ESTES PARK, COLO. – Treatment of hepatitis C infection is likely to shift from gastroenterology and hepatology clinics to primary care physicians’ offices, perhaps as early as next year.
That’s the prediction of Dr. Gregory T. Everson, who cited rapid progress in developing interferon-free treatment regimens as the driving force behind what is anticipated to be a huge change in clinical practice, given that there are an estimated 5 million or more patients with hepatitis C virus (HCV) infection in the United States
Five major pharmaceutical companies are developing oral, interferon-free HCV treatment regimens based upon still-investigational direct-acting antiviral agents (DAAs) that target HCV proteins and their functions. The clinical trials experience to date indicates these DAA-based regimens have substantially higher cure rates, far better tolerability and safety, and a much lower pill burden. Also, they are vastly simpler to administer than are current standard therapies. And all this is being achieved with a 12-week treatment duration instead of the 24 weeks required with standard therapy in 2013, Dr. Everson said at a conference on internal medicine sponsored by the University of Colorado.
"In the past I could say we really had pretty [intolerable] therapy, and it was pretty difficult for patients to take it. Interferon-free therapy is evolving rapidly, and I hope that it will be in primary care physicians’ backyards in the near future. I think this is probably going to be a treatment that you all provide," added Dr. Everson, professor of medicine and director of hepatology at the university.
Indeed, at hepatology clinics around the country, patients with early-stage HCV and their physicians are taking a "wait until next year" attitude toward starting treatment in anticipation that the Food and Drug Administration could approve the first of these new DAAs, sofosbuvir, before the year’s end.
The number of prescriptions for HCV therapy for treatment-naive patients at the University of Colorado clinic has plummeted in 2013 compared with 2012. The only patients starting treatment now are those with advanced HCV liver disease, to halt further disease progression and reduce the risk of developing hepatocellular carcinoma, according to Dr. Everson.
The FDA has granted Gilead Sciences priority review status for sofosbuvir, an oral inhibitor of nucleotide N55b polymerase, with a target decision date in early December. The application for marketing approval is for two indications. One involves sofosbuvir as part of a 12-week, triple-therapy regimen including pegylated interferon and ribavirin in treatment-naive patients with HCV genotypes 1, 4, 5, and 6, based in large part upon the highly favorable results of the phase III NEUTRINO trial (N. Engl. J. Med. 2013;368:1878-87).
The other proposed indication is sofosbuvir in combination with ribavirin as an interferon-free, 12-week regimen in patients with HCV genotypes 2 or 3, based upon the results of the FISSION and POSITRON trials (N. Engl. J. Med. 2013;368:1867-77).
In the NEUTRINO trial, 12 weeks of triple-therapy with sofosbuvir/interferon/ribavirin resulted in a 90% cure rate in patients with HCV genotype 1, which accounts for three-quarters of all HCV infections in the United States. The dropout rate due to side effects was a mere 2%. In contrast, today’s standard therapy, consisting of either of the protease inhibitors telaprevir (Incivek) or boceprevir (Victrelis) combined with pegylated interferon and ribavirin, has a 70%-75% cure rate. And many patients can’t tolerate or are ineligible for interferon.
"When I started treating hepatitis C patients 25 years ago, I was happy because the ALT would normalize in half the patients with genotype 1, but I wasn’t curing anybody. And now triple therapy with sofosbuvir, with a 90% cure rate, could be approved by the end of the year," Dr. Everson marveled.
In the FISSION trial, treatment-naive patients with HCV genotype 2 had a 97% cure rate with 12 weeks of sofosbuvir/ribavirin compared with 78% in those assigned to today’s standard regimen of 24 weeks of pegylated interferon/ribavirin. And sofosbuvir is just one pill per day, coupled with ribavirin at two or three pills twice daily.
In POSITRON, conducted in patients who had relapsed or were nonresponders to the standard 24 weeks of pegylated interferon/ribavirin, 12 weeks of sofosbuvir/ribavirin had an 86% response rate in patients with HCV genotype 2. With an additional 4 weeks of the interferon-free regimen, the cure rate climbed to 94%. Cure rates were lower in genotype 3 patients, but of note, the cure rate in treatment-experienced genotype 3 patients with cirrhosis more than tripled from 19% with 12 weeks of sofosbuvir/ribavirin to 61% with 16 weeks.
Other oral DAAs in the developmental pipeline include simeprevir, daclatasvir, and asunaprevir. The clinical trials experience to date demonstrate that combination therapy with more than one DAA boosts the cure rate even higher than with sofosbuvir/ribavirin. For example, in the phase II, open-label AVIATOR study, 12 weeks of a cocktail comprising three DAAs plus ribavirin brought a 96% cure rate in treatment-naive patients with HCV genotype 1 and a 93% cure rate in those who had previously failed on standard interferon-containing therapy. The AVIATOR cocktail is being formulated as a two-pills-per-day regimen.