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Sofosbuvir is a nucleotide analogue that inhibits NS5B-directed hepatitis C virus (HCV) RNA replication. In vitro studies suggest that sofosbuvir has anti-viral activity against all HCV genotypes and a high barrier to resistance. The current industry-funded, phase II companion studies evaluated the efficacy of sofosbuvir in combination with peginterferon and ribavirin in HCV-infected patients without cirrhosis.
Lawitz and colleagues randomized 122 treatment-naive patients with HCV genotype 1 in a 2:2:1 allocation to receive sofosbuvir (200 mg or 400 mg) or placebo daily in combination with peginterferon (180 µg weekly) plus ribavirin (1000–1200 mg daily) for 12 weeks. Patients with HCV genotypes 2 or 3 received open-label sofosbuvir plus peginterferon and ribavirin for 12 weeks. Some patients received an additional 12 to 36 weeks of peginterferon/ribavirin depending on viral response. In the randomized cohort, sustained virologic response (SVR) rates at 12 weeks post-treatment were 90%, 91%, and 58% in the 200 mg, 400 mg, and placebo groups, respectively. Although SVR rates were similar between the sofosbuvir groups, 3 patients in the 200-mg group had viral relapse versus none in the 400-mg group. Among the cohort with genotypes 2 and 3, the SVR rate was 92%. The most common adverse effects were peginterferon- and ribavirin-related.
Kowdley and colleagues randomized 316 treatment-naive patients with HCV genotypes 1, 4, or 6 in a 1:2:3 allocation to receive sofosbuvir (400 mg) daily in combination with peginterferon (180 µg weekly) and ribavirin (1000–1200 mg daily) for 12 weeks, the same drug regimen for 24 weeks, or the 12-week regimen followed by either sofosbuvir monotherapy or sofosbuvir plus ribavirin for another 12 weeks. SVR rates were 89%, 89%, and 87% at 24 weeks post-treatment for the 3 groups, respectively. SVR rates were 82% for 11 patients with genotype 4 and 100% for 5 patients with genotype 6. Baseline viral load and IL28B genotype did not affect SVR rates. As with the companion study, most adverse effects were associated with peginterferon and ribavirin and not with sofosbuvir. No evidence of HCV resistance was noted in either study.
Lawitz E et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic treatment-naïve patients with genotypes 1, 2, and 3 hepatitis C infection: A randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013 Mar 15; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S1473-3099(13)70033-1)
Kowdley KV et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): An open-label, randomised, multicentre phase 2 trial. Lancet 2013 Mar 15; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(13)60247-0)
Comment
Key observations from these trial findings include: (1) the average sustained virologic response rate was 90% for a 12-week sofosbuvir regimen in all HCV genotypes; (2) 12 weeks of therapy seems to be as effective as 24 weeks; (3) sofosbuvir should be administered at a dose of 400 mg daily; (4) sofosbuvir is well tolerated and adds no new adverse effects to the regimen; (5) resistance development does not seem to be a concern; and (6) traditional predictors of response, such as IL28B genotype and baseline viral load, do not seem to affect response rates. The ongoing phase III studies will hopefully verify the safety and efficacy of the sofosbuvir regimen. Future studies should evaluate its efficacy in patients who are treatment-experienced or have cirrhosis.