Liver Disease Control Science, Graduate School of Organic Pathology and Therapeutics, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan.
PLoS One. 2019 Jul 10;14(7):e0219022. doi: 10.1371/journal.pone.0219022. eCollection 2019.
Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy.
Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected.
Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2-4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023).
CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.
直接作用抗病毒（DAA）联合治疗慢性丙型肝炎病毒（HCV）感染时常会出现以血清丙氨酸氨基转移酶（ALT）升高为特征的药物性肝损伤。本研究旨在探讨与asunaprevir 联合 daclatasvir 治疗时 ALT 升高相关的药物代谢或转运相关基因的单核苷酸多态性（SNP）。
本研究共纳入 185 例日本慢性 HCV 基因 1b 感染患者，这些患者接受了 asunaprevir 联合 daclatasvir 治疗。选择可能与 asunaprevir 和 daclatasvir 药代动力学相关的代谢酶和转运体基因的标签 SNP 进行分析。
在所分析的标签 SNP 中，CYP3A4 rs4646437 与 ALT 升高显著相关（p = 0.013）：CC 基因型患者的最大 ALT 值高于非 CC 基因型患者（等位基因 T）。CC 基因型患者的 2-4 级比例明显高于非 CC 基因型患者（p = 0.028）。非 CC 基因型患者中无患者出现 ALT 升高≥2 级。多变量分析显示，rs4646437 CC 基因型和肝硬化是与 ALT 升高≥1 级相关的独立危险因素（比值比分别为 2.83 和 1.88；p 值分别为 0.040 和 0.045）。在探索性分析中，尽管 asunaprevir 和 daclatasvir 的血清浓度与最大 ALT 值或 rs4646437 基因型无关，但 ALT 升高≥1 级患者的 asunaprevir 浓度明显高于 ALT 升高<1 级患者（P = 0.023）。
在接受 ASV 联合 DCV 治疗的日本患者中，发现 CYP3A4 rs4646437 与 ALT 升高显著相关，且独立相关。值得注意的是，rs4646437 非 CC 基因型（等位基因 T）患者均未出现 ALT 升高≥2 级。在治疗前进行 SNP 基因分型可能有助于仔细监测患者，以确保安全完成治疗。
