Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

• Published in: PloS one 2019-07, Vol.14 (7), p.e0219022-e0219022
• Main Authors: Kato, Keizo, Shimada, Noritomo, Atsukawa, Masanori, Abe, Hiroshi, Itokawa, Norio, Matsumoto, Yoshihiro, Agata, Rie, Tsubota, Akihito
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Alanine; Alanine aminotransferase; Alanine transaminase; Alanine Transaminase - blood; Alleles; Amino acids; Antiviral agents; Antiviral drugs; Biology and life sciences; Care and treatment; Chemical and Drug Induced Liver Injury - blood; Chemical and Drug Induced Liver Injury - genetics; Chromosomes; Chronic infection; Cirrhosis; Combination therapy; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP3A - genetics; Diagnosis; Disease control; Drug dosages; Drug metabolism; Drug Therapy, Combination - adverse effects; Enzymes; Female; Gastroenterology; Genes; Genetic polymorphisms; Genotype; Genotype & phenotype; Genotypes; Genotyping; Health risk assessment; Hepacivirus - genetics; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatology; Hospitals; Humans; Imidazoles - administration & dosage; Imidazoles - adverse effects; Imidazoles - pharmacokinetics; Imidazoles - therapeutic use; Infection; Infections; Interferon; Internal medicine; Isoquinolines - administration & dosage; Isoquinolines - adverse effects; Isoquinolines - pharmacokinetics; Japan; Laboratories; Liver; Liver cirrhosis; Liver diseases; Male; Medical research; Medicine; Medicine and health sciences; Metabolism; Middle Aged; Multivariate Analysis; Nucleotides; Patient monitoring equipment; Pharmacokinetics; Pharmacology; Polymorphism, Single Nucleotide; Prostate cancer; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Therapy; Up-Regulation; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0219022

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