A 3-year follow-up study after treatment with simeprevir in combination with pegylated interferon-α and ribavirin for chronic hepatitis C virus infection

Fabien Zoulim, Christophe Moreno, Samuel S Lee, Peter Buggisch, Andrzej Horban, Eric Lawitz, Chris Corbett, Oliver Lenz, Bart Fevery, Thierry Verbinnen, Umesh Shukla, Wolfgang Jessner, Fabien Zoulim, Christophe Moreno, Samuel S Lee, Peter Buggisch, Andrzej Horban, Eric Lawitz, Chris Corbett, Oliver Lenz, Bart Fevery, Thierry Verbinnen, Umesh Shukla, Wolfgang Jessner

Abstract

Background: Simeprevir is approved with pegylated interferon and ribavirin (PR) for chronic hepatitis C virus (HCV) genotype (GT) 1 and GT4 infection in the USA and the European Union.

Methods: This 3-year follow-up study assessed the durability of sustained virologic response (SVR) (undetectable HCV RNA 12 or 24 weeks after treatment end), and evaluated the persistence of treatment-emergent NS3/4A protease inhibitor resistance in patients not achieving SVR following treatment with simeprevir plus PR in the parent study. The maintenance of SVR after the last post-therapy follow-up visit of the parent study (LPVPS) was assessed using HCV RNA measurements. The persistence of treatment-emergent NS3 amino acid substitutions in patients with no SVR at LPVPS was assessed using population sequencing. No study medications were administered.

Results: Overall, 249 patients were enrolled (200 with SVR at LPVPS; 49 with no SVR at LPVPS); 40 patients discontinued prematurely (18 with SVR; 22 with no SVR). All 200 enrolled patients who achieved SVR in the parent study maintained SVR until the last available visit in this study (median follow-up time: 35.8 months). The treatment-emergent NS3 amino acid substitutions detected at time of failure in the parent study in 43/49 enrolled patients were no longer detected in 37/43 (86.0%) at the end of this study (median follow-up time: 179.9 weeks [41.3 months]).

Conclusion: This 3-year follow-up study provides evidence for the long-term durability of SVR (100%) after successful treatment with simeprevir plus PR. Treatment-emergent NS3 amino acid substitutions became undetectable in the majority of patients.

Trial registration: NCT01349465; ClinicalTrials.gov .

Keywords: Direct-acting antivirals; Hepatitis C virus; NS3 amino acid substitutions; Pegylated interferon; Simeprevir; Sustained virologic response.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the relevant Institutional Review Board or Independent Ethics Committee at each study centre and met the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided informed, written consent to participate.

Consent for publication

Not applicable

Competing interests

FZ has provided consulting and has participated as a speaker for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen and MSD. CM has received grant support from AbbVie, Gilead Sciences and Janssen, and has participated as a speaker or advisor for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen and MSD. SSL has received grant support and has provided consulting for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Intercept, Janssen, Merck, Novartis, Pendopharm and Roche, and has participated in a speakers bureau for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and Pendopharm. PB has participated in a speakers’ bureau or advisory board for AbbVie, Bristol-Myers Squibb, Falk, Gilead Sciences, Janssen, Merz Pharma and MSD. AH has no conflicts of interest to disclose. EL has received grant support from AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck & Co., Roche, Salix, Santaris Pharmaceuticals, Tacere and Theravance, has acted as a consultant for AbbVie, Achillion Pharmaceuticals, Bristol-Myers Squibb, Enanta, Gilead Sciences, Janssen, Merck & Co., Novartis, Santaris Pharmaceuticals, Regulus, and Theravance, and has participated in sponsored lectures for AbbVie, Bristol-Myers Squibb, Gilead, Janssen and Merck & Co. CC, OL, BF, TV, US and WJ are employees of Janssen and may be shareholders of Johnson & Johnson.

Publisher’s Note

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Figures

Fig. 1
Fig. 1
Patient disposition. AE adverse event, LPVPS last post-therapy follow-up visit of the parent study, SVR sustained virologic response
Fig. 2
Fig. 2
Emerging NS3 amino acid substitutions at time of failure in simeprevir Phase IIb/III studies. Considering emerging amino acid substitutions at 18 NS3 positions of interest: 36, 41, 43, 54, 55, 80, 107, 122, 132, 138, 155, 156, 158, 168, 169, 170, 174 and 175. One patient had no sequencing data available. *Amino acid substitutions in patients with Q80K at baseline. #1: R155K or Q + D168E/V or A/V or S122R or G + R155K or D168A, includes one patient with I132L + R155K + D168E + N174G; #2: includes one patient with V132I + D168V. #3: includes one patient with V36M + R155K; #4: alone or in combination with I132L*, I170T* or N174S*
Fig. 3
Fig. 3
Time to return to baseline NS3 sequence* in the parent Phase IIb/III studies. *From time of failure; considering the 18 NS3 positions of interest: 36, 41, 43, 54, 55, 80, 107, 122, 132, 138, 155, 156, 158, 168, 169, 170, 174 and 175. EOS end of study, GT genotype, HCV hepatitis C virus

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