Up to 20% of HIV-infected people in sub-Saharan Africa are co-infected with hepatitis B virus (HBV) , as defined by positive HBsAg test, however, screening for chronic HBV infection is often not performed routinely in patients infected with HIV. The prevalence of HBsAg+ HBV co-infection is around 17% among HIV-infected patients in Ghana with predominantly HBV genotype E . Progression of liver disease is more rapid in HIV/HBV co-infection , and there is also an increased risk of hepatotoxicity of antiretroviral drugs . It is unclear whether HBV infection affects progression of HIV infection, or response to antiretroviral therapy (ART), particularly in Africa where only two large studies have been reported [5,6]. Occult HBV infection is characterized by a negative HBsAg test with positive HBV DNA, usually in patients with positive anti-HBc antibodies, and is common in Africa and Europe [7–9]. Occult HBV/HIV co-infection is poorly characterized and it is not clear whether such individuals are at increased risk of hepatotoxicity of ART, what is their long-term risk of developing liver disease or how they respond to ART. The aim of this observational study was to assess whether occult HBV infection influenced the outcome of first-line nonnucleoside reverse transcriptase inhibitor-based ART in a cohort attending a single government clinic in Kumasi, Ghana.
Between 2007 and 2008, a randomly selected sub-population of adult patients attending the HIV clinic at Komfo Anokye Teaching Hospital in Kumasi, Ghana underwent screening for HBV infection by HBsAg (Determine-HBsAg; Inverness Medical, Stockport, UK), with HBsAg results confirmed by Murex-v3-enzyme-immunoassay (Abbott Diagnostics, Maidenhead, UK), and HBV-DNA using a quantitative real-time PCR assay with a lower limit of quantification of 14 IU/ml, as previously described . Of 140 patients identified with a positive HBsAg result (16.7% of the population screened), 120 had started ART and had sufficient data for analysis. Of 83 patients identified with negative HBsAg and positive HBV DNA [median 76 IU/ml, interquartile range (IQR) 29–226], representing 9.9% of the population tested (and 25.8% of all ART-naive patients), 35 were found to have subsequently started ART. First-line ART in Kumasi consisted of zidovudine (or stavudine if anaemic), lamivudine and either efavirenz or nevirapine (if women). Both groups of co-infected patients were compared with 230 patients who had started ART with negative HBsAg and HBV DNA, in relation to demographic data and cumulative CD4 cell counts, BMI, alanine and aspartate transaminases (ALT/AST) and clinical events. Patients were followed every 3–6 months, in addition to an additional visit 1 month after starting ART, and outcome measures were compared for 2 years. Continuous variables were compared by either paired or unpaired t-tests or analysis of variance, and categorical variables by chi-squared tests. The study was approved by the Committee on Human Research Publications and Ethics at the Kwame Nkrumah University of Science and Technology, Ghana.
Baseline demographic characteristics and BMI at the start of ART were similar between the three groups, however, patients with both occult and HBsAg+ co-infection had higher median CD4 cell counts than non-co-infected patients: 160 and 163 versus 120 cells/μl (P = 0.009). More patients with HBsAg+ co-infection had hepatotoxicity (mostly ACTG Grade 1) than occult HBV co-infected or non-co-infected patients at baseline, and a higher proportion of non-co-infected patients started ART containing zidovudine rather than stavudine: 61 versus 45 and 46% (P = 0.04). HBV DNA levels were higher in HBsAg+ co-infected than in occult co-infected patients (mean 55 450 versus 994 IU/ml, P < 0.001). Response to ART, as defined by the surrogate markers of increase in CD4 cell count and BMI, is shown in Fig. 1a and b. There was no significant difference in increase in either marker at 1–2 years between the three groups. There was also no difference in the proportions of patients experiencing major clinical events or defaulting follow up between the three groups. A higher proportion of occult HBV co-infected patients had raised ALT/AST 1 month after starting ART compared with the other groups (P < 0.001), however, by 6 and 12 months the proportion with hepatotoxicity had reduced to levels similar to HBsAg+ co-infected patients, which were slightly higher than non-co-infected patients (Fig. 1c). There were no clear instances of patients stopping or switching antiretroviral medications due to hepatotoxicity, and no correlation of hepatotoxicity with any particular antiretroviral drug was apparent.
Our previous study identified nearly half of all patients with occult HBV infection having mutations in the S-gene (coding for HBsAg), indicating a high level of diagnostic escape mutants, hence a substantial underdiagnosis of HBV co-infection in this population using standard HBsAg assays . A substantial proportion (26%) of all ART-naive patients had occult HBV/HIV co-infection, however, this may still have been an underestimate as previous longitudinal studies have suggested HBV DNA detection is often intermittent . This is to our knowledge the first comparative study to describe the response of patients with occult HBV/HIV co-infection to ART. Our study is limited by relatively small numbers of patients with occult HBV/HIV co-infection, the absence of HIV-1 viral load outcome data and by both HBV co-infection groups starting ART at slightly higher CD4 cell counts than the non co-infected group making comparisons of CD4 responses problematic. It is possible that this was due to more co-infected patients starting ART after 2008, when guidelines for CD4 criteria for starting ART changed. Nonetheless, these preliminary findings suggest patients with occult HBV/HIV co-infection respond equally well to ART as those patients without HBV co-infection or patients with HBsAg+ co-infection. Although a higher (and substantial) proportion of occult HBV/HIV co-infected patients had raised ALT/AST after 1 month of ART, most elevations were low-grade and were of limited clinical relevance as no patients stopped or switched ART subsequently. It is not clear whether these elevations were mostly due to drug-induced hepatotoxicity or immune reconstitution inflammatory syndrome, both of which may occur within the first few weeks of ART. Two further questions arise in relation to patients with occult HBV/HIV co-infection: are they at increased risk of developing liver disease, and if so is ART containing lamivudine, as the sole agent active against HBV, adequate to reduce that risk? Larger longitudinal studies of longer duration are needed to answer these questions.
We thank patients and staff at Komfo Anokye Teaching Hospital for assistance with this study. We are grateful to Mauli Patel for assistance with laboratory testing in London.
Support for this work was provided by the South Tees Infectious Diseases Research Fund and the Royal Society.
Contributions: D.C. and A.M.G. designed the study, analysed data and wrote the manuscript; A.S., M.A., S.S., L.A., U.S. and R.P. assisted with data collection and critically reviewed the manuscript; G.F. oversaw virological assays and sequencing.
Conflicts of interest
A.M.G.: consultancy and speakers’ bureau: Abbott, Bristol Meyers Squibb, Gilead, Glaxo Smith Klein, Merck, Monogram Biosciences, Pfizer, Tibotec, Roche, ViiV Healthcare, Virco. Research support: Monogram Biosciences, Pfizer, Merk, Tibotec, Roche, ViiV Healthcare, Virco. There are no conflicts of interest for the other authors.
1. Burnett RJ, François G, Kew MC, Leroux-Roels G, Meheus A, Hoosen AA, Mphahlele MJ. Hepatitis B virus and human immunodeficiency virus co-infection in sub-Saharan Africa: a call for further investigation
. Liver Int
2. Anna Maria Gerettii, Patel M, Sarfo FS, Chadwick D, Verheyen J, Fraune M et al.Detection of highly prevalent hepatitis B virus co-infection among HIV-seropositive persons in Ghana.J Clin Micro
3. Thio CL, Seaberg EC, Skolasky R Jr, Phair J, Visscher B, Munoz A, Thomas DL. Multicenter AIDS Cohort StudyHIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS)
4. Law WP, Dore GJ, Duncombe CJ, Mahanintharit A, Boyd MA, Ruxrungtham K, et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996–2001
5. Hoffmann CJ, Charalambous S, Martin DJ, Innes C, Churchyard GJ, Chaisson RE, et al. Multicenter AIDS Cohort StudyHepatitis B virus infection and response to antiretroviral therapy (ART) in a South African ART program
. Clin Infect Dis
6. Idoko J, Meloni S, Muazu M, Nimzing L, Badung B, Hawkins C, et al. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria
. Clin Infect Dis
7. N’dri-Yoman T, Anglaret X, Messou E, Attia A, Polneau S, Toni T, et al. Occult HBV infection in untreated HIV-infected adults in Côte d’Ivoire
. Antivir Ther
8. Reuter S, Oette M, Wilhelm FC, Beggel B, Kaiser R, Balduin M, et al. Prevalence and characteristics of hepatitis B and C virus infections in treatment-naıve HIV-infected patients
. Med Microbiol Immunol
9. Nebbia G, Garcia-Diaz A, Ayliffe U, Smith C, Dervisevic S, Johnson M, et al. Predictors and kinetics of occult hepatitis B virus infection in HIV-infected persons
. J Med Virol