COMMENTARY

New Developments in the Management of Hepatitis B Virus/HIV Coinfection

Raymond T. Chung, MD

Disclosures

September 03, 2002

In This Article

HBV: Genomic Organization and Viral Lifecycle

HBV, like HIV, is both a blood-borne pathogen and a sexually transmitted disease. A member of the hepadnavirus family, HBV is a partially double-stranded DNA virus with a complex lifecycle.[1] Following entry into the hepatocyte, the viral DNA genome moves to the nucleus, where the partial double-strand becomes fully double-stranded and assumes a highly stable conformation in the nucleus. This DNA becomes the template for transcription of the 4 major gene products of the virus: S, core, pol, and X proteins. The HBV pol product is a dual-function DNA polymerase that carries out not only DNA-dependent DNA replication but also RNA-dependent DNA replication (reverse transcriptase) activity in synthesizing first-strand cDNA off the pregenomic RNA template. The S protein forms the outer envelope and can be detected as HBsAg. The core protein is produced from a fusion precore-core protein, which is proteolytically processed to yield the mature core as well as HBeAg, a surrogate marker of active HBV replication. The X protein's function is not fully defined but it appears to act as an activator of a variety of host growth-related genes.

Liver disease, in the form of a chronic inflammatory hepatitis, is mostly confined to persons who harbor replicative disease, usually marked by the active secretion of HBeAg and the detection of large copy numbers of HBV DNA (typically > 100,000 copies/mL) by PCR or a comparable amplification assay. Occasionally, a mutant form known as the precore mutant -- so named because a mutation leads to the premature truncation of the HBeAg in the precore portion of the core gene -- will produce a comparable clinical picture, but without detectable HBeAg. In this situation, detection of large copy numbers of HBV DNA will permit distinction from persons who are simple HBsAg carriers.[1]

Chronic replicative HBV causes liver disease because of a vigorous response directed at virus-infected hepatocytes by the cytolytic T lymphocyte.[1] While immunosuppression secondary to solid organ transplantation, receipt of chemotherapy or corticosteroids, or infection with HIV may diminish the strength of the cellular immune response and therefore modulate liver injury in the short term, HBV replication (and appearance of its markers) is enhanced under these conditions. Indeed, over the long term, it appears that the equilibrium between viral replication and host immune response is sufficiently perturbed to adversely affect the natural history of chronic HBV.

Thus, conditions that favor return of a functional immune response, while they may transiently worsen the course of HBV-related liver disease by recognizing target cells harboring significantly elevated levels of viral antigen, would with time be expected to restore a more favorable equilibrium. Indeed, there are reports of the development of immune reconstitution-related flares of HBV following initiation of HAART.[2] While these flares are uncommon in light of the inclusion of lamivudine in most HAART regimens, a flare should be suspected when serum liver enzymes rise, sometimes dramatically, within the first 12 weeks of initiation of HAART in an HBsAg-positive person. The recommendation that all HIV-infected persons be assessed for HBV status before antiretroviral therapy is initiated should permit selection of appropriate regimens to minimize the occurrence of flares.

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