First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-0034, Japan.
J Gastroenterol. 2018 Jun;53(6):780-786. doi: 10.1007/s00535-017-1405-3. Epub 2017 Nov 1.
Liver damage presented as alanine aminotransferase (ALT) elevation and high ALT-caused treatment discontinuation occurs with high frequency in Japanese patients receiving daclatasvir plus asunaprevir (DCV/ASV) therapy for hepatitis C virus (HCV) infection, and its mechanism is unknown.
A total of 247 Japanese patients consisting of two independent cohorts with genotype-1b HCV infection receiving DCV/ASV therapy were included. The association of ALT levels during therapy and single nucleotide polymorphisms (SNP) of five drug-metabolizing enzyme loci selected for their possible influence on NS3/4A and NS5A inhibitors was investigated.
Among five SNPs, we found a significant correlation between the presence of the UGT1A1 rs4148323 A allele and ALT elevation (Grade 3 elevation in AA 57%, AG 18%, and GG 4%, P = 8.4E - 06) and drug discontinuation (AA 22%, AG 11%, and GG 2.5%, P = 8.7E - 04), while no association was observed with ALT values at baseline (Grade 3 elevation AA 0%, AG 4%, and GG 2%, P = 0.5). In contrast, patients with risk A allele for drug-induced ALT elevation had a tendency to respond more favorably to treatment (AA 100%, AG 93%, and GG 90%, P = 0.29).
Through the analysis we suggest that the A allele in UGT1A1 rs4148323 (UGT1A16), which is highly prevalent in the Japanese population, should be considered a risk for the development of DCV/ASV therapy-induced ALT elevation. Pretreatment SNP testing of UGT1A16 might be beneficial for the prediction of liver damage induced by DCV/ASV or even by DCV/ASV plus beclabuvir.
日本丙型肝炎病毒（HCV）感染患者接受达卡他韦（DCV）联合asunaprevir（ASV）治疗时，丙氨酸氨基转移酶（ALT）升高和因 ALT 升高导致治疗中断的肝损伤发生率较高，其机制尚不清楚。
本研究共纳入 247 例基因型 1b HCV 感染的日本患者，他们来自两个独立的队列，均接受 DCV/ASV 治疗。研究分析了治疗期间 ALT 水平与五个药物代谢酶基因座的单核苷酸多态性（SNP）之间的关系，这些基因座的 SNP 可能影响 NS3/4A 和 NS5A 抑制剂。
在五个 SNP 中，我们发现 UGT1A1 rs4148323 A 等位基因的存在与 ALT 升高（AA 为 57%、AG 为 18%、GG 为 4%，P=8.4E-06）和药物停药（AA 为 22%、AG 为 11%、GG 为 2.5%，P=8.7E-04）显著相关，而与基线时的 ALT 值无相关性（AA 为 0%、AG 为 4%、GG 为 2%，P=0.5）。相比之下，药物诱导的 ALT 升高风险 A 等位基因的患者对治疗的反应更有利（AA 为 100%、AG 为 93%、GG 为 90%，P=0.29）。
通过分析，我们认为 UGT1A1 rs4148323（UGT1A16）中的 A 等位基因（UGT1A16）在日本人群中高度流行，应被视为 DCV/ASV 治疗引起的 ALT 升高的风险因素。在接受 DCV/ASV 治疗前进行 UGT1A1*6 的 SNP 检测可能有助于预测 DCV/ASV 甚至 DCV/ASV 联合 beclabuvir 引起的肝损伤。
