Search

BACKGROUND: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FUNDING: Bristol-Myers Squibb. FINDINGS: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responde

HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC90] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC90 range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC90 [L28A-R30S] of 720 nM or EC90 [L28T-R30S] of 128 nM against tested DAAs) or as L28T-L31I (EC90 [tested DAAs] of 5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Background: HCV GT3-infected patients are a challenging population in urgent need of optimally effective therapies. In a previous study in GT3 infection (ALLY-3), 12 weeks of DCV (pangenotypic NS5A inhibitor) plus SOF (nucleoside NS5B inhibitor) achieved 96% sustained virologic response at posttreatment week 12 (SVR12) in patients without cirrhosis and 63% in patients with cirrhosis. In ALLY-3+, the efficacy and safety of DCV+SOF with RBV for 12 vs 16 weeks were evaluated in HCV GT3 patients with compensated advanced fibrosis or cirrhosis. Method(s): Open-label, phase 3b study in HCV GT3-infected treatment-naive or -experienced patients with compensated advanced fibrosis or cirrhosis. Patients were randomized 1:1 to receive 12 weeks vs 16 weeks of DCV (60 mg QD) + SOF (400 mg QD) + RBV (weight based), stratified by advanced fibrosis or cirrhosis status. An interim analysis of efficacy (SVR at posttreatment week 4 [SVR4]) and safety outcomes is reported. SVR12 (primary endpoint) data will be available for presentation. Result(s): 50 patients were treated (12 weeks, 24; 16 weeks, 26). Most were male (80%), white (98%), and treatment experienced (74%; 10% prior relapse on SOF+RBV); 72% had cirrhosis and 52% had HCV RNA >=6 million IU/mL. Baseline characteristics were comparable between arms. Overall SVR4 by intention-to-treat analysis was 92%. In the 12- and 16-week arms, SVR4 was 88% and 96%, respectively. In the 12-week arm SVR4 was 83% in those with cirrhosis and 100% in those with advanced fibrosis; in the 16-week arm SVR4 was 94%, and 100%, respectively (Table). There were no virologic breakthroughs. Relapse occurred in 3 patients (1 in 16-week and 2 in 12-week arm). Four of 5 patients (80%) with prior relapse on SOF+RBV achieved SVR4. There was 1 death (12- week arm; not treatment-related). Treatment was well tolerated - the most common adverse events (AEs) were insomnia (30%), fatigue (26%) and headache (24%). One patient had a grade 3 hemoglobin reduction. Ther

Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY-3+ study (N = 50) evaluated DCV-SOF with ribavirin (RBV) in treatment-naïve (n = 13) or treatment-experienced (n = 37) genotype 3-infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open-label DCV-SOF (60 + 400 mg daily) with weight-based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). SVR12 (intention-to-treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12-week (91% observed) and 92% (24 of 26) in the 16-week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12-week (88% observed) and 89% (16 of 18) in the 16-week group; for treatment-experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12-week group) did not enter post-treatment follow-up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment-related serious AEs. Conclusion: The all-oral regimen of DCV-SOF-RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3-infected patients with advanced liver disease, irrespective of past HCV treatment experience.

Background: HCV GT3-infected patients are a challenging population in urgent need of optimally effective therapies. A previous study (ALLY-3) in GT-3 infection achieved 96 % SVR12 in patients without cirrhosis, and 63 % in patients with cirrhosis, following 12 weeks of daclatasvir (DCV) + sofosbuvir (SOF). ALLY- 3 + evaluated DCV + SOF + ribavirin (RBV) for 12 or 16 weeks in HCV GT-3 with advanced fibrosis/cirrhosis. Method(s): Open-label, phase 3b study in GT-3 treatment-naive or - experienced adults with compensated advanced fibrosis or cirrhosis. Patients were randomized 1:1 to 12 or 16 weeks of DCV (60 mg QD) + SOF (400 mg QD) + RBV (weight-based), stratified by advanced fibrosis/cirrhosis status. Interim efficacy (SVR4) and safety outcomes are reported. SVR12 (primary endpoint) data will be available for presentation. Result(s): 50 patients were treated. Most were male (80 %), white (98 %), and treatment-experienced (74 %; 10 % prior relapse on SOF + RBV); 72 % had cirrhosis, and 52 % had HCV-RNA >=6 million IU/mL. Overall SVR4 by intention-to-treat analysis was 92 %. SVR4 in the 12-week arm was 88 % (cirrhosis 83 %, advanced fibrosis 100 %) and in the 16-week arm was 96 % (cirrhosis 94 %, advanced fibrosis 100 %; Figure); 4/5 (80 %) with prior relapse on SOF + RBV achieved SVR4. There were 3 relapses, no virologic breakthroughs, and 1 treatment-unrelated death. Treatment was well tolerated-the most common adverse events (AEs) were insomnia (30 %), fatigue (26 %) and headache (24 %). There were no discontinuations for AEs. Conclusion(s): DCV + SOF + RBV for 12 or 16 weeks achieved high SVR4 rates of 88 and 96 %, respectively in HCV GT3-infected patients with compensated advanced fibrosis/cirrhosis, and was generally well tolerated. (Figure Presented).

Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY-3+ study (N = 50) evaluated DCV-SOF with ribavirin (RBV) in treatment-naive (n = 13) or treatment-experienced (n = 37) genotype 3-infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open-label DCV-SOF (60 + 400 mg daily) with weight-based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). SVR12 (intention-to-treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12-week (91% observed) and 92% (24 of 26) in the 16-week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12-week (88% observed) and 89% (16 of 18) in the 16-week group; for treatment-experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12-week group) did not enter post-treatment follow-up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment-related serious AEs. Conclusion(s): The all-oral regimen of DCV-SOF-RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3-infected patients with advanced liver disease, irrespective of past HCV treatment experience.Copyright © 2016 by the American Association for the Study of Li

BACKGROUND AND PURPOSE: Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection. METHODS: In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12). RESULTS: Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV. CONCLUSION: The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. Design In this Phase 2b double-blind, placebocontrolled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferonalfa: 2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCVRNA< lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa: 2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1

IMPORTANCE: The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE(S): To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS: Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES: The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULT(S): Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevati

Background: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. Method(s): We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. Finding(s): This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, int

IMPORTANCE: Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. OBJECTIVE: All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. INTERVENTIONS: All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Sustained virologic response at posttreatment week 12 (SVR12). RESULTS: One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5%CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.

Background & Aims Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. Methods Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). Results Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those exp

Background and Aims: Daclatasvir plus asunaprevir dual oral therapy (DCV+ASV) has demonstrated potent antiviral activity in HCV genotype 1b infection. This phase 3 study (AI447028) evaluated DCV+ASV in a broad range of patients, including those with cirrhosis. Method(s): Treatment-naive patients were randomly assigned (2:1; double-blinded) to receive DCV 60mg QD plus ASV 100mg BID (n = 203), or matching placebo (n = 102) for 12 weeks. The DCV+ASV group continued treatment for another 12 weeks; placebo recipients entered another DCV+ASV study. Patients with prior null/partial response to peginterferon/ribavirin (null/partial; N= 205), and those medically ineligible for, or previously intolerant of, peginterferon/ribavirin (ineligible/intolerant; N= 235) received DCV+ASV for 24 weeks. Primary endpoint was sustained virologic response at posttreatment Week 12 (SVR12). Result(s): Overall, patients were 49% male, 68% white, and 71% IL28B non-CC; 30% had cirrhosis. SVR12 rates among DCV+ASV-treated patients were 90%, 82%, and 82% in the naive, null/partial, and ineligible/intolerant groups (table). No differences in SVR12 rates were observed based on age, gender, race, or IL28B genotype; SVR12 rates were similar across all groups in noncirrhotic (85%; n = 437) and cirrhotic (84%; n = 206) patients. Serious AEs occurred in 6% and AEs leading to discontinuation (reversible elevated ALT/AST most common) in 2%, with no deaths. Grade 3/4 laboratory abnormalities were uncommon, including low incidences of ALT elevations (first 12 weeks) with DCV+ASV or placebo in naive patients (2% for both). Conclusion(s): DCV+ASV provided high SVR12 rates of 90% (treatmentnaive) and >80% (null/partial and ineligible/intolerant), including in cirrhotics, and was generally well tolerated in patients with HCV genotype 1b infection. (Table Presented).

The crossover bias theory for bloat [18] is a recent result which predicts that bloat is caused by the sampling of short, unfit programs. This theory is clear and simple, but it has some weaknesses: (1) it implicitly assumes that the population is large enough to allow sampling of all relevant program sizes (although it does explain what to expect in the many practical cases where this is not true, e.g., because the population is small); (2) it does not explain what is meant by its assumption that short programs are unfit. In this paper we discuss these weaknesses and propose a refined version of the crossover bias theory that clarifies the relationship between bloat and finite populations, and explains what features of the fitness landscape cause bloat to occur. The theory, in particular, predicts that smaller populations will bloat more slowly than larger ones. Additionally, the theory predicts that bloat will only be observed in problems where short programs are less fit than longer ones when looking at samples created by fitness-based importance sampling, i.e. samplings of the search space in which fitter programs have a higher probability of being sampled (e.g., the Metropolis-Hastings method). Experiments with two classical GP benchmarks fully corroborate the theory. Copyright 2008 ACM.

Elitism is commonly used in generational GP to ensure that the best individuals discovered in a generation are not lost, and are made available for possible further improvements to new generations. Using two GP systems and four problems, we show how elitism reduces the growth of mean program size.

Elitism, a technique which consists of copying, unchanged, one or more of the most fit individuals from one generation to the next, is widely used in generational evolutionary algorithms, including Genetic Programming (GP). Elitism ensures that the best individuals discovered in a generation (and hence in the whole run) are not lost, and, perhaps even more importantly, are made available to new generations for possible further improvements. In a recent study on the evolution of robustness in GP the average size of best of run individuals was reported to grow more slowly in the presence of elitism. This is an important finding, but no explanation was provided for why this happened nor whether this was a general effect. In this paper we model elitism mathematically and explain how, in general, elitism modulates the dynamics of the mean program size of the population, including both its positive and negative effects oil bloat. Experimental results with two GP systems and four different problems corroborate the theory