Itakura Jun, Kurosaki Masayuki, Takada Hitomi, Nakakuki Natsuko, Matsuda Syuya, Gondou Kouichi, Asano Yu, Hattori Nobuhiro, Itakura Yoshie, Tamaki Nobuharu, Yasui Yutaka, Suzuki Shoko, Hosokawa Takanori, Tsuchiya Kaoru, Nakanishi Hiroyuki, Takahashi Yuka, Maekawa Syinya, Enomoto Nobuyuki, Izumi Namiki
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo.
First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.
Hepatol Res. 2015 Oct;45(10):E115-21. doi: 10.1111/hepr.12474.
The presence of resistance-associated variants (RAV) may attenuate the efficacy of direct-acting antivirals (DAA) in combination therapy for hepatitis C. The aim of this study was to characterize the NS3 and NS5A regions of hepatitis C virus (HCV) in naturally occurring RAV.
The NS3 and NS5A regions of HCV were amplified by nested polymerase chain reaction and their nucleotide sequences were determined by direct sequencing in 493 genotype 1b patients naive to DAA-based therapies. The effect of baseline RAV on response to pegylated interferon and ribavirin therapy was analyzed in 65 patients after stratification by interleukin (IL)-28B genotype.
The incidence of RAV was 7.9% in NS3 (V36I/L, 1.2%; T54S, 2.8%; Q80K/R, 3.0%; A156S, 0.2%; and D168E/T, 2.4%) and 20.2% in NS5A (L31I/M, 2.2%; and Y93H, 19.0%). The incidence in interferon experienced and naive patients was similar. The incidence of Y93H in NS5A was significantly higher in the IL-28B TT genotype (rs8099917) than non-TT (27.1% vs 9.5%, P < 0.001). The virological response to pegylated interferon plus ribavirin therapy was not affected by the presence of RAV in IL-28B TT genotype.
RAV, especially Y93H in the NS5A region, were highly prevalent in DAA naive patients with genotype 1b HCV in Japan and were linked to IL-28B TT genotype. Interferon-based therapy could be an alternative for patients with RAV because these variants did not attenuate the response to that therapy. The analysis of RAV may impact the selection of the optimal treatment strategy.
耐药相关变异（RAV）的存在可能会削弱直接抗病毒药物（DAA）在丙型肝炎联合治疗中的疗效。本研究的目的是对自然发生的RAV中丙型肝炎病毒（HCV）的NS3和NS5A区域进行特征分析。
采用巢式聚合酶链反应扩增HCV的NS3和NS5A区域，并通过直接测序确定493例初治DAA治疗的1b型基因型患者的核苷酸序列。在根据白细胞介素（IL）-28B基因型分层后的65例患者中，分析基线RAV对聚乙二醇干扰素和利巴韦林治疗反应的影响。
NS3区域RAV的发生率为7.9%（V36I/L，1.2%；T54S，2.8%；Q80K/R，3.0%；A156S，0.2%；D168E/T，2.4%），NS5A区域为20.2%（L31I/M，2.2%；Y93H，19.0%）。接受过干扰素治疗和初治患者的发生率相似。NS5A区域Y93H在IL-28B TT基因型（rs8099917）中的发生率显著高于非TT基因型（27.1%对9.5%，P<0.001）。在IL-28B TT基因型中，RAV的存在不影响聚乙二醇干扰素加利巴韦林治疗的病毒学反应。
在日本，RAV，尤其是NS5A区域的Y93H，在初治1b型基因型HCV患者中高度流行，且与IL-28B TT基因型相关。基于干扰素的治疗可能是RAV患者的一种替代方案，因为这些变异不会削弱对该治疗的反应。RAV分析可能会影响最佳治疗策略的选择。
