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Objective: Hepatitis C virus (HCV) has been reported to exist in the circulation of patients in various forms such as free virions, immune complexes, and nucleocapsids. To clarify the clinical significance of serum HCV titers according to the forms of virus particles, we evaluated the immune complexed (IC) and nonimmune complexed (NIC) HCV RNA titers in 77 chronic hepatitis patients treated with interferon (IFN)., Methods: IC and NIC forms in pretreatment serum were separated by immunoprecipitation using antihuman immunoglobulin antibody, and quantified by reverse transcription polymerase chain reaction., Results: Serum titers of NIC HCV RNA were correlated with those of whole serum HCV RNA (r = 0.96, p < 0.01) and IC HCV RNA (r = 0.98, p < 0.01), but they were not with the aminotransferase levels, gamma-globulin concentration, and grading or staging of liver histology. Nonresponders to IFN had significantly high NIC HCV RNA titers compared with sustained responders (10(4.93 +/- 0.81) copies/ml vs 10(4.06 +/- 0.69) copies/ml, p < 0.01). It is noteworthy that the relative amount of NIC HCV RNA to whole serum HCV RNA was also significantly higher in nonresponders than in sustained responders (0.66 +/- 0.10 vs 0.50 +/- 0.11, p < 0.0001). Multivariate analysis showed that low NIC HCV RNA titer (p < 0.01) and genotype 2 (p = 0.02) were independent variables contributing to sustained response to IFN, but the whole serum HCV RNA titer was not., Conclusions: Pretreatment NIC HCV RNA titer is a more reliable predictive marker than genotype or whole serum HCV RNA of a sustained response to IFN monotherapy. This finding suggests that humoral immunity may affect the response to IFN.