Sofosbuvir/ledipasvir safe and effective for genotype 1 HCV

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, United States.

The advent of direct-acting antiviral agents has revolutionised 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 co-formulation. Results from these studies were previously presented in full at the EASL (European Association for the Study of the Liver) 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 (without cirrhosis only) – 12 weeks without ribavirin, or 8 weeks with or without ribavirin.

Taken together, the ION trials included 1952 randomised 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."