Prior Exposure to Lamivudine Increases Entecavir Resistance Risk in Chronic Hepatitis B Patients without Detectable Lamivudine Resistance

Abstract

The efficacy of entecavir (ETV) treatment in chronic hepatitis B (CHB) patients who were exposed to lamivudine (LAM) but had no detectable LAM resistance (LAM-R) is not well evaluated. In this study, we aimed to evaluate whether the probability of developing genotypic resistance to ETV in LAM-exposed patients with or without LAM-R is comparable to that in antiviral-naive patients. This retrospective cohort study included 500 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital in Korea. The patients were divided into three groups: nucleos(t)ide analogue (NA)-naive patients (group 1, n ‫؍‬ 142), patients who were previously exposed to LAM and had no currently or previously detected LAM-R (group 2, n ‫؍‬ 233), and patients with LAM-R when starting ETV (group 3, n ‫؍‬ 125). The overall median ETV treatment duration was 48.7 months. The probabilities of virologic breakthrough were significantly increased not only in group 3 (hazard ratio [HR] ‫؍‬ 14.4, P < 0.001) but also in group 2 (HR ‫؍‬ 5.0, P < 0.001) compared to group 1. Genotypic ETV resistance (ETV-R) developed more frequently in group 2 (HR ‫؍‬ 13.0, P ‫؍‬ 0.013) as well as group 3 (HR ‫؍‬ 43.9, P < 0.001) than in group 1: the probabilities of developing ETV-R in groups 1, 2, and 3 were <1.0%, 8.0%, and 28.2%, respectively, at month 48. The results of this study indicate that ETV-R occurred more frequently in LAM-exposed patients, even though they had no detectable LAM-R, than in NA-naive patients. Therefore, LAM-exposed CHB patients, regardless of the presence or absence of LAM-R, should be monitored more cautiously for the development of ETV-R during ETV monotherapy. E ntecavir (ETV) is an orally administered guanosine analogue that has been approved for treatment of chronic hepatitis B (CHB). In antiviral-naive CHB patients, ETV has shown excellent antiviral efficacy with remarkably low probabilities of genotype resistance (1.2%) and virologic breakthrough (0.8%) for up to 5 years of treatment (1). In contrast to antiviral-naive patients, the rates of genotypic resistance to ETV are much higher in patients with lamivudine (LAM) resistance (LAM-R) (i.e., 51% 5-year cumulative probability) (1). Consequently, ETV is now recommended as one of the first-line therapeutic regimens for antiviralnaive patients with CHB but not for patients who had developed LAM-R (2-4).The emergence of LAM-R variants has been relatively frequent even in antiviral-naive patients with CHB: approximately 20% of patients treated with LAM develop LAM-R at 1 year and 70% to 80% at 5 years of treatment (5-7). Although some selected cases that have succeeded in achieving treatment endpoints (i.e., hepatitis B e antigen [HBeAg] seroconversion and/or maintenance of complete virologic suppression) were able to discontinue LAM without developing LAM-R (8, 9), the rates of durable response after cessation of LAM have been low (10, 11). Unfortunately, the retreatment strategies for virologic relapse in those cases are still indefinite. Since LAM was the first...

2′‐Fluoro‐6′‐methylene carbocyclic adenosine and its phosphoramidate prodrug: A novel anti‐HBV agent, active against drug‐resistant HBV mutants

“…Studies involving ETV have revealed that its use as a first‐line therapeutic agent can reduce the rate of resistance (≤1%), even after 5 years of therapy . However, the current findings show that the long‐term use of the drug in naïve patients, as well as other antiviral drug‐resistant patients increase the incidence of ETV resistance . Sequential data support the fact that for ETV resistance, the mutation at residue rtT184, rtS202, rtM250, and rt169, is required.…”

“…103 However, the current findings show that the long-term use of the drug in naïve patients, as well as other antiviral drug-resistant patients increase the incidence of ETV resistance. 35,104,105 Sequential data support the fact that for ETV resistance, the mutation at residue rtT184, rtS202, rtM250, and rt169, is required. Furthermore, to adapt the ETV resistance by HBV polymerase over the preexisting LMV resistant, mutation rtM204V/rtL180M is necessary.…”

Efficacy of entecavir therapy for hepatitis B e‐antigen positive chronic hepatitis B patients with prior exposure to interferon or nucleoside/nucleotide analogues

“…Previous studies have focused on the outcome of LAM-resistant patients receiving ETV treatment as rescue therapy. [16][17][18][19] In Taiwan, CHB patients can be reimbursed by the Bureau of National Health Insurance (BNHI) for prescribed treatments, including interferon or nucleoside/nucleotide analogs (NA). However, the duration of reimbursement for treatment for HBeAg positive CHB patients is 24 weeks for interferon and 3 years for NA.…”

Tenofovir has inferior efficacy in adefovir-experienced chronic hepatitis B patients compared to nucleos(t)ide-naïve patients

“…A recent study showed that the efficacy of TDF was preferable to entecavir for achieving CVS in NA-experienced CHB patients without genotypic resistance, which suggests that previous antiviral treatment has clinical implications regarding the selection of an antiviral agent irrespective of preexisting genotypic resistance [14]. Likewise, our previous study showed that prior treatment with low-potency lamivudine affected the long-term efficacy of entecavir, even without genotypic resistance to lamivudine [4]. Drug-resistant mutations developed from previously used drugs are preserved in covalently closed circular DNA in the liver, and these mutations might attenuate the efficacy of subsequent drugs to which the virus was not previously exposed [15].…”

“…The primary goal of CHB therapy is to prevent disease progression and prolong survival through long-term suppression of hepatitis B virus (HBV) replication [1-3]. A recent cohort study reported that entecavir failed to show comparable efficacy in nucleos(t)ide analogue (NA)-experienced CHB patients and NA-naïve patients [4], which suggests the important role of previous treatment history in patients with CHB.…”