Short Duration AL-335, Odalasvir, With/Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis (original) (raw)
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Journal of Viral Hepatitis, 2018
SummaryThe phase 2, open‐label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6‐ or 8‐week regimen of simeprevir, daclatasvir and sofosbuvir in treatment‐naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early‐stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early‐stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty‐eight patients were treated (6‐week group: n = 59; 8‐week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early‐stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reaso...
Hepatology (Baltimore, Md.), 2016
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-naïve and prior null-responder HCV genotype (GT)1-infected patients receiving simeprevir+sofosbuvir±ribavirin for 12/24 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-naïve and -experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence/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 (QD)+sofosbuvir 400 mg QD for 12 or 8 weeks. Primary efficacy endpoint: SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 ...
Hepatology (Baltimore, Md.), 2015
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-analog 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-naïve 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 (QD)+sofosbuvir 400 mg QD for 12 weeks. The primary efficacy endpoint of the study was the proportion ...
F1000 - Post-publication peer review of the biomedical literature, 2015
Background/Aims-Risks and benefits of simeprevir plus sofosbuvir in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virologic responses (SVR) of simeprevir plus sofosbuvir with and without ribavirin in patients with Child-Pugh (CP)-B/C vs. CP-A cirrhosis and compared to matched untreated controls. Methods-Multicenter cohort of adults with HCV genotype 1 and cirrhosis treated with simeprevir plus sofosbuvir with/without ribavirin for 12 weeks. Controls were matched on treatment center, age, CP class and model for end-stage liver disease (MELD) score. Results-Of 160 patients treated with simeprevir plus sofosbuvir with/without ribavirin, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (IQR 8-11). SVR12 was achieved by 73% of CP-B/C vs. 91% of CP-A (p<0.01). CP-B/C vs. CP-A had more early treatment discontinuations (11% vs. 1%), adverse events requiring hospitalization (22% vs. 2%),
Journal of Viral Hepatitis, 2016
Background and aims: Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection have resulted in high rates of sustained virologic response (SVR) following 8 to 24 weeks of treatment. However, difficult-to-cure/cirrhotic patients typically require a longer treatment duration and less is known regarding the longterm durability of SVR or effect on liver disease progression; to assess this, the IMPACT study followed patients for a 3-year period after end of treatment. Methods: The Phase II, open-label, nonrandomized IMPACT study assessed the efficacy, safety, and pharmacokinetics of the combination of three DAAs (simeprevir, sofosbuvir, and daclatasvir) in HCV genotype 1/4-infected, treatment-naïve/-experienced cirrhotic patients with portal hypertension or decompensated liver disease. Patients from a single site in the United States were assigned to one of two groups by Child-Pugh (CP) score: CP A, CP score less than 7 and evidence of portal hypertension; CP B, CP score of 7 to 9. All patients received simeprevir 150 mg, daclatasvir 60 mg, and sofosbuvir 400 mg once-daily for 12 weeks between September 2014 and August 2015. All 40 patients included in the study (male, 63%; median age, 58.5 years) achieved SVR 12 and 24 weeks after end of treatment, and the combination was well tolerated. Results: All patients who reached the 3-year follow-up timepoint maintained SVR (CP A, 15/15; CP B, 18/18). CP scores and Model for End-stage Liver Disease scores remained relatively stable, and mean FibroScan and FibroTest scores declined. No new safety signals were identified. Conclusions: In the IMPACT study, virologic response to simeprevir, sofosbuvir, and daclatasvir was durable over 3 years (ClinicalTrials.gov number: NCT02262728).
Open forum infectious diseases, 2017
The Simeprevir ObservatioNal Effectiveness across practice seTtings (SONET) study evaluated the real-world effectiveness of simeprevir-based treatment for hepatitis C virus (HCV) infection. The SONET study was a phase 4, prospective, observational, United States-based study enrolling patients ≥18 years of age with chronic genotype 1 HCV infection. The primary endpoint was the proportion of patients who achieved sustained virologic response 12 weeks after the end of treatment (SVR12), defined as HCV ribonucleic acid undetectable ≥12 weeks after the end of all HCV treatments. Of 315 patients (intent-to-treat [ITT] population), 275 (87.3%) completed the study. Overall, 291 were treated with simeprevir + sofosbuvir, 17 with simeprevir + sofosbuvir + ribavirin, and 7 with simeprevir + peginterferon + ribavirin. The majority of patients were male (63.2%) and white (60.6%); median age was 58 years, 71.7% had genotype/subtype 1a, and 39.4% had cirrhosis. The SVR12 was achieved by 81.2% (255...
Antiviral Therapy
Background: Optimal treatment for patients with HCV genotype-3 infection and liver cirrhosis remains a medical priority. Daclatasvir+sofosbuvir and ribavirin is a recommended option for such patients, but clinical trial data are lacking for treatment >16 weeks. Methods: This was a single-arm, Phase III study of daclatasvir+sofosbuvir+ribavirin for 24 weeks in patients with compensated cirrhosis and HCV genotype-3 infection. The primary end point was sustained virological response at post-treatment week 12 (SVR12); the primary objective was to demonstrate statistical superiority to historical SVR12 data for 12 weeks' daclatasvir+sofosbuvir without ribavirin in genotype-3-infected patients with cirrhosis (95% CI lower bound >79.0%). Results: A total of 78 patients were treated (54 treatment-naive, 24 treatment-experienced including 8 with prior sofosbuvir exposure). SVR12 was achieved by 87% (68/78; 95% CI 77.7, 93.7%) of patients in the primary analysis of central laboratory data. One additional patient achieved SVR12 by local testing resulting in an overall SVR12 rate of 88% (95% CI 79.2, 94.6%) and the lower bound of the 95% CI above the historical threshold. SVR12 rates were 93% (50/54) for treatment-naive and 79% (19/24) for treatment-experienced patients. Of the nine non-SVR12 patients, four were lost to follow-up, two relapsed (both sofosbuvir-experienced), two had end-oftreatment virological failure and one discontinued early. There were no unexpected safety signals; only one patient discontinued for an adverse event. Conclusions: Daclatasvir+sofosbuvir+ribavirin for 24 weeks was well tolerated and efficacious in HCV genotype-3-infected patients with compensated cirrhosis, with SVR12 outcomes comparable to previously reported outcomes in patients treated with this regimen for 12-16 weeks. ClinicalTrials.gov ID NCT02673489. HCV genotype (GT)-3 is the second most common of the seven major HCV genotypes, and responsible for approximately 30% of global HCV infections [1], 30-40% of infections in parts of Europe and Australia [2-5], with an even higher prevalence (>60%) in parts of South East Asia [6]. GT-3 infection results in more rapid progression of HCV-associated liver disease and a higher risk of hepatocellular carcinoma, hospitalization and death than other genotypes [7-10], and has proven challenging to cure with oral direct-acting
The Lancet, 2014
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 effi cacy 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, stratifi ed 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 effi cacy 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 diff erence 29•3% [95% CI 20•1-38•6; p<0•0001). Adverse events in the fi rst 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 profi les associated with peginterferon alfa 2a plus ribavirin. Funding Janssen Infectious Diseases-Diagnostics.