Entecavir shows limited efficacy in HBeAg-positive hepatitis B patients with a partial virologic response to adefovir therapy☆
Introduction
Treatment of patients with chronic hepatitis B virus (HBV) infection remains an important challenge. With the currently approved treatment options the main goal of treatment is complete suppression of viral replication, because persistent HBV viraemia is associated with development of liver cirrhosis and hepatocellular carcinoma [1], [2]. Furthermore, a rapid virologic response after initiation of nucleos(t)ide analogue treatment is associated with lower rates of antiviral drug resistance in the long-term [3], [4], [5].
Adefovir dipivoxil (ADV) is an oral prodrug of adefovir, a phosphonate acyclic nucleotide analogue of adenosine monophosphate [6]. Previous studies demonstrated its efficacy in both patients with HBeAg-positive and patients with HBeAg-negative chronic HBV infection, showing significant virologic, biochemical, and histological improvement after 48 weeks of treatment [7], [8]. However, after 5 years of treatment resistance rates can reach up to 29% [9]. Furthermore, ADV demonstrates a relatively high rate of primary nonresponse, probably due to its suboptimal dosage [10], [11]. In the treatment of lamivudine (LAM)-resistant HBV infection, switching to ADV monotherapy resulted in significant HBV DNA decline, but several case series reported increased resistance rates compared to LAM-naïve patients [12], [13]. Entecavir (ETV) is a cyclopentyl guanosine analogue, and a potent and selective inhibitor of viral replication in vitro [14]. A large phase III study demonstrated its efficacy in nucleoside–naïve patients with HBeAg-positive chronic HBV infection. After 48 weeks of treatment with ETV a greater reduction in viral load was achieved compared to LAM (6.9 log10 vs. 5.4 log10) [15]. In LAM-refractory patients ETV is less effective, and results in a 5.1 log10HBV DNA decline after 48 weeks of treatment[16]. It has yet not been evaluated in patients with a partial virologic response to ADV therapy. Here we describe eight LAM-experienced and six LAM-naïve patients with chronic HBV infection and a persistently high level of viral replication after 12 months of treatment with ADV, who were switched to ETV monotherapy.
Section snippets
Study population
All adult patients with chronic hepatitis B, referred to the Erasmus Medical Center Rotterdam between September 2005 and February 2007 who had a persistently high viral load during ADV treatment and subsequently received rescue therapy with ETV 1 mg daily for at least 6 months were included. A persistently high viral load during ADV treatment was defined as presence of HBV DNA levels greater than 5 log10 copies/mL after 12 months of treatment and thereafter. All patients had repeatedly self-reported
Results
Baseline characteristics of all 14 patients who met inclusion criteria are listed in Table 1. Eleven (79%) patients were men and the median age was 40 (range: 23–73) years. Thirteen (93%) patients were HBeAg-positive, median ALT was 1.6 (0.9–5.8)× ULN, and median HBV DNA was 7.8 (5.2–10.1) log10 copies/mL.
Discussion
This is the first study to describe the efficacy of ETV as rescue therapy for patients with a persistently high viral load during ADV treatment. We showed that ETV monotherapy resulted in a limited HBV DNA decline in both LAM-experienced and -naïve patients with persistently high HBV DNA during ADV treatment. Only one of 14 patients achieved undetectable HBV DNA levels (<373 copies/mL), and none of the patients showed HBeAg loss or seroconversion. Two LAM-experienced patients demonstrated the
References (29)
- et al.
Predicting cirrhosis risk based on the level of circulating hepatitis B viral load
Gastroenterology
(2006) - et al.
A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B
Gastroenterology
(2005) - et al.
Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy
Hepatology
(2001) - et al.
Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years
Gastroenterology
(2006) - et al.
Virologic response and resistance to adefovir in patients with chronic hepatitis B
J Hepatol
(2006) - et al.
Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B
Gastroenterology
(2006) - et al.
Detection of HBV DNA using real time analysis
J Clin Virol
(2002) - et al.
Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient
J Hepatol
(2007) - et al.
Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient
J Hepatol
(2003) - et al.
Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure
J Hepatol
(2008)
Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient
Gastroenterology
Tenofovir disiproxil fumarate (TDF) versus emtricitabine plus TDF for treatment of chronic hepatitis B (CHB) in subjects with persistent viral replication receiving adefovir dipivoxil (ADV)
J Hepatol
Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level
JAMA
Incidence and predictors of emergence of adefovir resistant HBV during 4 years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB) (abstract)
J Hepatol
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H.L.A. Janssen received grants from and is consultant for: Bristol Myers Squibb, Gilead, Novartis, Roche and Schering-Plough. R.A. de Man received an unrestricted research grant from Biotest, clinical trial support from Bristol Myers Squibb and Gilead, and is a member of the Data safety monitoring board of Novartis. The other authors have nothing to declare.