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Try out PMC Labs and tell us what you think. Learn More. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. Similar high SVR rates have been observed in other small retreatment studies.
Presence of cirrhosis was determined by liver biopsy, transient elastography, or measurement of hepatic fibrosis see online supplementary appendix for details. Individuals who had received prior therapy with an NS5A inhibitor or any nucleoside or nucleotide polymerase inhibitors other than SOF were excluded from both studies. Participants were enrolled based on cirrhosis status. An interactive web response system was used to manage participant randomization and treatment asment. Randomization was stratified by prior regimen and genotype. Randomization was stratified by cirrhosis status.
The study was randomized due to clinical equipoise and not with the intent to compare treatment arms.
In both studies, dose reductions for RBV could be performed according to product label or investigator discretion. A detailed overview of the assessments performed in each study is presented in the online supplementary appendix Tables S1 and S2. In the A study, samples were collected at study entry and at the time of HCV virologic failure confirmation. Exploratory endpoints included prevalence of pre-existing RAS at baseline, and emergence of RAS upon virologic failure viral breakthrough or relapse.
An additional secondary efficacy endpoint was the proportion of participants with virologic failure. Sequencing analysis was performed to differentiate between relapse and reinfection as the cause of virologic failure.
In the A study, the primary safety endpoint was any AE of Grade 3 or higher or serious AE SAE while on-study treatment and up to 30 days post-treatment, or an AE that required permanent discontinuation of study treatment. Both studies were approved by the institutional review board or independent ethics committee at each participating site see online supplementary appendix for list of sites and committees. All participants provided written informed consent. Due to active retreatment of SOF-based regimen failures, a declining pool of eligible participants resulted in both studies closing early with a lower of participants enrolled than initially planned.
However, 87 participants were randomized and 82 received at least one dose of study drug. The A study was deed to randomize 40 participants 20 per armbut ultimately 7 participants were enrolled. Due to the lower than anticipated s of participants and early study closures, the studies were not statistically powered as originally planned.
The primary efficacy analyses for the RESCUE study were conducted in the full analysis set as-randomized populationwhich included all participants who took at least one dose of study drug. These participants were reased to the treatment groups as shown in Figure 1A. Due to these randomization errors, analyses were also performed in the as-treated analysis set as-treated populationwhich included participants who met the eligibility criteria and initiated study treatment.
In the A study, all 7 participants received study treatment and were included in the efficacy endpoint analyses.
In both studies, the primary safety analysis set included all participants who took at least one dose of study drug safety population. Laboratory abnormalities were graded using either the Gilead Sciences Inc. No statistical hypothesis testing was performed.
Five participants discontinued prior to study drug initiation due to site administrative issues.
Of the remaining 82 participants, 4 were reased treatment groups due to randomization errors Figure 1A. All participants completed study treatment. Baseline demographics and treatment characteristics for the as-treated population were generally well balanced across treatment arms Table 1.
Baseline demographic characteristics of participants from the RESCUE study as-treated population and A study as-randomized population. A post-hoc analysis of relevant baseline data for all study participants revealed that 6, who were originally diagnosed with compensated cirrhosis, most likely had decompensated disease at time of enrollment or historically.
All 6 individuals achieved SVR No participants experienced on-treatment virologic failure. Ten participants experienced relapse resulting in virologic failure 3 non-cirrhotic participants and 7 cirrhotic participants; Table 2. Sequencing confirmed the virologic failures were due to relapse. Eight of 9 participants with GT1a infection had an emergent substitution at position 30 and three had a substitution at position 93 Table 3.
The individual with GT1b who experienced virologic failure had emergent Y93H at relapse. Headache and fatigue were the most common AEs. Grade 4 laboratory abnormalities were observed in 1 individual at one time point only high aspartate aminotransferase and creatine kinase elevation at week 2. There were no SAEs or deaths. No AEs occurred that required permanent discontinuation of study treatment.
Two participants experienced a Grade 3 laboratory abnormality: increased direct bilirubin and decreased creatinine clearance. No Grade 4 laboratory abnormalities occurred. Two participants met the suspected renal toxicity endpoint definition. Both participants were receiving ART; one was taking Atripla and one was on ritonavir-boosted darunavir and dolutegravir.
It is also encouraging that high SVR rates were obtained in cirrhotic participants, given that these individuals are at a considerably higher risk of death and complications versus non-cirrhotic individuals. Nine of the 10 treatment failures were GT1a. Further studies are required to confirm this observation. This triple regimen may become a preferred salvage therapy for DAA-experienced individuals especially those individuals with a prior NS5A failure and for certain patient groups. A notable finding of our study was that 6 participants who were later identified as having probable decompensated cirrhosis all achieved SVR We extend our thanks to the participants and their families, participating sites, site investigators and study staff, and the A and Gilead Sciences study teams.
Gilead Sciences Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. National Center for Biotechnology InformationU. Liver Int. Author manuscript; available in PMC Jun 1. Edward Tam1 Anne F. Luetkemeyer2 Parvez S. Mantry3 Sanjaya K. Anne F. Parvez S. Sanjaya K. Minhee Kang 6 Harvard T. Robert S. Brown, Jr. Author information Copyright and information Disclaimer. Copyright notice.
The publisher's final edited version of this article is available at Liver Int. See other articles in PMC that cite the published article. Associated Data Supplementary Materials Supp info. Study assessments A detailed overview of the assessments performed in each study is presented in the online supplementary appendix Tables S1 and S2. Oversight of studies Both studies were approved by the institutional review board or independent ethics committee at each participating site see online supplementary appendix for list of sites and committees. Statistical analyses Due to active retreatment of SOF-based regimen failures, a declining pool of eligible participants resulted in both studies closing early with a lower of participants enrolled than initially planned.
Open in a separate window. Safety There were no SAEs or deaths. Acknowledgments We extend our thanks to the participants and their families, participating sites, site investigators and study staff, and the A and Gilead Sciences study teams. MK: None. References 1. Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study. Ann Intern Med. Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus ly treated in clinical trials of sofosbuvir regimens.
N Engl J Med. Safety and efficacy of ledipasvir plus sofosbuvir with or without ribavirin in hepatitis C genotype 1 patients who failed treatment with simeprevir plus sofosbuvir. Sofosbuvir plus ribavirin for the treatment of patients with chronic genotype 1 or 6 hepatitis C virus infection in Hong Kong. Aliment Pharmacol Ther. Ledipasvir and sofosbuvir for ly treated HCV genotype 1 infection. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to protease-inhibitor therapy: a randomised, double-blind, phase 2 trial SIRIUS Lancet Infect Dis. Infect Dis Ther. The natural history of hepatitis C virus HCV infection. Int J Med Sci. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a long-term prospective study.
Am J Gastroenterol. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Combination ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus infection: a review and clinical perspective. Ther Clin Risk Manag. Summary of product characteristics. Evaluation of proton pump inhibitor use on treatment outcomes with ledipasvir and sofosbuvir in a real-world cohort study. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
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