Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naive chronic hepatitis B

Haruhiko Kobashi, Shin Ichi Fujioka, Mitsuhiko Kawaguchi, Hiromitsu Kumada, Osamu Yokosuka, Norio Hayashi, Kazuyuki Suzuki, Takeshi Okanoue, Michio Sata, Hirohito Tsubouchi, Chifumi Sato, Kendo Kiyosawa, Kyuichi Tanikawa, Taku Seriu, Hiroki Ishikawa, Akinobu Takaki, Yoshiaki Iwasaki, Toshiya Osawa, Toshiyuki Takaki, Kosaku SakaguchiYasushi Shiratori, Kazuhide Yamamoto, Daniel J. Tenney, Masao Omata

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19 Citations (Scopus)

Abstract

Background: Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). Results: Case1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log10 copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log10 copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2. Conclusions: ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after <0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.

Original languageEnglish
Pages (from-to)403-410
Number of pages8
JournalHepatology International
Volume3
Issue number2
DOIs
Publication statusPublished - 2009

Keywords

  • Chronic hepatitis B
  • Drug resistance
  • Entecavir
  • HBV
  • Nucleoside-naive

ASJC Scopus subject areas

  • Hepatology

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    Kobashi, H., Fujioka, S. I., Kawaguchi, M., Kumada, H., Yokosuka, O., Hayashi, N., Suzuki, K., Okanoue, T., Sata, M., Tsubouchi, H., Sato, C., Kiyosawa, K., Tanikawa, K., Seriu, T., Ishikawa, H., Takaki, A., Iwasaki, Y., Osawa, T., Takaki, T., ... Omata, M. (2009). Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naive chronic hepatitis B. Hepatology International, 3(2), 403-410. https://doi.org/10.1007/s12072-008-9108-8