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Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study.

ABSTRACT: To shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue.In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. The primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858.Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). No patients experienced any serious adverse events.In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings.Center for AIDS Research, National Institutes of Health, US Department of Energy, National Center for Research Resources and the Office of Research Infrastructure Programs, Cheng Si-Yuan (China-International) Hepatitis Research Foundation, and Humanity and Health Medical Group.

SUBMITTER: Lau G

PROVIDER: S-EPMC5131925 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study.

Lau George G Benhamou Yves Y Chen Guofeng G Li Jin J Shao Qing Q Ji Dong D Li Fan F Li Bing B Liu Jialiang J Hou Jinlin J Sun Jian J Wang Cheng C Chen Jing J Wu Vanessa V Wong April A Wong Chris L P CL Tsang Stella T Y ST Wang Yudong Y Bassit Leda L Tao Sijia S Jiang Yong Y Hsiao Hui-Mien HM Ke Ruian R Perelson Alan S AS Schinazi Raymond F RF

The lancet. Gastroenterology & hepatology 20160725 2

<h4>Background</h4>To shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue.<h4>Methods</h4>In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment g ...[more]

PMID: 27917405

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Project description:BackgroundTreatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs.ObjectiveTo determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis.DesignOpen-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882).SettingSingle-center.Patients50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups.Intervention25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks.MeasurementsThe primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12).ResultsForty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up.LimitationNonrandomized study design and small sample of patients with early-stage fibrosis.ConclusionCombination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates.Primary funding sourceNational Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

Project description:Background:Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource. Objective:To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation). Design:Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649). Setting:Single center. Participants:10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors. Intervention:Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy. Measurements:The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis. Results:Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. Limitation:Nonrandomized study design and a small number of patients. Conclusion:Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection. Primary Funding Source:Merck Sharp & Dohme.

Project description:BackgroundDirect-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration.MethodsIn this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882.FindingsBetween Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs.InterpretationIn this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis.FundingNational Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.

Dataset Information

Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study.

Publications

Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study.

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