Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: The case for continuous antiviral therapy

Cho

Antimicrob Agents Chemother

et al. 2014

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...

Section: Fig 2 Breakthrough With Etv Therapy (A)supporting

confidence: 92%

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

Cho

Antimicrob Agents Chemother

et al. 2014

“…Accordingly, although total clearance of HBV DNA from plasma occurs 90% of the time with optimal treatment regimens (25,92), this does not correlate with cccDNA eradication and relapse is common after therapy is stopped, particularly in the eAg-negative disease state (168). Successfully treated patients achieve only a median 0.8-log reduction in cccDNA levels compared to untreated patients (203).…”

Section: Hepatitis B Virusmentioning

confidence: 99%

Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

Schiffer

Aubert

Weber

et al. 2012

J Virol

104

Human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), and herpes simplex virus (HSV) have been incurable to date because effective antiviral therapies target only replicating viruses and do not eradicate latently integrated or nonreplicating episomal viral genomes. Endonucleases that can target and cleave critical regions within latent viral genomes are currently in development. These enzymes are being engineered with high specificity such that off-target binding of cellular DNA will be absent or minimal. Imprecise nonhomologous-end-joining (NHEJ) DNA repair following repeated cleavage at the same critical site may permanently disrupt translation of essential viral proteins. We discuss the benefits and drawbacks of three types of DNA cleavage enzymes (zinc finger endonucleases, transcription activator-like [TAL] effector nucleases [TALENs], and homing endonucleases [also called meganucleases]), the development of delivery vectors for these enzymes, and potential obstacles for successful treatment of chronic viral infections. We then review issues regarding persistence of HIV-1, HBV, and HSV that are relevant to eradication with genome-altering approaches.

“…In accordance with national guidelines for liver diseases, the loss of the hepatitis B surface antigen (HBsAg) or seroconversion of HBsAg/anti-HBs are regarded as the end point of the treatment for HBeAg-negative CHB patients [1], and in HBeAg-negative CHB patients, duration of the treatment is generally much longer compared with HBeAg-positive patients [2]. An insufficient treatment course will result in the recurrence of hepatitis [3]. One of the major concerns with extended treatment regimens, particularly when patients are treated with nucleoside/nucleotide analogs is the increased incidence of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

De novo combination of lamivudine and adefovir versus entecavir monotherapy for the treatment of naïve HBeAg-negative chronic hepatitis B patients

Wang

Chen²,

Cao

et al. 2011

Hepatol Int

Purpose Either combination treatment or monotherapy using agents with a high genetic barrier are recommended for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to compare effect of naïve HBeAg-negative CHB patients with either de novo combination of lamivudine (LAM) and adefovir dipivoxil (ADV) or entecavir (ETV) monotherapy. Methods HBeAg-negative CHB patients (n = 71) with ALT levels between 2 and 10 times the upper normal limit and HBV DNA levels [10 4 copies/mL were enrolled. Patients were treated with either LAM 100 mg plus ADV 10 mg per day (n = 31) or ETV 0.5 mg per day (n = 40) for 48 weeks. Results The average reduction in HBV DNA level compared with baseline were 5.16 ± 1.69 log in the LAM ? ADV group and 5.36 ± 1.70 log in the ETV group by week 48 (P = 0.624). The virological response (VR) rates were 80.65 and 77.5%, the biochemical response (BR) rates were 93.55 and 90.00% at week 48 in the LAM ? ADV and ETV groups, respectively. There was no significant difference in the VR and BR between the two groups. During the 48-week treatment period, virological breakthrough and serious side effects were not noted in any patient. Conclusions Both LAM ? ADV combination therapy and ETV monotherapy are effective in naïve HBeAgnegative CHB patients, but further studies are needed to obtain long-term results.