Sofosbuvir/Ribavirin Effective for HCV Genotypes 2 and 3

Norra MacReady

May 09, 2014

The combination of sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin (Ribasphere, Kadmon) produces a sustained virologic response in patients with hepatitis C virus (HCV) genotypes 2 and 3, a new study shows. Patients with HCV genotype 3 had markedly lower response rates if they had cirrhosis compared with those without cirrhosis.

Stefan Zeuzem, MD, from the Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany, and colleagues report the results of the company-sponsored trial in an article published online May 4 in the New England Journal of Medicine.

"These findings provide further confirmation of important differences in response to treatment between HCV genotype 2 and genotype 3 and the need for a longer treatment duration with sofosbuvir–ribavirin in patients with HCV genotype 3 infection," the authors write.

The findings are published as Gilead Sciences comes under increasing fire for pricing sofosbuvir at between $80,000 and more than $90,000 for an average course of treatment in the United States. Clinicians have hailed the sofosbuvir–ribavirin regimen as a breakthrough in HCV treatment, but insurers are balking at picking up the tab, which could come to $200 billion if all 3.2 million candidates in the United States receive the therapy.

For this study, initially designed as a multicenter phase 3 trial, patients were eligible if their serum HCV RNA titers were 10,000 IU/mL or more, whether or not they had previously undergone treatment with an interferon-based regimen. They were randomly assigned, in a 4:1 ratio, to receive either the drug combination or placebo. Sofosbuvir was administered once a day in a dose of 400 mg. Ribavirin was administered twice a day for a total daily dose of 1000 mg for patients with a body weight less than 75 kg and 1200 mg if body weight was 75 kg or more. Both drugs were taken orally.

Initially, all patients were slated to take the drugs or placebo in a blinded fashion for 12 weeks; however, after the release of new data suggesting people with genotype 3 would benefit from prolonged treatment, the investigators unblinded the treatment groups and eliminated the placebo arm of the trial. The researchers treated patients with genotype 2 for 12 weeks as originally planned, whereas they treated those with genotype 3 for 24 weeks of the regimen. The researchers offered patients in the placebo group open-label treatment with the drug combination as part of another clinical trial.

Initially, 419 patients began the study, including 85 in the placebo group that was later terminated, leaving 73 patients with genotype 2 who were treated for 12 weeks, 250 with genotype 3 who were treated for 24 weeks, and 11 patients with genotype 3 who had completed 12 weeks of treatment before the study design was changed. Those patients did not undergo the additional 12 weeks of therapy.

At baseline, the mean age of patients with genotype 2 was 58 years (standard deviation [SD], 28 - 74 years). Patients with genotype 3 in the 12-week treatment group had a mean age of 46 years (SD, 30 - 59 years), and it was 48 years (SD, 19 - 69 years) in the 24-week group (P < .001 for comparison among groups). Men made up 55% of the genotype 2 and 12-week genotype 3 groups, and 62% of the 24-week genotype 3 group. Of the 73 patients with genotype 2, 41 (56%) had previously undergone treatment with an interferon-based regimen. Similarly, 9 (82%) and 145 (58%) of patients in the genotype 3 groups were veterans of interferon treatment, respectively. Cirrhosis was diagnosed in 11 (15%) of the patients with genotype 2 and in 2 (18%) and 60 (24%) of the patients with genotype 3, respectively.

Two weeks into treatment, HCV RNA had dropped below 25 IU/mL in 57 patients with genotype 2 (78%; 95% confidence interval [CI], 67% - 87%), 6 patients (55%; 95% CI, 23% - 83%) with genotype 3 treated for 12 weeks, and 214 patients (86%; 95% CI, 81% - 90%) in the 24-week group.

Four weeks after treatment cessation, HCV RNA remained below that level in 68 (93%; 95% CI, 85% - 98%), 5 (45%; 95% CI, 17% - 77%), and 218 (87%; 95% CI, 82% - 91%) patients, respectively. At 12 weeks after treatment, the numbers were 68 (93%; 95% CI, 85% - 98%), 3 (27%; 95% CI, 6% - 61%), and 213 (85%; 95% CI, 80% - 89%), respectively.

Among patients who completed treatment, relapses were seen in 5 (7%) patients with genotype 2 and 5 (45%) and 33 (13%) in the 2 genotype 3 groups, respectively. Two additional patients with genotype 3 treated for 24 weeks relapsed after posttreatment week 12.

Patients with HCV genotype 3 and cirrhosis who had previously been treated with interferon were the least likely to have a virologic response (29/47 patients [62%]).

Headaches and fatigue were the most common adverse effects in all 3 treatment groups. Nausea and insomnia were also commonly reported. No serious adverse events were reported among patients with genotype 2 or 3 treated for 12 weeks, but they were observed in 10 patients (4%) treated for 24 weeks. However, only 1 patient in each group discontinued treatment because of adverse events.

"This was another good study confirming much of what we already know about the treatment of this population with this drug," Rena Fox, MD, professor of medicine at the University of California, San Francisco, School of Medicine, told Medscape Medical News. "It included a substantial number of patients, which is encouraging because previous studies have been criticized for having small numbers of patients, so the more patients we study, the better."

"I found it interesting that patients with genotype 3 need a longer duration of treatment and that those who were cirrhotic or previously treated had lower response rates," said Dr. Fox, a hepatitis specialist who was not involved in this research. "The message here is that genotypes 2 and 3 are not the same, and cirrhotic patients are not the same as noncirrhotic patients."

As for the cost issues, she said, "those are being loudly and widely debated. We are all extremely happy to finally have a treatment that will be tolerable and effective for the majority of patients, [but it is frustrating that] it is priced at a point where most payers in this country will restrict how it can be prescribed."

This study was supported by Gilead Sciences. Dr. Fox has disclosed no relevant financial relationships. Dr. Zeuzem and all coauthors report receiving support from Gilead, among other companies. Complete conflict-of-interest information is available on the journal's Web site.

N Engl J Med. Published online May 4, 2014. Full text

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