Publications
| Genotypic Analysis of Lamivudine-Resistant Hepatitis B Virus in Chronic Patients Following Withdrawal of Long Term Lamivudine Treatment |
Authors: C. OSIOWY*, A. CHATTERJEE, E. GILES, J. BORLANG, T. MAZZULLI, J. HEATHCOTE National
Background:
Objectives: Maintenance of chronic Hepatitis B virus (HBV) patients on lamivudine (LMV) therapy despite the presence of drug-resistant HBV is a largely unresolved issue. Continuation of LMV therapy may lead to deleterious effects due to LMV-enhanced replication; however, treatment withdrawal is associated with reappearance of wild type (w.t.) virus, often followed by severe hepatitis flares. In this study, regions of the HBV genome from drug-resistant patients were sequenced and analyzed for the presence of mutations prior to and following the cessation of LMV treatment. The objective of the study was to determine a possible genotypic basis for observed HBV viral load levels following stopping LMV therapy.
Method: Nine HBV patients showing phenotypic LMV resistance were studied at approx. 3 to 6 month intervals during therapy and after treatment withdrawal. HBV DNA was extracted from serum specimens obtained at each study time point and amplified by PCR for sequence analysis. The YMDD motif region of the polymerase gene was also cloned in order to analyze strain populations over time.
Results: Following LMV withdrawal, 5 patients showed a typical pattern of rising HBV viral load with a shift from mutant to w.t. genotype within approx. 3 months. Several patients had decreasing viral loads following treatment cessation, and surprisingly, mutant virus was the dominant population for months following LMV withdrawal, with one case persisting for almost 1 year. Compensatory mutations within the polymerase gene were also observed in these patients.
Conclusions: Withdrawal of LMV therapy in patients having HBV drug resistance mutations normally results in rebound viral load levels with concurrent replacement of w.t. virus as the dominant population. In certain individuals, however, persistent LMV-resistant virus is observed in the presence of decreasing viral load. This is a unique observation, and suggests the presence of LMV dependency or the suppression of w.t. virus in these individuals.
Presented At:
72nd Conjoint Meeting on Infectious Diseases, Regina, Saskatchewan, 11/7/2004.
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1999 Microbiology Department, Mount Sinai Hospital, Toronto, ON, Canada.
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