THE CLINICAL-SIGNIFICANCE OF CHANGES IN GENETIC-HETEROGENEITY OF THE HYPERVARIABLE REGION-1 IN CHRONIC HEPATITIS-C WITH INTERFERON THERAPY

We examined changes in the hypervariable region 1 of the hepatitis C v irus (HCV) RNA that occurred with interferon therapy in 33 patients wi th chronic hepatitis C to assess the clinical significance of this reg ion, The 33 patients had HCV genotype 1b and were classified into thre e groups based on serum aminotransferase levels during and after thera py with alpha interferon; longterm responders (n = 9), short-term resp onders (n = 11), and nonresponders (n = 13), Changes in the genetic he terogeneity of the hypervariable region 1 were determined by using non isotopic polymerase chain reaction-single strand conformation polymorp hism (PCR-SSCP). HCV RNA levels were evaluated by reverse transcriptas e PCR and branched DNA probe assays, Changes in sequences were determi ned by cloning and sequencing analysis, Before therapy, the long-term responders had significantly lower degrees of heterogeneity and lower viral levels than nonresponders. There were no significant differences between short-term and nonresponders, With interferon therapy, viral levels and degree of heterogeneity decreased to a greater extent among longterm and short-term responders than among nonresponders, Sequenci ng analysis showed that the three groups had similar clone numbers ini tially, but longterm responders had rather homogeneous viral populatio ns, whereas short-term and nonresponders had heterogeneous populations , but that there were no nucleotide sequences or amino acid alignments that were specific for any group before, during, and 6 months after t herapy. Approximately half of short-term and nonresponders received a second course of interferon 7 to 10 months after the initial therapy; all showed an identical response to the second course of therapy regar dless of interim changes in the heterogeneity of hypervariable region 1, These findings suggest that (1) patients who were nonresponders or short-term responders had mixed viral populations that had differing s ensitivities to interferon, (2) the changes in the hypervariable regio n 1 (HVR 1) did not affect responsiveness to interferon, and (3) the l ower heterogeneity in the HVR 1 was associated with a long-term respon se to interferon only when the viral levels were low.