Elsevier

Journal of Hepatology

Volume 71, Issue 4, October 2019, Pages 666-672
Journal of Hepatology

Research Article
Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs

https://doi.org/10.1016/j.jhep.2019.06.002Get rights and content

Highlights

  • Patients achieve high SVR12 rates with sofosbuvir/velpatasvir/voxilaprevir after prior DAA failures.

  • Sofosbuvir/velpatasvir/voxilaprevir is a very safe and well tolerated combination.

  • GT3 cirrhotic patients with previous treatment with NS5A-inhibitors are poor responders.

  • GT3 is the only factor that impacts SVR12 rates in retreatment with sofosbuvir/velpatasvir/voxilaprevir.

Background & Aims

Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting.

Methods

This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded.

Results

A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific.

Conclusion

Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group.

Lay summary

Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.

Introduction

Current treatments with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection lead to elimination of the virus in more than 95% of patients, regardless of the HCV genotype or presence of advanced liver fibrosis.1 The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) guidelines both recommend combinations including an NS5A inhibitor with either a NS3/4 protease inhibitor, such as grazoprevir/elbasvir or glecaprevir/pibrentasvir, or a nucleotide analogue plus an NS5A inhibitor, such as sofosbuvir/velpatasvir, for durations ranging from 8 to 12 weeks.[2], [3], [4] Sofosbuvir/velpatasvir and glecaprevir/pibrentasvir combinations are pangenotypic and therefore, they are the preferred regimens to simplify HCV therapy.[5], [6], [7] Despite the high efficacy of these new combinations, the options for patients who do not achieve a sustained virological response (SVR) are limited.8 The latest approved retreatment regimen is combined therapy with sofosbuvir plus the NS55 inhibitor, velpatasvir, and the NS3/4 protease inhibitor, voxilaprevir (SOF/VEL/VOX),9 which is recommended in the AASLD and EASL guidelines for retreating patients previously failing DAA regimens.[2], [3], [4]

The SOF/VEL/VOX combination, evaluated in 2 phase II trials including DAA-experienced patients, yielded very high SVR rates.[10], [11] Later, the single-tablet SOF/VEL/VOX combination in a 12-week regimen was evaluated in 2 phase III trials including patients previously treated with a DAA-containing regimen.12 In POLARIS-1, 300 patients with HCV genotype (GT)1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned to receive either SOF/VEL/VOX (150 patients) or placebo (150 patients) once daily for 12 weeks. In addition, 114 patients infected with HCV other than GT1 were enrolled in the SOF/VEL/VOX group. In another study, POLARIS-4, patients with HCV GT1 to GT4 who had previously received a DAA regimen without an NS5A inhibitor were randomly assigned to receive SOF/VEL/VOX (182 patients) or sofosbuvir/velpatasvir (151 patients) for 12 weeks. A substudy was also carried out including 147 patients randomized to receive placebo in POLARIS-1 who did not achieve an SVR 12 weeks after completion of treatment (SVR12). These patients were retreated with 12 weeks of SOF/VEL/VOX and 97% achieved SVR12.13 Four patients had virological relapse; all were infected with GT1a but only one had liver cirrhosis. In total, 96% of patients in POLARIS-1, 98% in POLARIS-4, and 97% in the POLARIS-1 substudy achieved SVR, suggesting high efficacy of SOF/VEL/VOX as a retreatment regimen.

In these trials, all patients underwent baseline deep sequencing of the NS3, NS5A, and NS5B coding regions of HCV to detect genetic changes associated with resistance to the treatment received. Resistance-associated substitutions (RASs) were reported when they were detected in more than 15% of the sequence reads. Nonetheless, the presence of RASs did not have a significant impact on the rates of SVR12. The POLARIS-1 and POLARIS-4 trials showed that treatment with SOF/VEL/VOX for 12 weeks is an effective and safe option for retreating patients with HCV, although the data on its use in clinical practice are limited.

The aim of this study was to evaluate in the real-world setting the efficacy and safety of the fixed-dose combination of SOF/VEL/VOX for 12 weeks in patients with chronic hepatitis C of any genotype and with different degrees of liver fibrosis who had previously failed oral DAA therapy.

Section snippets

Study design

This is a prospective, nationwide, multicentre study evaluating the efficacy and safety of antiviral retreatment for HCV-infected patients who failed DAA regimens in routine clinical practice at 28 Spanish Hospitals. The inclusion criteria were adults with chronic hepatitis C, including those with compensated cirrhosis, who had previously failed combined therapy with 2 DAAs in an interferon-free regimen from January 2014 to December 2017. Patients coinfected with HIV and those with

Patient population

In total, 137 patients were included: 75% were men, median age was 56 years, 46 (34%) had compensated liver cirrhosis, and 6 (4%) were HIV coinfected. Most had HCV GT1 infection (1b 39%, 1a 22%, and non-subtyped 2%), whereas 22% had GT3, 10% GT4, and 5% GT2. Nine (7%) patients had a history of HCC, and 8 (6%) had received a liver transplant.

All patients had previously received a DAA-based interferon-free regimen with the following combinations: sofosbuvir-based regimen plus an NS5A inhibitor or

Discussion

The results of this real-world study show that the SOF/VEL/VOX combination is safe and effective for patients with previously treated HCV, supporting the results reported in clinical trials. The overall SVR12 rate was 95%, although GT3-infected patients, particularly those with underlying liver cirrhosis, had considerably lower SVR rates. Only 24 of 30 (80%) GT3-infected patients achieved SVR12, and this percentage decreased to 9 of the 13 (69%) with cirrhosis. Hence, GT3 can be considered a

Financial support

The authors received no financial support to produce this manuscript.

Conflicts of interest

Jordi Llaneras has no potential conflicts of interest to report. Mar Riveiro-Barciela has served as speaker for Gilead and MSD and has received grants from Gilead. Sabela Lens has received speaker/advisory fees from Abbvie, Gilead, Janssen and MSD. Moisés Diago has served as speaker/advisory for Abbvie, MSD and Gilead. Alba Cachero reports personal fees from Gilead. Javier García-Samaniego is consultant and speaker for Gilead, Abbvie and MSD. Isabel Conde has no potential conflicts of interest

Authors’ contributions

Jordi Llaneras, Mar Riveiro-Barciela, Rafael Esteban and Maria Buti: concept and design, experiments and procedures; discussing the results and writing of article. S. Lens, M. Diago, A. Cachero, J. García-Samaniego, I. Conde, A. Arencibia, J.I. Arenas, F. Gea, X. Torras, J.L. Calleja, J.A. Carrión, I. Fernández, R.M. Morillas, J.M. Rosales, I. Carmona, C. Fernández-Rodríguez, M. Hernández-Guerra, S. Llerena, V. Bernal, S. Daponte, J.M. González-Santiago, S. Montoliu, B. Figueruela, E. Badia, M.

Acknowledgments

We thank all patients for their participation and are especially grateful to the professionals comprising the multidisciplinary teams responsible for antiviral therapy in the 28 participating Spanish hospitals for their collaboration in this study.

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