Prevalance and Characterization of Lamivudine-Resistant Hep B
Objective: To determine the prevalence of hepatitis B virus (HBV) genotypic resistance to lamivudine, identify risk factors associated with lamivudine resistance, and characterize the pattern of HBV polymerase mutations in patients co-infected with HIV.
Design: Retrospective cross-sectional study.
Methods: Thirty-three chronic HBV-infected patients were identified from a cohort of 1719 HIV-infected individuals. Patient information was collected from case records, HBV DNA was measured on stored serum by polymerase chain reaction, and positive samples underwent sequencing of HBV polymerase, basal core promoter and precore regions.
Results: Three groups of patients were identified: group 1 were viraemic in the absence of lamivudine-resistance mutations, group 2 were viraemic in association with lamivudine-resistance mutations, and group 3 were not viraemic. Group 2 patients with lamivudine-resistant mutations had significantly higher HBV-DNA viral loads but did not differ in duration of lamivudine therapy, HBV genotype, HIV viral load or CD4 cell count compared with patients with wild-type HBV. Group 2 individuals also demonstrated significantly higher serum alanine aminotransferase (ALT) levels than group 1, who were higher than group 3. Unique mutations were detected in HBV polymerase, including rtV173L plus rtL180M plus rtM204V, which occurred in three patients. This virus has the in-vitro characteristics of a 'vaccine escape' mutant of HBV.
Conclusion: Genotypic HBV lamivudine resistance was found in 39% of HIV-HBV co-infected individuals treated with lamivudine as part of highly active antiretroviral therapy. These patients exhibited significantly elevated HBV viral loads and serum ALT, and three were infected with a lamivudine-resistant HBV strain that was potentially transmissible to HBV-vaccinated individuals.
Serological evidence of hepatitis B virus (HBV) infection is found in up to 90% of HIV-infected individuals worldwide, with considerable variation in prevalence according to geographical region and exposure risk. HIV co-infection results in considerable modification of the natural history of HBV infection, and is associated with higher rates of chronic infection as well as higher HBV-DNA levels, lower serum alanine aminotransferase (ALT) levels, and milder histological necro-inflammatory activity. Despite this, progression to cirrhosis is more common. Lamivudine is a nucleoside analogue that suppresses both HIV and HBV replication by inhibition of the reverse transcriptase of both viruses. The fficacy of lamivudine against HBV has been demonstrated in HIV-uninfected as well as HIV-HBV co-infected individuals. Unfortunately, the efficacy of lamivudine is limited by the emergence of resistance strains containing mutations that typically occur in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the catalytic domain (domain C) of the polymerase gene of both viruses. Mutations at this site of the HBV polymerase gene are of particular significance as the major neutralizing epitope of the envelope protein, the 'a' determinant, is also encoded in this region in an overlapping frame-shifted reading frame. Prolonged lamivudine therapy has been identified as the major risk factor for the development of resistance, and HIV-HBV co-infected individuals develop resistance at a rate of 20% annually, with projected rates of 90% after 4 years of therapy, which are marginally higher than rates in HBV patients not infected with HIV.
This study was performed to determine the prevalence of lamivudine resistance in a cohort of HIV-HBV co-infected individuals receiving lamivudine as a component of highly active antiretroviral therapy (HAART), to delineate the risk factors associated with the development of antiviral resistance and to characterize the genetic patterns of drug-resistant HBV.
Objective: To determine the prevalence of hepatitis B virus (HBV) genotypic resistance to lamivudine, identify risk factors associated with lamivudine resistance, and characterize the pattern of HBV polymerase mutations in patients co-infected with HIV.
Design: Retrospective cross-sectional study.
Methods: Thirty-three chronic HBV-infected patients were identified from a cohort of 1719 HIV-infected individuals. Patient information was collected from case records, HBV DNA was measured on stored serum by polymerase chain reaction, and positive samples underwent sequencing of HBV polymerase, basal core promoter and precore regions.
Results: Three groups of patients were identified: group 1 were viraemic in the absence of lamivudine-resistance mutations, group 2 were viraemic in association with lamivudine-resistance mutations, and group 3 were not viraemic. Group 2 patients with lamivudine-resistant mutations had significantly higher HBV-DNA viral loads but did not differ in duration of lamivudine therapy, HBV genotype, HIV viral load or CD4 cell count compared with patients with wild-type HBV. Group 2 individuals also demonstrated significantly higher serum alanine aminotransferase (ALT) levels than group 1, who were higher than group 3. Unique mutations were detected in HBV polymerase, including rtV173L plus rtL180M plus rtM204V, which occurred in three patients. This virus has the in-vitro characteristics of a 'vaccine escape' mutant of HBV.
Conclusion: Genotypic HBV lamivudine resistance was found in 39% of HIV-HBV co-infected individuals treated with lamivudine as part of highly active antiretroviral therapy. These patients exhibited significantly elevated HBV viral loads and serum ALT, and three were infected with a lamivudine-resistant HBV strain that was potentially transmissible to HBV-vaccinated individuals.
Serological evidence of hepatitis B virus (HBV) infection is found in up to 90% of HIV-infected individuals worldwide, with considerable variation in prevalence according to geographical region and exposure risk. HIV co-infection results in considerable modification of the natural history of HBV infection, and is associated with higher rates of chronic infection as well as higher HBV-DNA levels, lower serum alanine aminotransferase (ALT) levels, and milder histological necro-inflammatory activity. Despite this, progression to cirrhosis is more common. Lamivudine is a nucleoside analogue that suppresses both HIV and HBV replication by inhibition of the reverse transcriptase of both viruses. The fficacy of lamivudine against HBV has been demonstrated in HIV-uninfected as well as HIV-HBV co-infected individuals. Unfortunately, the efficacy of lamivudine is limited by the emergence of resistance strains containing mutations that typically occur in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the catalytic domain (domain C) of the polymerase gene of both viruses. Mutations at this site of the HBV polymerase gene are of particular significance as the major neutralizing epitope of the envelope protein, the 'a' determinant, is also encoded in this region in an overlapping frame-shifted reading frame. Prolonged lamivudine therapy has been identified as the major risk factor for the development of resistance, and HIV-HBV co-infected individuals develop resistance at a rate of 20% annually, with projected rates of 90% after 4 years of therapy, which are marginally higher than rates in HBV patients not infected with HIV.
This study was performed to determine the prevalence of lamivudine resistance in a cohort of HIV-HBV co-infected individuals receiving lamivudine as a component of highly active antiretroviral therapy (HAART), to delineate the risk factors associated with the development of antiviral resistance and to characterize the genetic patterns of drug-resistant HBV.
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