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Sofosbuvir/ledipasvir safe and effective for genotype 1 HCV
Liz Highleyman, 2014-10-20 17:30:00
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 earlier this month 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 unfavourable 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 haemoglobin - 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."
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