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Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B infection - The current long-term study of entecavir presents results for a cohort of patients treated continuously for 3years.
Articles in Press
Jnl of Hepatology March 2010
Osamu Yokosuka1, Koichi Takaguchi2, Shinichi Fujioka3, Michiko Shindo4, Kazuaki Chayama5, Haruhiko Kobashi6, Norio Hayashi7, Chifumi Sato8, Kendo Kiyosawa9, Kyuichi Tanikawa10, Hiroki Ishikawa11, Nobuyuki Masaki11, Taku Seriu11, Masao Omata12
ABSTRACT
Background & Aims
To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients.
Methods
in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples.
Results
After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA <400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) ∅1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA <400 copies/ml, 88% (52/59) had ALT ∅1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset.
Conclusions
Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.
Abbreviations: CHB, chronic hepatitis B, HCC, hepatocellular carcinoma, HBV, hepatitis B virus, HBeAg, hepatitis B e antigen, ALT, alanine aminotransferase, HAI, histologic activity index, ULN, upper limit of normal, PCR, polymerase chain reaction, ITT, intention-to-treat
Introduction
Chronic hepatitis B (CHB) affects 350-400 million people worldwide [1]. The prevalence is highest in the Asia-Pacific region, where 75% of all chronically infected individuals live and up to 25% of CHB patients die of liver cirrhosis, hepatic decompensation or hepatocellular carcinoma (HCC) [2]. In Japan, the prevalence of CHB ranges from 0.8% to 4%, with geographic variation within the country [2], [3], [4], [5]. The vast majority of CHB patients in Japan are infected with hepatitis B virus (HBV) of genotype C [6], [7]. Infection with genotype C virus has been associated with delayed HBeAg seroconversion, more advanced liver disease, and increased probability of HCC development [8], [9], [10], [11].
Recent studies have shown that CHB patients with moderate or elevated serum HBV-DNA are at highest risk of developing long-term complications, including cirrhosis and HCC [11], [12], [13], [14]. Yuen et al. showed that among Asian patients with CHB, disease progression was also seen in patients with persistently detectable viraemia and normal or minimally elevated levels of alanine aminotransferase (ALT), including patients who had achieved HBe seroconversion [12]. Consistent with these findings, current CHB treatment recommendations emphasize the importance of prolonged maximal HBV-DNA suppression and the avoidance of resistance [15], [16], [17].
Medications currently used for CHB include interferons (conventional and pegylated), lamivudine, adefovir, telbivudine, and entecavir. The interferons are efficacious in a subgroup of patients with genotype A infection, low baseline viral load and elevated baseline ALT but are often associated with treatment-limiting adverse events [18], [19], [20]. Lamivudine is well tolerated and initially efficacious, but the emergence of resistance in approximately 70% of patients after 4-5years limits its benefit during long-term therapy [21], [22]. Adefovir treatment is frequently associated with suboptimal HBV-DNA suppression and a cumulative probability of resistance of 29% at 5years among HBeAg(-) patients, and resistance appears to be higher in the HBeAg(+) population [23], [24], [25]. Treatment with telbivudine leads to virological breakthrough, with resistance in 21.6% of HBeAg(+) and 8.6% of HBeAg(-) patients after only 2years [26].
Entecavir has been shown to be highly effective at suppressing HBV-DNA replication to undetectable levels and normalizing ALT in Phase II studies of nucleoside-naïve CHB patients in Japan and in multinational studies [27], [28], [29], [30]. Treatment for 24weeks in the Japanese study ETV-047 showed that entecavir 0.5mg daily resulted in superior viral load reduction compared with lamivudine 100mg daily [28]. In the Japanese study ETV-053, treatment with entecavir 0.5mg daily for 52weeks resulted in significant histological improvement as well as viral load reduction and ALT normalization [27]. Immediately after completion of treatment in study ETV-047 or ETV-053, patients were eligible to enrol in rollover study ETV-060 and receive entecavir 0.5mg daily. We present the long-term efficacy, safety, and resistance results for patients treated with entecavir in Phase II studies who rolled over into study ETV-060, for a total entecavir treatment time of up to 3years (120-148weeks). A subset of patients received the approved dose of entecavir (0.5mg daily) continuously from Phase II baseline, and results for that cohort are also presented.
Discussion
The current long-term study of entecavir presents results for a cohort of patients treated continuously for 3years. The strengths of this study include its focus on a well-defined cohort followed closely over 3years and long-term follow-up liver biopsies on a subset of that cohort enabling a direct assessment of the effect of entecavir therapy on liver disease progression. These results show that long-term treatment with entecavir is well tolerated and achieves histological improvement, durable HBV-DNA suppression, and minimal resistance. Of 167 patients in the cohort, 86% (144) completed 96weeks in the follow-up study for a total of 2.5-3years of entecavir therapy, and only one patient discontinued treatment due to resistance emergence. In both global long-term studies of entecavir and in the present study, continuation of therapy beyond 2years resulted in approximately 90% of patients achieving or maintaining HBV-DNA levels below the PCR assay limit of detection of 300-400 copies/ml [32]. These results were consistent with the results of a sensitivity analysis (last observation carried forward), in which 85% of patients achieved HBV-DNA <400 copies/ml on their last HBV-DNA observation. This method accounts for patient drop-out and missing samples, both of which are common occurrences in long-term studies. However, the interpretation of this sensitivity analysis should be approached cautiously, as it assumes: (1) that subjects who discontinued treatment without achieving HBV-DNA <300 copies/ml would not have achieved it with longer treatment; (2) and that patients who achieved this end point prior to discontinuing would have maintained it over time.
The degree of viral suppression reported in this study is higher than that reported for a cohort of HBeAg(+) patients treated with lamivudine for 3years [33] and higher than that reported for cohorts of HBeAg(+) or HBeAg(-) patients treated with adefovir for 3years [23], [24]. In the current study, 84% of patients were HBeAg(+), and mean baseline HBV-DNA was 7.88log10 copies/ml, 1log higher than the baseline viral load in the adefovir study of HBeAg(-) patients. The rate of HBe seroconversion following entecavir treatment for 3years in this study (26%), is somewhat lower than previously reported for patients treated with adefovir or lamivudine for 3years (40% and 43%, respectively) [24], [33]. This may be related to the large proportion (92%) of HBV genotype C patients enrolled in this study, which has previously been associated with delayed HBe seroconversion [10], [34].
The results of long-term epidemiological-outcome studies have demonstrated that CHB patients with persistently detectable HBV-DNA are at highest risk of liver disease progression [12], [13], [14]. This suggests that long-term suppression of HBV-DNA should help minimize CHB complications. Liaw et al. demonstrated the value of antiviral therapy in a landmark study of CHB patients with cirrhosis or advanced fibrosis treated with long-term lamivudine [35]. Lamivudine-treated patients experienced lower rates of liver disease progression and HCC compared with those who received placebo, but the benefits were reduced by the emergence of lamivudine resistance.
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