WASHINGTON – Almost 100% of the patients with hepatitis C infection achieved a sustained virologic response rate 12 weeks after completing treatment with a fixed-dose oral combination of sofosbuvir and ledipasvir, with or without ribavirin, for 8 or 12 weeks, in a phase II study that enrolled previously untreated and treated patients, Dr. Eric Lawitz said at the annual meeting of the American Association for the Study of Liver Diseases.
The 100 patients in the study included those with cirrhosis and those who had previously failed treatment with protease inhibitors, said Dr. Lawitz, vice president of scientific and research development at the Texas Liver Institute, San Antonio. Treatment was well tolerated, and "all the regimens produced a consistently high sustained viral response rate, irrespective of the patient being either treatment naive or a protease failure," he said.
Dr. Eric Lawitz
"The addition of ribavirin had no impact on outcome and in [patients with] protease failures, the results were independent of the presence or absence of cirrhosis," he added.
Sofosbuvir is a nucleotide polymerase inhibitor with activity against hepatitis C virus genotypes 1-6 and a high barrier to resistance, dosed once daily. Ledipasvir is an NS5A inhibitor, effective against genotypes 1a and 1b. The fixed-dose combination of the two antivirals contains 400 mg of sofosbuvir and 90 mg of ledipasvir, dosed once a day, in a single pill, with no food effect, he said. Neither is approved by the Food and Drug Administration, but approval of sofosbuvir is expected in December.
The study enrolled 100 patients with hepatitis C infection, genotype 1, in two cohorts: 60 treatment-naive noncirrhotic patients were randomized to one of three regimens, 8 weeks of the fixed-dose combination, with or without ribavirin; or 12 weeks of the fixed-dose combination, without ribavirin. The second cohort was 40 patients who had failed treatment with one of the HCV protease inhibitors (telaprevir) and were treated with the fixed-dose combination for 12 weeks, with and without ribavirin. The primary efficacy endpoint was the sustained virologic response (undetectable virus) 12 weeks after completing treatment (SVR12). SVR24 results were also obtained.
The mean age of those enrolled was 50 years (the oldest was 73 years); about half were black or Hispanic. About 15% had IL288B CC, which he noted was relatively low. About half of the treatment-experienced patients had compensated cirrhosis.
All but one patient completed the trial (one patient withdrew consent). Overall, treatment resulted in rapid drops in HCV RNA, and an SVR12 rate of 97%, with no viral breakthroughs, Dr. Lawitz said. Of the 60 treatment-naive patients without cirrhosis, 58 achieved an SVR12. Among those who had failed protease inhibitor treatment, 39 of 40 achieved an SVR 12, this group included 21 of the 22 patients with cirrhosis (who were not treated with ribavirin).
The SVR24 rate was also 97%, and the concordance rate between the SVR12 and SVR24 results was 100%, Dr. Lawitz said.
Of the three patients who failed to achieve an SVR12, two failures were in the group of treatment-naive patients (one treated for 8 weeks without ribavirin; and another patient treated for 12 weeks without ribavirin, who was lost to follow-up) and the other treated for 12 weeks. There was one failure in the protease inhibitor–treated group, a patient who relapsed in the 12-week arm without ribavirin.
Treatment was well tolerated, with no severe adverse events attributed to treatment, and no discontinuations for adverse events in any of the arms. Adverse events and lab abnormalities were consistent with the safety profile of ribavirin, and 24% of patients in the ribavirin arms required a dose reduction because of anemia. Among patients on the ribavirin-free regimens, the only adverse event reported more than 5% was upper respiratory infections.
Phase III studies (ION-1, ION-2, and ION-3) are underway, and are evaluating 8, 12, and 24 weeks of treatment with the fixed-dose combination, with and without ribavirin, in treatment-naive and treatment-experienced individuals with HCV genotype 1.
The study was sponsored by Gilead Sciences, the manufacturer of both drugs, and the fixed-dose combination. Dr. Lawitz’s disclosures include having received grant or research support from Gilead and speaking and teaching for the company, as well as other manufacturers.