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AASLD 2013: Fixed-dose Sofosbuvir/Ledipasvir Cures Most Genotype 1 Hepatitis C

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At least 95% of newly treated genotype 1 hepatitis C patients and prior non-responders achieved sustained virological response using a fixed-dose combination of sofosbuvir plus ledipasvir, with or without ribavirin, according to findings from the LONESTAR study presented the 64th AASLD Liver Meeting last week in Washington, DC. While response rates were high overall, the 2 relapsers in the trial were not taking ribavirin.

The advent of direct-acting antiviral agents has revolutionized treatment of chronic hepatitis C. While these agents were initially tested as add-ons to interferon-based therapy, many people with HCV and their providers are awaiting all-oral regimens that dispense with pegylated interferon and its difficult side effects.

Eric Lawitz from the Texas Liver Institute reported results from the phase 2 LONESTAR trial, which evaluated a fixed-dose combination pill containing Gilead Sciences' HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus the NS5A inhibitor ledipasvir (formerly GS-5885), taken with or without ribavirin for 8 or 12 weeks.

LONESTAR enrolled 2 cohorts at a single center. Cohort 1 included 60 treatment-naive individuals without liver cirrhosis. Cohort 2 included 40 people, about half with cirrhosis, who did not achieve a cure with the current standard of care: triple therapy with the approved HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek) plus pegylated interferon/ribavirin.

Overall, two-thirds of participants were men, 9% were black, 40% were Hispanic, and the mean age was 50 years. Most (87%) had harder-to-treat HCV subtype 1a and only 15% had the favorable IL28B CC gene variant associated with interferon responsiveness. In Cohort 2, 55% had cirrhosis at study entry. Just over half (55%) had previously been treated with boceprevir while 45% had used telaprevir. All had experienced prior virological failure; people who stopped previous therapy due to adverse events were excluded.

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

Results

  • All participants completed therapy except for 1 who withdrew consent.
  • In Cohort 1, 95% of treatment-naive patients treated with sofosbuvir/ledipasvir for either 8 or 12 weeks achieved sustained virological response, or continued undetectable HCV RNA at 12 weeks post-treatment (SVR12).
  • The SVR12 rate was 100% in the 8-week sofosbuvir/ledipasvir plus ribavirin arm.
  • In Cohort 2, SVR12 rates were 95% for sofosbuvir/ledipasvir and 100% for sofosbuvir/ledipasvir plus ribavirin given for 12 weeks.
  • All patients without cirrhosis achieved sustained response, as did all but 1 of the cirrhotics (91%).
  • Response rates for all arms remained the same at 24 weeks post-treatment (SVR24); comparing favorably to historical rates of about 70% for patients without cirrhosis and 44% for cirrhotics in pivotal trials of boceprevir or telaprevir plus pegylated interferon/ribavirin.
  • The 95% response rates reflect 3 people who did not achieve SVR12/24: 1 patient in Cohort 1 who received sofosbuvir/ledipasvir alone for 8 weeks and 1 in Cohort 2 who received sofosbuvir/ledipasvir for 12 weeks experienced viral relapse, while 1 person in Cohort 1 who received sofosbuvir/ledipasvir for 12 weeks was lost to follow-up after reaching SVR8.
  • Both relapsers had HCV subtype 1a.
  • No one who took ribavirin relapsed.
  • 7 of the 9 patients with NS5A resistance mutations and all 28 people with NS3/4A (protease) resistance mutations at baseline nevertheless achieved sustained response.
  • 1 patient had evidence of the S282T mutation and multiple NS5A resistance mutations at the time of relapse at week 8; this person was retreated with sofosbuvir/ledipasvir plus ribavirin for 24 weeks and went on to achieve SVR12.
  • Sofosbuvir/ledipasvir was generally safe and well-tolerated with or without ribavirin.
  • 2 people receiving sofosbuvir/ledipasvir alone and 2 receiving ribavirin experienced serious adverse events, but no one discontinued treatment for this reason.
  • Grade 3-4 adverse events (0% vs 14%) and grade 3-4 laboratory abnormalities (7% vs 14%) were more common among those taking ribavirin.
  • Anemia was seen only in the ribavirin arms (19%).

Asked whether ribavirin is still important, Lawitz said these 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."

The Phase 3 ION trials are currently underway, testing sofosbuvir/ledipasvir with or without ribavirin for 8, 12, or 24 weeks in genotype 1 treatment-naive patients and prior non-responders, Lawitz noted.

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

11/11/13

Reference

E Lawitz, F Poordad, RH Hyland, et al. Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in >95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 215.