Abstract
AimsDrug-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.MethodsSubjects 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.ResultsAmong 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).ConclusionsCYP3A4 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.
Highlights
Antiviral therapy for chronic hepatitis C virus (HCV) infection has advanced dramatically in recent years
Among the tag single nucleotide polymorphisms (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
SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely
Summary
Antiviral therapy for chronic hepatitis C virus (HCV) infection has advanced dramatically in recent years. Asunaprevir [ASV; nonstructural protein (NS) 3/4A protease inhibitor] plus daclatasvir (DCV; NS5A replication-complex inhibitor) therapy is the first, interferon-free, DAA treatment regimen available for chronic HCV genotype 1 infection in Japan. Is still used in several Latin American and Asian countries (including Japan, China, and South Korea), and triple therapy with ASV, DCV, and beclabuvir (nonnucleoside NS5B thumb-1 polymerase inhibitor) is available in some countries [7,8,9] These treatment regimens often induce liver damage which is characterized by elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin levels [2, 3, 9]. Both ASV and DCV are metabolized primarily by cytochrome P450 family 3 subfamily A member 4 (CYP3A4)-mediated hepatic oxidative reactions [10,11,12,13]
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