|Home | About | Journals | Submit | Contact Us | Français|
Current Japanese guidelines recommend that patients should be switched from lamivudine to entecavir when they meet certain criteria. This analysis examines the efficacy and safety of long-term entecavir therapy in patients who were switched to entecavir after 24 weeks’ lamivudine therapy in Japanese studies ETV-047 and ETV-060.
The Phase II Japanese study ETV-047 assessed the efficacy of different entecavir doses when compared with lamivudine. A total of 33 Japanese patients who received lamivudine 100 mg daily in ETV-047 entered the open-label rollover study ETV-060 and subsequently received treatment with entecavir 0.5 mg daily. Hepatitis B virus (HBV) DNA suppression, alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroconversion, and resistance were evaluated among patients with available samples for up to 96 weeks. Safety was assessed throughout the treatment period.
After 96 weeks of entecavir therapy in ETV-060, 90% of patients achieved HBV DNA <400 copies/mL as compared to 21% of patients who completed 24 weeks of lamivudine therapy in ETV-047. Increasing proportions of patients achieved ALT normalization and HBeAg seroconversion following long-term entecavir treatment. No patients experienced virologic breakthrough, and substitutions associated with entecavir resistance were not observed in patients with detectable HBV DNA. Entecavir was well tolerated during long-term treatment.
Switching lamivudine-treated patients with chronic hepatitis B to entecavir results in increased virologic suppression with no evidence of resistance through 2 years of entecavir therapy. These findings support recommendations in the current Japanese treatment guidelines that stable lamivudine patients should be switched to entecavir.
Chronic hepatitis B virus (HBV) infection affects more than 350 million people worldwide, and is a leading cause of liver-related mortality . Although Japan has one of the lowest prevalence rates for chronic hepatitis B (CHB) (0.8%) among Asian countries, it is still estimated that over 1 million people are chronically infected with HBV . These individuals are at an increased risk of developing cirrhosis, liver failure or hepatocellular carcinoma (HCC) .
Lamivudine was the first nucleoside analog introduced for the treatment of CHB. In clinical trials, it demonstrated superior efficacy to placebo for HBV DNA suppression, alanine aminotransferase (ALT) normalization and hepatitis B e antigen (HBeAg) seroconversion [4, 5]. However, a major limitation of lamivudine therapy is the development of resistance, which occurs in up to 70% of patients through 4 years of therapy . Entecavir is a potent inhibitor of HBV replication . In global Phase III studies, entecavir demonstrated superior histologic, virologic and biochemical responses when compared with lamivudine in nucleoside-naïve patients and lamivudine-refractory patients at 48 weeks [8–10]. In the Japanese Phase II study ETV-047, treatment with entecavir resulted in a superior reduction in HBV DNA as compared to lamivudine . In contrast to lamivudine, entecavir has been shown to have a high genetic barrier to resistance; the cumulative probability of resistance through 5 years of treatment has been reported to be 1.2% . The genetic barrier is lower in patients who are infected with lamivudine-resistant HBV and consequently higher resistance rates are observed in this population with long-term treatment .
Current Japanese treatment guidelines recommend that all treatment-naïve CHB patients with ALT levels ≥31 IU/L should be treated, dependent on their viral load. The thresholds for treatment are HBV DNA ≥5 log10 copies/mL in HBeAg-positive patients, ≥4 log10 copies/mL in HBeAg-negative patients, and ≥3 log10 copies/mL in cirrhotic patients . Lamivudine, adefovir, and entecavir are currently approved for the treatment of CHB in Japan. Entecavir 0.5 mg once daily is the first choice therapy for treatment-naïve HBeAg-positive and negative patients aged 35 years or older. In treatment-naïve patients <35 years, the guidelines recommend treating first with interferon for HBeAg-positive patients, and treating HBeAg-negative patients with HBV DNA ≥7 log10 copies/mL with entecavir until undetectable HBV DNA is achieved, followed by a combination of entecavir and interferon for 4 weeks, and finally interferon monotherapy for 20 weeks. HBeAg-negative patients with HBV DNA <7 log10 copies/mL should be monitored or can receive interferon therapy. For patients who are lamivudine experienced, but not necessarily resistant, the guidelines also recommend that patients can be switched to entecavir 0.5 mg daily if they have received lamivudine therapy, and have HBV DNA <2.1 log10 copies/mL. Patients with HBV DNA ≥2.1 log10 copies/mL can also be switched to entecavir 0.5 mg once daily if they do not have viral breakthrough. Limited data on the efficacy of entecavir in this patient population are available; however, the design of the Japanese study ETV-047 and the rollover study ETV-060 presents an opportunity to assess the efficacy of this treatment option. This report examines the long-term efficacy, safety and resistance of entecavir 0.5 mg daily among patients who were directly switched from lamivudine following 24 weeks’ treatment in ETV-047.
Study ETV-047 was a Phase II, randomized, double-blind study conducted to evaluate the dose–response relationship of entecavir and compare the antiviral activity and safety of entecavir to lamivudine in Japanese patients with CHB. In ETV-047, 137 patients were randomized to receive one of three entecavir doses [0.01 mg (n = 35), 0.1 mg (n = 34) or 0.5 mg (n = 34), once daily] or lamivudine [100 mg (n = 34), once daily] for 24 weeks. The study design and complete inclusion criteria have been described previously . Briefly, eligible patients had HBeAg-positive or -negative CHB with compensated liver disease, HBV DNA ≥7.6 log10 copies/mL by PCR assay, <12 weeks’ prior therapy with anti-HBV nucleoside analogs and ALT levels 1.25–10 × upper limit of normal (ULN). After completion of treatment in ETV-047, all patients were eligible to enroll immediately in the rollover study ETV-060, with no gap in dosing.
The rollover study ETV-060 was designed to provide open-label entecavir for patients who had completed therapy in the Japanese Phase II program. Patients who completed 24 weeks of treatment in ETV-047 enrolled in ETV-060 and received 0.5 mg entecavir once daily. After 96 weeks of treatment in study ETV-060, patients could complete the study and were eligible to receive commercially available entecavir, which was approved by Japanese health authorities while study ETV-060 was ongoing.
The current analysis describes results for a subset of 33 patients who received lamivudine for 24 weeks in ETV-047 and entecavir 0.5 mg once daily for up to 96 weeks in ETV-060.
Efficacy assessments evaluated the proportions of patients who had available samples (non-completer = missing) every 24 weeks through 120 weeks’ treatment. Efficacy end points assessed included HBV DNA <400 copies/mL by PCR assay, ALT normalization (≤1.0 × ULN), HBeAg seroconversion among patients who were HBeAg-positive at baseline, and hepatitis B surface antigen (HBsAg) loss. Serum HBV DNA was determined by Roche Amplicor® PCR assay (Roche Diagnostics K.K., Tokyo, Japan; limit of quantification = 400 copies/mL) in a central laboratory. Clinical laboratory tests, PCR assays for HBV DNA, and serologic tests for HBV were performed at SRL, Inc. (Tokyo, Japan), the central clinical laboratory designated by the trial sponsor. On-treatment testing for resistance was carried out using a direct-sequencing PCR method.
Safety analyses include the incidence of adverse events, serious adverse events, laboratory abnormalities, and discontinuations due to adverse events on-treatment throughout treatment in study ETV-060. On-treatment ALT flares were defined as ALT >2 × baseline and >10 × ULN.
Resistance testing was performed using a direct-sequencing PCR method. Paired samples from all patients with HBV DNA ≥400 copies/mL were analyzed for substitutions associated with entecavir or lamivudine resistance at week 96 (72 weeks of entecavir therapy) or week 120 (96 weeks of entecavir therapy). Patients who discontinued therapy prior to week 120 had their last on-treatment sample analyzed. All patients with virologic breakthrough (≥1 log10 increase from nadir on two consecutive measurements) were also tested for resistance.
Of the 34 patients in ETV-047 who received treatment with lamivudine 100 mg once daily for 24 weeks, 33 entered ETV-060 and received treatment with entecavir 0.5 mg once daily. Two patients discontinued treatment during ETV-060: one due to an adverse event (depression) and the other due to insufficient effect. In addition, one patient completed treatment at week 76 (52 weeks of entecavir therapy) after meeting the criteria for protocol-defined complete response (undetectable HBV DNA by PCR assay, undetectable HBeAg and normal serum ALT).
Baseline demographic and disease characteristics for the switch cohort are presented in Table 1. The majority of patients (82%) in the cohort were male with a mean age of 43 years. The mean duration of entecavir therapy was 105.9 weeks (range 25–141 weeks). Baseline mean HBV DNA and ALT levels were 7.9 log10 copies/mL and 184 IU/L, respectively. Ninety-one percent of patients were HBeAg-positive and 88% had HBV genotype C infection.
After completion of 24 weeks of lamivudine treatment in ETV-047, 21% (7/33) of patients in the switch cohort had achieved HBV DNA <400 copies/mL (Fig. 1). Following the switch to entecavir, the proportion of patients achieving HBV DNA <400 copies/mL increased to 82% (27/33) by week 48 (24 weeks of entecavir therapy). Viral suppression was maintained with longer entecavir treatment, with 84% (26/31) and 90% (27/30) achieving HBV DNA <400 copies/mL at weeks 72 and 120, respectively (48 and 96 weeks of entecavir therapy). Mean HBV DNA levels decreased from a baseline of 7.90 to 3.52 log10 copies/mL after 24 weeks of lamivudine therapy in ETV-047, and reached 2.69 log10 copies/mL after 96 weeks of entecavir therapy in ETV-060 (week 120; Fig. 2). No viral breakthrough was observed during entecavir therapy.
ALT normalization (≤1.0 × ULN) was demonstrated in 76% (25/33) of patients after 24 weeks of lamivudine therapy in ETV-047 (Fig. 3). Following treatment with entecavir in ETV-060, ALT normalization was maintained in 90% (27/30) of patients achieving this end point by week 120. Minor fluctuations in the proportion of patients achieving ALT normalization were attributed to patients discontinuing entecavir therapy during the course of study ETV-060.
HBeAg seroconversion was assessed among the 30 patients in the switch cohort who were HBeAg-positive at baseline in ETV-047 (Table 1; Fig. 4). Three patients (10%) achieved HBeAg seroconversion during the initial 24-week lamivudine treatment period in ETV-047 (Fig. 4). Following switch to entecavir in ETV-060, two additional patients developed HBeAg seroconversion by week 120 (96 weeks of entecavir therapy). None of the patients in the switch cohort experienced HBsAg loss during treatment in ETV-047 or ETV-060.
Four of the 33 patients who received entecavir therapy in ETV-060 had HBV DNA ≥400 copies/mL either at treatment discontinuation or at week 120. One patient discontinued therapy at week 68 (44 weeks of entecavir therapy) due to insufficient effect. HBV DNA prior to treatment discontinuation was 3.1 log10 copies/mL, however, resistance testing revealed no substitutions associated with entecavir resistance. The remaining three patients had HBV DNA ≥400 copies/mL at weeks 96 and 120; however, only two patients had samples available for testing. Neither patient’s samples had substitutions associated with entecavir or lamivudine resistance either at weeks 96 or 120.
Entecavir was well tolerated during long-term treatment and the safety profile of patients in the switch cohort was consistent with that previously reported for patients who received continuous entecavir therapy in studies ETV-047 and ETV-060 (Table 2). Serious adverse events (Meniere’s disease, subcutaneous abscess and ALT flare) were reported in three patients (9.1%). The most frequently reported adverse events during treatment in ETV-060, occurring in ≥10% of patients, were nasopharyngitis (76%), diarrhea (21%), back pain (18%), influenza (18%), and allergic rhinitis (15%). One patient discontinued entecavir therapy due to depression, which the investigator considered was possibly related to entecavir therapy. An ALT flare (ALT >2 × baseline and >10 × ULN) occurred in one patient at week 18, and was judged a serious adverse event by the investigator, but was not associated with a change in HBV DNA. No deaths were reported during the study.
Profound long-term suppression of HBV DNA is required for patients to meet the goals of CHB therapy, which are to prevent cirrhosis, hepatic failure, HCC and liver-related death [14–16]. A major concern with long-term therapy is the increasing risk of selecting resistance mutations, especially for therapies with a low-genetic barrier to resistance, such as lamivudine. The current analysis presents results for a cohort of Japanese patients who were switched directly from lamivudine to long-term entecavir therapy. The results show that this switch cohort achieved additional HBV DNA suppression after the switch to entecavir. The proportion of patients with HBV DNA <400 copies/mL increased from 21% after 24 weeks of lamivudine treatment to 82% following an additional 24 weeks of entecavir treatment. Mean HBV DNA decreased from 3.52 log10 copies/mL at week 24 to 2.80 log10 copies/mL at week 48. Rates of HBV DNA suppression were maintained in this cohort, with 90% of patients achieving HBV DNA <400 copies/mL through 96 weeks of entecavir therapy (week 120). These results are comparable to those achieved by the cohort of patients who received entecavir 0.5 mg once daily in the Japanese Phase II studies and the rollover study ETV-060 . At baseline in ETV-060, 56% of this cohort had achieved HBV DNA <400 copies/mL, increasing to 83% through 96 weeks of entecavir therapy. Among patients with abnormal ALT levels at ETV-060 baseline, 88% of patients in the entecavir 0.5 mg cohort achieved normalized ALT levels at week 96 as compared to 90% of patients in the switch cohort. Rates of HBeAg seroconversion at week 96 in ETV-060 were also similar (20 vs. 19%, respectively). These rates of viral suppression also show comparison favorably to those reported for the global nucleoside-naïve cohorts treated for a similar period of time [18, 19]. The potent antiviral activity of entecavir and its high genetic barrier to resistance is expected to minimize the potential for resistance in the switch cohort, allowing long-term therapy for patients. Liver biopsies were not obtained from patients in the switch cohort; however, the histologic benefits of long-term entecavir therapy have been recently reported for a cohort of naïve Japanese patients in the ETV-060 rollover study . Following treatment with entecavir 0.5 mg daily for 3 years, all patients experienced histologic improvement and 57% experienced improvement in fibrosis score. In addition, the results from a separate global study have confirmed the histologic benefits of long-term entecavir treatment .
Previous Japanese (ETV-052/-060) and global (ETV-026) studies have examined the efficacy of entecavir in lamivudine-refractory patients. In these studies, entecavir demonstrated efficacy, with 54% of Japanese patients achieving HBV DNA <400 copies/mL through 3 years’ treatment [10, 22]. However, as a result of the lower genetic barrier in these patients, a major drawback of entecavir therapy in this population is the development of resistance. The cumulative probabilities of genotypic entecavir resistance among lamivudine-refractory patients were 33% through 3 years’ treatment in Japanese patients and 51% through 5 years’ treatment among patients in the global cohort [12, 22]. In the current study, no entecavir- or lamivudine-associated resistance substitutions were detected after 96 weeks of entecavir treatment. However, in contrast to the previous studies where the majority of patients had high baseline HBV DNA and documented lamivudine resistance [10, 23], patients in the switch cohort received entecavir after achieving variable degrees of HBV DNA suppression with 24 weeks of lamivudine therapy. Therefore, the fact that no resistance has been observed in this cohort to date is not unexpected. This observation is consistent with an analysis of lamivudine-refractory patients enrolled in the worldwide lamivudine-refractory study ETV-026. Patients with baseline HBV DNA <7 log10 copies/mL had a higher probability of achieving HBV DNA <300 copies/mL as compared to those who had baseline HBV DNA ≥7 log10 copies/mL (73 vs. 16%) . Furthermore, among the 42 entecavir-treated patients in ETV-026 who achieved HBV DNA <300 copies/mL through 96 weeks of therapy, only one patient subsequently developed entecavir resistance.
Current recommendations on the treatment of patients with documented lamivudine resistance suggest that patients should receive a second drug without cross resistance. The combination of lamivudine and adefovir has been shown to be superior to adefovir monotherapy for the treatment of lamivudine resistance, especially in preventing the selection of adefovir resistance [25–27]. Although only short-term clinical data are available for tenofovir, rates of viral suppression among lamivudine-experienced or -resistant patients who received tenofovir monotherapy do not differ significantly from those of treatment-naïve patients [28, 29]. Small studies have also shown pegylated interferon alpha-2a to be a safe and beneficial treatment option for lamivudine-experienced patients . However, the treatment options for Japanese lamivudine-resistant patients are more limited, since neither tenofovir nor pegylated interferon alpha-2a are currently approved in Japan.
The Japanese guidelines recommend that patients with detectable YMDD mutations should receive treatment with a combination of lamivudine and adefovir . However, the guidelines also allow patients who have received <3 years of lamivudine therapy, have HBV DNA <400 copies/mL, and no breakthrough hepatitis or YMDD mutations to switch directly to entecavir. The results presented in this analysis suggest that the strategy of switching to entecavir is an effective one that may avoid the additional cost and potential toxicity of combination treatment with lamivudine and adefovir. Among patients in the switch cohort, 96 weeks of entecavir treatment was well tolerated and the safety profile was comparable with previous experience in Japanese patients. One patient experienced an ALT flare (ALT >2 × baseline and >10 × ULN) 18 weeks after initiating entecavir, which was not associated with a change in HBV DNA. This low rate of ALT flares is consistent with previous findings and demonstrates that lamivudine-treated patients can be switched safely to entecavir with a minimal risk of such flares [10, 22].
In summary, the data from the switch cohort presented in this analysis demonstrate that CHB patients can be switched from lamivudine to long-term entecavir. The treatment with entecavir resulted in increased rates of virologic suppression with no evidence of resistance through 2 years of therapy. These findings support recommendations in the current Japanese treatment guidelines that patients on stable lamivudine therapy with no YMDD mutations should be switched to entecavir.
Taku Seriu and Hiroki Ishikawa are employees of Bristol-Myers Squibb. Masao Omata serves as an advisor for Bristol-Myers Squibb. In addition to the authors, other study investigators included Kazuyuki Suzuki, Yoshiyuki Ueno, Osamu Yokosuka, Hidetsugu Saito, Naohiko Masaki, Yoshiyuki Arakawa, Yasunobu Matsuda, Shunichi Okada, Eiji Tanaka, Yoshiaki Katano, Etsuro Orito, Shinichi Kakumu, Noboru Hirashima, Takashi Kumada, Takeshi Okanoue, Kazuhiro Katayama, Michio Kato, Harumasa Yoshihara, Taizo Hijioka, Kosaku Sakaguchi, Keisuke Hino, Norio Horiike, Shotaro Sakisaka, Ryukichi Kumashiro, Keisuke Hamasaki, Masataka Seike, Yutaka Sasaki, Katsuhiro Hayashi, Teruaki Kawanishi, Mitsuhiko Kawaguchi and Keiji Kita. The study coordinating committee included Yasushi Shiratori and Hirohito Tsubouchi and the study efficacy and safety committee included Chifumi Sato, Kendo Kiyosawa and Kyuichi Tanikawa. Financial support for this research was provided by Bristol-Myers Squibb.