Low Prevalence of Ongoing Hepatitis B Viremia in HIV-Positive Individuals with Isolated Antibody to Hepatitis B Core Antigen

To the Editor: An isolated antibody test for IgG antibody to hepatitis B core antigen (anti-HBc) is frequent in HIV-1–infected individuals, especially if they are coinfected with hepatitis C virus (HCV). 1–4 In a recent study, 42% of HIV-positive subjects who were negative for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface antigen (anti-HBs) were positive for anti-HBc. 5 This finding may represent resolved hepatitis B virus (HBV) infection with loss of anti-HBs, occult chronic HBV infection with loss of detectable HBsAg, or a false-positive result. Occult HBV infection is generally defined as a positive test for HBV DNA in a patient who has negative HBsAg and anti-HBs. 6 The frequency of hepatitis B viremia in patients with isolated anti-HBc is controversial. In a study of HIV-1–negative individuals with HCV infection, occult HBV infection was described in 33% of subjects and was more frequent in those with isolated anti-HBc. 7 In a study of HIV-1–infected subjects, HBV DNA was found in ∼60% of subjects with isolated anti-HBc. 8 However, in a recent study of 85 HIV-1–positive subjects with isolated anti-HBc, no patient was HBV DNA positive. 9 Thus, the relative contribution of occult hepatitis B viremia to the high frequency of isolated anti-HBc in patients with HIV-1 infection is still uncertain. We prospectively tested 84 HIV-1–infected individuals who were negative for HBsAg and anti-HBs for both anti-HBc and HBV DNA. To detect HBV DNA, we used an ultrasensitive assay (HBV TMA Assay; Gen-Probe, Inc., San Diego, CA). This qualitative test has demonstrated 95% detection of HBV DNA at ≥15 IU/mL (1 IU = 3–6 genome equivalent of HBV). This threshold of detection is much lower than those for many commercially available quantitative tests for HBV DNA (eg, the Hepatitis B Virus DNA Ultraquant test (Specialty Labs, Santa Monica, CA) measures values down to 0.01 pg/mL or ∼1500 copies/mL). Of 84 HIV-positive persons who were negative for HBsAg and anti-HBs, we found that 42 (50%) were positive for anti-HBc (isolated anti-HBc). Individuals coinfected with HIV and HCV were more likely to have isolated anti-HBc than were subjects with HIV infection alone (80% vs. 29%, respectively; P < 0.001). Subjects who were negative for anti-HBc had current and nadir CD4 cell counts similar to those of patients who had isolated anti-HBc (mean current CD4 cell count, 431 vs. 445/mm3, respectively; mean nadir CD4 cell count, 203 vs. 254/mm3, respectively; both comparisons not significantly different by the Wilcoxon rank sum test [Table 1]). In a multivariate model, isolated anti-HBc was associated with HCV antibody seropositivity but not with age, current and nadir CD4 cell counts, HIV-1 RNA level, or use of antiretroviral therapy (Table 2).TABLE 1: Risk Variables for HIV-Positive Subjects Who Tested Negative for Anti-HBs and HBsAgTABLE 2: Multivariate Analysis of Potential Risk Variables Associated with Isolated Anti-HBc in an HIV-1–Positive CohortThe 84 subjects were then tested for HBV DNA with an ultrasensitive assay. As expected, no subject who was negative for anti-HBc had detectable HBV DNA. Of 42 subjects positive for isolated anti-HBc, only 1 was positive for HBV DNA by ultrasensitive testing. This subject had documented HBV infection 7 years previously (HBsAg positive, anti-HBs positive), with subsequent loss of HBsAg and anti-HBs. Thus, the prevalence of HBV DNA positivity among this population of HIV-positive subjects with isolated anti-HBc was 2.4% (95% confidence interval, 0.06%–12%). The finding that 1 patient with documented previous hepatitis B infection had positive HBV DNA but negative HBsAg supports that idea that occult hepatitis B viremia may occur even after apparent clearance of infection (as judged by surface antigenemia). However, our study also shows that only a small proportion of HIV-positive subjects with isolated anti-HBc will have detectable HBV DNA using an ultrasensitive assay. There are several possible explanations for the low prevalence of HBV DNA among anti-HBc–positive subjects in this study. First, the level of hepatitis B viremia may have been lower than the threshold of detection of the assay used in this study. To address the issue of sensitivity, we used a qualitative assay with a threshold of detection much lower than those of quantitative assays used clinically. Second, a significant proportion of our subjects was receiving antiretroviral therapy that could affect HBV DNA levels: 50% were taking lamivudine, 4.8% were taking tenofovir, and 4.8% were taking tenofovir plus lamivudine. The average duration of use of ≥1 of these medications in our cohort was 32 months (range, 1–78 months). Although the rate of resistance to lamivudine is high (up to 20% after 12 months of use of the drug 10), use of this agent or tenofovir may have suppressed HBV levels in some patients. However, we also did not find HBV DNA in any of the subjects who were not receiving therapy that suppresses HBV. Finally, the low prevalence of HBV DNA among our cohort may be explained by the lack of ongoing occult infection with this virus. In conclusion, in HIV-positive individuals, isolated anti-HBc is common and is associated with HCV coinfection. Patients with HIV/HCV coinfection who do not have serologic evidence for HBV when screened with HBsAg and anti-HBs will be positive for anti-HBc in over three quarters of cases. A positive HBV DNA test is uncommon for HIV-positive subjects with isolated anti-HBc, even when an ultrasensitive qualitative assay is used. Thus, ongoing occult hepatitis B viremia in HIV-positive patients with isolated anti-HBc is rare. The implication of this finding for whether such individuals should be immunized against hepatitis B is under investigation. Rajesh T. Gandhi, MD Alysse Wurcel, BS Barbara McGovern, MD Hang Lee, PhD Janet Shopis, BS Colleen P. Corcoran, NP Sarah Toner, BS Christina Giachetti, PhD Janel Dockter Paul E. Sax, MD Chinweike Ukomadu, MD, PhD