Influence of viral quasispecies on effectiveness of interferon therapy in chronic hepatitis C patients

The quasispecies nature of hepatitis C virus genome distribution is most evident in hypervariable regions of the putative envelope 2 domain. Eight patients with chronic hepatitis C treated with interferon‐α were studied as to heterogeneity of the hypervariable regions to clarify the implications of quasispecies. More than 10 recombinant clones generated from polymerase chain reaction‐amplified products of the hypervariable regions were sequenced. The sets of clones derived from long‐term responders before interferon therapy showed a significantly lower (p < 0.05) degree of sequence complexity of the hypervariable region 1 quasispecies than those from short‐term ones or nonresponders. The values of nucleotide diversity (the average number of nucleotide differences per site between two randomly chosen sequences) in hypervariable region 1 before interferon therapy were also significantly lower (p < 0.05) for long‐term responders (mean, 2.31 × 10) than for short‐term ones or nonresponders (13.02 × 10−2). In some cases, nucleotide diversity decreased remarkably during interferon therapy, whereas the values remained unchanged in other cases. In one interesting case, a short‐term response was first noted with the nucleotide diversity decreasing from 13.98 × 10−2 to 0.21 × 10−2; namely, the diversity of the quasispecies was significantly reduced, and then a long‐term response was observed after an additional course of interferon therapy. Thus, the degree of quasispecies' complexity and diversity of hypervariable region 1 was closely correlated with the responsiveness to interferon therapy in chronic hepatitis C patients, and thus may have some influence on interferon efficacy. (Hepatology 1994;20:1121–1130).