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

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http://www.springerlink.com/content/n561v2124k2774w2/

Journal Hepatology International

Publisher Springer New York

ISSN 1936-0533 (Print) 1936-0541 (Online)

Category Case Report

DOI 10.1007/s12072-008-9108-8

Subject Collection Medicine

SpringerLink Date Wednesday, December 10, 2008

Case Report

Two cases of development of entecavir resistance during entecavir treatment for

nucleoside-naive chronic hepatitis B

Haruhiko Kobashi1 , Shin-ichi Fujioka2, Mitsuhiko Kawaguchi2, Hiromitsu Kumada3,

Osamu Yokosuka4, Norio Hayashi5, Kazuyuki Suzuki6, Takeshi Okanoue7, Michio

Sata8, Hirohito Tsubouchi9, Chifumi Sato10, Kendo Kiyosawa11, Kyuichi

Tanikawa12, Taku Seriu13, Hiroki Ishikawa13, Akinobu Takaki1, Yoshiaki Iwasaki1,

Toshiya Osawa2, Toshiyuki Takaki2, Kosaku Sakaguchi1, Yasushi Shiratori1,

Kazuhide Yamamoto1, J. Tenney14 and Masao Omata15

(1) Department of Gastroenterology and Hepatology, Graduate School of Medicine,

Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan

(2) Department of Medicine, Okayama Saiseikai General Hospital, Okayama, Japan

(3) Center of Liver Disease, Toranomon Hospital, Kanagawa, Japan

(4) Department of Medicine and Clinical Oncology, Graduate School of Medicine,

Chiba University, Chiba, Japan

(5) Department of Gastroenterology and Hepatology, Graduate School of Medicine,

Osaka University, Osaka, Japan

(6) First Department of Internal Medicine, Iwate Medical University, Morioka,

Japan

(7) Molecular Gastroenterology and Hepatology, Graduate School of Medical

Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

(8) Department of Gastroenterology, Kurume University School of Medicine,

Fukuoka, Japan

(9) Digestive Disease and Life-style Related Disease Health Research, Human and

Environmental Sciences, Graduate School of Medical and Dental Sciences,

Kagoshima University, Kagoshima, Japan

(10) Department of Analytical Health Science, Graduate School of Allied Health

Sciences, Tokyo Medical and Dental University, Tokyo, Japan

(11) Division of Hepatology and Gastroenterology, Department of Internal

Medicine, Shinshu University School of Medicine, Matsumoto, Japan

(12) International Institute for Liver Research, Kurume University, Kurume,

Japan

(13) Bristol-Myers Squibb Japan, Pharmaceutical Research Institute, Tokyo,

Japan

(14) Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA

(15) Department of Gastroenterology, Faculty of Medicine, University of Tokyo,

Tokyo, Japan

Received: 27 June 2008 Accepted: 2 October 2008 Published online: 9 December

2008

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 Case 1: 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