Iio Etsuko, Shimada Noritomo, Takaguchi Koichi, Senoh Tomonori, Eguchi Yuichiro, Atsukawa Masanori, Tsubota Akihito, Abe Hiroshi, Kato Keizo, Kusakabe Atsunori, Miyaki Tomokatsu, Matsuura Kentaro, Matsunami Kayoko, Shinkai Noboru, Fujiwara Kei, Nojiri Shunsuke, Tanaka Yasuhito
Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Otakanomori Hospital, Kashiwa, Japan.
Hepatol Res. 2017 Nov;47(12):1308-1316. doi: 10.1111/hepr.12898. Epub 2017 May 6.
This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy.
Overall, 530 Japanese patients who were infected with hepatitis C virus genotype 1 received SOF/LDV therapy for 12 weeks, and resistance-associated variants (RAVs) in the hepatitis C virus non-structural protein (NS)5A and NS5B regions were assessed at baseline and virological relapse by direct sequencing.
Sustained virological response (SVR) rates did not significantly differ between patients with and without NS5A Y93H/N (94.2% [113/120] vs. 97.7% [345/353]), but the SVR rate was significantly lower in patients with prior DCV/ASV therapy compared to those without (69.2% [18/26] vs. 98.4% [496/504], P < 0.001). Among 26 patients with prior DCV/ASV therapy, the prevalence of NS5A multi-RAVs (≥2) was similar between responders and non-responders (61% [11/18] vs. 75% [5/8]), but all patients without RAVs achieved SVR. Multivariate analysis showed that prior DCV/ASV therapy and history of hepatocellular carcinoma were independently associated with treatment failure (odds ratio, 37.55; 95% confidence interval, 10.78-130.76; P < 0.001 for prior DCV/ASV therapy; odds ratio, 4.42; 95% confidence interval, 1.09-18.04; P = 0.03 for the history of HCC). All SOF/LDV failure patients (n = 8) with prior DCV/ASV treatment had two or more factors of cirrhosis, IL28B unfavorable genotype, and baseline NS5A multi-RAVs. The multiple NS5A RAVs had increased but NS5B substitutions, C316N/A207T/A218S or L159F, had not changed at the time of relapse.
Prior DCV/ASV therapy is associated with failure of SOF/LDV therapy due to multiple RAVs.
本研究探讨了索磷布韦（SOF）/来迪帕司韦（LDV）疗法对既往接受过与未接受过达卡他韦（DCV）/阿舒瑞韦（ASV）治疗的慢性丙型肝炎患者的治疗效果。
总体而言，530例丙型肝炎病毒1型感染的日本患者接受了SOF/LDV治疗12周，并通过直接测序在基线和病毒学复发时评估丙型肝炎病毒非结构蛋白（NS）5A和NS5B区域的耐药相关变异（RAV）。
有与无NS5A Y93H/N的患者持续病毒学应答（SVR）率无显著差异（94.2%[113/120]对97.7%[345/353]），但既往接受过DCV/ASV治疗的患者SVR率显著低于未接受过的患者（69.2%[18/26]对98.4%[496/504]，P<0.001）。在26例既往接受过DCV/ASV治疗的患者中，应答者与无应答者之间NS5A多RAV（≥2）的发生率相似（61%[11/18]对75%[5/8]），但所有无RAV的患者均实现了SVR。多因素分析显示，既往DCV/ASV治疗和肝细胞癌病史与治疗失败独立相关（比值比为37.55；95%置信区间为10.78 - 130.76；既往DCV/ASV治疗P<0.001；比值比为4.42；95%置信区间为1.09 - 18.04；肝细胞癌病史P = 0.03）。所有既往接受过DCV/ASV治疗的SOF/LDV治疗失败患者（n = 8）均有两个或更多肝硬化、IL28B不利基因型和基线NS5A多RAV因素。复发时多个NS5A RAV增加，但NS5B替代，C316N/A207T/A218S或L159F未改变。
既往DCV/ASV治疗与因多个RAV导致的SOF/LDV治疗失败相关。
