The present invention provides compositions and methods of treating hepatitis virus infection, particularly hepatitis C virus infection. The invention provides methods of treating a hepatitis virus infection, involving administering a first form and a second form of IFN-α to provide a multiphasic pharmacokinetic profile. The multiphasic antiviral agent serum concentration profile that is achieved effects an initial rapid drop in viral titer, followed by a further decrease in viral titer over time, to achieve a sustained viral response. The invention further provides compositions that are effective in achieving a multiphasic IFN-α profile. Compositions of the invention comprise at least a first form of interferon-α (IFN-α) that has a first pharmacokinetic profile and a second form of IFN-α that has a second pharmacokinetic profile, where the second form of IFN-α has a longer mean residence time than that of the first form of IFN-α. The invention further provides compositions comprising C-terminally modified IFN-α.