Serial density analysis of hepatitis C virus particle populations in chronic hepatitis C patients treated with interferon-alpha

Abstract

In interferon treatment of chronic hepatitis C patients, the biochemical and virological responses mostly parallel each other. However, some patients who show persistent ALT normalization display continued viremia after cessation of therapy. High-density hepatitis C virus (HCV) particles, which are immune complex forms, are reported to be less infectious both in vitro and in vivo. To assess whether high-density HCV contributes to the response discrepancies and to clarify the association with patient outcome, sera were examined from chronic hepatitis C patients who were treated with interferon-alpha. This study included 10 sustained responders with viremia (SR + ve), 5 SR without viremia, 3 transient responders (TR), and 3 nonresponders (NR). The SR + ve patients were defined as those with continued ALT normalization and serum HCV-RNA positivity at 24 weeks after therapy completion. Serum samples obtained before and 24 weeks after therapy were ultracentrifuged on 35% sucrose. The ratio between high-density and low-density HCV was determined by quantification of HCV-RNA titers in the bottom and top fractions by competitive reverse transcription and by the polymerase chain reaction, and expressed as the bottom/top (B/T) ratio. The B/T ratios before therapy were 1:1 in all groups of patients, and 1:1 after therapy in TR and NR groups. Five out of 6 SR + ve patients who showed 1:1 ratio after therapy relapsed within 1 year. In contrast, all SR + ve patients whose ratios were 10-100:1 continued to show ALT normalization. These findings demonstrate that patients who have high-density HCV dominance after therapy show persistent ALT normalization despite viremia, which can be explained by predominance of the neutralized immune complex.