Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy

Abstract

Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V ؎ L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (>300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (>1 log 10 rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved <300 copies/mL HBV DNA subsequently developed ETVr. Conclusion: Long-term monitoring showed low rates of resistance in nucleoside-naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance. ( A pproximately 400 million people worldwide have chronic hepatitis B virus (HBV) infections, with a risk for chronic, life-threatening liver disease. 1 Antiviral therapy for HBV can provide suppression of viral replication and halt disease progression. 2,3 However, therapeutic benefits are diminished with the emergence of drug-resistant virus, which occurs most often with prolonged therapy and incomplete viral suppression. 4 Resistance to nucleoside/nucleotide antivirals arises through substitutions in the HBV polymerase reverse transcriptase domain (RT), that arise spontaneously through low-fidelity replication and are enriched through drug-selective pressure. 2,3 Antiviral therapies are characterized by their barrier to resistance, which includes three components: (1) the potency of the antiviral in suppressing viral replication, (2) a "genetic barrier", i.e., the number of genetic changes required to effectively reduce drug susceptibility that results in virologic breakthrough, and (3) the replication fitness of the resistant virus. These factors act together to determine the levels of resis...

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

“…In the current study, for the subset of patients who received entecavir 1 mg daily throughout the treatment period, the cumulative rate of entecavir resistance was 30% through 3 years. This is consistent with the rate observed in the entire lamivudine-refractory, long-term treatment cohort and in multinational studies of lamivudine-refractory patients through 3 years (36%) [49]. Combining entecavir with an antiviral with a different resistance profile, such as tenofovir or adefovir, may result in less frequent resistance emergence.…”

“…The rate of genotypic resistance to entecavir reported here is consistent with the rate that has been observed in multinational populations of lamivudine-refractory patients [49]. In nucleoside-naive patients, emergence of entecavir resistance is rare because of entecavir's potent viral load reduction and high genetic barrier to resistance [49,50].…”

“…In nucleoside-naive patients, emergence of entecavir resistance is rare because of entecavir's potent viral load reduction and high genetic barrier to resistance [49,50]. Substitutions at M204 ± L180 were detected at baseline for all patients described in this report and have been shown in previous studies to reduce in vitro susceptibility to entecavir by approximately eightfold [51].…”

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

“…Because these NAs share a common target for the viral reverse transcriptase (RT), resistance mutations to these reagents have been reported only in RT domains. Among these NAs, ETV is one of the most potent anti‐HBV reagents; it has a very low resistance rate in treatment‐naive patients7, 8, 9, 10, 11 and has long been used as a first‐line reagent. To date, a limited number of ETV‐resistant mutations have been reported.…”

The saga of entecavir

“…Molecular modeling suggests that the additional changes at T1874, S202, or M250 probably decrease access to the binding pocket in the reverse transcriptase domain of the mutants, which are still growth deficient relative to the wild-type HBV [28]. The high genetic barrier requiring three substitutions for resistance explains why the cumulative probability of genotypic resistance to entecavir after 5 years of therapy is only 1.2% (n = 108) [29]. However, this barrier is reduced to one substitution in patients who already have two lamivudine-resistant mutations.…”