Simeprevir with peginterferon α-2a/ribavirin for chronic hepatitis C virus genotype 1 infection in treatment-experienced patients: an open-label, rollover study.

BACKGROUND: This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients. METHODS: Patients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). RESULTS: Phase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies. CONCLUSIONS: The majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNα-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted. TRIAL REGISTRATION: NCT01323244 . (date of registration: March 24, 2011).

Efficacy and safety of simeprevir with PegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4.

BACKGROUND & AIMS: Simeprevir (SMV) is a once-daily (QD), oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of genotype (GT) 1 and GT4 infection. This Phase III, open-label, single-arm study (RESTORE; NCT01567735) evaluated efficacy/safety of SMV with peginterferon-α-2a/ribavirin (PR) in patients with chronic HCV GT4 infection. METHODS: 107 patients were included. Treatment-naïve (n=35) and prior relapse patients (n=22) received SMV 150mg QD+PR (12 weeks), followed by PR alone (12 or 36 weeks, response-guided [HCV RNA <25IU/ml detectable/undetectable at week 4 and <25IU/ml undetectable at week 12]). Prior non-responders (partial, n=10; null, n=40) received SMV/PR (12 weeks), followed by PR for 36 weeks. The primary endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). RESULTS: Median age: 49.0years; 28.0% Black/African; 7.5% IL28B CC; 28.8% METAVIR F4. Overall, 65.4% (70/107) of patients achieved SVR12 (82.9% [29/35] treatment-naïve; 86.4% [19/22] prior relapsers; 60.0% [6/10] prior partial responders; 40.0% [16/40] prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% [31/35] and 90.9% [20/22]), SVR12 rates were high: 93.5% [29/31] and 95.0% [19/20], respectively. Overall on-treatment failure and relapse rates were 23.4% (25/107) and 14.6% (12/82), respectively. Adverse events (AEs) were mainly grade 1/2; serious AEs were infrequent (4.7%) and considered unrelated to SMV. CONCLUSIONS: Efficacy and safety of SMV 150mg QD for 12 weeks with PR in treatment-naïve or -experienced patients with chronic HCV GT4 infection were in line with previous reports for HCV GT1 infection.

Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1 and HIV-1: a phase 3 study.

BACKGROUND: Simeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency virus (HIV) coinfection accelerates progression of liver disease. This uncontrolled, open-label trial explored the safety and efficacy of simeprevir in patients with HCV genotype 1/HIV type 1 (HIV-1) coinfection. METHODS: Patients received simeprevir (150 mg once daily) with pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) for 12 weeks. Noncirrhotic HCV treatment-naive patients and prior relapsers received response-guided therapy (RGT) with peg-IFN/RBV for 24 or 48 weeks. Prior null responders, prior partial responders, and patients with cirrhosis received peg-IFN/RBV for 48 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS: One hundred and six patients (93 on antiretroviral therapy) were enrolled and treated. SVR12 rates were 79.2% in HCV treatment-naive patients, 57.1% in prior null responders, 86.7% in prior relapsers, and 70.0% in prior partial responders. Fifty-four of 61 eligible patients (88.5%) met RGT criteria for 24 weeks of peg-IFN/RBV, of whom 87.0% (47/54) achieved SVR12. SVR12 rates were 80.0% (36/45) and 63.6% (14/22) for patients with METAVIR scores of F0-F2 and F3-F4, respectively. Common adverse event (AE) rates were consistent with peg-IFN/RBV therapy (fatigue, headache, nausea, neutropenia). Most AEs were grade 1/2; serious AEs occurred in 5.7% of patients, none of which were fatal. CONCLUSIONS: Simeprevir was generally well tolerated with safety similar to that observed in HCV-monoinfected patients and high SVR12 rates in HCV treatment-naive patients, prior relapsers, prior partial responders, and prior null responders with HIV-1 coinfection. CLINICAL TRIALS REGISTRATION: NCT01479868.

Very early viral kinetics on interferon treatment in chronic hepatitis C virus genotype 4 infection.

BACKGROUND: Interferon (IFN)-resistant hepatitis C virus strains limit efficacy of antiviral combination therapy in patients infected with genotypes 1 and 4. A single test dose of IFN was useful to identify non-responders to IFN-alpha2b/ribavirin (RBV) or likely non-responders to pegylated (PEG)-IFN-alpha2a/RBV therapy in genotype 1 patients. Our aim was to investigate this approach in genotype 4 patients. METHODS: Viral load was measured in 46 patients before and 24 h after 10 megaunits (MU) IFN-alpha2b, and before and during 2 weeks of daily 5 MU IFN-alpha2b administration. Thereafter, patients received 48 weeks combination therapy with either 180 microg PEG-IFN-alpha2a/week (n=33), 1.5 microg/kg PEG-IFN-alpha2b/week (n=7) or 5 MU IFN-alpha2b/2 days (n=6), along with 1-1.2g RBV/day. For prediction analysis the largest group (PEG-IFN-alpha2a) was evaluated only. RESULTS: Median 24 h log10 change after 10 MU IFN-alpha2b was 1.15 (range 0.08-2.48) and after 5 MU IFN-alpha2b was 0.81 (-0.12-2.22; P<0.0001). Log10 changes after 2 weeks on 5 MU IFN-alpha2b daily and 24 h after 10 MU were the best predictors of early virological response (defined by negativity of a standard qualitative PCR) to PEG-IFN-alpha2a/RBV combination therapy (area under curve [AUC]=0.97; P<0.001, receiver operating characteristics), 24 h log10 change after 10 MU was the best predictor of sustained virological response (SVR; AUC=0.91, P=0.001). CONCLUSION: As in genotype 1 patients, there is large variation in IFN responsiveness, including the presence of resistant strains, in genotype 4 patients. A 24 h log10 change after 10 MU IFN-alpha2b is an excellent predictor of SVR on PEG-IFNalpha2a/RBV combination therapy. This test may be useful to obtain homogeneous groups for clinical studies and could help in clinical decision making.

Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomised, double-blind, non-inferiority phase 3 trial.

BACKGROUND: We did a phase 3 study in previous non-responders with chronic hepatitis C virus (HCV) genotype 1 infection and compensated liver disease that related to the standard of care for these patients at the time this study was initiated. We investigated whether simeprevir is non-inferior in terms of efficacy to telaprevir, each in combination with peginterferon alfa-2a and ribavirin. METHODS: We did this randomised, double-blind, phase 3 trial at 169 investigational sites in 24 countries. We enrolled adults (≥18 years) with chronic HCV genotype 1 infection, compensated liver disease, and plasma HCV RNA higher than 10 000 IU/mL who were null or partial responders during at least one previous course of peginterferon alfa-2a and ribavirin treatment. We randomly assigned (1:1) patients (stratified by HCV genotype 1 subtype [1a plus other/1b] and previous treatment response [partial or null]) to receive simeprevir (150 mg once a day) plus telaprevir placebo (three times a day 7-9 h apart) or telaprevir (750 mg three times a day) plus simeprevir placebo (once a day) in combination with peginterferon alfa-2a and ribavirin for 12 weeks followed by 36 weeks of peginterferon alfa-2a and ribavirin alone. The primary efficacy endpoint was sustained virological response 12 weeks after end of treatment (SVR12) in the intention-to-treat and the per-protocol population. We compared groups with the Cochran-Mantel-Haenszel test. We established a non-inferiority margin of 12%. Adverse events were reported descriptively. This trial is registered with ClinicalTrials.gov, number NCT01485991. FINDINGS: Patient screening began on Jan 19, 2012, and the last visit was on April 7, 2014. We included 763 patients (472 previous null responders [62%]). Simeprevir and peginterferon alfa-2a and ribavirin was non-inferior to telaprevir and peginterferon alfa-2a and ribavirin for SVR12 (54% [203/379] vs 55% [210/384]; difference -1·1%, 95% CI -7·8 to 5·5; p=0·0007). SVR12 was achieved in 70% (101/145) versus 68% (100/146) of previous partial responders and 44% (102/234) versus 46% (110/238) of previous null responders with simeprevir and peginterferon alfa-2a and ribavirin and telaprevir and peginterferon alfa-2a and ribavirin treatment, respectively. We recorded differences between treatment groups in simeprevir or telaprevir-related adverse events (69% [261/379] in the simeprevir group vs 86% [330/384] in the telaprevir group), serious adverse events (2% [8/379] vs 9% [33/384]), and adverse events leading to simeprevir or telaprevir discontinuation (2% [7/379] vs 8% [32/384]). INTERPRETATION: Simeprevir once a day with peginterferon alfa-2a and ribavirin was well tolerated in HCV genotype 1-infected previous non-responders and was non-inferior to telaprevir, thus providing an alternative treatment in areas of the world where all-oral HCV regimens are not available or accessible. FUNDING: Janssen.

Rapid suppression of hematopoiesis by standard or pegylated interferon-alpha.

BACKGROUND & AIMS: Treatment of chronic hepatitis C with interferon (IFN)-alpha often has hematotoxic effects. We evaluated the effects of acute vs. chronic and standard vs. pegylated IFN-alpha on hematopoiesis. METHODS: We studied hematopoiesis in 46 patients with chronic hepatitis C receiving single high-dose IN-Falpha2b followed by daily dose standard or weekly pegylated IFN before combination antiviral therapy. RESULTS: Single high-dose therapy resulted in a significant drop in hemoglobin (HB), leukocytes, and platelet count. Although platelets, stimulated by a significant increase in thrombopoietin (TPO), and leukocytes recovered quickly, HB remained below baseline for 7 days. Daily standard or weekly pegylated IFN-alpha leads to a more pronounced drop in all 3 lineages with concomitant increases in TPO and erythropoietin (EPO). No difference was observed between standard and pegylated IFN, except for HB, which fell more during pegylated IFN therapy. Consecutive combination antiviral therapy aggravated the anemia but not the drop in leukocytes or thrombocytes. CONCLUSIONS: The drop in all 3 hematopoietic lineages through IFN-alpha treatment, high-dose standard, standard daily dose, or pegylated, is caused by a combination of bone marrow inhibition and probably some other rapid acting mechanisms. Hematopoietic growth factors are increased as a consequence but cannot overcome the bone marrow suppression.