Sofosbuvir: the final nail in the coffin for hepatitis C?

In The Lancet Infectious Diseases, Eric Lawitz and colleagues report results from their randomised phase 2 trial, in which they showed a more than 90% cure rate of hepatitis C in patients given a combination of pegylated interferon alfa-2a (peginterferon), ribavirin, and sofosbuvir, a novel nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase. Among the 60 or so drugs under development for HCV, nucleoside inhibitors seem to be the most promising of the three classes of direct-acting antivirals currently in phase 3 trials (fi gure): NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors, which can be subdivided into nucleoside inhibitors or non-nucleoside inhibitors. Nucleoside inhibitors, namely sofosbuvir, seem to be best in terms of resistance profi le, activity against all virus genotypes, adverse events, and antiviral potency. And as such, the emergence of sofosbuvir is an important milestone in the fi ght against hepatitis C. The fi rst such milestone was the approval of interferon alfa in the early 1990s. The addition of ribavirin to interferon alfa in 1998 doubled response rates; and once weekly peginterferon was introduced in combination with ribavirin in 2001. In 2003, the protease inhibitor BILN 2061 (Boehringer Ingelheim, Ingelheim, Germany) provided the fi rst proof of concept for direct-acting antivirals against HCV. 8 years later, the protease inhibitors boceprevir and telaprevir were approved for treatment of HCV genotype-1. Boceprevir and telaprevir improved sustained viral response rates (SVR) from about 40–44% to 68–75% in treatment-naive patients with genotype-1. SVR means patients are cured and has been associated with prevention of hepatocellular carcinoma and even improvements in overall mortality. However, these protease inhibitors have several limitations: activity against genotype-1 only, dosing every 8 h, and many potentially serious drug interactions. Both protease inhibitors have to be given in combination with peginterferon plus ribavirin because monotherapy results in rapid emergence of drug-resistant variants, which explains why previous null-responders to peginterferon plus ribavirin had SVRs of only 30–40% when given triple therapy with peginterferon, ribavirin, and a NS3/4A protease inhibitor. Boceprevir and telaprevir add to the adverse event profi le of peginterferon plus ribavirin, especially in patients with cirrhosis—namely, a doubling of anaemia. A need for new drugs clearly exists. Ideally, novel direct-acting antivirals should fulfi l the following requirements: oral administration once daily, few sideeff ects and drug interactions, short treatment duration, high barrier to resistance, and eff ectiveness against all major HCV genotypes. New drugs should also help in the development of an oral interferon-sparing regimen. Lawitz and colleagues’ trial forms the basis for the phase 3 testing of sofosbuvir. The investigators not only showed high SVR with sofosbuvir but also the activity against HCV genotypes 1–3. No drug-resistant variants were seen with 400 mg daily sofosbuvir, and only two patients had viral relapse. Therefore, a daily dose of 400 mg sofosbuvir was chosen as the dose for further Published Online March 15, 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70074-4