Proof-of-Concept Studies of Interferon-free Regimens
With more than 30 direct-acting antiviral agents (DAAs) in clinical trials, the hepatitis C community (scientists, physicians, patients) expect that the right combinations of DAAs will emerge, permitting treatment of hepatitis C virus (HCV) genotype 1 with interferon (IFN)-free regimens. In 2012, the first report of sustained virologic response (SVR) with an IFN-free regimen in patients with genotype 1 was published. In this study, 4 of 11 (36%; 2 of 9 with genotype 1a, 2 of 2 with genotype 1b) noncirrhotic null responders to pegylated IFN (PEG-IFN) and ribavirin (RBV) achieved SVR after a 24-week course of asunaprevir, a protease inhibitor, and daclatasvir, a NS5A inhibitor. Whereas the number of patients studied was small and the SVR rate was low in patients with genotype 1a, these data provided proof of concept that SVR can be achieved without IFN or RBV in patients with HCV genotype 1. These data have encouraged the evaluation of many other IFN-free regimens.
IFN-free Regimens Expected to Be Approved in 2014/2015
In late 2013, two new DAAs for genotype 1 were approved by the US Food and Drug Administration (FDA): simeprevir, a protease inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor. Both drugs are to be used with PEG-IFN and RBV. Although sofosbuvir was also approved to be used with RBV (without PEG-IFN) for IFN-ineligible patients, the SVR rate of the 2-drug regimen is substantially lower than the 3-drug regimen: 68% to 76% versus 89%.[2-4] Many experts have advocated the off-label combination of simeprevir and sofosbuvir based on data from a phase 2 study, and this approach is endorsed by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America HCV guidelines. However, only 167 patients were included in that study, and the cost of this off-label combination is substantially higher than the approved regimens.
Two IFN-free regimens for HCV genotype 1 are expected to be approved by the FDA in late 2014. Phase 3 trials of both regimens have been completed and results published.
The ION-1, 2, and 3 trials compared sofosbuvir plus ledipasvir, an NS5A inhibitor coformulated as a single pill, with or without RBV, for 8 to 24 weeks (Table 1) (Fig. 1). In the ION-1 trial in treatment naive patients (16% with cirrhosis), SVR rates after 12 weeks of therapy were 97% and 98% in the groups with or without RBV, respectively; results in the 24-week treatment groups were 99% and 98% with and without ribavirin respectively. In the ION-3 trial, the possibility of shortening the duration of treatment to 8 weeks was tested in treatment naive patients with no to moderate fibrosis (Metavir F0-F2); SVR rates after 8 weeks of therapy were 93% and 94% in the groups with or without RBV, respectively, and 95% after 12 weeks of treatment without RBV. In the ION-2 trial in treatment-experienced patients (20% with cirrhosis), SVR rates after 12 weeks of therapy were 96% and 94% in the groups with or without RBV, respectively, and 99% in patients who received 24 weeks of treatment, with or without RBV. Anemia was reported in 0.5% of patients in the RBV-free groups compared to 9.2% in the RBV-containing groups. Fewer than 1% of patients in the ION studies discontinued treatment due to treatment-related adverse events.
Click HERE to see the table of results and read the rest of the report