AASLD 2013: 100% of Hard-to-treat Patients Cured with Sofosbuvir/Ledipasvir + Ribavirin or GS-9669

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Interferon-free regimens of sofosbuvir and ledipasvir plus either ribavirin or GS-9669 taken for 12 weeks produced sustained response in 100% of treatment-experienced genotype 1 chronic hepatitis C patients with advanced liver fibrosis or cirrhosis, according to the latest findings from the ELECTRON trial presented yesterday at the 64th AASLD Liver Meeting in Washington, DC. A related analysis of previously untreated people without cirrhosis found that reducing treatment duration to 6 weeks led to relapses.

Gilead Science's Phase 2 ELECTRON trial program has tested the nucleotide HCV polymerase inhibitor sofosbuvir (formerly GS-7977) in various all-oral regimens for increasingly difficult-to-treat patient populations.

A 12-week dual regimen of sofosbuvir plus ribavirin cures most people with easier-to-treat HCV genotypes 2 or 3, and an advisory committee of the U.S. Food and Drug Administration last month recommended approval for this indication.

The dual regimen was not adequate, however, for prior non-responders with HCV genotype 1. Researchers then tried adding the NS5A inhibitor ledipasvir (GS-5885), finding that the triple regimen taken for 12 weeks produced a sustained virological response rate at 12 weeks post-treatment (SVR12) of 100% for both treatment-naive patients and prior non-responders without cirrhosis.

The analysis presented at the Liver Meeting by Edward Gane of Auckland Clinical Studies evaluated a once-daily fixed-dose tablet containing 400 mg sofosbuvir and 90 mg ledipasvir, taken with either ribavirin or the non-nucleoside polymerase inhibitor GS-9669, for the most difficult-to-treat group: treatment-experienced genotype 1 patients with advanced fibrosis or cirrhosis.

Researchers first enrolled 20 treatment-experienced genotype 1 patients with cirrhosis (Metavir stage F4) who were randomly assigned to receive the sofosbuvir/ledipasvir fixed-dose combination either with or without ribavirin for 12 weeks.

Next, 50 treatment-experienced genotype 1 patients with advanced fibrosis or cirrhosis (stage F3-F4) were randomized to receive the sofosbuvir/ledipasvir fixed-dose tablet plus either ribavirin or GS-9669, again for 12 weeks.

About 70% of treatment-experienced participants were men, about 90% were white, and the mean age was approximately 56 years. About three-quarters had harder-to-treat HCV subtype 1a and about one-quarter had the favorable IL28B CC gene pattern.

Researchers also aimed to determine a minimum effective duration of sofosbuvir/ledipasvir/ribavirin for easier-to-treat patients. This analysis enrolled 25 genotype 1 treatment-naive participants with absent-to-moderate fibrosis (stage F0-F2). All were treated with the sofosbuvir/ledipasvir fixed-dose tablet plus ribavirin for 6 weeks and compared against previously studied patients.

Just over half of the treatment-naive group were men, most were white, and the average age was 51 years. Most (84%) had HCV subtype 1a and 20% had the favorable IL28B variant.

Results

"In treatment-experienced patients with advanced fibrosis/cirrhosis, either ribavirin or GS-9669 may enhance the efficacy of sofosbuvir/ledipasvir given for 12 weeks," the investigators concluded.

"The optimal duration of sofosbuvir/ledipasvir in treatment-naive genotype 1 patients (even with the addition of ribavirin) is more than six weeks," they added.

11/4/13

Reference

EJ Gane, CA Stedman, RH Hyland, et al. Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 73.