From Pages to Practice
In this week’s issue of NEJM, Bourlière and colleagues report findings from two international phase 3 trials (POLARIS-1 and POLARIS-4) that investigated the efficacy and safety of a three-drug regimen — sofosbuvir, velpatasvir, and voxilaprevir — in patients with HCV who did not respond to prior DAA treatment. In phase 2 studies, the addition of voxilaprevir, a protease inhibitor of NS3-NS4A, to sofosbuvir and velpatasvir was effective in patients with various HCV genotypes.
POLARIS-1 enrolled 416 patients who previously had been treated with DDA regimens including an NS5A inhibitor and experienced DAA treatment failure. Those with HCV genotype 1 infection were randomized to the three-drug regimen or placebo. Those who with non-genotype 1 infection were assigned to the active regimen as very few patients with non-genotype 1 experience DAA treatment failure. POLARIS-4 enrolled 333 patients who had received any DAA regimen that did not include an NS5A inhibitor. Patients with HCV genotypes 1, 2 or 3 were randomised to receive the three-drug regimen or sofosbuvir-velpatasvir. Patients with other genotypes were assigned to receive sofosbuvir-velpatasvir-voxilaprevir.
In both trials, the primary efficacy end point was rates of SVR (defined as serum HCV RNA <15 IU per mL at 12 weeks after the end of treatment). In POLARIS-1, the SVR rate associated with the three-drug regimen among patients who had received treatment with an NS5A inhibitor was 96% (95% confidence interval, 93–98); this rate was significantly higher than the pre-specified comparison rate of 85% (P<0.001). SVR rates were similar among patients with HCV genotypes 1, 3, 4, and 6. None of the placebo recipients had an SVR. In POLARIS-4, the SVR rate associated with the three-drug regimen among patients who had been treated with any DAA except an NS5A inhibitor was 98%, and again significantly higher than the comparison SVR rate of 85% (P<0.001). However, the SVR for patients receiving the sofosbuvir-velpatasvir regimen was 90% and not significantly higher than the pre-specified rate of 85% (P=0.09). SVR rates were similar in patients with various HCV genotypes and among patients with and without compensated cirrhosis.
In the POLARIS-1 trial, 78% of patients on the three-drug regimen had adverse events, versus 70% in the placebo group. In the POLARIS-4 trial, 77% of patients on the three-drug regimen had adverse events, versus 74% on the sofosbuvir-velpatasvir regimen. Headache, fatigue, diarrhea, and nausea were common adverse events. One patient who received the three-drug regimen in POLARIS-1 discontinued treatment due to angioedema. None of the patients in POLARIS-4 who received the three-drug regimen discontinued treatment due to adverse events.
A 12-week course of sofosbuvir-velpatasvir-voxilaprevir was associated with a higher SVR rate among patients who failed to respond to prior treatment with a DAA regimen. However, the generalizability of these results are limited, and in particular, cannot be applied to patients coinfected with hepatitis B or human immunodeficiency virus. In 2015, when the initial trials of sofosbuvir-velpatasvir were reported, questions about cost and accessibility were addressed in an accompanying editorial. These same questions remain with the results of both POLARIS 1 and 4.