Meaden, C.; Chan, S.W.; Mills, P.R.; Warnes, T.W.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA107
Academic Journal
Background: Interferon resistance in hepatitis C is a major problem. Double-stranded RNA dependent protein kinase (PKR) is a key mediator of the anti-viral effects of IFN. The viral proteins E2 and NS5A bind to and inhibit PKR function in vitro. Mutations in key regions of E2 (PKR-elF2 phosphorylation homology domain-PePHD) and NS5A (PKR binding domain, including the "interferon sensitivity determining region", ISDR) prevent this binding. It is not known whether mutations in PePHD ore associated with treatment response and there is conflicting data for ISDR from different geographical areas. Aim: We wanted to determine whether there was a correlation between the number of mutations in PePHD and the PKR binding domain (including ISDR) and interferon response. Methods: Pre-treatment serum samples from 27 treatment naive patients infected with genotype 3 were analysed by direct sequencing of PePHD and the PKR binding domain. All had received between 3 and 12 months of alpha-interferon at a dose of at least 3 MU 3 times per week. There were 9 sustained responders (SR), 13 transient responders (TR), and 5 non-responders (NR). Results: For PePHD the mean number of mutations was SR = 0.8 (range 0-2), TR = 0.2 (range 0-1) and NR = 0.2 (range 0-1). There was no significant difference in the frequency of mutations, SR vs NR p = 0.31 and SR vs (TR+NR) p = 0.15. For the PKR binding domain, including ISDR the mean number of mutations was SR = 1 (range 0-2), TR = 1.6 (range 0-4), and NR = 0.2 (range 0-2). There was no significant difference in the frequency of mutations, SR vs NR p = 1.0 and SR vs (TR+NR) p = 0.66. There was no significant difference for ISDR alone. Conclusion: The results ore consistent with European studies and differ from Japanese studies. The intrinsically higher frequency of mutant strains in Japanese populations may account for this difference.


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