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To evaluate the efficacy, safety and adherence to hepatitis C (HCV) therapy in patients attending tertiary hepatitis clinics who are receiving opioid replacement therapy.A non-randomized, open-label study. Participants were treated with pegylated interferon alpha-2a and weight-based ribavirin for 24 weeks (genotype non–1, n = 31) or 48 weeks (genotype 1, n = 22).Four tertiary hospital hepatitis clinics in Australia.Fifty-three patients with chronic HCV who were receiving opioid replacement therapyPatients were monitored for virological response, adverse events and adherence. They were also screened for psychiatric illness prior to and throughout the study utilizing two validated instruments: the Mini International Neuropsychiatric Interview (MINI) and Beck Depression Interview (BDI)-II.The overall sustained virological response (SVR) rate was 57% (71% genotype non-1 versus 36% genotype 1), and was similar in active injectors (63%) and non-injectors (53%). The psychological profile of patients based on validated instruments did not change on therapy. The pattern and frequency of adverse effects were comparable to non-opioid replacement patients. Eighty-five per cent of patients were adherent to therapy by 80/80/80 criteria and only two patients who had an end-of-treatment response relapsed, one of whom was not an active injector.Patients on opioid replacement therapy, even if they continue to inject actively, can achieve comparable sustained virological response rates to other populations with pegylated interferon alpha-2a and ribavirin therapy, suffer no excess rates of adverse effects or psychological complications and have good adherence to therapy.