Prevalence, Incidence, and Clinical Relevance of the Reverse Transcriptase V207I Mutation Outside the YMDD Motif of the Hepatitis B Virus Polymerase during Lamivudine Therapy

Abstract

The reverse transcriptase V207I mutation within the hepatitis B virus (HBV) polymerase is associated with resistance to lamivudine in vitro. The prevalence of this mutation in treatment-naïve patients was 1% (1/96). A follow-up of the patient carrying this mutation prior to treatment revealed no loss of sensitivity of HBV to lamivudine in vivo.Treatment of chronic hepatitis B with lamivudine (3TC) leads to a substantial proportion of resistant hepatitis B virus (HBV) (3). Resistance-associated mutations outside the active site of the HBV polymerase (YMDD motif) include amino acid exchanges at the reverse transcriptase codon L180M (rtL180M) or the rtV207I codon (4, 7, 10). The 50% inhibitory concentration for HBV carrying the rtV207I mutation is 20 nM of 3TC, leading to a 3.6-fold resistance in vitro (4, 10). However, the relevance of this amino acid exchange to the resistance of HBV to 3TC in vivo is completely unknown.We investigated 96 consecutive, chronic HBV carriers. HBV polymerase sequences were analyzed at baseline (n ϭ 96), after 1 year (n ϭ 96), and after 2 years of 3TC treatment (n ϭ 92). Fifty patients carried HBV genotype A, and 46 were infected with HBV genotype D. The case patient was an immunocompetent male who was 19 years old at initiation of 3TC treatment. He carried HBV genotype A and was coinfected with hepatitis C virus (HCV) genotype 1a but tested negative for human immunodeficiency virus. The patient had received pegylated alpha interferon (pegIFN-␣; 80 g per week) and ribavirin (600 mg per day) 12 months prior to 3TC treatment due to his HCV infection without any effect on HBV DNA levels, concentration of serum hepatitis B surface antigen, or the status of hepatitis Be (HBe) antigen. He had never received 3TC or famciclovir before. At baseline of 3TC treatment (100 mg daily), his viral load was log 10 8.3 HBV DNA copies/ml, while the HCV RNA level was below the detection limit of the PCR assay (lower log 10 2 HCV RNA copies/ml). The HBe antigen test was positive, and the alanine aminotransferase (ALT) value at baseline was 20 U/ml (the normal value is below 22 U/ml).Serum hepatitis surface antigen and HBe antigen levels were determined by enzyme-linked immunosorbent assay (Abbott, Wiesbaden, Germany). HBV copy numbers were quantified by real-time PCR (LightCycler-DNA Master SYBR Green; Roche Diagnostics, Basel, Switzerland) as described previously (8). Genotypic HBV resistance was analyzed by sequencing the HBV polymerase from codons rt103 to rt244 (1). Viral population kinetics were investigated by cloning amplicons of the HBV polymerase into Escherichia coli (TOPO-TA cloning system; Invitrogen, Karlsruhe, Germany). Fifteen clones were sequenced from each sample as described previously (11).The prevalence of the rtV207I mutation in treatment-naïve patients was 1% (1/96). This patient was the case reported in this article. One additional patient carried wild-type HBV at baseline, but the rtV207I mutation emerged at month 24 of treatment in combination with the rtL180M and rtM204V exchange...

Mutations in Pol gene of hepatitis B virus in patients with chronic hepatitis B before and after therapy with nucleoside/nucleotide analogues

“…The rtV173L substitution was identified in only 3 patients and was associated with mutation rtM204V/I. Similar drug resistance profile has also been reported in other studies (Zoulim and Locarnini, 2009;Arreses;2011;Zöllner, 2005). Delaney et al analyzed the prevalence of rtV173L mutation and its relation to rtL180M and rtM204V/I (Delaney, 2003).…”

HBV lamivudine resistance among hepatitis B and HIV coinfected patients starting lamivudine, stavudine and nevirapine in Kenya

“…Each subject had a single mutation: rtI233V, rtA181S or rtV207I. These mutations have been associated with reduced in vitro susceptibility to adefovir (rtI233V, rtA181S) and lamivudine (rtV207I) in some reports [6–8].…”

The L80I Substitution in the Reverse Transcriptase Domain of the Hepatitis B Virus Polymerase Is Associated with Lamivudine Resistance and Enhanced Viral Replication In Vitro

“…Early studies that used in vitro assays established that rtM204I and rtM204V mutants replicate less efficiently than wild-type HBV (19,21). It was subsequently observed that the replication impairment imparted by rtM204V/I can be partially or completely overcome not only by further rt changes (particularly rtL180M [12,23], rtV173L [10], and/or rtV207I [36]) but also by the presence of the precore (PC) G1896A mutation, which creates a premature stop codon (pcW28*) and prevents HBeAg synthesis (5,31). Mutations that affect the core protein have also been shown to confer a replication advantage (29).…”