SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.
Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.
They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.
The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.
Dr. Kris Kowdley
High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.
Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.
"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."
Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.
"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.
"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.
"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."
Dr. Zobair N. Younossi
Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.
"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."
"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."
The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.
All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.