NS5A mutations predict biochemical but not virological response to interferon-alpha treatment of sporadic hepatitis C virus infection in European patients

The NS5A region of the hepatitis C virus (HCV) genome has been reported by Japanese but not European investigators to be a significant factor in predi cting interferon (IFN) response patients with HCV of genotype 1. We correla ted the NS5A region with treatment outcome in patients with sporadic HCV in fection. Twenty-eight patients (10 men, 18 women, mean age 60 +/- 2 years) with histologically proven HCV chronic hepatitis, genotype 1b, were treated with 6 MU IFN-alpha for 6 months. The 6954-7073 area of the NS5A region wa s directly sequenced for nucleotide and amino acids mutations and the resul ts were related to biochemical and virological response. None of the patien ts had a strain with nucleotide sequence identical to the Japanese HCV-J. H owever, in five strains the nucleotide mutations led to synonymous amino ac ids and the amino acid sequences were identical to the prototype Japanese s train. Only 2/28 patients had four or more amino acid mutations (mutant str ains) while 21 demonstrated an intermediate type and five belonged to the w ild-type. The most frequent non-synonymous substitution was at position 698 2 (A -->G) corresponding to an amino acid change at codon 2218 (His --> Arg ). All patients with the wild-type were biochemical nonresponders while the two patients with the mutant strains had a sustained biochemical response. Twenty-three percent of the intermediate type had a sustained biochemical response. NS5A mutations predict the biochemical but not the virological re sponse of patients. Virological response was poor and unrelated to the type of HCV strain. Biochemical responders had significantly lower amino acid m utations (1.14 +/- 0.19) compared with nonresponders (2.57 +/- 1.4, P < 0.0 03) as well as lower aminotransferase values (P < 0.01). Hence, mutational analysis of the NS5A region showed that our patients have a mutational prof ile similar to the European studies with a wild-type that is slightly diffe rent from the Japanese HCV-J sequence. The biochemical, but not the virolog ical response to IFN-alpha is similar to the Japanese studies, with no resp onse of the patients with wild-type sequence, a good response in the limite d number of patients with mutant strains and 23% response rate in the patie nts with intermediate type sequences.