WASHINGTON – The addition of ribavirin to a fixed-dose combination of sofosbuvir and ledipasvir, two potent direct-acting hepatitis C antiviral drugs, increased the response rate from 70% to 100% in previously-treated patients with chronic hepatitis C infection and fibrosis or cirrhosis.
That finding emerged from a phase II study presented by Dr. Edward Gane at the annual meeting of the American Association for the Study of Liver Diseases.
Sofosbuvir, a nucleotide polymerase inhibitor, has potent antiviral activity against HCV genotypes 1-6, and ledipasvir, an NS5A inhibitor, has potency against genotypes 1a and 1b1. Both are taken once a day orally. To date, more than 2,000 people have been treated with the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg), which is now in phase III trials, said Dr. Gane, chief hepatologist and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital.
The study evaluated the efficacy and safety of the sofosbuvir-ledipasvir fixed-dose combination for 12 weeks in treatment-experienced patients with HCV genotype 1 and advanced fibrosis or cirrhosis. The investigators also looked at the shortest duration of the combination required in treatment-naive patients with genotype 1 who did not have cirrhosis. The primary endpoint was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12).
Most of the patients were white, and most were male. Their mean age was 51-61 years, and most had genotype 1a (60%-85%).
Patients were divided into three different groups:
• Treatment-experienced patients with HCV genotype 1 and cirrhosis, treated with the fixed dose combination without ribavirin (10 patients) or with ribavirin (9 patients) for 12 weeks.
Among those on the fixed-dose combination only, 70% reached SVR12. When ribavirin was added, SVR12 was reached by all patients.
• Treatment-naive patients with HCV genotypes 2 and 3, treated with the fixed-dose combination and ribavirin (10 patients) for 12 weeks. Again, 100% of these patients reached SVR12.
• An exploratory cohort of 25 treatment-naive noncirrhotic patients with HCV genotype 1 treated with the fixed-dose combination plus ribavirin for 6 weeks. Fewer of these patients (68%) reached SVR 12.
Sofosbuvir-ledipasvir, with or without ribavirin, "was generally safe and well-tolerated," with no serious adverse events reported or treatment discontinuations, Dr. Gane said. In general, adverse events were mild, and grade 3/4 laboratory abnormalities were infrequent and consistent with the safety profile of ribavirin, he added.
"In the historically difficult to treat treatment-experienced patients with cirrhosis, the addition of ribavirin ... enhances the efficacy of sofosbuvir plus ledipasvir when given for 12 weeks," Dr. Gane said.
The optimal duration of this combination in genotype 1 patients appears to be more than 6 weeks, he added, "with unacceptable relapse rates" when treatment is reduced to 6 weeks.
Importantly, the study also found that the efficacy of the combination was not reduced in patients with resistance-associated variants at baseline, Dr. Gane said.
Patients in the studies were enrolled in the ELECTRON or ELECTRON 2 studies.
Neither sofosbuvir or ledipasvir is approved by the Food and Drug Administration, but at an Oct. 25 meeting, an FDA advisory panel unanimously recommended the approval of sofosbuvir for two groups of patients with chronic hepatitis C infection: treatment-naive adults with genotype 1 and 4 infections, in combination with pegylated interferon and ribavirin; and for adults with genotype 2 and 3 infections, in combination with ribavirin. An approval decision is expected by Dec. 8.
Dr. Gane disclosed that he served on the advisory board committees for Gilead, Roche, AbbVie, Achillion, Janssen, Novartis, and Vertex within the previous 12 months. The study was funded by Gilead Sciences, maker of the fixed-dose combination. Several of the authors of the study are Gilead employees.