LONDON – A single daily pill containing two novel antiviral agents produced sustained virologic response rates of more than 90% in as little as 8-12 weeks in three multicenter, open-label phase III studies involving 1,952 patients with chronic hepatitis C virus infection.
The combination pill, containing fixed doses of 400 mg sofosbuvir and 90 mg ledipasvir, was given alone or together with ribavirin but without pegylated interferon (peg-IFN) for 8, 12, or 24 weeks in the ION-1, ION-2, and ION-3 trials. Results of the first two trials showed that a 12-week course of sofosbuvir/ledipasvir was enough to clear the virus in the majority of patients, but results of the latter showed that an 8-week regimen of the daily pill was sufficient.
The findings of all three studies were published online in the New England Journal of Medicine to coincide with their presentation at the International Liver Congress sponsored by the European Association for the Study of the Liver.
Dr. Nezam H. Afdhal
"The real advance seen in the ION trials is that the sofosbuvir-ledipasvir combination tablet enables us to treat almost all genotype 1 patients with a short duration of 8-12 weeks of treatment," Dr. Nezam Afdhal* of Beth Israel Deaconess Medical Center, Boston, said in a press statement issued by his institution, which was one of the key centers involved in the studies.
Since patients who were unable to be treated with peg-IFN were included in the studies, these data could potentially expand the population of patients who could now be treated, as well as increase the overall cure rate, Dr. Afdhal added. Patients with compensated cirrhosis also were included in the ION-1 (n = 136) and ION-2 trials (n = 88).
ION-1 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1402454]) and ION-2 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1316366]) were designed to investigate the efficacy and safety of the sofosbuvir/ledipasvir fixed-dose combination given with or without ribavirin for 12 and 24 weeks in patients with chronic genotype 1 hepatitis C virus (HCV) infection who were treatment experienced and treatment naive, respectively. Results showed that similar cure rates could be achieved in patients regardless of the duration of the regimen.
Indeed, sustained virologic response at 12 weeks after the end of treatment (SVR12) in ION-1 in treatment-naive patients (n = 865) was 99% with the daily pill alone and 97% if ribavirin also was given. There was little benefit of continuing therapy for up to 24 weeks, with SVR12 of 98% for the daily pill given alone and 99% with additional ribavirin.
SVR12 in previously treated patients in the ION-2 trial (n = 440) was 94% with the daily pill alone and 96% if ribavirin also was given for 12 weeks. There was little benefit of continuing therapy for 24 weeks, with SVR12 of 99% for the daily pill used alone and together with ribavirin.
ION-3 (N. Engl. J. Med. 2014 Apr. 11 [doi:10.1056/NEJMoa1402355]) looked at whether 8 weeks of treatment was as effective as 12 weeks of treatment. The open-label study included 647 patients with HCV genotype 1 infection without cirrhosis who had not been previously treated. SVR at 8 weeks was 94%, versus 95% for the 12-week regimen. The addition of ribavirin did not increase the SVR, which was 93% at 8 weeks, showing that a shorter regimen was just as effective as the 12-week course.
Adverse events were more common in the ribavirin-treated patients than in those who received only the combined sofosbuvir/ledipasvir pill. The most common adverse events seen in the trials – fatigue, headache, insomnia, and nausea – were linked to ribavirin therapy.
"With cure rates well in excess of 90% with as little as 8 weeks of treatment for some patients, these data represent a significant advance in the race to develop a new, all-oral treatment for hepatitis C," said Dr. Markus Peck-Radosavljevic, the Secretary General of EASL. He noted, in a press statement issued by the association, that avoiding the use of both peg-IFN and ribavirin had the potential to bring forward more patients for treatment as it is likely to be much more tolerable.
Gilead Sciences funded the trials. Dr. Afdhal has received research support, honoraria, or other fees in the past 12 months from Gilead Sciences, Abbott, BMS, Boehringer Ingelheim, Echosens, Janssen, GSK, Idenix, Ligan, Merck, Medgenics, Novartis, Quest, Springbank, TRIO Healthcare, and Vertex. Dr. Peck-Radosavljevic made no disclosures.
*Correction 5/8/2014: In a previous version of the story Dr. Afdhal's name was misspelled. This version has been updated.