Real World SOF/VEL/VOX Retreatment Outcomes and Viral Resistance Analysis for HCV Patients With Prior Failure to DAA Therapy

David A. Smith; Daniel Bradshaw; Jean L Mbisa; Carmen F. Manso; David F Bibby; Joshua B Singer; Emma C Thomson; Ana da Silva Filipe; Elihu Aranday-Cortes; M. Azim Ansari; Anthony Brown; Emma Hudson; Jennifer Benselin; Brendan Healy; Phil Troke; John McLauchlan; Eleanor Barnes; William L. Irving


J Viral Hepat. 2021;28(9):1256-1264. 

In This Article

Abstract and Introduction


Sustained viral response (SVR) rates for direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection routinely exceed 95%. However, a small number of patients require retreatment. Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is a potent DAA combination primarily used for the retreatment of patients who failed by DAA therapies. Here we evaluate retreatment outcomes and the effects of resistance-associated substitutions (RAS) in a real-world cohort, including a large number of genotype (GT)3 infected patients. 144 patients from the UK were retreated with SOF/VEL/VOX following virologic failure with first-line DAA treatment regimens. Full-length HCV genome sequencing was performed prior to retreatment with SOF/VEL/VOX. HCV subtypes were assigned and RAS relevant to each genotype were identified. GT1a and GT3a each made up 38% (GT1a n = 55, GT3a n = 54) of the cohort. 40% (n = 58) of patients had liver cirrhosis of whom 7% (n = 4) were decompensated, 10% (n = 14) had hepatocellular carcinoma (HCC) and 8% (n = 12) had received a liver transplant prior to retreatment. The overall retreatment SVR12 rate was 90% (129/144). On univariate analysis, GT3 infection (50/62; SVR = 81%, p = .009), cirrhosis (47/58; SVR = 81%, p = .01) and prior treatment with SOF/VEL (12/17; SVR = 71%, p = .02) or SOF+DCV (14/19; SVR = 74%, p = .012) were significantly associated with retreatment failure, but existence of pre-retreatment RAS was not when viral genotype was taken into account. Retreatment with SOF/VEL/VOX is very successful for non-GT3-infected patients. However, for GT3-infected patients, particularly those with cirrhosis and failed by initial SOF/VEL treatment, SVR rates were significantly lower and alternative retreatment regimens should be considered.


Sustained virological response (SVR) rates for patients chronically infected with hepatitis C virus (HCV) and treated with direct-acting antiviral (DAA) therapies in clinical trials and real-world cohorts are often >95%.[1–3] Treatment failure is associated with multiple host and viral factors including advanced fibrosis or cirrhosis, HCV subtype[4–6] and the presence of resistance-associated substitutions (RAS) in HCV-encoded proteins that are targeted by DAA.[7] This leaves a small percentage of HCV-infected patients who have been failed by first-line therapies and are therefore by definition "difficult to treat". For patients who have been failed by pan-genotypic regimens such as SOF/VEL and glecaprevir and pibrentasvir, (GLE/PIB) retreatment options are limited. Currently the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD), recommend a combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) for these patients.[8,9]

Retreatment of patients previously failed by predominantly first-generation NS5A inhibitor-containing DAA therapy with SOF/VEL/VOX has been evaluated in both the POLARIS-1 and POLARIS-4 phase-II and III studies.[10] In these studies, SOF/VEL/VOX showed a very high SVR rate in GT1-infected patients (222/228; 97% SVR); however, a slightly lower SVR rate was observed in GT3 patients (126/132; 95% SVR). In addition, a number of studies have evaluated the observed real-world outcomes of SOF/VEL/VOX retreatment. The largest cohort (n = 573) reported by Belperio et al,[11] showed lower SVR rates than in the POLARIS 1 and 4 studies for all genotypes (GT1: 429/473; 91% SVR, GT2: 18/20; 90% SVR, GT3: 42/46; 91% SVR, GT4: 12/12; 100% SVR). This study also showed that the SVR rate for those who had received SOF/VEL as first-line therapy, was reduced for GTs 1–3 (GT1: 15/19; 79% SVR, GT2: 13/15; 87% SVR, GT3: 11/13; 85% SVR). In an Italian cohort,[12] the SVR rate was 95% (162/169) with cirrhosis and hepatocellular carcinoma (HCC) being associated with treatment failure, however, there was no significant difference between the SVR rates of patients with different genotypes (GT1: 98/101; 97% SVR, GT2: 17/17; 100% SVR, GT3: 33/36; 91% SVR, GT4: 14/15; 93% SVR). Finally, Llaneras et al[13] reported an overall SVR rate of 95% (128/135) with 100% in patients with GT1 (82/82) and GT2 (7/7) infection, 80% (24/30) in GT3 and 93% (13/14) in GT4. SVR rates were significantly lower in patients with cirrhosis (89%, p = .05), or those with GT3 infection (80%, p < .001), whilst patients with GT3 infection and cirrhosis had the lowest SVR rate (69%).

Despite these studies there remains limited data on SOF/VEL/VOX retreatment from the real-world setting, particularly for patients with GT3 infection following unsuccessful therapy with pan-genotypic DAA regimens. These data are required to inform optimal retreatment strategies. In this paper, we report the outcomes of 144 patients failed by first-line DAA therapy and retreated with SOF/VEL/VOX. We then analyse the effect of clinical characteristics and RAS on SOF/VEL/VOX retreatment.