = 19.3; 95% CI: 4.41 to 84.4] and baseline ALT (aOR = 1.01; 95% CI: 1.00 to 1.03) were significant predictors of increased risk for hepatotoxicity at 24 weeks. After adjusting for d4T use and baseline ALT, HIV/HCV coinfection (aOR = 56.7; 95% CI: 5.03 to 636.92) increased the risk for hepatotoxicity at 48 weeks, whereas female sex (aOR = 0.05; 95% CI: 0.004 to 0.62) and older age (aOR = 0.81; 95% CI: 0.68 to 0.95) were protective against hepatotoxicity at 48 weeks. Data from survival analysis and Cox proportional hazard models provided similar results (not shown).
In one of the few studies to date of the effect of HCV on HIV treatment outcomes in sub-Saharan Africa, we observed comparable HIV and immunologic responses to ART between HIV/HCV-coinfected and HIV-monoinfected populations. The proportion of subjects who experienced an elevated ALT was small, although the HIV/HCV-coinfected group had a significantly higher risk of hepatotoxicity at both 24 and 48 weeks after ART initiation. Thus, we found that HCV does not significantly impact response to ART in the short term in our program population.
The overall prevalence of HCV in this cohort was noted to be similar to United States–based studies and other recent studies in Nigeria.7 The predominant mode of HCV transmission in sub-Saharan Africa is still unknown although iatrogenic causes such as unsterile injections are thought to be common.8 Interestingly, HCV antibody was detected in 262 of 1431 (18.3%) patients in this cohort, but the prevalence of chronic HCV, defined as detectable HCV RNA, was only 6%. Few sub-Saharan Africa studies have used molecular methods to determine the prevalence of HCV; these may be important given recent concerns about false-positive HCV antibody testing in sub-Saharan Africa. In a cohort of HIV-infected pregnant women in Malawi, only 2 of 108 women who were anti–HCV positive had a positive recombinant immunoblot assay suggesting recent or past infection and all were HCV RNA negative.5 In the Rakai Community Cohort Study from Uganda, a high prevalence of HCV seroreactivity (14%) was observed in patients without evidence of HCV viremia.6 Collectively, these findings suggest that HCV RNA testing is needed to determine the true prevalence of chronic HCV coinfection in HIV cohorts in sub-Saharan Africa.
In this study, there were no significant differences in CD4+ T-cell counts and HIV RNA levels at either baseline or after ART initiation between HIV/HCV-coinfected and HIV-monoinfected groups. The findings are consistent with most other studies on HIV/HCV coinfection in sub-Saharan Africa and developed countries,2,3,9 but differ from HIV/hepatitis B virus coinfection where CD4+ T-cell counts are lower at baseline with chronic hepatitis B.10
Although the finding was not significant, we did observe slightly less robust changes in CD4+ T-cell counts at 24 and 48 weeks after ART initiation in HIV/HCV-coinfected patients compared with HIV-monoinfected patients. Poorer immunologic recovery after ART initiation has been observed in other studies, especially within the first 24 weeks; however, the impact of this initial impaired immune response is thought to have little if any effect on overall morbidity or mortality.11 Encouragingly, we found that there was no effect of HCV on HIV virologic response after ART initiation, which is consistent with other studies from Nigeria,12 suggesting there is minimal effect of HCV on the efficacy of ART in controlling HIV viral replication.
Although there was a significantly higher rate of hepatotoxicity among HIV/HCV-coinfected patients compared with HIV-monoinfected patients at 24 and 48 weeks after ART initiation, the percentage of patients with hepatotoxicity was low. We were not able to correlate these hepatotoxic events with clinical status, and it is unknown if severe elevations in ALT resulted in any significant morbidity or mortality. A number of studies have found HCV and hepatitis B virus to be associated with increased risk for elevated transaminases after ART initiation in HIV-infected individuals.13,14 Notably, the overall incidence of severe elevations (>5× upper limit of normal) even in resource-limited settings is small and most cases are asymptomatic.13 Several mechanisms of hepatotoxicity after ART initiation have been proposed, including: immune-mediated damage to HCV-infected hepatocytes from immune reconstitution syndrome, direct effects of drug toxicity, and steatosis from antiretroviral agents resulting in accelerated inflammation and fibrosis. Of particular concern is the effect of more hepatotoxic ART drugs, such as d4T, didanosine, NVP, and lopinavir/ritonavir, which may also contribute to hepatic damage in HIV-infected populations.15 In this cohort, we did not find an association between specific ART and hepatotoxic events in the short term (see Table, Supplemental Digital Content 1, http://links.lww.com/QAI/A372). Additional research is needed into pathogenesis of these hepatotoxic events and the effect of these events on long-term liver-related outcomes.
To our knowledge, this is the largest study of HIV/HCV-coinfected individuals in sub-Saharan Africa, where HCV infection was confirmed by both serologic and molecular methods, providing more accurate data about the true prevalence of chronic HCV infection in HIV-infected populations in these settings. We were also able to assess HIV virologic endpoints in a setting where HIV RNA testing is not routinely available, further confirming the findings from developed countries of minimal effect of HCV on response to ART. Limitations of this study included the relatively short follow-up period after ART initiation, which prevented us from determining whether HCV has any long-term effect on HIV outcomes. Data on important confounders such as alcohol consumption, status of underlying liver disease, and TB therapy were not available. Furthermore, we could not determine whether there was any significant effect of HCV on mortality or other morbidities in HIV-infected individuals including long-term liver-related complications.
In summary, HCV RNA testing is important for the diagnosis of chronic HCV infection in sub-Saharan Africa. Our data demonstrate that HIV/HCV-coinfected patients respond as well to ART as HIV-monoinfected subjects. Because the risk of severe hepatotoxicity was small, ART should not be withheld from HIV/HCV-coinfected patients in sub-Saharan Africa, but coinfected patients should be monitored more closely for hepatotoxicity.
The authors are thankful to the staff and patients of the HIV Clinic at JUTH, Harvard PEPFAR, and AIDS Prevention Initiative in Nigeria programs for supporting the care of HIV patients at JUTH.
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