Michael Schlag

Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region

Hepatitis C virus (HCV) NS3 polymorphism Q80K is mainly found in patients with HCV genotype (G) 1a, and has been associated with a reduced treatment response to simeprevir with pegylated interferon (P) and ribavirin (R). Prevalence of Q80K among G1 patients may vary geographically. Q80K prevalence in the North-American G1 population in a recent study was 34%. We conducted a post hoc meta-analysis of Q80K polymorphism prevalence among HCV G1-infected patients enrolled in simeprevir and telaprevir Phase II/III studies. Baseline HCV NS3/4A protease sequences were analysed by population sequencing to determine Q80K prevalence. Overall, of 3349 patients from 25 countries in the European region analysed, 35.8%, 63.8% and 0.3% of patients had G1a, G1b and other/unknown HCV G1 subtypes, respectively. Q80K was detected at baseline in 7.5% of HCV G1 patients overall. Examination by subtype showed that 19.8%, 0.5% and 18.2% of patients with G1a, G1b and other/unknown HCV G1 subtypes had the Q80K polymorphism, respectively. Among countries in the European region with sequencing data available for either ⩾20 patients with G1a and/or ⩾40 G1 patients overall, the Q80K prevalence in G1 ranged from 0% in Bulgaria to 18.2% in the UK. Q80K prevalence also varied within G1a across different countries. HCV subtype 1a was correctly determined in 99% of patients by the LiPA v2 assay. A low overall prevalence of Q80K was observed in HCV G1-infected patients in the European region, compared with North America. However, the prevalence varied by country, due to differing ratios of G1a/G1b and differing Q80K prevalence within the G1a populations.

Efficacy of a 12-Week Simeprevir Plus Peginterferon/Ribavirin (PR) Regimen in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 4 (GT4) Infection and Mild-To-Moderate Fibrosis Displaying Early On-Treatment Virologic Response.

Background HCV GT4 accounts for up to 20% of HCV infections worldwide. Simeprevir, given for 12 weeks as part of a 24- or 48-week combination regimen with PR is approved for the treatment of chronic HCV GT4 infection. Primary study objectives were assessment of efficacy and safety of simeprevir plus PR in treatment-naïve patients with HCV GT4 treated for 12 weeks. Primary efficacy outcome was sustained virologic response 12 weeks post-treatment (SVR12). Additional objectives included investigation of potential associations of rapid virologic response and baseline factors with SVR12. Methods This multicentre, open-label, single-arm study (NCT01846832) evaluated efficacy and safety of simeprevir plus PR in 67 patients with HCV GT4 infection. Patients were treatment-naïve, aged 18–70 years with METAVIR F0–F2 fibrosis. Patients with early virologic response (HCV RNA <25 IU/mL [detectable/undetectable in IL28B CC patients or undetectable in IL28B CT/TT patients] at Week 2 and undetectable at Weeks 4 and 8) were eligible to stop all treatment at the end of Week 12, otherwise PR therapy was continued to Week 24. Results Of 67 patients treated, 34 (51%) qualified for 12-week treatment including all but one patient with IL28B CC genotype (14/15). All patients in the 12-week group had undetectable HCV RNA at end of treatment, and 97% (33/34) achieved SVR12. No new safety signals with simeprevir plus PR were identified. The proportion of patients experiencing Grade 3–4 adverse events was lower in the 12-week group than in the 24-week group. Conclusions Our findings on simeprevir plus PR therapy shortened to 12 weeks in patients with HCV GT4 infection with favourable baseline characteristics and displaying early on-treatment virologic response are encouraging. No new safety signals were associated with simeprevir plus PR in this study. Trial Registration NCT01846832

An Open-Label Trial of 12-Week Simeprevir plus Peginterferon/Ribavirin (PR) in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 1 (GT1).

Background Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12. Methods In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression. Results Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen. Conclusions Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen. Trial Registration ClinicalTrials.gov NCT01846832

Simeprevir and daclatasvir for 12 or 24 weeks in treatment-naïve patients with HCV genotype 1b and advanced liver disease.

We investigated the efficacy and safety of simeprevir plus daclatasvir in treatment‐naïve patients with chronic, genotype 1b hepatitis C virus infection and advanced liver disease, excluding patients with pre‐defined NS5A resistance‐associated substitutions.

Clinical impact of pharmacokinetic interactions between the HCV protease inhibitor simeprevir and frequently used concomitant medications

Aims Direct‐acting antiviral agents (DAAs) for the treatment of hepatitis C (HCV) can be associated with drug–drug interactions (DDIs) with concomitant medications. The practical clinical implications of such DDIs are poorly understood. We assessed the clinical impact of possible pharmacokinetic (PK) interactions between simeprevir and frequently prescribed concomitant medications. Methods This post hoc analysis pooled data from nine studies which evaluated simeprevir (SMV)‐based interferon‐free HCV treatment. Three classes of frequently used concomitant medications of interest (CMOIs) were analysed [antihypertensive drugs (AHDs), anxiolytic drugs (AXDs) and lipid‐lowering drugs (LLDs)] and categorized as amber or green according to their DDI potential with SMV (green: no DDIs; amber: potential/known PK interactions). Concomitant medications not recommended to be coadministered with SMV were not included. The composite primary endpoint was defined as the frequency of either discontinuation, interruption or dose modification of the CMOI during 12 weeks of SMV treatment. Results Few patients met the composite endpoint in the various subgroups. Patients on amber CMOIs tended to experience CMOI modification more often (13.4–19.4%) than those on green CMOIs (3.1–10.8%). There was no difference in the frequency of adverse events between patients taking green and those taking amber CMOIs. Conclusions In this large pooled analysis, coadministration of the evaluated commonly prescribed medications with known or potential PK interactions with SMV was manageable and resulted in few adjustments of concomitant medications. Our method could serve as a blueprint for the evaluation of the impact of DDIs.

PTH-137 Safety and efficacy of simeprevir (SMV) plus PEG-IFN/RBV in treatment-naÏve chronic hepatitis c genotype 1 patients eligible for 12 weeks of treatment

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.