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Antiviral activity, dose–response relationship, and safety of entecavir following 24-week oral dosing in nucleoside-naive Japanese adult patients with chronic hepatitis B: a randomized, double-blind, phase II clinical trial

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Abstract

Purpose

A randomized, double-blind, multicenter study (ETV-047) was conducted to evaluate the dose–response relationship of entecavir and compare its antiviral activity and safety with lamivudine in Japanese patients with chronic hepatitis B (CHB).

Methods

One hundred thirty-seven nucleoside-naive adult patients with CHB were randomized to once-daily oral doses of entecavir 0.01, 0.1, or 0.5 mg or lamivudine 100 mg for 24 weeks. The primary efficacy end point used to evaluate the dose–response relationship was mean change from baseline in serum hepatitis B virus (HBV) DNA level at week 22, as determined by polymerase chain reaction assay.

Results

Entecavir demonstrated a clear dose–response relationship, with mean change from baseline in serum HBV DNA level of −3.11, −4.77, and −5.16 log10 copies/ml with entecavir 0.01, 0.1, and 0.5 mg, respectively. Entecavir 0.5 mg was superior to lamivudine 100 mg for the mean change in HBV DNA level (−5.16 vs. −4.29 log10 copies/ml; P = 0.007). The overall incidence of adverse events was comparable between treatment groups. Two patients discontinued treatment because of adverse events (one with liver cirrhosis [entecavir 0.5 mg] and one with grade 4 serum alanine aminotransferase (ALT) elevation, nausea, and malaise [lamivudine 100 mg]). Serum ALT flares were observed in four patients; flares were associated with 2 log10 reductions or more in HBV DNA level and resolved without dose interruption.

Conclusion

Entecavir 0.01–0.5 mg is well tolerated and produces a dose-dependent reduction in viral load in nucleoside-naive Japanese patients with CHB. Compared with lamivudine 100 mg, entecavir 0.1 mg demonstrated noninferiority and entecavir 0.5 mg was superior in this population.

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Authors and Affiliations

  1. Division of Liver Disease, Department of Internal Medicine, Akashi Municipal Hospital, 1-33 Takasyo-machi, Akashi-shi, Hyogo, Japan

    Michiko Shindo

  2. Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

    Kazuaki Chayama

  3. Department of Gastroenterology and Hepatology, Saitama Medical University, Saitama, Japan

    Satoshi Mochida

  4. Department of Hepatology, Sapporo Kosei General Hospital, Hokkaido, Japan

    Joji Toyota

  5. Department of Gastroenterology, Gifu Municipal Hospital, Gifu, Japan

    Eiichi Tomita

  6. Department of Hepatology, Toranomon Hospital, Tokyo, Japan

    Hiromitsu Kumada

  7. Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Osamu Yokosuka

  8. Department of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan

    Michio Sata

  9. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan

    Norio Hayashi

  10. Department of Internal Medicine, Iwate Medical University, Iwate, Japan

    Kazuyuki Suzuki

  11. Department of Gastroenterology, Saiseikai Suita Hospital, Osaka, Japan

    Takeshi Okanoue

  12. Department of Digestive Disease and Lifestyle-Related Disease, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Hirohito Tsubouchi

  13. Pharmaceutical Research Institute, Bristol-Myers Squibb Japan, Tokyo, Japan

    Hiroki Ishikawa & Taku Seriu

  14. Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Masao Omata

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  1. Michiko Shindo
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  2. Kazuaki Chayama
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  3. Satoshi Mochida
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  13. Hiroki Ishikawa
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  14. Taku Seriu
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  15. Masao Omata
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Correspondence to Michiko Shindo.

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Shindo, M., Chayama, K., Mochida, S. et al. Antiviral activity, dose–response relationship, and safety of entecavir following 24-week oral dosing in nucleoside-naive Japanese adult patients with chronic hepatitis B: a randomized, double-blind, phase II clinical trial. Hepatol Int 3, 445–452 (2009). https://doi.org/10.1007/s12072-009-9135-0

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  • DOI: https://doi.org/10.1007/s12072-009-9135-0

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