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No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients

Published:August 08, 2018DOI:https://doi.org/10.1016/j.jhep.2018.07.023

      Highlights

      • 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.

      Graphical abstract

      Keywords

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      References

      Author names in bold designate shared co-first authorship

        • Cooke G.S.
        • Lemoine M.
        • Thursz M.
        • Gore C.
        • Swan T.
        • Kamarulzaman A.
        • et al.
        Viral hepatitis and the Global Burden of Disease: a need to regroup.
        J Viral Hepat. 2013; 20: 600-601
        • Mohd Hanafiah K.
        • Groeger J.
        • Flaxman A.D.
        • Wiersma S.T.
        Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence.
        Hepatology. 2013; 57: 1333-1342
        • The Polaris Observatory HCV Collaborators
        Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.
        Lancet. 2017; 2: 161-176
        • Perz J.F.
        • Armstrong G.L.
        • Farrington L.A.
        • Hutin Y.J.
        • Bell B.P.
        The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.
        J Hepatol. 2006; 45: 529-538
        • AASLD IDSA HCV Guidance Panel
        Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus.
        Hepatology. 2015; 62: 932-954
        • Lam B.P.
        • Jeffers T.
        • Younoszai Z.
        • Fazel Y.
        • Younossi Z.M.
        The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment.
        Therap Adv Gastroenterol. 2015; 8: 298-312
        • Holmes J.A.
        • Thompson A.J.
        Interferon-free combination therapies for the treatment of hepatitis C: current insights.
        Hepat Med. 2015; 7: 51-70
      1. Nelson DR. HCV-TARGET International Registry Do Phase III Trials Translate into Real World [Presentation]. In: 15th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD); 2015 26–28 June; Berlin, Germany; 2015.

      2. Welzel TM, Nelson DR, Morelli G, Di Bisceglie AM, Reddy KR, Kuo A, et al. Safety and Efficacy of Sofosbuvir and Ribavirin for the Treatment of HCV Genotype 2 and 3: Results of the HCV-TARGET Study [Abstract 1057]. In: 66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2015 13–17 November; San Francisco, CA; 2015. p. 727A–728A.

      3. Dieterich DT, Bacon B, Curry M, Flamm SL, Guest L, Kowdley K, et al. Ledipasvir/Sofosbuvir +/- Ribavirin in Patients Co-infected with HCV and HIV: Real-World Heterogeneous Population from the TRIO Network [Poster #SAT-134]. In: European Association for the Study of the Liver (EASL); 2016 13–17 April; Barcelona, Spain; 2016.

      4. Dieterich DT, Bacon B, Flamm SL, Kowdley K, Milligan S, Tsai N, et al. Final Evaluation of 955 HCV Patients Treated with 12 Week Regimens Containing Sofosbuvir +/- Simeprevir in the Trio Network: Academic and Community Treatment of a Real-World, Heterogeneous Population [Abstract P0775]. In: Digestive Disease Week (DDW); 2015 17–19 May; Washington, DC; 2015.

      5. Younossi ZM, Bacon B, Dieterich DT, Flamm SL, Kowdley K, Lawitz E, et al. Evaluation of Access to Care in Patients Prescribed Sofosbuvir-Containing Regimens: Data From the TRIO Network [Abstract Tu1033]. In: Digestive Disease Week 2015 (DDW); 2015 17–19 May; Washington, DC; 2015. p. S1090.

      6. Dieterich D, Bacon B, Flamm S, Kowley K, Milligan S, Tsai N, et al. Final evaluation of 955 HCV patients treated with 12 week regimens containing sofosbuvir +/-simeprevir in the trio network: Academic and community treatment of a real-world, heterogeneous population [Abstract P0775]. In: 50th Annual Meeting of the European Association for the Study of the Liver (EASL); 2015 22–26 April; Vienna, Austria; 2015. p. S621.

        • Wyles D.
        • Mangia A.
        • Cheng W.
        • Shafran S.
        • Schwabe C.
        • Ouyang W.
        • et al.
        Long-term persistence of HCV NS5A resistance associated substitutions after treatment with the HCV NS5A inhibitor, ledipasvir, without sofosbuvir.
        Antivir Ther. 2017;
        • Wang C.
        • Sun J.H.
        • O'Boyle 2nd, D.R.
        • Nower P.
        • Valera L.
        • Roberts S.
        • et al.
        Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir.
        Antimicrob Agents Chemother. 2013; 57: 2054-2065
      7. Lawitz E, Flamm S, Yang JC, Pang PS, Zhu Y, Svarovskaia E, et al. Retreatment of Patients Who Failed 8 or 12 Weeks of Ledipasvir/Sofosbuvir-Based Regimens With Ledipasvir/Sofosbuvir for 24 Weeks. In: European Association for the Study of the Liver (EASL). The 50th International Liver Congress; 2015 April 22–26; Vienna, Austria; 2015.

      8. Gane EJ, Shiffman ML, Etzkorn K, Morelli G, Stedman C, Davis MN, et al. Sofosbuvir/Velpatasvir in Combination With Ribavirin for 24 Weeks Is Effective Retreatment for Patients Who Failed Prior NS5A-Containing DAA Regimens: Results of the Retreatment Study [Presentation PS-024]. In: European Association for the Study of the Liver (EASL); 2016 13–17 April; Barcelona, Spain; 2016.

        • Lam A.M.
        • Espiritu C.
        • Bansal S.
        • Micolochick Steuer H.M.
        • Niu C.
        • Zennou V.
        • et al.
        Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.
        Antimicrob Agents Chemother. 2012; 56: 3359-3368
        • Dutartre H.
        • Bussetta C.
        • Boretto J.
        • Canard B.
        General catalytic deficiency of hepatitis C virus RNA polymerase with an S282T mutation and mutually exclusive resistance towards 2'-modified nucleotide analogues.
        Antimicrob Agents Chemother. 2006; 50: 4161-4169
        • Svarovskaia E.S.
        • Dvory-Sobol H.
        • Parkin N.
        • Hebner C.
        • Gontcharova V.
        • Martin R.
        • et al.
        Infrequent development of resistance in genotype 1–6 hepatitis C virus-infected subjects treated with sofosbuvir in phase II and 3 clinical trials.
        Clin Infect Dis. 2014; 59: 1666-1674
        • Lawitz E.J.
        • Dvory-Sobol H.
        • Doehle B.P.
        • Worth A.S.
        • McNally J.
        • Brainard D.M.
        • et al.
        Clinical resistance to velpatasvir (GS-5816), a Novel pan-genotypic inhibitor of the hepatitis C virus NS5A protein.
        Antimicrob Agents Chemother. 2016; 60: 5368-5378
        • Lenz O.
        • Verbinnen T.
        • Lin T.I.
        • Vijgen L.
        • Cummings M.D.
        • Lindberg J.
        • et al.
        In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
        Antimicrob Agents Chemother. 2010; 54: 1878-1887
        • McPhee F.
        • Friborg J.
        • Levine S.
        • Chen C.
        • Falk P.
        • Yu F.
        • et al.
        Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir.
        Antimicrob Agents Chemother. 2012; 56: 3670-3681
        • Pilot-Matias T.
        • Tripathi R.
        • Cohen D.
        • Gaultier I.
        • Dekhtyar T.
        • Lu L.
        • et al.
        In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450.
        Antimicrob Agents Chemother. 2015; 59: 988-997
        • Romano K.P.
        • Ali A.
        • Aydin C.
        • Soumana D.
        • Ozen A.
        • Deveau L.M.
        • et al.
        The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors.
        PLoS Pathog. 2012; 8: e1002832
        • Summa V.
        • Ludmerer S.W.
        • McCauley J.A.
        • Fandozzi C.
        • Burlein C.
        • Claudio G.
        • et al.
        MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants.
        Antimicrob Agents Chemother. 2012; 56: 4161-4167
      9. Taylor JG, Appleby T, Barauskas O, Chen X, Dvory-Sobol H, Gong R, et al. Preclinical Profile of the Pangenotypic HCV NS3/4A Protease Inhibitor GS-9857 [Poster P0899]. In: European Association for the Study of the Liver (EASL). 50th International Liver Congress.; 2015 22–26 April; Vienna, Austria; 2015.

      10. Lawitz E, Dvory-Sobol H, Yang JC, Stamm LM, Taylor JG, Brainard DM, et al. Characterization of HCV Resistance From a 3-Day Monotherapy Study of GS-9857, a Novel Pangenotypic NS3/4A Protease Inhibitor [Poster 718]. In: American Association for the Study of Liver Diseases (AASLD); 2015 13–17 November; San Francisco, CA; 2015.

        • Manns M.P.
        • Gane E.
        • Rodriguez-Torres M.
        • Stoehr A.
        • Yeh C.T.
        • et al.
        Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naive patients with chronic hepatitis C: a randomized phase II study.
        Hepatology. 2012; 56: 884-893
        • Xue W.
        • Pan D.
        • Yang Y.
        • Liu H.
        • Yao X.
        Molecular modeling study on the resistance mechanism of HCV NS3/4A serine protease mutants R155K, A156V and D168A to TMC435.
        Antiviral Res. 2012; 93: 126-137
        • Pan D.
        • Xue W.
        • Zhang W.
        • Liu H.
        • Yao X.
        Understanding the drug resistance mechanism of hepatitis C virus NS3/4A to ITMN-191 due to R155K, A156V, D168A/E mutations: a computational study.
        Biochim Biophys Acta. 2012; 1820: 1526-1534
        • Dietz J.
        • Susser S.
        • Vermehren J.
        • Peiffer K.H.
        • Grammatikos G.
        • Berger A.
        • et al.
        Patterns of resistance-associated substitutions in patients with chronic HCV infection following treatment with direct-acting antivirals.
        Gastroenterology. 2018; 154: e974
        • Bourliere M.
        • Gordon S.C.
        • Flamm S.L.
        • Cooper C.L.
        • Ramji A.
        • Tong M.
        • et al.
        Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection.
        N Engl J Med. 2017; : 2134-2146
      11. VOSEVI™, Gilead Sciences Incorporated. VOSEVI™ (sofosbuvir, velpatasvir, and voxilaprevir) tablets, for oral use. US Prescribing Information. Foster City, CA Revised: July. In; 2017.

      12. VOSEVI™, Gilead Sciences Ireland UC. VOSEVI™ 400 mg/100 mg/100 mg film-coated tablets sofosbuvir/velpatasvir/voxilaprevir. Summary of Product Characteristics (SmPC). County Cork, Ireland. Revised: July. In; 2017.

        • Pawlotsky J.M.
        • Hepatitis C.
        Virus resistance to direct-acting antiviral drugs in interferon-free regimens.
        Gastroenterology. 2016; 151: 70-86
        • Boyd S.D.
        • Tracy L.
        • Komatsu T.E.
        • Harrington P.R.
        • Viswanathan P.
        • Murray J.
        • et al.
        US FDA perspective on elbasvir/grazoprevir treatment for patients with chronic hepatitis C virus genotype 1 or 4 infection.
        Clin Drug Investig. 2017; 37: 317-326
        • Komatsu T.E.
        • Boyd S.
        • Sherwat A.
        • Tracy L.
        • Naeger L.K.
        • O'Rear J.J.
        • et al.
        Regulatory analysis of effects of hepatitis C virus NS5A polymorphisms on efficacy of elbasvir and grazoprevir.
        Gastroenterology. 2017; 152: 586-597
        • Shih I-h.
        • Vliegen I.
        • Peng B.
        • Yang H.
        • Hebner C.
        • Paeshuyse J.
        • et al.
        Mechanistic characterization of GS-9190 (tegobuvir), a novel non-nucleoside inhibitor of hepatitis C virus NS5B polymerase.
        Antimicrob Agents Chemother. 2011; 55: 4196-4203
        • Lohmann V.
        • Korner F.
        • Koch J.
        • Herian U.
        • Theilmann L.
        • Bartenschlager R.
        Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.
        Science. 1999; 285: 110-113
        • Dvory-Sobol H.
        • Wong K.A.
        • Ku K.S.
        • Bae A.
        • Lawitz E.J.
        • Pang P.S.
        • et al.
        Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients.
        Antimicrob Agents Chemother. 2012; 56: 5289-5295
        • Sullivan J.C.
        • De Meyer S.
        • Bartels D.J.
        • Dierynck I.
        • Zhang E.Z.
        • Spanks J.
        • et al.
        Evolution of treatment-emergent resistant variants in telaprevir phase III clinical trials.
        Clin Infect Dis. 2013; 57: 221-229
        • Howe A.Y.
        • Long J.
        • Nickle D.
        • Barnard R.
        • Thompson S.
        • Howe J.
        • et al.
        Long-term follow-up of patients receiving boceprevir for treatment of chronic hepatitis C.
        Antiviral Res. 2015; 113: 71-78
        • Lenz O.
        • Verbinnen T.
        • Fevery B.
        • Tambuyzer L.
        • Vijgen L.
        • Peeters M.
        • et al.
        Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies.
        J Hepatol. 2015; 62: 1008-1014
        • Buti M.
        • Gordon S.C.
        • Zuckerman E.
        • Lawitz E.
        • Calleja J.L.
        • Hofer H.
        • et al.
        Grazoprevir, elbasvir, and ribavirin for chronic hepatitis C virus genotype 1 infection after failure of pegylated interferon and ribavirin with an earlier-generation protease inhibitor: final 24-week results from C-SALVAGE.
        Clin Infect Dis. 2016; 62: 32-36
      13. Roberts SK, Cooper CL, Lawitz E, Reddy KR, Thompson AJ, Zeuzem S, et al. SOF/VEL/VOX Results in High SVR12 Rates When Administered for 12 Weeks in DAA-Experienced Patients or for 8 Weeks in DAA-Naïve Patients: an Integrated Analysis of the POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4 Studies [Poster SAT-280]. In: The International Liver Congress™ 2017: European Association for the Study of the Liver (EASL); 2017 19–23 April; Amsterdam, the Netherlands; 2017.

        • Gane E.J.
        • Shiffman M.L.
        • Etzkorn K.
        • Morelli G.
        • Stedman C.
        • Davis M.N.
        • et al.
        Sofosbuvir/velpatasvir in combination with ribavirin for 24 weeks is effective retreatment for patients who failed prior NS5A containing DAA regimens: results of the GS-US-342-1553 study [Abstract PS024].
        J Hepatol. 2016; 64: S147-S148
      14. Poordad P, Pol S, Asatryan A, Buti M, Shaw D, Hézode C, et al. MAGELLAN-1, Part 2: glecaprevir and pibrentasvir for 12 or 16 weeks in patients with chronic hepatitis C virus genotype 1 or 4 and prior direct-acting antiviral treatment failure [Presentation]. In: The International Liver Congress™ 2017: European Association for the Study of the Liver (EASL); 2017 19–23 April; Amsterdam, the Netherlands 2017.

      15. Pilot-Matias T, Krishnan R, Schnell G, Tripathi R, Beyer J, Reisch T, et al. Resistance Analysis in the MAGELLAN-1 Study (Part 2): Glecaprevir/Pibrentasvir Therapy in HCV-Infected Patients Who Had Failed Prior DAA Regimens Containing NS3/4A Protease and/or NS5A Inhibitors [Presentation SAT-204]. In: The International Liver Congress™ 2017: European Association for the Study of the Liver (EASL); 2017 19–23 April; Amsterdam, the Netherlands; 2017.