Antiviral effect of entecavir in chronic hepatitis B: Influence of prior exposure to nucleos(t)ide analogues

Background & Aims

Entecavir is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B patients, but data on the efficacy in NA-experienced subjects are limited.

Methods

In a multi-center cohort study we investigated 161 chronic hepatitis B patients (34% NA-experienced) treated with entecavir monotherapy.

Results

During a median follow-up of 11 (3–23) months, 82 (79%) of 104 NA-naïve patients achieved virologic response (VR), defined as HBV DNA <80 IU/ml, and none of the patients (0%) developed genotypic entecavir-resistance. VR was demonstrated in 31 (54%) of 57 NA-experienced patients during a median follow-up of 12 (3–31) months. Patients with lamivudine-resistant mutations at the start of entecavir monotherapy had a reduced probability of achieving VR compared to lamivudine-naïve patients (HR 0.14; 95% CI 0.04–0.58; p = 0.007). Antiviral efficacy was not decreased by prior treatment with lamivudine when lamivudine-resistance had never developed (HR 0.81; 95% CI 0.43–1.52; p = 0.52). Prior adefovir therapy without development of adefovir-resistance (HR 0.84; 95% CI 0.43–1.64; p = 0.61) and presence of adefovir-resistance (HR 0.86; 95% CI 0.27–2.71; p = 0.80) did not influence antiviral response to entecavir. Switching to a tenofovir-containing treatment regimen resulted in viral load decline in patients with entecavir-resistance associated mutations.

Conclusions

Entecavir proved to be efficacious in NA-naïve patients. The antiviral efficacy of entecavir was not influenced by prior treatment with adefovir or presence of adefovir-resistance. Entecavir should not be used in patients with previous lamivudine-resistance, yet it may still be an option in lamivudine-experienced patients in case lamivudine-resistance never developed.

Introduction

Nucleos(t)ide analogues (NA) target the reverse transcriptase of hepatitis B virus (HBV), and are potent inhibitors of viral replication. In the absence of antiviral drug resistance continued NA therapy is able to suppress viral replication over prolonged periods, and can result in delay or even prevention of clinical progression to liver cirrhosis and hepatocellular carcinoma [1].

Entecavir (ETV) is a cyclopentyl guanosine analogue and a potent and selective inhibitor of HBV replication in vitro[2]. In the phase III registration trials it resulted in superior virologic, biochemical, and histological efficacy after one year of therapy compared to lamivudine (LAM) in both HBeAg-positive and HBeAg-negative chronic HBV patients [3], [4]. Moreover, ETV proved to have a high genetic barrier to resistance with only 1.2% of NA-naïve HBV patients demonstrating genotypic resistance to ETV after five years of ETV monotherapy [5]. In LAM-refractory chronic HBV patients ETV appeared to be less potent and the frequency of resistance was increased [6], [7]. After five years of treatment 51% of LAM-refractory patients showed genotypic ETV-resistance and in 43% a virologic breakthrough was observed as well [8]. However, study populations of registration trials consist of selected groups of HBV patients and results cannot always be translated to clinical practice. Furthermore, as the increasing number of patients who experienced treatment failure to different NA-treatment regimens poses a growing problem for the clinician, data on the efficacy of ETV in these NA-experienced patient groups is warranted.

The aim of this cohort study was to asses the efficacy of ETV in both NA-naïve and NA-experienced chronic hepatitis B patients, and to explore baseline factors associated with virologic response (VR) to ETV.