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


This cohort represents both the largest reported cohort of patients retreated with SOF/VEL/VOX in the UK, and one of the largest cohorts of GT3-infected patients retreated with SOF/VEL/VOX. Our results show that retreatment of patients with SOF/VEL/VOX who have been failed by first-line therapy is very effective for GT1. However, patients with GT3 infection, cirrhosis or prior treatment with SOF/VEL or SOF +DCV have significantly lower SVR rates with SOF/VEL/VOX retreatment.

Our data shows that GT3-infected patients achieved lower SVR rates to SOF/VEL/VOX retreatment; the lowest SVR12 rates (42%) were observed in patients with GT3 infection, cirrhosis and prior SOF/VEL exposure. This is consistent with the data from Llaneras et al,[13] which also showed a SVR rate of 81% for GT3-infected patients and 69% for GT3-infected patients with cirrhosis. However, Papaluca et al[19] have shown an SVR rate of 90% in GT3 infected patients with cirrhosis. Belperio et al[11] have shown that GT1-infected patients with prior SOF/VEL exposure had a reduced SVR rate of 79% (15/19), yet a GT3-infected group with prior SOF/VEL exposure had a SVR rate of 85% (11/13) which is greater than the 75%(12/16) that was observed in our study but, these numbers remain small.

The overall prevalence of RAS was very high, but the presence of RAS in the NS3, NS5A or NS5B protein was not associated with SVR; this is in line with the analysis of RAS data from the POLARIS-1 and 4 studies by Sarrzin et al.[20] When RAS were analysed separately the presence of the NS5A inhibitor RAS Y93H was significantly associated with treatment failure across the whole cohort. However, when the genotype is included in the model used to test association, Y93H is no longer significantly associated with outcome. This data suggests that viral genotype is the more important viral factor for SOF/VEL/VOX retreatment outcome than the presence of RAS. PIB has been shown to be more effective than other NS5A inhibitors against viruses harbouring the Y93H RAS in-vitro.[21] This suggests that GLE/PIB may be a more effective treatment for patients with the Y93H RAS. Thus, RAS testing to guide retreatment therapy could be an effective way to increase retreatment SVR rates. One of the limitations of this study is that the time between previous treatment failure and pre-retreatment resequencing varied greatly in this cohort and in some cases was as long as 32 months. As RAS which have an effect on viral fitness tend to disappear over time, this study may underestimate the RAS present at previous DAA treatment failure.

At present SOF/VEL/VOX is the only recommended retreatment regimen for patients previously failed by a NS5A inhibitor-containing regimen in England. These data suggest that whilst SOF/VEL/VOX may be a preferred regimen for non-GT3 infected patients, an alternative retreatment regimen for GT3-infected patients should also be considered, particularly those with cirrhosis and previous exposure to a DAA regimen containing SOF/VEL or SOF +DCV. Prior exposure to NS5A inhibitors can result in the emergence and long-term presence of RAS[22,23] whereas the highly resistant SOF variant S282T in NS5B is rarely found after treatment failure and, when detected, it is more transient.[24,25] This would suggest that prior exposure to NS5A inhibitors in VEL/SOF and DCV +SOF regimens has a greater impact on retreatment. In addition to using SOF/VEL/VOX for 24 rather than 12 weeks or adding ribavirin,[26] one current alternative to SOF/VEL/VOX for GT3 patients is off-label use of GLE/PIB +SOF +/-RBV. This combination was effective in a small retreatment trial[27] and could represent an effective retreatment option for GT3 patients with prior exposure to SOF/VEL. Further retreatment options include adopting a resistance guided approach to treatment, increasing the SOF/VEL/VOX treatment duration or adding ribavirin. Where SOF/VEL/VOX retreatment has failed there are rescue therapy options. A recent study by Dietz J et al[28] also showed that SOF/VEL/VOX +/-RBV (Rescue SVR = 100% 4/4) and GLE/PIB +SOF +/- RBV (Rescue SVR = 79% 11/14) were effective rescue therapies in patients failed by SOF/VEL/VOX with GLE/PIB +/- RBV also being successfully used to retreat two patients.

In summary, our study shows that retreatment outcomes for patients failed by first-line DAA therapy are 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 such as GLE/PIB +SOF should be considered.