Yoshida Kanako, Hai Hoang, Tamori Akihiro, Teranishi Yuga, Kozuka Ritsuzo, Motoyama Hiroyuki, Kawamura Etsushi, Hagihara Atsushi, Uchida-Kobayashi Sawako, Morikawa Hiroyasu, Enomoto Masaru, Murakami Yoshiki, Kawada Norifumi
Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Int J Mol Sci. 2017 May 3;18(5):962. doi: 10.3390/ijms18050962.
We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.
我们评估了基于直接作用抗病毒药物（DAA）的治疗失败后，丙型肝炎病毒中主要耐药相关替代位点（RASs）在长期随访期间的转变情况。通过直接测序检测了20例simeprevir/聚乙二醇干扰素/利巴韦林（SMV/PEG-IFN/RBV）治疗失败患者和25例达卡他韦/阿舒瑞韦（DCV/ASV）治疗失败患者的非结构（NS）3/4A、NS5A、NS5B中的RASs以及NS5A中的缺失情况。对于SMV/PEG-IFN/RBV治疗，20例患者中有16例在治疗失败时，NS3/4A的D168位点检测到RAS，但NS5A和NS5B未检测到。在中位随访期64周内，16例患者中有9例D168位点的RAS优势减弱。在25例DCV/ASV治疗失败患者中，D168、L31和Y93位点的RASs分别在57.1%、72.2%和76.9%的患者中被发现。10例先前接受SMV/PEG-IFN/RBV治疗的患者中有3例检测到NS5A缺失。突破患者的RASs数量超过复发患者（平均3.9个对2.7个，<0.05）。15例患者中有6例在80周内NS3/4A的D168位点的RAS优势减弱。Y93H在复发时出现，然后在治疗后130周时逐渐下降99%。出现的RASs与治疗临床过程相关，且在更长时间的随访中未被检测到。
