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Better convenience and tolerability and sustained therapeutic concentrations might improve interferon (IFN) treatment for chronic hepatitis C virus (HCV) infection. In an open-label, randomized study, controlled release free (chemically unmodified) recombinant human IFN-α2b in poly(ether-ester) microspheres (CR-rhIFN-α2b), was injected at doses of 160, 320, 480 or 640 μg every 2 weeks for 12 weeks with concomitant weight-based oral ribavirin in 32 treatment-naïve patients with chronic HCV genotype 1. Treatment was well tolerated, with 31 patients (97%) successfully completing the study. Full doses of CR-rhIFN-α2b were administered on 96% of scheduled occasions. Flu-like symptoms were generally mild and brief. Injection site reactions developed in 13 patients (41%), and neutropenia occurred in six of eight patients receiving 640 μg. In the 320, 480 and 640 μg groups, 62-75% of patients achieved a ≥2 log10 HCV RNA reduction by 4 weeks and 88-100% by 12 weeks. For those groups, the pooled median time to ≥2 log10 reduction was 11 days (95% confidence interval, 7-35 days). In those groups, viral reduction below the limit of detection was accomplished in 25% of patients by 4 weeks and in 62% by 12 weeks. The 160-μg dose was less potent. After CR-rhIFN-α2b injection, stable plateau levels of serum IFN-α2b were generally reached within 72 h. Treatment-emergent neutralizing antibodies to IFN-α2b were observed in one patient. No antibodies to host plant proteins were detected. CR-rhIFN-α2b with ribavirin cotherapy was well tolerated and displayed potent early antiviral activity in patients with chronic HCV genotype 1.