Lack of ‘occult’ hepatitis B virus infection in HIV-infected patients

Abstract

Despite the normalization of transaminases and seroconversion after primary hepatitis B virus (HBV) infection, most adults do not eradicate the virus. HBV DNA has been detected by polymerase chain reaction (PCR) in serum and in peripheral blood mononuclear cells a long time after recovery from HBV infection [1,2]. Moreover, the reactivation of HBV infection after its apparent clearance may occur spontaneously and, more frequently, after immune suppression [3–5]. In addition, HBV DNA may persist in the liver after the loss of hepatitis B serum antigen (HBsAg) in the serum [6]. All these findings support the concept that HBV not only does not go away but somehow may remain ‘active’ after primary infection. Occult hepatitis B has been defined as the presence of low levels of serum HBV DNA, often only detected by PCR, in HBsAg-negative individuals [7]. The prevalence of this phenomenon has been claimed to depend on the level of endemicity of HBV in a region or specific population. It may be more frequent in individuals with hepatitis C virus (HCV) co-infection [8,9]. Among the underlying mechanisms that could explain the lack of other serological markers of HBV replication in individuals with positive serum HBV DNA are an interference between HBV and HCV, and the selection of HBV ‘escape variants’ caused by mutations in the S gene precluding HBsAg synthesis [10,11]. We hypothesized that states of immunosuppression, such as HIV infection, might result in a more frequent escape of HBV replication in individuals ‘cured’ after a previous episode of acute infection. Chronic states of low-level HBV replication might lead to breakthrough HBV viraemia and overt hepatitis (HBV reactivation) at some point in HIV-infected individuals. On the basis of this rationale, we searched for the presence of serum HBV DNA using a sensitive PCR assay in a cross-sectional study conducted on a large group of well-characterized HIV-positive patients with past exposure to HBV. All HIV-infected patients with negative serum HBsAg, positive anti-hepatitis B core antibodies, and not receiving lamivudine or tenofovir attending our clinic during 2000 were selected for the study. The main demographics and laboratory data from this population were recorded, including CD4 cell counts, plasma HIV-RNA and transaminase levels. A frozen sera retrieved from these individuals was tested for the presence of HBV DNA using an ultrasensitive quantitative PCR assay (HBV Monitor, Roche Diagnostics, Almere, the Netherlands), which has a lower limit of detection of 200 HBV-DNA copies/ml. A total of 85 patients (64 men and 21 women), with a median age of 37 years, were included in the study. The median (range) CD4 lymphocyte count was 506 (48–1485) cells/mm3, and the median (range) plasma HIV-RNA level was less than 50 (< 50–175 764) copies/ml. Most subjects were former intravenous drug users, and were anti-HCV positive. Median (range) transaminase levels were aspartate aminotransferase 49 IU/ml (14–328) and alanine aminotransferase 57 IU/ml (11–465). Serum HBV DNA was undetectable in all the subjects. Occult hepatitis B has been a matter of debate over the past few years [8–11], given its clinical and epidemiological implications. In HIV-infected patients, who often are co-infected with HCV, the recognition of silent HBV infections may be of particular relevance. On one hand, more severe HCV liver disease and much poorer response to interferon-based anti-HCV therapy may occur in individuals with low-level HBV replication [9,12–15]. The mechanism for the latter effect may be the downregulation of the interferon receptor gene expression in the liver by HBV [16]. On the other hand, a reactivation of HBV infection may eventually occur as a result of the immune suppression associated with HIV, as has been reported for cancer patients receiving chemotherapy [4,5,17,18]. Our results suggest that occult HBV infection is not a frequent phenomenon (if it exists at all) among HIV/HCV co-infected individuals. The population we studied included patients with a wide degree of immunosuppression, and yet a sensitive PCR failed to detect HBV DNA in any single specimen. The reasons for the discrepancy between our data and other studies, in which up to 46% of anti-hepatitis B core-positive/HBsAg-negative individuals were HBV DNA positive, are unclear [8–11]. However, an interference with HCV, known to inhibit HBV replication, does not explain the difference, given that many of those studies included HCV-infected patients [19]. Differences among the assays used might largely explain the discordance across studies. Whereas occult HBV infection with low levels of HBV replication could explain poorer responses to anti-HBC therapy and the resurgence of overt HBV hepatitis, our results suggest that this eventuality is rather rare in the setting of HIV infection.