Jim Kling

October 28, 2013

SAN DIEGO, California — New data from 4 phase 3 trials with the hepatitis C (HCV) drug sofosbuvir (SOF) and ribavirin (RBV) show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. Twenty-four-week sustained virologic response (SVR) is essentially identical to 12-week SVR, bolstering confidence that the drug combination represents a cure. Those with genotype 3 infections are better served with a 16-week course of treatment.

The new work extends the results of the studies out to 24 weeks after treatment cessation. Twenty-four weeks was the traditional milestone for HCV treatments, but in recent years, the US Food and Drug Administration and industry have gravitated toward the 12-week time point. However, with new drugs set to greatly affect HCV treatment, it is important to consider this older benchmark, according to Kris Kowdley, MD, director of the Liver Center of Excellence at the Digestive Disease Institute at the Virginia Mason Medical Center in Seattle, Washington, who presented the research here at the American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course.

"We're in a brave new world of hepatitis C treatments, and we're very quickly reaching all oral, interferon-free, short-duration regimens, so I think it remains valuable to continue following patients to 24 weeks, and possibly 48 weeks, posttreatment to see if the assumption [of a cure] really holds up. We can also learn more about late relapses and possible questions about resistance," Dr. Kowdley told Medscape Medical News.

The research drew from 4 phase 3 studies: Sofosbuvir With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naive Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection (NEUTRINO), which enrolled treatment-naive patients with genotype (GT) 1, 4, 5, and 6 infection, each of whom received 12 weeks of SOF, peg-interferon (PEG), and ribavirin (RBV); Phase 3 Study of Sofosbuvir and Ribavirin (FISSION), which enrolled treatment-naive GT 2/3 patients to receive either 12 weeks of SOF+RBV or 24 weeks of PEG+RBV; GS-7977 + Ribavirin for 12 Weeks in Subjects With Chronic Genotype 2 or 3 HCV Infection Who Are Interferon Intolerant, Interferon Ineligible or Unwilling to Take Interferon (POSITRON), which enrolled GT 2/3 patients unable or unwilling to receive interferon, who were randomly assigned to receive 12 weeks of SOF+RBV or placebo; and Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection (FUSION), which enrolled treatment-experienced GT2/3 patients who received 12 or 16 weeks of SOF+RBV.

For all studies, the primary end point was sustained virologic response (HCV RNA < 25 IU/mL) at 12 weeks posttreatment (SVR12).

In the studies, participants had a mean age of 53 years (range, 19 - 77 years) and a mean body mass index of 28 kg/m2 (range, 17 - 56 kg/m2). Demographics were consistent with those of the HCV-infected population in the United States. Six percent of the participants were receiving opioid replacement therapy.

Table 1. 12-Week SVR Rates

  GT 1,4,5,6 GT 2 and 3
SOF/PEG/RBV (n = 327) SOF/RBV (n = 253) PEG/RBV (n = 243) SOF/RBV (n = 207) Placebo (n = 71) SOF/RBV 12 week (n = 100) SOF/RBV 16 week (n = 95)
Overall 91% 67% 67% 78% 0% 50% 73%
GT 2 N/A 97% 78% 93% 0% 86% 94%
GT 3 N/A 56% 63% 61% 0% 30% 62%
Noncirrhotic 93% 72% 74% 81% 0% 61% 76%
Cirrhotic 80% 47% 38% 61% 0% 31% 66%

Compensated cirrhosis at baseline was found in 17% of patients in the NEUTRINO study, 21% in FISSION, 18% in POSITRON, and 33% in FUSION.

In all studies, SVR12 was higher in patients without cirrhosis. Patients with GT 2 experienced higher SVR12 rates than those with GT 3.

SVR 24 rates were similar to SVR 12 rates.

Table 2. SVR12 vs SVR24

  SVR12 SVR24
Treatment-naïve patients    
GT 1, 4, 5, 6 overall 91% 91%
GT 1 90% 90%
GT 4 96% 96%
GT 5 and GT 6 100% 100%
Treatment-naive and experienced GT 2, 3 patients    
Treatment-naive 67% 67%
Interferon unable 78% 78%
Previously treated (12 week regimen) 51% 50%
Previously treated (16 week regimen) 73% 72%

The additional data back up the 12-week SVR. "In all the studies, the 24-week results are almost identical [to the 12-week SVR]. We detected durability of that response," said Dr. Kowdley. The studies also suggest that interferon is not needed to achieve SVR in genotypes 2 and 3, although Dr. Kowdley said that trials of interferon-sparing regimens are underway.

The results further underscore the anticipation that physicians have toward sofosbuvir and other new drugs. "I think 2 years ago there was a standing-room only meeting in San Francisco, where Pharmasset (which originally developed sofosbuvir), dropped just unbelievable results, and we all thought this was too good to be true," Tim Little, MD, a physician with Puget Sound Gastroenterology in Seattle, Washington, who attended the presentation, told Medscape Medical News.

"I don't know that there's anything incredibly new about (this study), but it's confirmation that this dramatic result that this very small group of investigators presented is actually real, and I think we can all understand that this is as good as they said it was going to be, or almost as good," Dr. Little said.

On October 25, an FDA advisory committee unanimously recommended approval of sofosbuvir based on the 12-week results. The FDA is expected to make a decision by December 8.

The research was funded by Gilead Bioscences, which is sponsoring sofosbuvir. Dr. Kowdley has received research funding from Gilead and is a member of the company's advisory committee. Dr. Little has disclosed no relevant financial relationships.

American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course: Abstract 38. Presented October 15, 2013.


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