Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy

BACKGROUND & AIMS: Data on patients with chronic hepatitis C virus (HCV) infection who failed voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment and rescue treatment options for these patients are limited.METHODS: Samples of 40 patients with HCV genotypes (GT) 1-4 who failed VOX/VEL/SOF as retreatment were collected within the European Resistance Study Group. Population based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients.RESULTS: The majority of VOX/VEL/SOF failure patients were infected with HCV GT3a (n=18, 45%) or GT1a (n=11, 28%) and had cirrhosis (n=28, 70%). Previous treatments included a NS3-inhibitor (30%), a NS5A-inhibitor (100%) and SOF (85%). Baseline RASs available in a subgroup of patients before VOX/VEL/SOF (78%) included rarely NS3 RAS with exception of Q80K in GT1a (40%), typical NS5A RASs pattern in the majority of patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure available in 98% of patients showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n=2) or with sofosbuvir±ribavirin (n=15), VOX/VEL/SOF±ribavirin (n=4) or VEL/SOF and ribavirin (n=1) for 12 to 24 weeks. Sustained virologic response was achieved in 15/19 (79%) patients with final treatment outcome. Of these, two GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF and G/P+SOF+R, respectively, and two patients with cirrhosis died during treatment or before reaching SVR12.CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3 and GT1a infected patients with cirrhosis and was not associated with specific RASs pattern within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in the majority of patients.