Hepatitis C virus (HCV) is a single-stranded hepacivirus with six major genotypes. Approximately 3.5 million people in the United States and 150 million people worldwide are infected with HCV. Chronic HCV infection can lead to cirrhosis, hepatic decompensation, hepatocellular carcinoma, and death. A 12-week course of combination direct-acting antiviral agents (DAAs) — sofosbuvir (an NS5B inhibitor) and velpatasvir (an NS5A inhibitor) — leads to a sustained virologic response (SVR) in more than 90% of patients with HCV, regardless of genotype or presence of cirrhosis. However, no approved retreatment options currently exist for the estimated 15 million people worldwide who do not have a sustained response to these medications.
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.
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Ramya Ramaswami is a 2016-2017 NEJM editorial fellow. She is a medical oncologist within the National Health Services of the United Kingdom. Ramya received her medical degree, postgraduate medical and oncology training from Imperial College London, and a masters in public health from Columbia University, Mailman School of Public Health. Her clinical and research interests include cancer prevention, viral driven cancers, as well as disparities and access issues in global oncology.