BACKGROUND: Liver damage presented as alanine aminotransferase (ALT) elevation and high ALT-caused treatment discontinuation occurs with high frequency in Japanese patients receiving daclatasvir plus asunaprevir (DCV/ASV) therapy for hepatitis C virus (HCV) infection, and its mechanism is unknown. METHODS: A total of 247 Japanese patients consisting of two independent cohorts with genotype-1b HCV infection receiving DCV/ASV therapy were included. The association of ALT levels during therapy and single nucleotide polymorphisms (SNP) of five drug-metabolizing enzyme loci selected for their possible influence on NS3/4A and NS5A inhibitors was investigated. RESULTS: Among five SNPs, we found a significant correlation between the presence of the UGT1A1 rs4148323 A allele and ALT elevation (Grade 3 elevation in AA 57%, AG 18%, and GG 4%, P = 8.4E - 06) and drug discontinuation (AA 22%, AG 11%, and GG 2.5%, P = 8.7E - 04), while no association was observed with ALT values at baseline (Grade 3 elevation AA 0%, AG 4%, and GG 2%, P = 0.5). In contrast, patients with risk A allele for drug-induced ALT elevation had a tendency to respond more favorably to treatment (AA 100%, AG 93%, and GG 90%, P = 0.29). CONCLUSIONS: Through the analysis we suggest that the A allele in UGT1A1 rs4148323 (UGT1A1*6), which is highly prevalent in the Japanese population, should be considered a risk for the development of DCV/ASV therapy-induced ALT elevation. Pretreatment SNP testing of UGT1A1*6 might be beneficial for the prediction of liver damage induced by DCV/ASV or even by DCV/ASV plus beclabuvir.
BACKGROUND:Liver damage presented as alanine aminotransferase (ALT) elevation and high ALT-caused treatment discontinuation occurs with high frequency in Japanese patients receiving daclatasvir plus asunaprevir (DCV/ASV) therapy for hepatitis C virus (HCV) infection, and its mechanism is unknown. METHODS: A total of 247 Japanese patients consisting of two independent cohorts with genotype-1b HCV infection receiving DCV/ASV therapy were included. The association of ALT levels during therapy and single nucleotide polymorphisms (SNP) of five drug-metabolizing enzyme loci selected for their possible influence on NS3/4A and NS5A inhibitors was investigated. RESULTS: Among five SNPs, we found a significant correlation between the presence of the UGT1A1rs4148323 A allele and ALT elevation (Grade 3 elevation in AA 57%, AG 18%, and GG 4%, P = 8.4E - 06) and drug discontinuation (AA 22%, AG 11%, and GG 2.5%, P = 8.7E - 04), while no association was observed with ALT values at baseline (Grade 3 elevation AA 0%, AG 4%, and GG 2%, P = 0.5). In contrast, patients with risk A allele for drug-induced ALT elevation had a tendency to respond more favorably to treatment (AA 100%, AG 93%, and GG 90%, P = 0.29). CONCLUSIONS: Through the analysis we suggest that the A allele in UGT1A1rs4148323 (UGT1A1*6), which is highly prevalent in the Japanese population, should be considered a risk for the development of DCV/ASV therapy-induced ALT elevation. Pretreatment SNP testing of UGT1A1*6 might be beneficial for the prediction of liver damage induced by DCV/ASV or even by DCV/ASV plus beclabuvir.
Entities:
Keywords:
ALT elevation; DCV/ASV therapy; HCV; UGT1A1*6 SNP
Authors: Gregory T Everson; Karen D Sims; Paul J Thuluvath; Eric Lawitz; Tarek Hassanein; Maribel Rodriguez-Torres; Tadesse Desta; Trevor Hawkins; James M Levin; Federico Hinestrosa; Vinod Rustgi; Howard Schwartz; Zobair Younossi; Lynn Webster; Norman Gitlin; Timothy Eley; Shu-Pang Huang; Fiona McPhee; Dennis M Grasela; David F Gardiner Journal: Liver Int Date: 2015-12-06 Impact factor: 5.828
Authors: Fred Poordad; William Sievert; Lindsay Mollison; Michael Bennett; Edmund Tse; Norbert Bräu; James Levin; Thomas Sepe; Samuel S Lee; Peter Angus; Brian Conway; Stanislas Pol; Nathalie Boyer; Jean-Pierre Bronowicki; Ira Jacobson; Andrew J Muir; K Rajender Reddy; Edward Tam; Grisell Ortiz-Lasanta; Victor de Lédinghen; Mark Sulkowski; Navdeep Boparai; Fiona McPhee; Eric Hughes; E Scott Swenson; Philip D Yin Journal: JAMA Date: 2015-05-05 Impact factor: 56.272