In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.
The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR24 rate of 93%, with 1 patient having a confirmed relapse.
Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR12, including 3 who did not have an SVR4. The SVR24 rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.
"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.
He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.
Sofosbuvir Stands Alone (Almost)
Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.
Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.
They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).
In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR12.
In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR4 of 72%.
In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR4 of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.
The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.
Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.
Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.