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

Background/Aims

To evaluate the off-treatment durability of response in HBeAg-negative chronic hepatitis B patients who achieved a protocol-defined ‘Response’ (HBV-DNA < 0.7 MEq/mL and ALT < 1.25 × ULN) with entecavir at 48 weeks and the efficacy of entecavir in patients treated beyond one year.

Methods

Entecavir-treated and lamivudine-treated patients who achieved a protocol-defined ‘Response’ were evaluated off-treatment for HBV-DNA < 300 copies/mL and ALT normalisation. Entecavir- and lamivudine-treated patients who achieved a protocol-defined ‘Virological Response’ (HBV-DNA < 0.7 MEq/mL but ALT ⩾ 1.25 × ULN) at 48 weeks, continued blinded treatment until they achieved Response or 96 weeks, whichever came first.

Results

Among ‘Responders’ who discontinued treatment after 48 weeks, 7/257 (3%) entecavir-treated and 10/201 (5%) lamivudine-treated patients sustained HBV-DNA below 300 copies/mL at 24-weeks off-treatment. Among the 54 patients who continued blinded treatment in the second year, 7/26 (27%) entecavir-treated and 6/28 (21%) lamivudine-treated patients normalised ALT and 22/26 (85%) entecavir-treated and 16/28 (57%) lamivudine-treated patients maintained HBV-DNA < 300 copies/mL at end-of-dosing. The safety profiles of both drugs remained comparable through a second year of treatment.

Conclusions

The majority of protocol-defined Responders relapsed after 1 year when treatment was discontinued. Treatment with entecavir beyond 1 year provided continued virological and biochemical benefit.

Introduction

Knowledge of the scope and impact of HBeAg-negative chronic hepatitis B (CHB) has increased markedly in the last 20 years [1], [2]. Owing to improved diagnostic tests and a better understanding of the natural history of HBV infection, HBeAg-negative CHB is now recognised as a major variant of chronic infection throughout the world [3]. HBeAg-negative infection presumably arises by spontaneous mutation in the pre-core mRNA or core promoter regions of the HBV genome that reduces expression of the HBe antigen [4], [5], [6]. As the number of individuals with persistent HBV infection continues to grow, an increasing proportion with pre-core and core promoter mutants of HBV are now recognised as having HBeAg-negative disease.

The development of HBeAg-negative HBV infection and the interplay of the mutant virus with host immune responses are poorly understood [4], [6], but appears to involve loss of immunological control when synthesis of HBeAg wanes. Although serum HBV-DNA levels of HBeAg-negative virus are usually lower than wild-type (HBeAg-positive) virus, fluctuations in immune response over several years or decades exacerbate hepatic damage. Moreover, when diagnosed, patients with HBeAg-negative disease have typically been infected for a longer period than those with HBeAg-positive infection. The long duration of infection, along with the fluctuating cycle of viral replication and hepatic inflammation, eventually leads to cirrhosis in approximately 40% of patients and hepatocellular carcinoma in 14% of patients [4], [5]. Suppression of HBV replication has been shown to reduce the magnitude of hepatocellular injury and may reduce the morbidity and mortality associated with HBeAg-negative CHB [7], [8].

The one-year results from the double-blind study (www.clinicaltrials.gov identifier: NCT00035789) comparing entecavir with lamivudine in HBeAg-negative CHB patients have been previously reported [9]. In this phase III trial; 648 HBeAg-negative CHB patients with no previous experience with a nucleoside analogue were randomised (1:1) to entecavir 0.5 mg or lamivudine 1.0 mg daily for a minimum of 52 weeks. After 1 year of treatment, entecavir demonstrated superiority to lamivudine for the primary endpoint of histological improvement [9]. Entecavir was also shown to be superior to lamivudine for secondary endpoints, including mean reduction in HBV-DNA (5.0 vs 4.5 log₁₀ copies/mL, p < 0.001), proportions of patients achieving HBV-DNA < 300 copies/mL (90% vs 72%, p < 0.001) and ALT normalisation (78% vs 71%, p < 0.05). At the time the trial was designed, there was no consensus regarding the duration of therapy recommended for patients with HBeAg-negative CHB, and even today, duration of treatment remains ill defined. However, given the potent suppression of HBV replication seen with entecavir in vitro and in vivo during the phase 1 and phase 2 studies [10], [11], it was important to establish whether patients could achieve a sustained response off-therapy based on specified response criteria. This protocol allowed patients to either stop or continue blinded treatment depending on the protocol-defined ‘Response’ criteria evaluated at Week 48. We present the efficacy and safety results for a major cohort of HBeAg-negative patients who achieved a protocol-defined ‘Response’ and discontinued successful study therapy after Week 52; and for a smaller sub-cohort who had achieved a ‘Virological Response’ and continued treatment during year 2.