Encouraging Results from the ION-3 Study of Treatment-naïve Patients with Hepatitis C without Cirrhosis

An 8-week course of treatment with a fixed dose combination of ledipasvir plus sofosbuvir produced sustained virologic response in more than 90 percent of treatment-naive patients with genotype 1 hepatitis C.

On Friday at the 2014 European Association for the Study of the Liver (EASL) International Liver Congress in London, Kris Kowdley, MD, from the Virginia Mason Medical Center in Seattle, WA, presented data from the phase III randomised ION-3 study aimed at determining whether an 8-week regimen of ledipasvir plus sofosbuvir is effective in the treatment of treatment-naïve, non-cirrhotic patients with HCV-G1, or whether ribavirin or a longer treatment duration of 12 weeks is necessary to achieve higher sustained virologic response (SVR) rates.

Ledipasvir is an NS5A replication (replicase) inhibitor with picomolar potency against HCV genotype 1a and genotype 1b (HCV-G1a) and (HCV-G1b). Sofosbuvir is an RNA polymerase inhibitor with potent antiviral activity against HCV G1-6 with a high barrier to resistance.

A once-daily fixed-dose of oral ledipasvir plus sofosbuvir combination (400 mg/90 mg) demonstrated high SVR rates in the phase II LONESTAR study when used in a 12-week regimen in previously treatment naïve patients who did not have cirrhosis.

In the ION-3 study, 647 treatment-naïve, non-cirrhotic patients with HCV-G1 were stratified by HCV subtype (ie, HCV-G1a or HCV G1b) and randomised to receive treatment with either a) ledipasvir plus sofosbuvir for 8 weeks, b) ledipasvir plus sofosbuvir with ribavirin for 8 weeks, or c) a fixed dose of ledipasvir plus sofosbuvir for 12 weeks in the absence of ribavirin.

The inclusion criteria were broad‑‑there was no upper age limit, no body mass index (BMI) limit, and opiate substitution therapy was allowed in the study. The average age of the patients was approximately 50 years, the majority of the patients were male, a substantial minority of the patients were black or Hispanic, the average BMI was 28, the majority of the patients had HCV-G1, and 80% of higher of patients had a high viral load.

Kowdley said “high rates of biological response (SVR rates of 94% or higher) were achieved in all three groups, and we found no difference in efficacy between the 8-week regimen and 12-week regimen treatment groups.” The SVR12 (sustained virologic response at 12 weeks) rate was 94% with 8-week ledipasvir plus sofosbuvir without ribavirin, 93% with 8-week ledipasvir plus sofosbuvir with ribavirin, and 95% with 12-week ledipasvir plus sofosbuvir without ribavirin.

Kowdley said “this fixed dose combination of ledipasvir plus sofosbuvir with or without ribavirin was safe and well tolerated, and ribavirin primarily contributed to a higher incidence of adverse events and laboratory abnormalities.”

Adverse events (most of which included fatigue, nausea, insomnia, and irritability) were numerically higher in the ledipasvir plus sofosbuvir plus ribavirin group (76% versus 67% and 67%), and the rate of grade 3 to 4 adverse events was not significant across the three groups.

Only four patients of the 647 patients discontinued treatment due to adverse events and only 8% of patients had grade 3 to 4 laboratory abnormalities. A 2g decrease in haemoglobin was seen in the group receiving ribavirin but there was no change in the mean haemoglobin in the groups receiving ledipasvir plus sofosbuvir alone.

According to Kowdley, “host and viral factors traditionally associated with lower SVR rates did not affect SVR12 rates.” He showed a forest plot illustrating that there were no significant differences in SVR rates in patients with male versus female gender, black versus non-black race, HCV G1a versus HCV G1b, high versus low viral load, high versus low BMI, and presence of IL28c antibodies versus non-IL28c antibodies.

Responding to a question from the audience about the effectiveness of shorter treatment durations (ie, shorter than 8 weeks), Kowdley said, “six week ledipasvir plus sofosbuvir therapy appears not to be optimal, with a 65%-67% SVR rate given that duration. Whether a third antiviral agent may be appropriate or whether 6 or 8 weeks of therapy [is better] remains to be explored.”

Reference

Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial interferon-free therapy for hepatitis C virus genotype 1. NEJM, 2014: 370 (3): 222-32.