SummarySimeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment‐naїve and treatment‐experienced genotype 4‐infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site‐directed mutants or chimeric replicons with patient‐derived NS3 protease sequences was assessed in a transient replicon assay. Simeprevir remained active against most (83/91 [91%]) baseline isolates tested in the chimeric replicon assay. Eight baseline isolates reduced simeprevir activity; these carried I132L or D168E substitutions reducing simeprevir median activity by 4.6‐ and 39‐fold, respectively. Six of these eight isolates were from patients achieving sustained virologic response. Baseline NS3 Q80K polymorphism was not observed in the genotype 4‐infected patients. Of the 107 simeprevir‐treated patients, 37 did not achieve sustained virologic response for any reason. Of the 32 patients who failed treatment and had sequencing information, 28 (88%) had emerging mutations at NS3 positions 80, 122, 155, 156 and/or 168 at time of failure, similar to those in genotype 1. Emerging mutations were mainly D168V and D168E alone or combined with mutations at position 80. In general, isolates obtained at time of failure displayed high‐level in vitro resistance to simeprevir (fold change ≥50) in a chimeric replicon assay with a median simeprevir fold change value of 440, consistent with observed mutations. In conclusion, emerging mutations in genotype 4 patients failing simeprevir+peginterferon/ribavirin treatment were similar to those in genotype 1 and conferred high‐level resistance to simeprevir.

Introduction HPC3014 is a Phase 3, open-label study to assess if response to SMV+Peg-IFN/RBV at Week 2 can allow shortening of treatment to 12 weeks, irrespective of baseline and on-treatment factors. Method Treatment-naïve chronic HCV G1-infected patients with no-to-moderate fibrosis (METAVIR F0–F2) were recruited. In patients with HCV-RNA <25 IU/mL (detectable/undetectable [Roche COBAS®Taqman® lower limit of quantification: 25 IU/mL, lower limit of detection: 15 IU/mL]) at Week 2 and undetectable at Weeks 4 and 8, all treatments were stopped at Week 12 (12-week group). If these criteria were not met, Peg-IFN/RBV was continued to Week 24 (in one case extended to Week 48). Results 123/163 (76%) patients treated were eligible for the 12-week group (53% male, 92% white, 40%G1a/60%G1b, 76% METAVIR F0/1 and 26/59/15% IL28B CC/CT/TT). Treatment was well tolerated in the 12-week group; all patients completed therapy and none failed on treatment; 33% (41/123) of patients relapsed and 3% (4/123) were lost to follow-up. Grade 3 AEs at least possibly related to SMV were experienced by 5% (6/123) of patients. No grade 4 AEs were considered related to SMV; 3% (4/123) of patients experienced an SAE (considered not related to SMV). AEs of special interest in >10% of patients were pruritus (36%), rash (any type, 17%), neutropenia (20%), dyspnoea (15%) and anaemia (11%). Overall SVR12 in the 12-week group was 66% (81/123) but was higher in patients with IL28BCC genotype (94%), patients with baseline viral load ≤800,000 IU/mL (82%), those with mild fibrosis (F0–F1) (74%), and those with undetectable HCV-RNA at Week 2 (77%). Amongst patients with undetectable HCV-RNA at Week 2, SVR12 rates still varied based on baseline factors. Conclusion Week 2 response alone did not predict treatment outcomes as other baseline factors such as IL28B genotype, baseline viral load and fibrosis score seemed to influence SVR rates. Multivariate analyses are ongoing using factors associated with higher SVR rates shown in this analysis in order to create a strong model to select patients with a good chance of SVR after 12 weeks of therapy. Disclosure of interest G. Foster Conflict with: BMS, Gilead, Janssen, GSK, Roche, Springbank, Tekmira, T. Asselah Conflict with: AbbVie, Janssen, Gilead, BMS, Merck, Roche, C. Moreno Conflict with: AbbVie, Astellas, BMS, Gilead, Janssen, MSD, Roche, C. Sarrazin Conflict with: Abbott, Abbvie, BMS, Gilead, Janssen, Merck/MSD, Qiagen, Roche, Siemens, M. Gschwantler Conflict with: AbbVie, BMS, Gilead, Janssen, MSD, Roche, A. Craxi: None Declared, P. Buggisch Conflict with: AbbVie, BMS, Gilead, Janssen, MSD, Roche, R. Ryan Conflict with: Janssen, O. Lenz Conflict with: Janssen, G. Van Dooren Conflict with: Janssen, I. Lonjon-Domanec Conflict with: Janssen, M. Schlag Conflict with: Janssen, M. Buti Conflict with: Gilead, Janssen, MSD.

Purpose: To assess whether Week-2 response with SMV+Peg-IFN/RBV can allow shortening treatment to 12 weeks, irrespective of baseline and on-treatment factors.

Aims: HCV genotype 4 (GT4) is highly prevalent in the Middle East and Sub-Saharan Africa, and is expanding in Europe. To prevent disease progression, short and effective regimens are needed for these patients. This study aims to assess whether treatment with simeprevir+Peg-IFN/ribavirin can be shortened to 12 weeks, based on early viral kinetics, in patients with mild-to-moderate fibrosis.

replaced by alternative therapies, although many regions of the world are only now starting to utilize telaprevir and boceprevir triple therapies and will likely continue using other interferon-based regimens for some time. The combination of the nucleoside analogue, sofosbuvir, with peginterferon and ribavirin administered for 12 weeks has yielded high rates of sustained virological response for genotype 1 and was approved by regulatory agencies in the US and Europe in 2013. Rates of SVR were generally similar across all subpopulations, although patients with cirrhosis had lower rates of SVR. This regimen is considered the treatment of choice for patients with genotype 1 contemplating interferon-based therapy, according to recent treatment recommendations from AASLD/IDSA and EASL. The treatment recommendations also suggest that triple therapy with simeprevir, a second generation protease inhibitor also recently approved by regulatory authorities, can be considered as alternate therapy for patients with genotype 1 who can tolerate an interferon-based regimen. Combination of simeprevir with peginterferon and ribavirin achieved significantly higher rates of sustained virological response (SVR) compared to peginterferon and ribavirin alone in patents treated for 24–48 weeks. Patients with cirrhosis also had lower rates of SVR compared to non-cirrhotics. This regimen is specifically not recommended for patients with genotype 1a with baseline Q80K polymorphism due to the substantially lower rate of SVR. The EASL guidelines also indicate that combination of peginterferon, ribavirin, and daclatasvir (NS5A inhibitor) may be used to treat HCV specifically genotype 1b in the EU. This drug is currently not available in the U.S. The future role of peginterferon-based regimens will likely depend on many factors which will be specific to different geographic regions of the world, including cost-effectiveness, frequency of favorable IL28B genotype, and accessibility of newer DAA regimens.

Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-α and ribavirin in Japan, Canada, and USA.

P1127 SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR TREATMENT OF CHRONIC HCV GENOTYPE 1 INFECTION IN TREATMENT-NAIVE EUROPEAN PATIENTS IN THE QUEST-1 AND QUEST-2 PHASE III TRIALS G.R. Foster, I.M. Jacobson, G.J. Dore, M. Fried, M. Manns, P. Marcellin, F. Poordad, E.S. Affonso de Araujo, M. Peeters, O. Lenz, S. Ouwerkerk-Mahadevan, G. De La Rosa, R. Kalmeijer, R. Sinha, M. Beumont-Mauviel. Queen Mary’s, University of London, London, United Kingdom; Weill Cornell Medical College, New York, NY, United States; The Kirby Institute, University of New South Wales, Darlinghurst, NSW, Australia; University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Medizinische Hochschule Hannover, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany; Hopital Beaujon, Service d’Hepatologie, INSERM U 481, Clichy, France; Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States; Hospital das Clinicas of the University of Sao Paulo School of Medicine, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil; Janssen Infectious Diseases BVBA, Beerse, Belgium; Janssen Research & Development, Beerse, Belgium; Janssen Global Services, LLC, Titusville, NJ, United States; Janssen Research & Development, Titusville, NJ, United States; Janssen Infectious Diseases BVBA, Beerse, Belgiumv, Beerse, Belgium E-mail: g.r.foster@qmul.ac.uk