Abstract
AimsLiver injury can occur during antiviral therapies with direct-acting antivirals (DAAs), potentially necessitating discontinuation of the therapies, with consequent worsening of the sustained viral response (SVR) rates, in patients with hepatitis C virus (HCV). To clarify the mechanisms involved in serum transaminase level elevation, we performed a retrospective evaluation of the serum concentrations of daclatasvir and asunaprevir, both classified as DAAs, in patients receiving treatment with a combination of the two drugs.MethodsSubjects were 278 Japanese patients with genotype-1b HCV who received daclatasvir plus asunaprevir therapy for more than 4 weeks. Serum concentrations of both the DAAs were measured at 4 weeks after the initiation of therapy.ResultLiver injuries including serum AST and/or ALT level elevation to 150 U/L or over were found in 34 patients (12.2%). Multivariate logistic regression analysis identified serum asunaprevir concentrations as being significantly associated with developing liver injury, with an odds ratio of 1.046 (95% confidence interval 1.011–1.082, p<0.05). Serum asunaprevir concentrations showed correlation with the extent of liver fibrosis, estimated by peripheral platelets counts and serum albumin levels and baseline and FIB4 index and serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at 4 weeks of the therapy; the concentrations were significantly higher among patients showing 3.0 or more of M2BPGi levels than among those with the levels less than 3.0; on the other hand, no such correlation/difference was found in serum daclatasvir concentrations.ConclusionHigh serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy.
Highlights
Treatment using direct-acting antivirals (DAAs) with or without ribavirin (RBV) has resulted in markedly improved sustained viral response (SVR) rates in patients with hepatitis C virus (HCV)
High serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy
246 patients (88.5%) were infected with HCV strains not harboring either NS5A-L31M/V or NS5A-Y93H substitutions, 6 (2.2%) were infected with HCV strains with NS5A-L31M/V substitutions, and 26 (9.4%) were infected with strains with NS5A-Y93H substitutions
Summary
Treatment using direct-acting antivirals (DAAs) with or without ribavirin (RBV) has resulted in markedly improved sustained viral response (SVR) rates in patients with hepatitis C virus (HCV). 3 types of DAAs have been used in patients with HCV: NS3/4A protease inhibitors, NS5A replication complex inhibitors, and nucleotide/non-nucleotide NS5B polymerase inhibitors. In Japan, dual oral therapy with daclatasvir (DCV), an NS5A replication complex inhibitor, and asunaprevir (ASV), a second-generation NS3/4A protease inhibitor, was approved in July 2014 as the first interferon-free treatment regimen for patients with genotype 1b HCV. In patients receiving DCV plus ASV therapy, presence of resistance-associated substitutions (RASs), especially Y93H and L31M/V substitutions in NS5A region, at the baseline was shown to be associated with virologic failure [1]. The pre-treatment examination of NS5A-RASs had contributed to an improvement in the therapeutic efficacy of DCV plus ASV therapy in real-world clinical practice, deterioration of the therapeutic efficacy of DCV plus ASV therapy had been reported in patients in whom the therapy had to be discontinued due to the appearance of adverse events [4]
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