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Sofosbuvir/Ledipasvir Coformulation Cures 95% of Genotype 1 Hepatitis C

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Between 95% and 100% of treatment-naive patients and prior non-responders with genotype 1 chronic hepatitis C achieved sustained virological response using a fixed-dose combination of sofosbuvir plus ledipasvir, with or without ribavirin, according to findings from the Phase 2 LONESTAR study published in the February 8, 2014, edition of The Lancet.

The advent of direct-acting antivirals that target different steps of the HCV lifecycle has revolutionized hepatitis C treatment, but many patients and providers are waiting for all-oral regimens to avoid the difficult side effects of interferon.

Eric Lawitz from the Texas Liver Institute and colleagues conducted the LONESTAR trial to evaluate a fixed-dose combination pill containing Gilead Sciences' recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi, formerly GS-7977) plus the NS5A inhibitor ledipasvir (formerly GS-5885), taken with or without ribavirin for 8 or 12 weeks.

This open-label study enrolled 2 cohorts at a single center in Texas. Cohort A included 60 treatment-naive individuals without liver cirrhosis. Cohort B included 40 people, about half with cirrhosis, who did not achieve a cure with pegylated interferon and ribavirin plus one of the first-generation HCV protease inhibitors, boceprevir (Victrelis) or telaprevir (Incivek).

Overall, two-thirds of participants were men, just under 10% were black, and the average age was 50 years. Most (nearly 90%) had harder-to-treat HCV subtype 1a and only 15% had the favorable IL28B CC gene variant associated with interferon responsiveness. In Cohort B, 55% had cirrhosis at study entry.

Treatment-naive participants in Cohort A were randomly assigned (1:1:1) to receive a once-daily fixed-dose tablet containing 400 mg sofosbuvir and 90 mg ledipasvir, either with 1000-1200 mg/day weight-based ribavirin for 8 weeks, without ribavirin for 8 weeks, or without ribavirin for 12 weeks. Treatment-experienced patients in Cohort B were randomized (1:1) to receive sofosbuvir/ledipasvir, either with or without ribavirin, for 12 week.

The primary study endpoint was sustained virological response, or continued undetectable HCV viral load at 12 weeks post-treatment (SVR12), which is considered a cure.

Results

  • In Cohort A, 95% of treatment-naive patients treated with sofosbuvir/ledipasvir for 8 weeks and 95% taking the 2-drug regimen for 12 weeks achieved SVR12.
  • The SVR12 rate was 100% for participants taking sofosbuvir/ledipasvir plus ribavirin for 8 weeks.
  • In Cohort B, 95% of patients taking sofosbuvir/ledipasvir alone and 100% taking sofosbuvir/ledipasvir plus ribavirin for 12 weeks achieved SVR12.
  • 2 patients (1 treatment-naive and 1 treatment-experienced) had post-treatment viral relapse, both of whom had HCV subtype 1a and were not taking ribavirin.
  • Sofosbuvir/ledipasvir was generally safe and well-tolerated with or without ribavirin.
  • 1 treatment-experienced patient using the 3-drug regimen had a serious adverse event of anemia, thought to be related to ribavirin.
  • The most common adverse events were nausea, anemia, upper respiratory tract infections, and headache.

"These findings suggest that the fixed-dose combination of sofosbuvir/ledipasvir alone or with ribavirin has the potential to cure most patients with genotype 1 HCV, irrespective of treatment history or the presence of compensated cirrhosis," the researchers concluded. "Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin."

"Patients in the 12-week group of cohort A had a similar response to patients in the 8-week groups, suggesting that 8 weeks of treatment might be sufficient for non-cirrhotic patients who have not previously been treated for HCV," they elaborated in their discussion. "The results in cohort B indicate that 12 weeks of the sofosbuvir plus ledipasvir combination might be an effective treatment for patients who had not achieved sustained virological response with a protease-inhibitor regimen, even in those with compensated cirrhosis."

"In both cohorts, patients with baseline characteristics historically associated with poor response to interferon-based treatment -- non-CC IL28B genotype, black race, high baseline viral load -- had SVR12 rates similar to patients without those characteristics," they added.

Asked about the importance of using ribavirin after presenting these findings at the AASLD Liver Meeting this past November, Lawitz said the results confirm that "for a large proportion of patients we can remove ribavirin without impacting SVR," and "outside clinical trials, anything we can do to improve compliance is a benefit."

Gilead has since reported data from the Phase 3 ION trials evaluating sofosbuvir/ledipasvir with or without ribavirin in genotype 1 treatment-naive patients and prior non-responders with or without cirrhosis. Across the 3 studies, the coformulation alone or with ribavirin taken for 8, 12, or 24 weeks again cured more than 90% of treatment-naive and treatment-experienced participants.

Results from the Phase 2 ELECTRON trial, also reported at the Liver Meeting, showed that Gilead's non-nucleoside polymerase inhibitor GS-9669 as a third agent instead of ribavirin produced SVR12 rates of 100% for difficult-to-treat genotype 1 patients.

Gilead announced on February 10 that it has requested U.S. Food and Drug Administration (FDA) approval of the sofosbuvir/ledipasvir coformulation, putting it on track for approval by the end of the year.

2/11/14

Reference

E Lawitz, FF Poordad, PS Pang, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. The Lancet 383(9916):515-523. February 8, 2014.