Rekha Sinha

Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial

BACKGROUND TMC125 (etravirine) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against NNRTI-resistant HIV-1 in phase IIb trials. The aim of DUET-2 is to examine the efficacy, tolerability, and safety of TMC125 in treatment-experienced patients. METHODS In this continuing randomised, double-blind, placebo-controlled, phase III trial, HIV-1-infected patients on failing antiretroviral therapy with evidence of resistance to currently available NNRTIs and at least three primary protease inhibitor mutations were eligible for enrolment if on stable (8 weeks unchanged) antiretroviral therapy with plasma HIV-1 RNA greater than 5000 copies per mL. Patients were randomly assigned to receive either TMC125 (200 mg) or placebo, each given twice daily with darunavir-ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors, and optional enfuvirtide. The primary endpoint was the proportion of patients with confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00255099. FINDINGS 591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11-26; p=0.0003). The type and frequency of adverse events were much the same in the two groups. INTERPRETATION In treatment-experienced patients, treatment with TMC125 led to better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial

BACKGROUND Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. METHODS In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782. FINDINGS Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration. INTERPRETATION Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. FUNDING Janssen Infectious Diseases-Diagnostics.

Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. METHODS In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. FINDINGS 209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32·2%, 95% CI 23·3-41·2; p<0·0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment). INTERPRETATION Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin. FUNDING Janssen Infectious Diseases-Diagnostics.

Simeprevir Increases Rate of Sustained Virologic Response Among Treatment-Experienced Patients With HCV Genotype-1 Infection: A Phase IIb Trial

BACKGROUND & AIMS Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. METHODS We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. RESULTS Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo. CONCLUSIONS In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.

Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2).

Hepatitis C virus (HCV)–infected patients with cirrhosis are historically a difficult‐to‐treat population and are at risk of hepatic decompensation. In the phase 2 COSMOS study that evaluated simeprevir (HCV NS3/4A protease inhibitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) ± ribavirin for 12 or 24 weeks in HCV genotype (GT)1–infected patients, high rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were achieved, including in patients with cirrhosis (METAVIR score F4). This phase 3, open‐label, single‐arm study (OPTIMIST‐2 [NCT02114151]) evaluated the efficacy and safety of 12 weeks of simeprevir + sofosbuvir in HCV GT1–infected treatment‐naive or treatment‐experienced patients with cirrhosis. Patients (aged 18‐70 years) with chronic HCV GT1 infection and documented presence of cirrhosis received oral simeprevir 150 mg once daily + sofosbuvir 400 mg once daily for 12 weeks. The primary efficacy endpoint of the study was the proportion of patients achieving SVR12 versus a composite historical control (SVR12 rate of 70%). Safety and patient‐reported outcomes were assessed. Overall, 103 patients received treatment. SVR12 with simeprevir + sofosbuvir (83%, 95% confidence interval 76%‐91%) met the primary objective of superiority versus the historical control (70%). SVR12 rates for treatment‐naive and treatment‐experienced patients were 88% (44/50) and 79% (42/53), respectively. Adverse events occurred in 72 (70%) patients, with most (64%) being grade 1 or 2. Serious adverse events (none considered related to study treatment) occurred in five (5%) patients, and three (3%) patients discontinued all study treatment due to adverse events. Patient‐reported outcomes improved from baseline to follow‐up week 12. Conclusion: Simeprevir + sofosbuvir for 12 weeks achieved superiority in SVR12 rates versus the historical control in treatment‐naive and treatment‐experienced HCV GT1‐infected patients with cirrhosis and was generally safe and well tolerated. (Hepatology 2016;64:360‐369)

Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study.

Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)‐infected patients. The phase 2 COSMOS study reported high SVR rates in treatment‐naive and prior null‐responder HCV genotype (GT) 1‐infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST‐1 (NCT02114177) was a multicenter, randomized, open‐label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1‐infected treatment‐naive and treatment‐experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non‐CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%‐100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76‐89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12‐week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8‐week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12‐week arm) and three (2%, 8‐week arm) patients experienced a serious adverse event (all unrelated to study treatment). Conclusion: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1‐infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370‐380)

Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: Pooled safety analysis from Phase IIb and III studies

This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon‐α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in ‘Photosensitivity’ were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild‐to‐moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir‐treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient‐reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response‐guided therapy. Simeprevir is well tolerated in HCV genotype 1‐infected patients.

Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents

Objectives:To evaluate the pharmacokinetics, weight-based dose selection and short-term safety and tolerability of etravirine in HIV-1-infected children and adolescents. Design:Phase I, nonrandomized, open-label study in two stages. Methods:Children and adolescents aged at least 6 years to 17 years or less on a stable lopinavir/ritonavir-based antiretroviral regimen with HIV-1 RNA plasma viral load less than 50 copies/ml were enrolled. In both stages, etravirine (4 mg/kg twice daily in stage I, 5.2 mg/kg twice daily in stage II), added to the existing antiretroviral regimen, was administered for 7 days followed by a morning dose and 12-h pharmacokinetic assessment on day 8. Pharmacokinetic parameters were determined using noncompartmental analysis. Data were compared with those previously established in HIV-1-infected adults on a similar etravirine (200 mg twice daily) combination antiretroviral regimen. Results:Twenty-one patients were recruited to each stage; 19 and 20 had evaluable pharmacokinetics in stages I and II, respectively. Mean (SD) maximum plasma concentrations in stages I and II were 495 (453) and 757 ng/ml (680), respectively; area under the plasma concentration–time curve over 12 h was 4050 (3602) and 6141 ng h/ml (5586), respectively. Statistical/qualitative comparisons showed comparable exposures with adults in stage II; however, the upper 90% confidence interval fell outside the predefined range. Plasma viral load remained undetectable on day 8 in all patients, and etravirine was well tolerated at both doses. Conclusion:Etravirine 5.2 mg/kg was well tolerated in this study and this dose was selected for further investigation in clinical trials.

Simeprevir plus peginterferon/ribavirin for HCV genotype 1-infected treatment-naïve patients in China and South Korea

Approximately one‐third of patients with hepatitis C virus (HCV) genotype (GT) 1 infection live in East Asia. This study evaluated the efficacy, pharmacokinetics, safety, and tolerability of simeprevir plus peginterferon alpha‐2a and ribavirin (PR) in HCV GT1‐infected, treatment‐naïve, Asian patients with compensated liver disease.

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

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