Evaluation of Resistance-Associated Substitutions in NS5A Using Direct Sequence and Cycleave Method and Treatment Outcome with Daclatasvir and Asunaprevir for Chronic Hepatitis C Genotype 1.
BACKGROUND
The aim of this study was to evaluate the efficacy of daclatasvir plus asunaprevir therapy in patients infected with hepatitis C virus and determine its relevance to resistant variants.


METHODS
A total of 629 consecutive patients infected with hepatitis C virus genotype 1 were assessed. Daclatasvir (60 mg/day) plus asunaprevir (200 mg/day) was given for 24 weeks. The virological responses and resistance-associated substitutions of hepatitis C virus mutants were examined by the direct sequence and cycleave methods were evaluated.


RESULTS
Overall, 89.4% (555/621) of patients exhibited a sustained virological response (SVR). The SVR rates in the patients with wild type, mixed, and mutant type Y93 by direct sequencing were 92.5% (520/562), 70.3% (26/37), and 42.9% (9/21), respectively. The SVR rates in the patients with 100%, 90%, 80%-30%, and 20%-0% Y93 wild by the cycleave method were 93.4% (456/488), 88.2%(30/34), 56.0%(14/25), and 36.8%(7/19), respectively. In contrast, the SVR rates for the wild type and mixed/mutant type L31 by direct sequencing were 90.2% (534/592) and 72.4% (21/29), respectively. In the multivariate analyses, the wild type Y93, no history of simeprevir therapy, the wild type L31, and low HCV RNA level were independent factors of SVR.


CONCLUSIONS
NS5A resistance-associated substitutions, especially Y93H, were major factors predicting the SVR. Although direct sequencing can predict the SVR rate, the cycleave method is considered to be more useful for predicting the SVR when used in combination.
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Tatsuya
http://orcid.org/0000-0003-4106-6527
T
Ide
Department of Internal Medicine, Saga Medical School, Saga, Japan.
Yuichiro
Y
Eguchi
Third Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.
Masaru
M
Harada
Asakura Medical Association Hospital, Fukuoka, Japan.
Kunihide
K
Ishii
Yame General Hospital, Fukuoka, Japan.
Masaru
M
Morita
Nagata Hospital, Fukuoka, Japan.
Yasuyo
Y
Morita
Kurume University Medical Center, Fukuoka, Japan.
Gen
G
Sugiyama
Saiseikai Futsukaichi Hospital, Fukuoka, Japan.
Hirofumi
H
Fukushima
Saga Central Hospital, Saga, Japan.
Yoichi
Y
Yano
Omuta City Hospital, Fukuoka, Japan.
Kazunori
K
Noguchi
Shin Koga Clinic, Fukuoka, Japan.
Hiroki
H
Nakamura
Kurume Chuo Hosipital, Fukuoka, Japan.
Junjiro
J
Hisatomi
Kumamoto Central Hospital, Kumamoto, Japan.
Hiroto
H
Kumemura
Chikugo City Hospital, Fukuoka, Japan.
Miki
M
Shirachi
Department of Internal Medicine, Saga Medical School, Saga, Japan.
Shinji
S
Iwane
Department of Internal Medicine, Saga Medical School, Saga, Japan.
Michiaki
M
Okada
Third Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.
Yuichi
Y
Honma
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Teruko
T
Arinaga-Hino
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Ichiro
I
Miyajima
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Kei
K
Ogata
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Reiichiro
R
Kuwahara
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Keisuke
K
Amano
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Toshihiro
T
Kawaguchi
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Ryoko
R
Kuromatsu
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
Takuji
T
Torimura
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