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


Baseline Characteristics of Patients

Outcomes were available for 144 patients who were retreated with SOF/VEL/VOX. The mean age was 56 years (49–63 IQR) with 84% (n = 121) of the cohort being male. Overall, 40% (n = 58) had cirrhosis, with 7% (n = 4) decompensated. Of 10% (n = 14) had HCC and 8% (n = 12) had received a liver transplant prior to retreatment (Table 1). The median time from the end of previous treatment to pre-retreatment sequencing analysis was 13 months (2–32 Range). GT1a and GT3a were the two most common subtypes, each making up 38% (GT1a n = 55, GT3a n = 54) of the cohort, 17 other subtypes were identified from genotypes 1, 2, 3, 4 and 6, with GT1b, GT4r and GT3b making up 6% (n = 9), 4% (n = 6), and 3% (n = 5) of the cohort respectively (Figure 1).

Figure 1.

HCV Subtypes of the 144 patients failed by first-line DAA therapy and retreated with SOF/VEL/VOX. The percentage prevalence of each subtype is shown broken down by HCV genotype. Sequences which could not be assigned to subtypes have been labelled with the appropriate genotype

Effectiveness of Retreatment With SOF/VEL/VOX

The overall SVR12 rate for patients retreated with SOF/VEL/VOX was 91% (n = 129) (Figure 2). The majority of patients who did not achieve an SVR (n = 15) experienced a post-treatment relapse (n = 10). One patient experienced an on-treatment breakthrough (patient's HCV RNA was undetectable during treatment and then became detectable again during treatment.) and two were non-responders (patients who never achieve undetectable HCV RNA). Relapse/breakthrough/non-response was not reported by the treating clinician for the remaining two patients. Poor adherence to retreatment was not reported for any of the patients who did not achieve an SVR.

Figure 2.

Retreatment SVR12 rates for patients retreated with SOF/VEL/VOX according to baseline and treatment characteristics for the whole cohort (n = 144). The SVR rate for each variable is shown with 95% confidence intervals shown. Daclatasvir (DCV), Sofosbuvir (SOF), Glecaprevir (GLE), Pibrentasvir (PIB), Grazoprevir (GZR), Elbasvir (EBR), Ledipasvir (LDV), Paritaprevir (PTV), Ombitasvir (OBV) Ritonavir (r), Dasabuvir (DAS), Velpatasvir (VEL)

Evaluating the factors associated with outcome using univariable logistic regression, GT3 infection (52/64; SVR = 81%, p = .009) and cirrhosis (47/58; SVR = 81%, p = .01) were both significantly associated with treatment outcome (Figure 3). Patients whose initial regimen was either SOF/VEL or SOF +DAC were also less likely to achieve SVR on retreatment (12/17, 71% = 0.02 and 14/19, 74%, p = .012 respectively). Patients with GT3 infection, cirrhosis and prior treatment with SOF/VEL had the lowest SVR rate of 42% (3/7). However, one of these patients only received 4 weeks of SOF/VEL/VOX (p = .03) (Supplementary Table 2). Multivariable analysis using logistic regression with SVR as the response variable and GT, presence/absence of cirrhosis and previous treatment regimen included as explanatory variables, revealed that prior treatment with SOF/VEL had the largest effect on SVR and remained the only variable significantly associated with outcome (p = .03) (Supplementary Figure 1). However, with the exception of one GT1 patient previously treated with SOF/VEL, all patients with prior SOF/VEL or SOF +DCV treatment had GT3 infection which confounded this result (Table 1). When GT3-infected patients were analysed separately, cirrhosis and prior treatment regimen were no longer significantly associated with outcome, in both the univariable and multivariable analysis.

Figure 3.

Univariate analysis of clinical factors associated with SVR for patients retreated with SOF/VEL/VOX according to baseline and treatment characteristics for the whole cohort (n = 144). The log odds ratio with 95% confidence intervals shown calculated using logistic regression. Values for which the SVR rate was 100% have not been included. Reference values used in regression when number of values is greater than two (ref), Daclatasvir (DCV), Sofosbuvir (SOF), Glecaprevir (GLE), Pibrentasvir (PIB), Grazoprevir (GZR), Elbasvir (EBR), Ledipasvir (LDV), Paritaprevir (PTV), Ombitasvir (OBV) Ritonavir (r), Dasabuvir (DAS), Velpatasvir (VEL)

Effect of Resistance-associated Substitutions on Retreatment Outcome

Among the 144 patients retreated with SOF/VEL/VOX and with available outcomes, 70% (101/144) had detectable RAS prior to retreatment. 16% had NS3 inhibitor RAS, 51% NS5A inhibitor RAS and 34% SOF RAS. However, the majority of SOF RAS were detected in GT3a sequences (Supplementary Figure 2). Of the viral sequences in 15 patients failed by SOF/VEL/VOX retreatment, 12/15 (80%) had detectable RAS prior to retreatment compared to 89/129 (68%) in those subsequently achieving SVR. However, despite the high prevalence of RAS, the presence of a RAS in a particular protein or combination of proteins was not significantly associated with the outcome (Table 2). When each RAS (Full list in Table 3) was considered independently using logistic regression, A30K and Y93H RAS in NS5A were associated with retreatment failure in the whole cohort (A30K p = .02, Y93H p = .01) (Table 3). The A30K RAS is unique to GT3a (it is wild-type in GT3b) and the Y93H substitution was much more common in GT3 patients compared to other genotypes (Supplementary Figure 2). When the analysis is limited to GT3 patients, the SVR rates for patients with these RAS were still reduced (for A30K SVR, 71% and Y93H SVR, 78%) but this was no longer statistically significant (A30K p = .2, Y93H p = .3). In addition, when the genotype is added as a cofactor to the logistic regression Y93H is no longer associated with the outcome. Whilst individually the A30K and Y93H RAS are common, the combination of A30K + Y93H is found rarely and is not associated with treatment outcome in this cohort (Supplementary Figure 3). No other RAS was significantly associated with outcome within the whole cohort or within a specific genotype of patients.