Characterization of naturally occurring protease inhibitor-resistance mutations in genotype 1b hepatitis C virus patients.
OBJECTIVE
Protease inhibitor (PI)-resistant hepatitis C virus (HCV) variants may be present in substantial numbers in PI-untreated patients according to recent reports. However, influence of these viruses in the clinical course of chronic hepatitis C has not been well characterized.


METHODS
The dominant HCV nonstructural 3 (NS3) amino acid sequences were determined in 261 HCV genotype 1b-infected Japanese patients before pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, and investigated the patients' clinical characteristics as well as treatment responses including sustained virological response (SVR) rate. HCV-NS3 sequences were also determined in 39 non-SVR patients after completion of the therapy.


RESULTS
Four single mutations (T54S, Q80K, I153V, and D168E) known to confer PI resistance were found in 35 of 261 patients (13.4%), and double mutations (I153V plus T54S/D168E) were found in 6 patients (2.3%). Responses to PEG-IFN/RBV therapy did not differ between patients with and without PI-resistance mutations (mutation group, SVR 48%; wild-type group, SVR 40%; P = 0.38). On the other hand, two mutations appeared in two non-SVR patients after PEG-IFN/RBV therapy (I153V and E168D, 5.1%).


CONCLUSIONS
PI-resistance-associated NS3 mutations exist in a substantial proportion of untreated HCV-1b-infected patients. The impact of these mutations in the treatment of PIs is unclear, but clinicians should pay attention to avoid further development of PI resistance.
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Hiroko
H
Shindo
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan. maekawa@yamanashi.ac.jp.
Shinya
S
Maekawa
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Kazuki
K
Komase
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Ryota
R
Sueki
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Mika
M
Miura
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Makoto
M
Kadokura
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Kuniaki
K
Shindo
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Fumitake
F
Amemiya
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Takatoshi
T
Kitamura
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Yasuhiro
Y
Nakayama
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Taisuke
T
Inoue
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Minoru
M
Sakamoto
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Shun-Ichi
S
Okada
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
Yasuhiro
Y
Asahina
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
Namiki
N
Izumi
Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Masao
M
Honda
Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Shuichi
S
Kaneko
First Department of Internal Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Nobuyuki
N
Enomoto