Data from pivotal international phase III clinical trials showed superior efficacy, safety, and convenience for a new wave of direct-acting oral agents. The breakthrough will benefit physicians in all practice settings, including primary care.
Plenary session October 15, 2013, with Kris V. Kowdley, MD, FACG; Benaroya Research Institute, Seattle, Fred Poordad, MD, Texas Liver Institute, UT San Antonio, and Christophe Moreno, PhD, Erasme Hospital, Brussels Belgium Moderator: Zobair M. Younossi, MD, FACG, Center for Integrated Research Inova Fairfax Hospital
Whatever your practice setting, you are seeing patients with chronic hepatitis C, whether you know it or not. More than 3 million Americans have chronic hepatitis C, with as many as 167 million more infected worldwide. It is the leading cause of liver cancer in the US, as well as a major cause of cirrhosis and the need for liver transplant. Hepatitis C is responsible for approximately 15,000 deaths annually.
Although current standard treatments are reasonably effective, they are expensive, inconvenient, and burdened with adverse effects. In this plenary session highlighting the most important new data presented at ACG 2013, three international teams released the results of large phase 3 clinical trials showing superior efficacy, safety, and convenience for the new wave of direct-acting oral agents against the hepatitis C virus. The data raise the possibility that for the first time, we may have all-oral regimens for this deadly condition-and they may be available within a year. People with chronic hepatitis C being cared for in any practice setting will welcome (and demand) new regimens such as these, which will allow them to avoid or lessen interferon injections and, more importantly, to avoid interferon’s serious adverse effects.
Current standard regimens for chronic hepatitis C are often year-long and involve weekly injections of pegylated interferon-alpha, plus a current protease inhibitor (ribavirin). Adverse effects have been a major limitation and include anemia, depression, and flu-like symptoms. And standard treatment has been least effective against genotype (GT) 1, which is the most common in the US. GTs 2 and 3 are less common but more responsive to standard treatment. The experimental regimens whose data were presented at ACG were highly effective against GT 1, in addition to GTs 2 and 3. GTs 4, 5, and 6 are the least common in the US but cause serious public health concerns in Africa and Asia.
You will be hearing much more about these 3 experimental direct-acting regimens against hepatitis C virus and their favorable results in these trials. What all 3 have in common is that they act directly against the hepatitis C virus:
1. Faldaprevir, a protease inhibitor with once-daily dosing: In the STARTVerso1 trial, adding faldaprevir to an interferon+ribavirin regimen significantly increased SVR12 rates (sustained virological response at 12 weeks) and was well-tolerated in patients with chronic hepatitis C with GT 1. About 80% of treatment-arm patients achieved viral cure at 12 weeks, compared with 52% of patients receiving only interferon/ribavirin plus placebo (P < .0001); 88% of patients treated with faldaprevir were well enough to stop all treatment at week 24. The drug was well tolerated.
2. Sofosbuvir, a nucleotide analog hepatitis C polymerase inhibitor: This is a complex double-blinded randomized placebo-controlled trial, actually four studies in one:
- NEUTRINO: Treatment-naive patients with GT 1, 4, 5, and 6 infection received 12 weeks of sofosbuvir with interferon and ribavirin.
- FISSION: GT 2/3 patients were randomized to either 12 weeks of sofosbuvir+ribavirin or 24 weeks of interferon+ribavirin.
- POSITRON: Interferon-ineligible, -intolerant, or -unwilling GT 2/3 patients randomized to receive either 12 weeks of sobosbuvir+ribavirin or placebo.
- FUSION: Treatment-experienced GT 2/3 patients were randomized to either 12 or 16 weeks of sofosbuvir+ribavirin.
The primary endpoint for all 4 studies was SVR12. The use of sofosbuvir, with or without interferon, was associated with marked improvement in SVR12 rates for most tested subtypes; SVR12 was 91% in the treatment arm for GT 1 patients. Previously treated patients with GT 3 infection may benefit from extending treatment to 16 weeks. Sofosbuvir was extremely well tolerated.
3. Experimental protease inhibitors ABT-450/r, ABT-267, and/or ABT-333 (direct-acting antiviral agents, or DAAs) used in interferon-free regimens for GT 1 patients, with our without ribavirin-the Aviator Trial: Overall, SVR12 was 98.7% in treatment-naive patients, and 93.3% in non-responders to previous treatment. Twelve-week regimens were as effective as 24-week regimens.
This is incredibly effective treatment, with lower adverse effects, and for most patients, the treatment duration can be short (12 weeks). At what cost? The presenters allowed that these will be expensive drugs once they reach the market (probably within a year), but challenged policy-makers to consider the total cost of currently standard care-including treatment, visits, and hospitalizations for all the adverse effects of regimens that include injected interferon.