Primary infection with a lamivudine-resistant hepatitis B virus

Hepatitis B virus (HBV) and HIV share common routes of transmission and are often found simultaneously in at-risk individuals. Antiretroviral therapies generally include lamivudine, which also possesses a strong activity against HBV replication. Unfortunately, prolonged treatment with this molecule is associated with the emergence of both HIV- and HBV-resistant strains. We now describe the case of an HIV-infected patient who, despite lamivudine treatment, developed an acute hepatitis B infection. This case raises several important questions about hepatitis B prevention and the treatment of lamivudine-resistant HBV. A 35-year-old man was diagnosed in April 1999 with HIV-1. Homosexuality was considered to be the main risk factor for HIV infection. In August 1999, HIV treatment was initiated with lamivudine (150 mg twice a day), stavudine (40 mg twice a day) and efavirenz (600 mg a day). This treatment was well tolerated and very efficient, achieving an undetectable HIV viral load and CD4 cell count of approximately 500/mm3. No clinical event occurred during the following year. He was admitted in January 2001 with severe jaundice, hyperthermia (38°C), major asthenia and persisting weight loss. Laboratory tests showed increased transaminase (aspartate aminotransferase 1038 UI/l; alanine aminotransferase 1775 UI/l), bilirubin (176 μM/l) and alkaline phosphatase (442 UI/l) plasma levels and a slightly increased prothrombin time (16.5/14.7). Antiretroviral treatment was stopped because of possible liver toxicity, and extensive laboratory testing was conducted. Apart from the alterations in liver function parameters, viral serologies did not show any markers for hepatitis C virus, hepatitis A virus, Epstein–Barr virus or cytomegalovirus primary infection. In contrast, hepatitis B surface antigen was positive concomitantly with the presence of hepatitis B core IgM and IgG and hepatitis B e antigen. The kinetics of the appearance of HBV markers in the past 6 months (Fig. 1) was retrospectively investigated on frozen samples and unambiguously permitted to diagnose a primary HBV infection. Of note was the fact that this patient had been under permanent lamivudine therapy (150 mg twice a day), known to be a potent inhibitor of HBV replication, since August 1999. It was therefore suspected that the HBV strain responsible for primary infection was resistant to lamivudine. Sequencing of the polymerase encoding region was performed on HBV DNA extracted from the two hepatitis B surface antigen-positive serums (November 2000 and January 2001). Both samples contained the now well-described lamivudine resistance conferring mutation rtM204V on the catalytic site (YMDD), associated with the upstream rtL180M change (polymerase numbering according to the recently proposed nomenclature [1]).Fig. 1.: Biological parameters of hepatitis B virus primary infection. The upper limits of normal are 32 and 35 IU/l for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), respectively. Hepatitis B virus (HBV) virological markers corresponding to several follow-ups are indicated in the table beneath. Antiretroviral and lamivudine (3TC) treatments are shown above the graph. AZT, Zidovudine; HBc, hepatitis B core; HBeAb, antibodies to hepatitis B e antigen or anti-HBe; HBeAg, hepatitis B e antigen; HBsAb, antibodies to hepatitis B surface antigen or anti-HBs; HBsAg, hepatitis B surface antigen; HBV-DNA, HBV viral load (Monitor, Roche, France); HIV VL, HIV viral load (Monitor). The arrows indicate the samples that were used to characterize HBV lamivudine resistance-specific mutations.This is, to our knowledge, the first report of a primary infection with a lamivudine-resistant HBV strain. This demonstrates the ability of such lamivudine-resistant HBV strains to be transmitted from one individual to another, and raises the problem of anti-HBV treatment in this particular setting. HBV resistance to lamivudine is very common in HIV–HBV co-infected patients, and the risk of the propagation of such resistant viral strains is of therapeutic concern because of rapidly evolving liver disease in the context of HIV–HBV co-infection [2,3]. The rather low HBV replication level in this case of primary infection (534 000 and 708 000 copies/ml, in November and January, respectively) could be explained by the decreased replication fitness of rtM204V/L180M mutants [4]. In other aspects, the natural history of this mutant HBV infection resembles that described for wild-type strains, with an incubation period exceeding 2 months, an absence of the direct cytopathogenicity of the virus, as shown by normal transaminase levels in November when the virus was detected in the absence of specific antibodies, and finally cytolysis contemporary to the immune response [5]. We may conclude from this case that HBV lamivudine-resistant strains may spread and could pose a problem with therapeutic management, especially in HIV-infected patients. Even though preliminary data using adefovir dipivoxyl seem promising, there is currently no approved drug to treat lamivudine-resistant HBV. Therefore, in the absence of serological markers for HBV immunization, HBV vaccination should be highly recommended in this high-risk group of patients. Of note was the fact that vaccination was denied to our patient because of a severe atopic history and dramatic anaphylactic events in response to several drugs. Vincent Thibaulta Camille Aubron-Olivierb Henri Aguta Christine Katlamab