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Differential effect of interferon therapy on hepatitis C virus 1B quasispecies in the non-structural 5A gene.

Recently we reported a close correlation between the degree of mutations in the amino acid residues 2209 to 2248 of the non-structural protein 5A gene (NS5A:2209-2248) of HCV-1b and the response to interferon therapy. The aim of this study is to elucidate the significance of NS5A:2209-2248 quasispecies in therapeutic failure with interferon.

Methods. Sequential changes in NS5A:2209-2248 quasispecies were compared before and just after interferon therapy (total dose 240-800MU), for 20 patients with chronic hepatitis related to HCV-1b, who did not respond to interferon. The amino acid sequences of major quasispecies were determined with direct sequencing of HCV genome amplified by nested-PCR. The populational changes of quasispeceis were evaluated with cloning of PCR products in 7 patients including 5 non-responders and 2 complete responders. Amino acid sequences of the NS5A:2209-2248 with 4 to 9 substitutions compared to the prototype HCV-J were defined as mutant type, those with 1 to 3 mutations as intermediate type, and those with identical sequence to HCV-J as wild type.

Results. By direct sequencing, the major quasispecies was invariably the wild type before and after therapy in 10 patients. In 9 patients, it was the intermediate type before therapy, but it changed to the wild type in 5 patients after therapy, and remained the intermediate type in other 4 patients. In one patient, the major quasispecies was the mutant type before therapy but changed to the intermediate type after therapy. Thus, the number of amino acid substitutions in NS5A:2209-2248 significantly decreased after therapy (median 1 to 0, p=0.0235). By the analysis of cloned PCR products, the population of NS5A quasispieces were heterogeneous in each patient before therapy. In 5 non-responders, the quasispecies with the smaller number of amino acid substitutions in NS5A:2209-2248 were preferentially selected after therapy. Meanwhile, 2 complete responders had solely quasispecies with three or more amino acid substitutions before therapy, all of which were eradicated by interferon.

Conclusion. HCV detected in sera after interferon therapy has less amino acid substitutions in NS5A:2209-2248 than those detected before therapy. Such interferon resistant HCV had already existed before therapy as minor quasispecies in non-responders, and were selected by interferon resulting in the therapeutic failure.

From: American Gastroenterology Association Digestive Disease Week meeting in Washington in May 1997
I.Sakuma, N.Enomoto, Y.Asahina, M.Kurosaki, F.Marumo, C.Sato. Second Department of Internal Medicine and Division of Health Science, Tokyo Medical and Dental University, Tokyo, Japan.

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