Single Nucleotide Polymorphisms Associated with Elevated Alanine Aminotransferase in Patients Receiving Asunaprevir Plus Daclatasvir Combination Therapy for Chronic Hepatitis C

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2019 Jul 11

PMID 31291311

Citations 2

Authors

Keizo Kato

Noritomo Shimada

Masanori Atsukawa

Hiroshi Abe

Norio Itokawa

Yoshihiro Matsumoto

Rie Agata

Akihito Tsubota

Affiliations

Soon will be listed here.

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.

Citing Articles

The Role of CYPs and Transporters in the Biotransformation and Transport of the Anti-hepatitis C Antiviral Agents Asunaprevir, Daclatasvir, and Beclabuvir: Impact of Liver Disease, Race and Drug-drug Interactions on Safety and Efficacy.

Murray M Curr Drug Metab. 2024; 25(2):96-109.

PMID: 38441017 DOI: 10.2174/0113892002288832240213095622.

Genetic Susceptibility to Hepatocellular Carcinoma in Patients with Chronic Hepatitis Virus Infection.

Yang T, Chan C, Yang P, Huang Y, Lee M Viruses. 2023; 15(2).

PMID: 36851773 PMC: 9964813. DOI: 10.3390/v15020559.

References

Iio E, Shimada N, Abe H, Atsukawa M, Yoshizawa K, Takaguchi K . Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol. 2016; 52(1):94-103. DOI: 10.1007/s00535-016-1225-x. View

Crettol S, Venetz J, Fontana M, Aubert J, Pascual M, Eap C . CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients. Ther Drug Monit. 2008; 30(6):689-99. DOI: 10.1097/FTD.0b013e31818a2a60. View

Bronowicki J, Pol S, Thuluvath P, Larrey D, Martorell C, Rustgi V . Randomized study of asunaprevir plus pegylated interferon-α and ribavirin for previously untreated genotype 1 chronic hepatitis C. Antivir Ther. 2013; 18(7):885-93. DOI: 10.3851/IMP2660. View

Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V . FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology. 2007; 46(1):32-6. DOI: 10.1002/hep.21669. View

Uchida Y, Naiki K, Kouyama J, Sugawara K, Nakao M, Motoya D . Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy. PLoS One. 2018; 13(10):e0205600. PMC: 6181393. DOI: 10.1371/journal.pone.0205600. View

Eley T, He B, Chang I, Colston E, Child M, Bedford W . The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor. Antivir Ther. 2014; 20(1):29-37. DOI: 10.3851/IMP2773. View

Shiozaki T, Ueno T, Nagashima H, Yamahira N, Hiraoka M, Eley T . Single- and multiple-ascending dose studies to evaluate the safety, tolerability, and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects. Int J Clin Pharmacol Ther. 2015; 53(4):292-302. DOI: 10.5414/CP202186. View

Sezaki H, Suzuki F, Hosaka T, Akuta N, Fujiyama S, Kawamura Y . The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver Int. 2017; 37(9):1325-1333. DOI: 10.1111/liv.13384. View

Manns M, Pol S, Jacobson I, Marcellin P, Gordon S, Peng C . All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet. 2014; 384(9954):1597-605. DOI: 10.1016/S0140-6736(14)61059-X. View

10.

Coelho A, de Moura R, Guimaraes R, Brandao L, Crovella S . Antiretroviral therapy immunologic non-response in a Brazilian population: association study using pharmaco- and immunogenetic markers. Braz J Infect Dis. 2018; 22(5):392-401. PMC: 9427971. DOI: 10.1016/j.bjid.2018.09.002. View

11.

Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K . Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014; 59(6):2083-91. PMC: 4315868. DOI: 10.1002/hep.27113. View

12.

Liu M, He H, Zhang Y, Hu Y, He F, Luo J . IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients. Acta Pharmacol Sin. 2017; 38(3):415-423. PMC: 5342670. DOI: 10.1038/aps.2016.153. View

13.

Maekawa S, Sato M, Kuratomi N, Inoue T, Suzuki Y, Tatsumi A . Association between alanine aminotransferase elevation and UGT1A1*6 polymorphisms in daclatasvir and asunaprevir combination therapy for chronic hepatitis C. J Gastroenterol. 2017; 53(6):780-786. DOI: 10.1007/s00535-017-1405-3. View

14.

Eley T, He B, Huang S, Li W, Pasquinelli C, Rodrigues A . Pharmacokinetics of the NS3 Protease Inhibitor, Asunaprevir (ASV, BMS-650032), in Phase I Studies in Subjects With or Without Chronic Hepatitis C. Clin Pharmacol Drug Dev. 2016; 2(4):316-27. DOI: 10.1002/cpdd.52. View

15.

Gandhi Y, Eley T, Fura A, Li W, Bertz R, Garimella T . Daclatasvir: A Review of Preclinical and Clinical Pharmacokinetics. Clin Pharmacokinet. 2018; 57(8):911-928. DOI: 10.1007/s40262-017-0624-3. View

16.

Morcos P, Moreira S, Brennan B, Blotner S, Shulman N, Smith P . Influence of chronic hepatitis C infection on cytochrome P450 3A4 activity using midazolam as an in vivo probe substrate. Eur J Clin Pharmacol. 2013; 69(10):1777-84. DOI: 10.1007/s00228-013-1525-5. View

17.

Sharaki O, Zeid M, Moez P, Zakaria N, Nassar E . Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients. Mol Biol Rep. 2014; 42(1):105-17. DOI: 10.1007/s11033-014-3747-8. View

18.

Schirmer M, Rosenberger A, Klein K, Kulle B, Toliat M, Nurnberg P . Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes. Pharmacogenomics. 2007; 8(5):443-53. DOI: 10.2217/14622416.8.5.443. View

19.

Akuta N, Sezaki H, Suzuki F, Kawamura Y, Hosaka T, Kobayashi M . Relationships between serum asunaprevir concentration and alanine aminotransferase elevation during daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. J Med Virol. 2015; 88(3):506-11. DOI: 10.1002/jmv.24360. View

20.

de Almeida T, de Azevedo M, Pinto J, Ferry F, da Silva G, Junqueira de Castro I . Drug metabolism and transport gene polymorphisms and efavirenz adverse effects in Brazilian HIV-positive individuals. J Antimicrob Chemother. 2018; 73(9):2460-2467. PMC: 6105872. DOI: 10.1093/jac/dky190. View