Association between lamivudine sensitivity and the number of substitutions in the reverse transcriptase region of the hepatitis B virus polymerase

Abstract

This study aimed to identify the viral factors responsible for poor sensitivity to lamivudine (LAM). We analyzed 49 LAM-treated chronic hepatitis B patients infected with hepatitis B virus (HBV) genotype C. Serum HBV DNA reached a level below the detection limit of the sensitive PCR assay in 31 (63.3%) within the first 24 weeks of LAM therapy (good responder group). Of the patients who did not achieve undetectable levels of HBV DNA within 24 weeks (poor responder group), 15 (83.3%) experienced virological breakthrough, whilst only four patients in the good responder group (12.9%) experienced virological breakthrough. Multivariate analysis revealed that failure to achieve a reduction in viral load to undetectable levels within 24 weeks was independently associated with the occurrence of virological breakthrough. Sequence analysis of the HBV genome revealed that point mutations in the precore region (G1896A) and enhancer I (A1287G/C) were observed more frequently in the good responder group than in the poor responder group (P = 0.002 and 0.019 respectively), and the number of substitutions in the reverse transcriptase domain of the polymerase was significantly higher in the good responders than in the poor responders (P = 0.026). In conclusion, determining the sequence of preexisting HBV, especially for enhancer I, the precore region, and the RT domain of the polymerase region, may be useful in predicting sensitivity to LAM therapy.

Initial Virological Response and Viral Mutation with Adefovir Dipivoxil Added to Ongoing Lamivudine Therapy in Lamivudine-Resistant Chronic Hepatitis B

“…We have previously studied the association between lamivudine sensitivity and amino acid substitutions in the reverse transcriptase (RT) region of HBV polymerase and found that sequence analysis of the RT domain is useful for predicting sensitivity to LAM therapy [29].…”

Antiviral Resistance Mutations and Genotype-Associated Amino Acid Substitutions in Treatment-Naïve Hepatitis B Virus-Infected Individuals from the Indian Subcontinent

“…In our study, HBeAg-negative variants had a higher number of rt amino acid substitutions compared to the HBeAg-positive group. It is reasoned that higher number of rt amino acid changes in the active domain may affect the enzyme activity reducing the replication efficacy of the virus and contribute to treatment response [44] . Follow-up of these individuals is essential to identify if a greater number of rt amino acid substitutions in HBeAg-negative patients can reduce the risk of treatment failure.…”

Strategy to Overcome Drug Resistance That Develops during Treatment of Chronic Hepatitis B in Children

“…It is well known that drug resistance is associated with HBV DNA titer at week 24 after the initiation of lamivudine treatment [45][46][47]. Yuen et al studied the positive relationship between lamivudine resistance and HBV DNA level for 159 Chinese HBeAg positive patients.…”

“…The patient with complete virologic response has a very low risk of resistance [45][46][47]. In that case, the clinician should treat with the same regimen and monitor the response every 3∼6 months [48,49].…”

“…Recent studies have also shown that lower basal viral load is associated with complete virologic response [57,61,63]. Moreover, early intervention is associated with the low incidence of lamivudine resistance [45][46][47]. Yuen et al reported that resistance rate was 12% in the group of ≤3 log as basal HBV DNA level, whereas it was 64% in the group of ≥ 4 log [46].…”