Clinical Therapeutics/Volume 32, Number 4, 2010

A 24-Week, Parallel-Group, Open-Label, Randomized Clinical Trial Comparing the Early Antiviral Efficacy of Telbivudine and Entecavir in the Treatment of Hepatitis B e Antigen–Positive Chronic Hepatitis B Virus 10 0 Infection in Adult Chinese Patients 2

c, n I Ye, MD; Ming-Hua Zheng, MD; Ke-Qing Shi, MD; Zhi-Juan Dai, MD;, Chao and Yong-Ping Chen, MD ca i al i d e c Hospital of Wenzhou Department of Infection and Liver Diseases, Liver Research Center, FirstrAffiliated M Medical College, Wenzhou, China ta m e p nand 66 to receive entecavir. The er ABSTRACT to receive telbivudine o m c i x of hepa-o mean reductions Background: Because drug-resistant strains t from baseline in serum HBV-DNA E C titis B virus (HBV) have developed, and because serum wereu 4.99 and 4.69 log copies/mL at week 12, respecb and 6.00 and 5.80 log copies/mL at week 24 r HBV-DNA levels may rebound in patients who receive itively, t© h r o treatment with nucleoside/nucleotide for up (both time points, P = NS between groups). At week 12, t fanalogues r ig a largelyt unmet s to 2 years, there y remains clinical need HBV-DNA was undetectable in 43.1% (28/65) of the i p o for agents to induce potent virologic suppression in the group and 34.8% (23/66) of the entecavir Ncourse of HBVDinfection. telbivudine Coof the disease initial stage group (P = NS); at week 24, it was undetectable in 10

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Objective: The aim of this work was to compare the early antiviral effectiveness of telbivudine and entecavir in the treatment of patients with hepatitis B e antigen (HBeAg)-positive HBV. Methods: In this parallel-group, open-label trial, adult Chinese patients with previously untreated HBeAg-positive HBV (HBV-DNA concentration: ≥6 log10 copies/mL; alanine aminotransferase [ALT] level: ≥2 times the upper limit of normal) were randomized to receive telbivudine 600 mg or entecavir 0.5 mg daily for 24 weeks. Blood samples were collected at the baseline and at 12 and 24 weeks after the treatment. The primary end point was the mean reduction from baseline in serum HBV-DNA concentration at week 24. Secondary end points included mean reduction from baseline in serum HBV-DNA concentration at week 12, the absence of serum HBV-DNA, absence of serum HBeAg, HBeAg seroconversion at week 24, the normalization of serum ALT at week 24, and occurrence of adverse events through week 24. Results: A total of 131 patients were enrolled in the study: 91 men and 40 women, with a mean (SD) age of 32.5 (8.9) years. All patients were ethnic Han Chinese. The baseline demographic characteristics and serum HBV-DNA concentrations in the 2 treatment groups were well matched. Sixty-five patients were randomized April 2010

67.7% (44/65) of the telbivudine group and 57.6% (38/66) of the entecavir group (P = NS). At week 12, HBeAg absence and seroconversion rates were significantly greater in the telbivudine group than the entecavir group (absence: 20.0% [13/65] vs 3.0% [2/66], respectively [P = 0.002]; seroconversion: 13.8% [9/65] vs 3.0% [2/66] [P = 0.030]). However, at week 24, HBeAg absence and seroconversion rates were comparable between the telbivudine and entecavir groups (absence: 36.9% [24/65] vs 28.8% [19/66] [P = NS]; seroconversion: 24.6% [16/65] vs 13.6% [9/66] [P = NS]). In addition, the normalization of ALT levels was observed in 78.5% (51/65) and 74.2% (49/66) of patients treated with telbivudine and entecavir, respectively, at week 24 (P = NS). The adverse events were upper respiratory tract infection (12.3% of telbivudine patients vs 9.1% of entecavir patients), fatigue (6.2% vs 7.6%), diarrhea (1.5% vs 3.0%), and coughing (0% vs 1.5%), most of which were mild to moderate. Elevated creatinine

This work was presented in part at the 45th Annual Meeting for the European Association for the Study of the Liver, April 14–18, 2010, Vienna, Austria. Accepted for publication March 18, 2010. doi:10.1016/j.clinthera.2010.04.001 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved.

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Clinical Therapeutics phosphokinase was noted in 8 telbivudine-treated patients (12.3%). There were no statistically significant differences in rates of adverse events between groups except for creatinine phosphokinase. Conclusion: In this study of ethnic Han Chinese adults with previously untreated HBeAg-positive HBV infection, there were no statistically significant differences in effectiveness or tolerability between telbivudine 600 mg and entecavir 0.5 mg at the end of 24 weeks of treatment. ChiCTR.org identifier: ChiCTR-TRC00000341. (Clin Ther. 2010;32:649–658) © 2010 Excerpta Medica Inc. Key words: hepatitis B, HBV, HBeAg, telbivudine, entecavir, seroconversion.

INTRODUCTION Although more than 20 years have elapsed since the availability of an effective vaccine to prevent hepatitis B virus (HBV) infection, the virus continues to play an important role in human disease, infecting ~350 million people worldwide.1 An estimated >1 million people die annually from HBV-related disease, such as hepatic cirrhosis or hepatocellular carcinoma.2 It has been reported that the risk of developing hepatic cirrhosis and hepatocellular carcinoma is directly proportional to serum HBV-DNA concentration, a measure of viral load.3,4 With the advent of the oral nucleoside/nucleotide analogues, the incidence of the complications of chronic HBV infection has declined.5,6 However, the clinical benefits of these nucleoside/nucleotide analogues are limited because of the emergence of resistant strains and the low rate of a sustained response (ie, the serum HBV-DNA level rebounds in many patients following treatment lasting up to 2 years).7–10 Several studies have reported that the initial viral response (ie, the decrease in the serum HBV-DNA level during the first 12 and 24 weeks of treatment) is a useful predictor for the emergence of resistant virus in patients with chronic HBV infection.11,12 Thus, in patients with a prolonged treatment, the more the viral load declines in the initial stage of treatment, the better the outcome will be.13 Therefore, an unmet clinical need remains for agents that are able to induce potent virologic suppression in the initial stage of the disease course. It has been reported that telbivudine and entecavir are associated with better outcomes compared with other nucleoside/nucleotide analogues (eg, lamivudine, adefovir) that have been approved by the Chinese health 650

authority, the State Food and Drug Administration, based on direct measures of antiviral efficacy (such as HBV-DNA detection) and on several clinical measures (such as alanine aminotransferase [ALT] and HBV serologic tests).14–16 Entecavir has a high genetic barrier to resistance; more mutations are required to produce a reduction in susceptibility.4 In addition, treatment with telbivudine, also a nucleoside analogue, has a higher rate of hepatitis B e antigen (HBeAg) seroconversion than other analogues.17 Moreover, both drugs can suppress HBV replication rapidly and effectively (ie, to undetectable range in ~4 weeks).18 Recent studies have reported that antiviral efficacy for chronic HBV infection and the emergence of drug resistance are closely related to the degree of viral suppression achieved within the first 24 weeks of therapy.19,20 However, a search of the literature did not identify any published direct comparisons of these agents for the treatment of patients with chronic HBV infection. Therefore, we designed this prospective, parallelgroup, open-label, randomized clinical trial to compare the early antiviral effectiveness of telbivudine and entecavir in the treatment of patients with HBeAg-positive chronic HBV infection.

Patients and METHODS This study was conducted in agreement with the ethical principles of the Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical College, consistent with the Good Clinical Practice Guideline. The study was performed according to Consolidated Standards of Reporting Trials checklist criteria.21 Written informed consent was obtained from each patient before the initiation of the study.

Patients Outpatients at the First Affiliated Hospital of Wenzhou Medical College were eligible for the trial if they were aged 18 to 65 years, had HBeAg-positive chronic HBV infection and compensated liver disease with a serum ALT value ≥2 times the upper limit of normal (ULN), and had never received treatment with nucleosides or nucleotides for HBV. In addition, to evaluate the virologic suppressive effect of the 2 drugs of interest, patients were required to have a serum HBV-DNA concentration ≥6 log10 copies/mL at screening. Based on the investigators’ clinical experience, HBV-DNA concentrations were categorized as follows: level 1, Volume 32 Number 4

M.-H. Zheng et al. HBV-DNA 6 log10 to