associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 protease inhibitors and NS5A inhibitors.
Clinical efficacy and safety
The efficacy of sofosbuvir was eva luated in five Phase 3 studies in a total of 1,568 subjects with genotypes 1 to 6 chronic hepatitis C. One study was conducted in treatment-naïve subjects with genotype 1, 4, 5 or 6 chronic hepatitis C in combination with peginterferon alfa 2a and ribavirin and the other four studies were conducted in subjects with genotype 2 or 3 chronic hepatitis C in combination with ribavirin including one in treatment-naïve subjects, one in interferon intolerant, ineligible or unwilling subjects, one in subjects previously treated with an interferon-based regimen, and one in all subjects irrespective of prior treatment history or ability to receive treatment with interferon. Subjects in these studies had compensated liver disease including cirrhosis. Sofosbuvir was administered at a dose of 400 mg once daily. The ribavirin dose was weight-based at 1,000-1,200 mg daily administered in two divided doses, and the peginterferon alfa 2a dose, where applicable, was 180 μg per week. Treatment duration was fixed in each study and was not guided by subjects' HCV RNA levels (no response guided algorithm).
Plasma HCV RNA values were measured during the clinical studies using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate for all studies which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR12).
Clinical studies in subjects with genotype 1, 4, 5 and 6 chronic hepatitis C
Treatment-naïve subjects - NEUTRINO (study 110)
NEUTRINO was an open-label, single-arm study that eva luated 12 weeks of treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or 6 HCV infection.
Treated subjects (n = 327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were male; 79% were White; 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU/mL; 17% had cirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6. Table 5 presents the response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin.
Table 5: Response rates in study NEUTRINO
SOF+PEG+RBV
12 weeks
(n = 327)
Overall SVR12
91% (296/327)
Outcome for subjects without SVR12
On-treatment virologic failure
0/327
Relapsea
9% (28/326)
Otherb
1% (3/327)
a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
b. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).
Response rates for selected subgroups are presented in Table 6.
Table 6: SVR12 rates for selected subgroups in NEUTRINO
SOF+PEG+RBV
12 weeks
(n = 327)
G
