HBV Precore Mutants

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HBV Precore Mutants Associated with Higher HBV Replication in Patients with Lamivudine Resistance

By Brian Boyle, MD

Chronic hepatitis B virus (CHB) infection is a leading cause of liver disease and death worldwide. Hepatitis B e antigen (HBeAg) negative CHB results from the selection of hepatitis B virus (HBV) unable to secrete HBeAg. HBeAg-negative CHB has become the major form of HBV disease in many parts of the world.

Several mutations can cause HBeAg-negative CHB, the most common of which is a guanine to adenine transition at nucleotide position 1,896 (G1896A). This change, which creates a stop codon at codon 28 of the precore (PC) protein, causes premature termination of the PC protein.

The only therapeutic agents approved for treatment of HBV are interferon alfa, Epivir-HBV (lamivudine) and Hepsera (adefovir). Epivir-HBV and Hepsera are considered to be just as, if not more, effective as interferon alfa, but are safer and better tolerated.

Unfortunately, resistance to Epivir-HBV increases with the duration of therapy, rising to as high as 66% after 3 years. The YMDD (tyrosine-methionine-aspartate-aspartate) motif is most common mutation conferring Epivir-HBV resistance and affects the active site YMDD in the C domain of the HBV polymerase protein, causing the methionine (M) residue to be replaced with either isoleucine or valine.

Patients experiencing Epivir-HBV failure usually have an acute exacerbation of their liver disease and long-term data indicate that liver histology worsens in conjunction with the rising HBV viral loads.

During Epivir-HBV therapy for HBV, drug resistance develops at a similar rate in patients with HBeAg positive or HBeAg negative disease. In the absence of PC mutations, Epivir-HBV resistant HBV mutants have been shown to replicate inefficiently in vitro; however, it is unknown whether the presence of PC mutations affects replication efficiency or antiviral sensitivity. In a study published in Hepatology, a recombinant HBV baculovirus system was used in an effort to address these issues.

In the study, HBV baculoviruses encoding the G1896A PC stop codon mutation were generated in wild-type (WT) and Epivir-HBV resistant backgrounds, resulting in a panel of 6 related recombinant HBV baculoviruses. In vitro assays were performed to compare the sensitivities of the PC mutant viruses with Epivir-HBV and Hepsera (adefovir) and to compare relative replication yields.

These assays indicated that the PC mutation does not significantly affect sensitivities to either Hepsera or Epivir-HBV. Wild-type HBV and PC mutant HBV showed similar levels of replication, whereas the replication levels of the Epivir-HBV resistant mutants were greatly reduced in HBeAg positive HBV. However, the presence of the PC mutation was found to compensate for the replication deficiency in each of the Epivir-HBV resistant mutants, increasing the replication yields of each virus.

The authors conclude, "These observations have direct clinical relevance in the setting of lamivudine therapy for HBeAg negative CHB. In a recent study of Greek patients with HBeAg negative CHB, Hadziyannis et al. noted that virological breakthrough because of the development of HBV resistance to lamivudine was almost invariably followed by serum alanine aminotransferase elevations.

"The elevations exceeded baseline values in almost 75% of patients and reached greater than 8 times the upper limit of normal in the majority of cases, increases that were more characteristic of acute hepatitis. The restoration of the replication yield for the lamivudine-resistant HBVs also containing the G1896A precore stop codon provides a possible basis for the disease exacerbation observed in these patients.

"Because the G1896A precore mutant is an "immune elimination escape" mutant, HBeAg negative lamivudine-resistant HBVs, which replicate more efficiently and produce higher viral loads, may become directly cytopathic. Alternatively, the selection of these viruses means that new viral epitopes may now be presented to the immune system, resulting in increases in necroinflammatory activity.

"Closer virologic and biochemical monitoring of HBeAg negative CHB patients undergoing long-term lamivudine monotherapy would appear warranted. Taken collectively, the clinical and virologic data strongly support the case for the use of alternative drugs and combination chemotherapy. Such strategies can be expected to minimize the long-term risk for the development of drug resistant virus, especially in the setting of HBeAg negative CHB."

01/03/03

Reference
R Chen and others. Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro. Hepatology 2003; 37:27-35.


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