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IDWeek 2014: Sofosbuvir/Ledipasvir Safe and Effective for Genotype 1 HCV

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A single-tablet regimen containing the hepatitis C virus (HCV) nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir -- the combination in Gilead Science's recently approved Harvoni pill -- was well-tolerated and cured 97% of patients with HCV genotype 1 in the Phase 3 ION trials, researchers reported at the IDWeek 2014 meeting last week in Philadelphia.

The advent of direct-acting antiviral agents has revolutionized treatment for chronic hepatitis C, especially with the long-awaited arrival of all-oral regimens that dispense with interferon and its difficult side effects.

Mark Sulkowski from Johns Hopkins University Medical School and colleagues presented pooled findings from a trio of pivotal Phase 3 studies that supported to the approval of the sofosbuvir/ledipasvir coformulation. Results from these studies were previously presented in full at the EASL International Liver Congress this past April:

  • ION-1:(n=865) previously untreated HCV genotype 1 (16% with cirrhosis) -- 12 vs 24 weeks with or without ribavirin;
  • ION-2:(n=440) prior non-responders HCV genotype 1 (20% with cirrhosis) -- 12 vs 24 weeks with or without ribavirin;
  • ION-3:(n=647) previously untreated HCV genotype 1 (non-cirrhotic only) -- 12 weeks without ribavirin, or 8 weeks with or without ribavirin.

Taken together, the ION trials included 1952 randomized and treated patients. A majority (60%) were men, most were white, 16% were black, and the median age was 53 years. Looking at factors associated with poorer response, 74% had harder-to-treat HCV subtype 1a (vs 1b), 23% were treatment-experienced (including 12% who had previously tried triple therapy with the first-generation HCV protease inhibitors boceprevir [Victrelis] or telaprevir [Incivek]), 12% had compensated liver cirrhosis, 26% had a body mass index >30, 75% had an unfavorable IL28B gene pattern, and most (82%) had high HCV viral load >800,000 IU/mL.

The primary endpoint in all the trials was sustained virological response, or continued undetectable HCV RNA viral load, at 12 weeks after completion of treatment (SVR12).

Results

  • Overall, 97% of all patients achieved SVR12:

o   ION-1: 97% to 99%;

o   ION-2: 94% to 99%;

o   ION-3: 93% to 95%.

  • Among the 3% of participants who did not achieve SVR12:

o   1.8% relapsed after completing therapy;

o   0.1% experienced viral breakthrough while still on treatment;

o   1.3% were lost to follow-up or withdrew consent.

  • Overall, there was no significant difference in response rates between patients treated for 12 or 24 weeks.
  • In ION-3, relapse was more common in the 8-week arm compared with the 12-week arm (5% vs 1%), mostly occurring in people with high baseline HCV viral load.
  • A cut-off of 6 million IU/mL was found to be the threshold for poorer response with 8 weeks of treatment in an ad hoc analysis.
  • People with cirrhosis had somewhat poorer response in the 12-week compared with 24-week treatment arms -- confirming that people with cirrhosis should not be treated for only 8 weeks.
  • There was no significant difference in response rates between people who did or did not receive ribavirin.
  • Sofosbuvir/ledipasvir was generally safe and well-tolerated.
  • Serious adverse events were uncommon (2% with and 3% without ribavirin), as were treatment discontinuations due to adverse events (1% with or without ribavirin).
  • The most common side effects were fatigue, headache, nausea, and insomnia.
  • A majority of adverse events -- including decreased hemoglobin -- occurred more often among people who received ribavirin.

"All-oral, interferon-free therapy with ledipasvir/sofosbuvir for 8, 12, or 24 weeks resulted in high SVR in genotype 1 HCV," the researchers concluded. "Addition of ribavirin did not increase rate of SVR and resulted in more frequent adverse events and laboratory abnormalities."

10/15/14

Reference

M Sulkowski, KKowdley, P Ruane, et al. Ledipasvir/Sofosbuvir is Safe and Effective as a Single-Tablet-Regimen for Treatment of Patients with Genotype 1 Chronic Hepatitis C Virus, Including those with Compensated Cirrhosis. IDWeek 2014. Philadelphia, October 8-12, 2014. Abstract 1223