D. Luo

Telaprevir twice daily is noninferior to telaprevir every 8 hours for patients with chronic hepatitis C.

BACKGROUND & AIMS We performed an open-label, multicenter, phase 3 study of the safety and efficacy of twice-daily telaprevir in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis. METHODS Patients were randomly assigned to groups treated with telaprevir 1125 mg twice daily or 750 mg every 8 hours plus peginterferon alfa-2a and ribavirin for 12 weeks; patients were then treated with peginterferon alfa-2a and ribavirin alone for 12 weeks if their level of HCV RNA at week 4 was <25 IU/mL or for 36 weeks if their level was higher. The primary objective was to demonstrate noninferiority of telaprevir twice daily versus every 8 hours in producing a sustained virological response 12 weeks after the end of therapy (SVR12) (based on a -11% lower limit of the 95% lower confidence interval for the difference between groups). RESULTS At baseline, of 740 patients, 85% had levels of HCV RNA ≥800,000 IU/mL, 28% had fibrosis (F3-F4), 14% had cirrhosis (F4), 57% were infected with HCV genotype 1a, and 71% had the non-CC IL28B genotype. Of patients who were treated with telaprevir twice daily, 74.3% achieved SVR12 compared with 72.8% of patients who were treated with telaprevir every 8 hours (difference in response, 1.5%; 95% confidence interval, -4.9% to 12.0%), so telaprevir twice daily is noninferior to telaprevir every 8 hours. All subgroups of patients who were treated with telaprevir twice daily versus those who were treated every 8 hours had similar rates of SVR12. The most frequent adverse events (AEs) in the telaprevir phase were fatigue (47%), pruritus (43%), anemia (42%), nausea (37%), rash (35%), and headache (26%); serious AEs were reported in 9% of patients. Rates of AEs and serious AEs were similar or slightly higher among patients treated with telaprevir every 8 hours. CONCLUSIONS Based on a phase 3 trial, telaprevir twice daily is noninferior to every 8 hours in producing SVR12, with similar levels of safety and tolerability. These results support use of telaprevir twice daily in patients with chronic HCV genotype 1 infection, including those with cirrhosis. ClinicalTrials.gov, Number: NCT01241760.

Telaprevir Activity in Treatment-Naive Patients Infected Hepatitis C Virus Genotype 4: A Randomized Trial

BACKGROUND This partially blinded, randomized, phase 2a C210 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 4 infection. METHODS Twenty-four patients received telaprevir 750 mg every 8 hours for 15 days (T; n = 8), telaprevir in combination with pegylated interferon alfa-2a and ribavirin (Peg-IFN/RBV) for 15 days (TPR; n = 8), or Peg-IFN/RBV plus placebo for 15 days (PR; n = 8), followed by Peg-IFN/RBV for 46 or 48 weeks. The primary objective was to assess the effect of telaprevir on HCV RNA levels. RESULTS HCV RNA levels decreased slightly with T and PR; TPR produced substantial, rapid declines. On day 15, median reductions in the HCV RNA load from baseline were -0.77, -4.32, and -1.58 log10 IU/mL for T, TPR, and PR, respectively, and 0 patients in the T group, 1 in the TPR group, and 0 in the PR group had undetectable HCV RNA. Five of 8 patients who received telaprevir monotherapy had viral breakthrough within 15 days of treatment. Adverse event incidence was similar across treatments and comparable with the incidences from previous clinical trials. One patient (in T group) had a serious adverse event (considered unrelated to telaprevir) that led to treatment discontinuation. CONCLUSIONS Telaprevir with Peg-IFN/RBV had greater activity than Peg-IFN/RBV treatment or telaprevir monotherapy against HCV genotype 4. Telaprevir was generally safe and well tolerated. Further investigation of telaprevir combination therapy in patients with HCV genotype 4 infection is warranted.

5 REALIZE TRIAL FINAL RESULTS: TELAPREVIR-BASED REGIMEN FOR GENOTYPE 1 HEPATITIS C VIRUS INFECTION IN PATIENTS WITH PRIOR NULL RESPONSE, PARTIAL RESPONSE OR RELAPSE TO PEGINTERFERON/RIBAVIRIN

5 REALIZE TRIAL FINAL RESULTS: TELAPREVIR-BASED REGIMEN FOR GENOTYPE 1 HEPATITIS C VIRUS INFECTION IN PATIENTS WITH PRIOR NULL RESPONSE, PARTIAL RESPONSE OR RELAPSE TO PEGINTERFERON/RIBAVIRIN S. Zeuzem, P. Andreone, S. Pol, E.J. Lawitz, M. Diago, S. Roberts, R. Focaccia, Z.M. Younossi, G.R. Foster, A. Horban, P.J. Pockros, R. Van Heeswijk, S. de Meyer, D. Luo, G. Picchio, M. Beumont. Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany; Universita di Bologna, Bologna, Italy; Universite Paris Descartes, INSERM Unite 567, and Assistance Publique-Hopitaux de Paris, Cochin Hospital, Paris, France; Alamo Medical Resarch, San Antonio, TX, USA; Hospital General de Valencia, Valencia, Spain; Department of Gasteroenterology, Alfred Hospital, Melbourne, VIC, Australia; Emilio Ribas Infectious Diseases Institute, Sao Paulo, Brazil; Center for Liver Disease, Inova Fairfax Hospital, Falls Church, VA, USA; Institute of Cell and Molecular Science, Queen Mary University of London, London, UK; Medical University of Warsaw, Warsaw, Poland; Scripps Clinic and The Scripps Research Institute, La Jolla, CA, USA; Tibotec BVBA, Beerse, Belgium; Tibotec Inc., Titusville, NJ, USA E-mail: zeuzem@em.uni-frankfurt.de Background: The Phase 3 study REALIZE evaluated telaprevir (T) in combination with pegylated-IFN alfa-2a (P) and ribavirin (R) in well-characterised prior PR treatment-failure patients. Methods: REALIZE was a randomised, international, multicentre, double-blind, placebo-controlled trial to evaluate the efficacy, safety and tolerability of T (750mg q8h) plus P (180mg/w) and R (1000– 1200mg/d) compared with PR alone in G1 HCV-infected patients with prior PR treatment failure including non-responders (nulland partial-responders) and relapsers. The treatment arms (randomised 2:2:1, stratified by viral load and type of prior response) were: 1) T/PR for 12 weeks, followed by PR for 36 weeks (T12/PR48); 2) PR for 4 weeks followed by T/PR for 12 weeks, then PR for 32 weeks (Lead-in T12/PR48); 3) PR for 48 weeks (Pbo/PR48). The primary objective was to evaluate the superior efficacy of the T/PR arms for non-responders and relapsers. Secondary objectives included the evaluation of a lead-in and efficacy in prior nulland partialresponders separately. HCVRNA was quantified with the COBAS TaqMan v2.0 assay (LLOQ=25 IU/mL). ESAs were not allowed for anaemia management. Results: 833 patients were screened, 663 randomised, and 662 treated. 70% of patients were male, 93% were Caucasian, 26% had cirrhosis, and 89% had baseline HCVRNA ≥800,000 IU/mL.

Risk factors predictive of anemia development during telaprevir plus peginterferon/ribavirin therapy in treatment-experienced patients

BACKGROUND & AIMS Anemia is a common adverse event associated with telaprevir-based triple therapy of chronic, genotype 1 hepatitis C. Identification of patients at risk of developing anemia could allow evaluation of suitability for therapy, and aid in determining frequency of anemia monitoring and treatment management. METHODS This post-hoc analysis utilized data from the no lead-in telaprevir, peginterferon and ribavirin arm of the REALIZE study. Anemia was defined as a single occurrence of hemoglobin <10 g/dl at any point during treatment. Pre-treatment factors with potential to act as prognostic indicators of anemia including age, sex, BMI, and baseline hemoglobin were analysed by univariate and multivariate logistic regression analyses. Nomograms (graphical representations of risk factors) were developed to predict the likelihood of developing anemia. RESULTS Among the 265 patients, 102 (38%) had anemia, with 78/102 (77%) developing anemia on or before week 12. Most patients developed anemia after week 2 and an inverse correlation was found between week 2 hemoglobin and the likelihood of developing anemia. Overall, 60% of patients (60/100) with week 2 hemoglobin <13 g/dl subsequently developed anemia. The multivariate analysis revealed older age (>45 years), lower BMI (≤25 mg/m(2)) and baseline hemoglobin (continuous variable) were significantly associated with the probability of developing anemia during telaprevir treatment. CONCLUSIONS These analyses indicate the potential of using predictive risk factors such as low baseline and on-treatment hemoglobin to identify patients at risk of developing anemia on telaprevir-based triple therapy, which may increase the potential for treatment success by careful patient monitoring.

P1185 INTERIM SVR12 RESULTS FROM THE TELAPREVIR PHASE 3B REPLACE STUDY IN TREATMENT-NAIVE STABLE LIVER TRANSPLANT PATIENTS WITH GENOTYPE 1 HCV INFECTION

P1185 INTERIM SVR12 RESULTS FROM THE TELAPREVIR PHASE 3B REPLACE STUDY IN TREATMENT-NAIVE STABLE LIVER TRANSPLANT PATIENTS WITH GENOTYPE 1 HCV INFECTION X. Forns, D. Samuel, D. Mutimer, S. Fagiouli, M. Navasa, K. Agarwal, M. Berenguer, M. Colombo, K. Herzer, F. Nevens, R. Van Solingen-Ristea, D. Luo, I. Dierynck, J. Witek. Liver Unit, Hospital Clinic, CIBEREHD and IDIBAPS, Barcelona, Spain; Centre Hepatobiliaire, Hospital Paul Brousse, University Paris South Villejuif, Paris, France; Queen Elizabeth Hospital and NIHR BRU, Birmingham, United Kingdom; Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Liver Unit, Hospital Clinic Barcelona, Barcelona, Spain; Kings College Hospital, London, United Kingdom; La Fe Hospital and CIBEREHD, Valencia, Spain; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano, Milan, Italy; Liver Transplantation Unit, University Hospital Essen, Essen, Germany; University Hospitals KU Leuven, Leuven, Belgium; Janssen Research & Development, LLC, Titusville, NJ, United States; Janssen Infectious Diseases BVBA, Beerse, Belgium E-mail: xforns@clinic.ub.es

An OPTIMIZE Study Retrospective Analysis for Management of Telaprevir-Treated Hepatitis C Virus (HCV)-Infected Patients by Use of the Abbott RealTime HCV RNA Assay

ABSTRACT Protease inhibitor (PI)-based response-guided triple therapies for hepatitis C virus (HCV) infection are still widely used. Noncirrhotic treatment-naive and prior relapser patients receiving telaprevir-based treatment are eligible for shorter, 24-week total therapy if HCV RNA is undetectable at both weeks 4 and 12. In this study, the concordance in HCV RNA assessments between the Roche High Pure System/Cobas TaqMan and Abbott RealTime HCV RNA assays and the impacts of different HCV RNA cutoffs on treatment outcome were evaluated. A total of 2,629 samples from 663 HCV genotype 1 patients receiving telaprevir/pegylated interferon/ribavirin in OPTIMIZE were analyzed using the High Pure System and reanalyzed using Abbott RealTime (limits of detection, 15.1 IU/ml versus 8.3 IU/ml; limits of quantification, 25 IU/ml versus 12 IU/ml, respectively). Overall, good concordance was observed between the assays. Using undetectable HCV RNA at week 4, 34% of the patients would be eligible for shorter treatment duration with Abbott RealTime versus 72% with the High Pure System. However, using <12 IU/ml for Abbott RealTime, a similar proportion (74%) would be eligible. Of the patients receiving 24-week total therapy, 87% achieved a sustained virologic response with undetectable HCV RNA by the High Pure System or <12 IU/ml by Abbott RealTime; however, 92% of the patients with undetectable HCV RNA by Abbott RealTime achieved a sustained virologic response. Using undetectable HCV RNA as the cutoff, the more sensitive Abbott RealTime assay would identify fewer patients eligible for shorter treatment than the High Pure System. Our data confirm the <12-IU/ml cutoff, as previously established in other studies of the Abbott RealTime assay, to determine eligibility for shortened PI-based HCV treatment. (The study was registered with ClinicalTrials.gov under registration no. NCT01241760.)

Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease

Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1‐ or 4‐infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct‐acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment‐naïve or treatment‐experienced adults with Child‐Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7–9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS‐331007 (sofosbuvir metabolite) was 2.2‐, 1.5‐, 1.2‐ and 1.2‐fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.

Incidence of virological failure and emergence of resistance with twice-daily vs every 8-h administration of telaprevir in the OPTIMIZE study

The OPTIMIZE study demonstrated noninferior efficacy between telaprevir (TVR) twice daily (bid) vs every 8‐h (q8h) administration. This analysis compared the selective pressure of both dosing regimens by characterisation of the hepatitis C virus (HCV) variants emerging in genotype 1 (G1) HCV‐infected patients who did not achieve sustained virological response (SVR). HCV NS3•4A population sequencing was performed at baseline and time of failure (viral breakthrough, stopping rule or relapse). TVR‐resistant variants were classified by fold change in inhibitory concentration (IC50). Baseline TVR‐resistance was low (<5%) and did not preclude achieving SVR in either arm. The proportion of patients with TVR‐resistant variants at time of failure was similar in the bid (15%) and q8h (17%) dosing arms. The majority of variants and virological failures occurred in G1a patients, and mutations V36M, R155K and R155T (G1a), and V36A, T54A and A156S (G1b) were significantly enriched in both treatment arms. The number and type of emerging TVR‐resistant variants in non‐SVR patients were comparable between treatment arms and were consistent with previous observations. No differences in viral resistance profiles were observed between TVR‐based treatment arms in non‐SVR patients, indicating a similar selective pressure of TVR bid and q8h dosing.

798 EFFICACY OF TELAPREVIR DOSED TWICE DAILY VERSUS EVERY 8 HOURS BY IL28B GENOTYPE: RESULTS FROM THE PHASE III OPTIMIZE STUDY

798 EFFICACY OF TELAPREVIR DOSED TWICE DAILY VERSUS EVERY 8 HOURS BY IL28B GENOTYPE: RESULTS FROM THE PHASE III OPTIMIZE STUDY M. Buti, K. Agarwal, Y. Horsmans, W. Sievert, E. Janczewska, S. Zeuzem, L. Nyberg, R.S. Brown Jr., C. Hezode, M. Rizzetto, R. Parana, S. De Meyer, R. DeMasi, D. Luo, J. Witek. Hospital Valle Hebron and Ciberehd del Instituto Carlos III, Barcelona, Spain; Kings College Hospital, London, UK; Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium; Monash Medical Centre and Monash University, Melbourne, VIC, Australia; Outpatients Clinic for Hepatology, Myslowice, Poland; Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany; Kaiser Permanente, San Diego, CA, Columbia University College of Physicians and Surgeons, New York, NY, USA; Hopital Henri Mondor, Creteil, France; University of Torino, Torino, Italy; Medical School, Federal University of Bahia, Bahia, Brazil; Janssen Infectious Diseases BVBA, Beerse, Belgium; Janssen Research & Development LLC, Titusville, NJ, USA E-mail: 14100abf@comb.cat

HIV-1 resistance rarely observed in subjects using darunavir once-daily regimens across clinical studies

Background: Darunavir 800 mg once daily (QD) is indicated for HIV-1–infected treatment-naïve and treatment-experienced (without darunavir resistance-associated mutations [RAMs]) individuals, and has been evaluated in phase 2/3 studies with durations between 48 and 192 weeks. Objective: To summarize the development (or identification) of post-baseline resistance (RAMs and antiretroviral phenotypic susceptibility) among subjects receiving darunavir QD dosing. Methods: Seven phase 2/3 studies with available genotypes/phenotypes for subjects treated with ritonavir- or cobicistat-boosted darunavir 800 mg QD regimens were assessed: ARTEMIS (NCT00258557; n = 343), GS-US-299-0102 (NCT01565850; n = 153), GS-US-216-0130 (NCT01440569; n = 313), ODIN (NCT00524368; n = 294), INROADS (NCT01199939; n = 54), MONET (NCT00458302; n = 256), and PROTEA (NCT01448707; n = 273). Genotypic analyses were conducted at baseline (except switch studies enrolling virologically suppressed subjects [MONET, PROTEA]). Criteria for post-baseline resistance testing and evaluation of the development (or identification [switch studies]) of RAMs (respective IAS-USA mutations) varied slightly across studies. Results: Among 1686 subjects treated with darunavir 800 mg QD regimens, 184 had protocol-defined virologic failure; 182 had post-baseline genotypes analyzed. Overall, 4/1686 (0.2%) developed (or had identified [switch studies]) primary protease inhibitor and/or darunavir RAMs (ARTEMIS, n = 1; GS-US-216-0130, n = 1; ODIN, n = 1; MONET, n = 1). Only 1/1686 (<0.1%) subject lost darunavir phenotypic susceptibility (ODIN; possibly related to prior ritonavir-boosted lopinavir virologic failure). Among 1103 subjects using a nucleos(t)ide reverse transcriptase inhibitor (N[t]RTI) backbone, 10 (0.9%) developed ≥ 1 N(t)RTI RAM (8 had the emtricitabine RAM M184I/V). Conclusions: Darunavir has a high genetic barrier to resistance. Across a diverse population of HIV-1–infected subjects treated with darunavir 800 mg QD regimens, the development of darunavir resistance was rare (<0.1%).