No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients
Author(s): ,
Steven L. Flamm
Affiliations:
Northwestern Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
,
Stefan Zeuzem
Affiliations:
Medizinische Klinik 1, Goethe University Hospital, Frankfurt, Germany
,
Marc Bourliere
Affiliations:
Hôpital Saint Joseph, Marseilles, France
,
Stuart C. Gordon
Affiliations:
Henry Ford Health System, Detroit, MI, USA
,
Hongmei Mo
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Diana M. Brainard
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Robert H. Hyland
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Luisa M. Stamm
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Brian P. Doehle
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Gregory Camus
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Ross Martin
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Evguenia Svarovskia
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
,
Hadas Dvory-Sobol
Affiliations:
Gilead Sciences, Inc, Foster City, CA, USA
Corresponding author. Address: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
,
Stuart K. Roberts
Affiliations:
Alfred Health Gastroenterology Department and Monash University Melbourne, Australia
,
Kris V. Kowdley
Affiliations:
Swedish Medical Center, Seattle, WA, USA
,
K. Rajender Reddy
Affiliations:
University of Pennsylvania, Philadelphia, PA, USA
,
Michael P. Manns
Affiliations:
Hannover Medical School, Hannover, Germany
,
Curtis L. Cooper
Affiliations:
University of Ottawa, Ottawa, Ontario, Canada
Christoph Sarrazin
Affiliations:
St. Josefs-Hospital, Wiesbaden, Germany
EASL LiverTree™. Dvory-Sobol H. Dec 1, 2018; 256732
Hadas Dvory-Sobol
Hadas Dvory-Sobol

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Graphical abstract

Graphical abstract

SOF/VEL/VOX for 12 weeks resulted in a 96% SVR12 rate in NS5A inhibitor-experienced patients. SOF/VEL/VOX for 12 weeks resulted in a 98% SVR12 rate in DAA-experienced patients naïve to NS5A inhibitors. 83% of DAA-experienced patients had baseline NS3 and/or NS5A RASs. 79% of NS5A inhibitor-experienced patients had baseline NS5A RASs. Baseline RASs had no impact on virologic response in DAA-experienced patients following 12 weeks SOF/VEL/VOX.

Background & Aims

In phase III studies, the fixed dose combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) administered for 12 weeks led to a sustained virologic response at 12 weeks (SVR12) in 96% of NS5A inhibitor-experienced patients, and an SVR12 rate of 98% in DAA-experienced patients who had not previously received an NS5A inhibitor. Herein, we evaluate the relationship between the presence of detectable resistance-associated substitutions (RASs) at baseline and treatment outcome, and whether RASs were selected for in cases of virologic failure.

Methods

NS3, NS5A, and NS5B deep sequencing analyses were performed at baseline for all patients and at the time of virologic failure. Results are reported using a 15% cut-off.

Results

A total of 82.7% of NS5A inhibitor-experienced patients (205/248) had baseline NS3 and/or NS5A RASs; 79% had baseline NS5A RASs. SVR12 rates were similar in patients with or without NS3 and/or NS5A RASs, and with or without VOX- or VEL-specific RASs. RASs at NS5A position Y93 were present in 37.3% of patients and 95% achieved SVR12. All patients with ≥2 NS5A RASs achieved SVR12. Baseline NS3 and/or NS5A RASs were present in 46.6% (83/178) of non-NS5A inhibitor DAA-experienced patients, all of whom achieved SVR12. All patients with baseline NS5B nucleoside inhibitor RASs, including two patients with S282T, achieved SVR12. Treatment-selected resistance was seen in one of seven patients who relapsed.

Conclusions

Baseline RASs had no impact on virologic response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Selection of viral resistance with virologic relapse was uncommon.

Lay summary

In phase III studies, 12 weeks of treatment with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) cured 97% of patients with hepatitis C virus who failed prior treatment with direct-acting antiviral drugs. Herein, we show that the presence of pretreatment drug resistance did not affect treatment outcome in these patients who had previously received direct-acting antivirals. We also showed that new drug resistance was rare in patients who failed treatment with SOF/VEL/VOX for 12 weeks. This has important implications for the selection of best retreatment strategies for these patients.

Keyword(s)
NS5A, Resistance-associated substitutions, Direct-acting antivirals, SOF, VEL, VOX, Pan-genotypic
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