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

Abstract

Aims: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Fig 1. SVR rates according to the grade classification for ALT elevation.

There is no significant association between grades of ALT elevation and SVR rates (p = 0.962 by Cochran–Armitage test for trends). The SVR rates in patients with grades 2–4 ALT elevation are numerically higher than those in patients with grades 0–1, although there is no significant difference (p = 0.172 by Fisher’s exact test). SVR, sustained virological response; ALT, alanine aminotransferase.

Fig 2. Maximum ALT values according to rs4646437 genotypes.

Maximum ALT values in patients with genotype CC (median, 31 IU/mL; range, 9–740 IU/mL) are significantly higher than those in patients with genotype non-CC (median, 21.5 IU/mL; range, 8–71 IU/mL; p = 0.013 by Mann-Whitney U test). ALT, alanine aminotransferase.

Fig 3. Grades of ALT elevation according to rs4646437 genotypes.

Among 157 patients with rs4646437 genotype CC, 91 patients (58.0%) are grade 0, 43 (27.4%) are grade 1, 11 (7.0%) are grade 2, 7 (4.5%) are grade 3, and 5 (3.2%) are grade 4. Among 28 patients with rs4646437 genotype non-CC, 22 patients (78.6%) are grade 0, 6 (21.4%) are grade 1, and none (0%) are grades 2–4. The proportion of grades 2–4 in patients with genotype CC are significantly greater than those in patients with genotype non-CC (p = 0.028).

Fig 4. Maximum ALT levels according to gender and rs4646437 genotypes.

The median of maximum ALT values is 33 IU/L (range, 9–740 IU/L) in females with rs4646437 genotype CC, 25.5 IU/L (range, 14–70 IU/L) in females with genotype non-CC, 25 IU/L (range, 9–561 IU/L) in males with genotype CC, and 19 IU/L (range, 8–71 IU/L) in males with genotype non-CC (p = 0.019 by Kruskal-Wallis test). Maximum ALT levels in males with genotype non-CC are significantly or marginally lower than those in females with genotype CC (p = 0.018) and males with genotype CC (p = 0.084; both by Steel-Dwass test). In contrast, females with genotype CC have a high propensity for ALT elevation, compared to other subgroups. *¹p = 0.503, *²p = 0.976, *³p = 0.084, *⁴p = 0.460, *⁵p = 0.279, *⁶p = 0.018.