Data on new treatment options and combinations of therapies to treat chronic viral hepatitis C infection were presented at the 78th annual scientific meeting of the American College of Gastroenterology in San Diego in a scientific session dedicated to liver disease. Three research teams reported on trials of several experimental treatments, including interferon-free drug combinations and direct-acting antiviral agents effective against genotypes 2 and 3 of the hepatitis C virus, as well as new agents which have the potential to shorten the duration of therapy.
These studies highlight how rapidly medical research is advancing in hepatitis C, says Kris V. Kowdley, MD, FACG, director of the Liver Center of Excellence in the Digestive Disease Institute at Virginia Mason Medical Center, and Clinical Professor of Medicine at the University of Washington in Seattle. The new wave of direct-acting oral agents has the potential to transform therapy for patients living with hepatitis C, both in terms of their safety and efficacy profiles, but also in terms of the possibility of reducing the duration of, or completely eliminating the need for, interferon injections.
Faldaprevir STARTVerso1 Trial: Up to 89 Percent of Patients Eligible to Stop Treatment at 24 Weeks
Final results of the STARTVerso1 Phase 3 trial of faldaprevir plus pegylated interferon and ribavirin in chronic hepatitis C infection in treatment-naÃ¯ve patients infected with genotype1 were presented by Christophe Moreno, MD, PhD, of the HÃ´pital Universitaire Erasme in Brussels, Belgium and colleagues. This randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of faldaprevir, an investigational protease inhibitor.
Treatment-naÃ¯ve patients with chronic hepatitis C genotype 1 were randomized to receive 24 weeks of pegylated interferon and ribavirin with faldaprevir placebo (arm 1); or faldaprevir 120 mg for 12 or 24 weeks (response guided; arm 2); or faldaprevir 240 mgs for 12 weeks (arm 3). Patients in arms 2 and 3 also received pegylated interferon and ribavirin for 24 weeks. Patients with early treatment success (ETS) at week 8 in Arms 2 and 3 stopped all treatment at week 24. Early treatment success was defined in the protocol as virus at week 4 below limit of quantification [BLQ] and at week 8 below limit of detection.
The investigators reported that in previously untreated patients with genotype-1 hepatitis C virus (HCV) who received once-daily faldaprevir plus PegIFN/RBV, 79 percent and 80 percent in the 120mg and 240mg arms, respectively, achieved viral cure when measured 12 weeks after treatment was completed (SVR12). This is compared with 52 percent of patients receiving PegIFN/RBV plus placebo (p<0.0001).
Anemia, rash and gastrointestinal issues were the most common Grade 2-4 adverse events in placebo, faldaprevir 120mg and faldaprevir 240mg arms, respectively. In total, up to 89 percent of patients treated with faldaprevir were eligible to stop all treatment at week 24. The study was supported by a grant from Boehringer Ingelheim.
In the STARTVerso1 study, faldaprevir has shown efficacy in achieving viral cure for treatment-naÃ¯ve patients with HCV, with the potential for a shorter treatment duration. These results are particularly promising, as the study evaluated genotype 1a and 1b HCV patients, including difficult to treat patients such as those with liver cirrhosis, comments Moreno.
Sofosbuvir with Ribavirin and Pegylated Interferon Shortens Treatment for HCV Genotype 1
Kris V. Kowdley, MD, FACG, reported results of four multi-center randomized trials of combination therapies of sofosbuvir for patients with chronic hepatitis C.
Among genotype 1 patients receiving sofosbuvir plus ribavirin and pegylated interferon, the sustained viral response rate was 91 percent at 12 weeks after end of treatment, comments Kowdley, highlighting findings from the NEUTRINO study, one of four trials of sofosbuvir reported by Kowdley and his colleagues.
The four studies reported included the NEUTRINO trial, in which treatment- naÃ¯ve patients with genotype 1,4, 5 and 6 received 12 weeks of sofosbuvir and pegylated interferon plus ribavirin; FISSION in which treatment-naÃ¯ve patients with genotype 2 or 3 were randomized to receive either 12 weeks of sofosbuvir plus ribavirin or 24 weeks of pegylated interferon plus ribavirin; POSITRON in which interferon-ineligble, -intolerant or unwilling genotype 2 or 3 patients were randomized to receive 12 weeks of sofosbuvir plus ribavirin or placebo; and FUSION in which treatment-experienced genotype 2 or 3 patients were randomized to receive 12 or 16 weeks of sofosbuvir and ribavirin.
In the FISSION, POSITRON and FUSION trials, patients with genotype 2 infection had rates of sustained viral response at 12 weeks after the end of treatment (97 percent VR-12 FISSION; 93 percent SVR-12 POSITRON and 86 percent SVR-12 FUSION) that were higher than those patients with genotype 3 (56 percent SVR-12 FISSION; 61 percent SVR-12 POSITRON; and 30 percent SVR-12 FUSION).
Researchers concluded that previously treated patients with genotype 3 hepatitis C infection may benefit from extending treatment to 16 weeks. Currently, no direct-acting antiviral agents have yet been approved for patients with genotype 2 or 3 Hepatitis C infection. This work was supported by a grant from Gilead Sciences Inc.
The sofosbuvir results seen in these four pivotal studies represent a significant advance in hepatitis C treatment, says Kowdley. First, they indicate that we should be able to shorten therapy for many patients to just 12 weeks. Second, for the first time we have Phase 3 evidence that we can do away with debilitating interferon injections for some patients. Sofosbuvir has the potential to usher in a new era of simple, tablet-based treatment for hepatitis C that boosts cure rates and is much easier for patients to take and to tolerate.
Results of the Aviator Study of an Interferon-Free Regimen for Hepatitis C
Kowdley was also the lead author on a study on the safety and efficacy of interferon-free regimens for hepatitis C patients with genotype 1 using a combination of three experimental direct-acting anti-viral agents (DAA) ABT-450/r, ABT-267, and ABT-333 with or without ribavirin. This trial, known as Aviator, treated 247 subjects in the 12 and 24 week arms of three DAA plus ribavirin.
Overall, the sustained viral response at 12 weeks post treatment was 98.7 percent in treatment naÃ¯ve patients and 93.3 percent in null responders (those patients with hepatitis C virus who failed to respond to prior therapy with other drugs). Comparable responses were seen with 12 and 24 weeks of treatment, supporting selection of a 12-week duration of therapy in these populations. Consistently high SVR rates were achieved in naÃ¯ve and prior null responder patients with a three direct acting anti-viral agent regimen, across HCV subtype, IL28B genotype baseline HCV-RNA or severity of fibrosis, concluded Dr. Kowdley. The design, study conduct, analysis and financial support of this clinical trial were provided by Abbvie.
According to Kowdley, "The high sustained viral response rates across patient types in the Aviator study were very encouraging. This study, one of the largest phase 2 trials of interferon-free therapy for HCV, was designed to identify the most effective regimens for treating HCV genotype 1 infection. It is noteworthy that the trial included a large number of prior interferon null responders, a population that typically has a poorer response to treatment than treatment-naÃ¯ve patients. Aviator was the first trial to show that a highly active interferon-free regimen could achieve high SVR rates in null responders. The fact that a well-tolerated 12-week regimen of 3 DAA+ribavirin showed consistently high SVR rates regardless of baseline predictors of poor response suggest that it could be an effective treatment even in difficult-to-treat patients."
Hepatitis C is a liver disease affecting as many as 170 million people worldwide. The virus is primarily spread through direct contact with the blood of an infected person. Hepatitis C infection increases the risk of chronic liver disease, cirrhosis, liver cancer and death. Of the six main genotypes of hepatitis C, genotypes 1, 2 and 3 are the most widespread. Genotype 1 is the most common genotype in the United States and the most difficult to treat with interferon-based therapies. Patients with genotypes 2 and 3 are more likely than individuals with genotype 1 to respond to therapy with pegylated interferon or the combination of pegylated interferon and ribavirin.
Source: American College of Gastroenterology