Therapy of Hepatitis C — Back to the Future

Abstract

A book on hepatitis C would read like a marriage of an Orson Welles mystery and a Shakespearean play-awash in enigma, tragedy, despair, resilience , redemption, and triumph. It is only fitting that treatment of hepatitis C virus (HCV) infection stands at center stage of such a book. After the initial introduction of interferon alfa as the mainstay of therapy, the field stalled for more than 10 years. Although the introduction of riba-virin combination therapy and pegylated inter-ferons had increased response rates, the real breakthrough came with the development of direct-acting antiviral agents (DAAs). 1 The first generation of DAAs in combination with pegin-terferon and ribavirin showed improved response rates, but they were accompanied by worsening side effects that have precluded a great majority of patients from benefiting from therapy. In a previous article in the Journal, we reviewed the current and future therapies for HCV infection and commented on the rapidly shifting therapeutic landscape. 1 We speculated that highly effective interferon-free regimens would be available and should revolutionize the treatment of HCV infection in the near future. Now, just 1 year after that review, we would have to say that the future is here. The results of several phase 3 studies of inter-feron-free combination regimens of DAAs reported in the Journal now 2-4 and recently 5-9 (Table 1) unequivocally show the superiority of two such regimens over the standard-of-care treatment (a combination of peginterferon, ribavirin, and a protease inhibitor) for HCV genotype 1 infection. A previous editorial in the Journal highlighted the significantly improved response rates (rates of sustained virologic response of 93% to 99%) with a coformulated regimen of sofosbuvir (a nucleotide NS5B inhibitor) and ledipasvir (an NS5A inhibitor) among patients with HCV genotype 1 infection, as compared with the rates with the previously approved interferon-based single-DAA combination therapy. 13 Other studies reported in the Journal show similarly high response rates with a different combination of DAAs among patients with HCV genotype 1 infection. 2,3,8,9 This regimen includes three DAAs-ABT-450 (an NS3/4A inhibitor) coadministered with ritonavir (ABT-450/r), om bit-asvir (an NS5A inhibitor), and dasabuvir (a non-nucleoside NS5B inhibitor)-with or without ribavirin. These studies evaluated the efficacy and safety of this regimen in patients who either were previously untreated or were previously treated with peginterferon and ribavirin but without a sustained virologic response. In addition, safety and efficacy in patients with compensated cirrhosis were examined specifically in one study. 3 Like the studies of sofosbuvir and ledipasvir, these studies could use historical controls (treat-ment responses in previous phase 3 studies with the regimen of peginterferon, ribavirin, and a protease inhibitor) for comparison because of the anticipated wide difference in therapeutic margins between the old and new treatments. In both studies involving patients without cir-rhosis who were previously untreated or previously treated, the sustained-virologic-response rates were all about 96%, 8,9 findings that suggest that patients with a previous nonresponse to pegin-terferon and ribavirin are not particularly difficult to treat with this regimen. Patients with cir-rhosis did not have quite as robust a response to this regimen, though the response rate was still more than 90%. 3 The study involving patients with cirrhosis also evaluated a treatment duration of either 12 weeks or 24 weeks and showed a modestly higher response rate in the 24-week group