No abstract

No abstract

In patients with chronic hepatitis C and cirrhosis or bridging fibrosis, 180 microg of peginterferon alfa-2a administered once weekly is significantly more effective than 3 million units of standard interferon alfa-2a administered three times weekly.

This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).

Administration of interferon (IFN) 3 times weekly in patientsInterferon ␣ (IFN) is an essential component of therapy for patients with chronic hepatitis C (CHC) virus infection; however, 3 MIU IFN ␣-2b administered 3 times weekly for 48 weeks produces low sustained virological responses (13%-19%). 1,2 Previously, attempts at improving responses to IFN ␣-n3 monotherapy through daily administration met with limited success, because a trend for improved response was only observed in patients with hepatitis C virus (HCV) genotype non-1 infections. 3 More recently, the addition of ribavirin to the standard IFN regimen has resulted in improved sustained virologic responses (38%-43%), but at the cost of additional toxicity. 1,2 IFN has a half-life of approximately 8 hours, and, consequently, a 3-times-weekly dosing schedule may be insufficient to maintain adequate serum concentrations. 4 Pegylated interferon ␣-2a (PEG[40kd] IFN ␣-2a) was developed in an attempt to improve the pharmacological profile of IFN ␣-2a. Covalent attachment of a branched 40-kd polyethylene glycol moiety to IFN ␣-2a results in more sustained absorption (time to peak plasma concentration increased Ͼ7-fold), reduced clearance (10-fold), and a smaller volume of distribution (4-fold), thereby permitting once-weekly dosing. 5,6 This study evaluated the safety and efficacy of 4 doses of once-weekly PEG(40kd) IFN ␣-2a administered for 48 weeks compared with 3 MIU IFN ␣-2a 3 times weekly in the treatment of patients with CHC. The primary intention of the study was to establish the most appropriate dose of PEG(40kd) IFN ␣-2a for subsequent, larger trials. MATERIALS AND METHODSPatient Selection. The target population comprised patients with CHC but without associated bridging fibrosis or cirrhosis (fibrosis score 3 and 4) 7 on pretreatment liver biopsies, who had not previously been treated with IFN therapy. The definition of CHC required documentation of persistently abnormal serum alanine aminotransferase (ALT) activity (2 occasions Ն14 days apart), a positive anti-HCV antibody (anti-HCV-EIA version 2), a pretreatment liver biopsy obtained within 12 months before study treatment consistent with chronic hepatitis (as determined by a central pathologist), and detectable pretreatment HCV RNA by a polymerase chain reaction assay (AMPLICOR HCV MONITOR™ version 1.0, Roche Diagnostics, Branchburg, NJ; lower limit of quantitation of 2,000 copies/mL) within 35 days before the first dose of study medication.Patients were excluded during screening for any of the following reasons: liver disease from causes other than CHC; white blood cell count Ͻ1,500/mm 3 ; platelet count Ͻ90,000/mm 3 ; serum creatinine Abbreviations: IFN, interferon alfa; CHC, chronic hepatitis C; PEG(40kd) IFN ␣-2a, 40-kd pegylated interferon ␣-2a; MIU, million international units; ALT, alanine aminotransferase; HCV, hepatitis C virus; SRB, Safety Review Board; HAI, histological activity index.From the