No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients.
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.
['Sarrazin|Christoph|C|', 'Cooper|Curtis L|CL|', 'Manns|Michael P|MP|', 'Reddy|K Rajender|KR|', 'Kowdley|Kris V|KV|', 'Roberts|Stuart K|SK|', 'Dvory-Sobol|Hadas|H|', 'Svarovskia|Evguenia|E|', 'Martin|Ross|R|', 'Camus|Gregory|G|', 'Doehle|Brian P|BP|', 'Stamm|Luisa M|LM|', 'Hyland|Robert H|RH|', 'Brainard|Diana M|DM|', 'Mo|Hongmei|H|', 'Gordon|Stuart C|SC|', 'Bourliere|Marc|M|', 'Zeuzem|Stefan|S|', 'Flamm|Steven L|SL|']
D000621:Aminoisobutyric Acids D000998:Antiviral Agents D002219:Carbamates D003521:Cyclopropanes D024882:Drug Resistance, Viral D004359:Drug Therapy, Combination D005838:Genotype D019698:Hepatitis C, Chronic D006576:Heterocyclic Compounds, 4 or More Rings D059014:High-Throughput Nucleotide Sequencing D006801:Humans D047029:Lactams, Macrocyclic D007930:Leucine D047028:Macrocyclic Compounds D011392:Proline D011810:Quinoxalines D019233:Retreatment D000069474:Sofosbuvir D013449:Sulfonamides D000072230:Sustained Virologic Response D017211:Treatment Failure D016896:Treatment Outcome D017361:Viral Nonstructural Proteins
Resistance-associated substitutions SOF VEL VOX NS5A Direct-acting antivirals Pan-genotypic