Itakura Jun, Kurosaki Masayuki, Higuchi Mayu, Takada Hitomi, Nakakuki Natsuko, Itakura Yoshie, Tamaki Nobuharu, Yasui Yutaka, Suzuki Shoko, Tsuchiya Kaoru, Nakanishi Hiroyuki, Takahashi Yuka, Maekawa Shinya, Enomoto Nobuyuki, Izumi Namiki
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.
First Department of Internal Medicine, University of Yamanashi, Chuou Yamanashi, Japan.
PLoS One. 2015 Sep 14;10(9):e0138060. doi: 10.1371/journal.pone.0138060. eCollection 2015.
BACKGROUND & AIMS: The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.
Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.
By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001).
Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.
丙型肝炎病毒（HCV）耐药相关变异体（RAV）的存在会降低直接抗病毒药物（DAA）的疗效。本研究的目的是确定RAV对基于干扰素治疗的敏感性。
采用直接测序和深度测序检测NS5A区域的Y93H RAV。29例基线时可检测到RAV的基因1b型患者接受simeprevir、聚乙二醇干扰素和利巴韦林联合治疗。确定治疗期间以及突破或复发时Y93H RAV比例的纵向变化。
通过直接测序，在基线时同时存在Y93H变异体和野生型病毒且HCV RNA仍可检测到的患者中，57%在治疗早期（7天内）Y93H RAV变得不可检测或比例下降。通过深度测序，基线时Y93H RAV相对于Y93野生型的比例为52.7%（5.8%-97.4%），在开始治疗的7天内显著降至29.7%（0.16%-98.3%）（p = 0.023）。29例中有21例（72.4%）Y93H RAV比例降低，14例（48.7%）观察到显著降低超过10%。Y93H RAV的HCV RNA下降幅度（-3.65±1.3 logIU/mL/天）显著大于Y93野生型（-3.35±1.0 logIU/mL/天）（p<0.001）。
Y93H RAV比Y93野生型对基于干扰素的治疗更敏感。
