TUESDAY AUG 27, 2013 | REUTERS
Last Updated: 2013-08-27 17:58:11 -0400 (Reuters Health)
By Megan Brooks
NEW YORK (Reuters Health) – In a mid-stage trial in patients with chronic hepatitis C virus (HCV)-1 and unfavorable treatment characteristics, the all-oral interferon-free regimen of sofosbuvir and ribavirin produced a high sustained virologic response (SVR) rate, researchers report.
Sofosbuvir (Gilead Sciences) is an experimental nucleotide analogue that inhibits HCV replication. It was granted priority review designation by the U.S. Food and Drug Administration in June.
In the August 28 issue of JAMA, Dr. Anuoluwapo Osinusi of the National Institutes of Health, Bethesda, Maryland, and colleagues report on a randomized, two-part, phase II study of sofosbuvir plus weight-based or low-dose once-daily ribavirin in a treatment-naive HCV genotype 1 patient population with “unfavorable treatment characteristics.”
In the first part of the study, 10 subjects with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. Ninety percent of patients achieved the primary outcome – undetectable HCV viral load 24 weeks after treatment completion (SVR24).
In the second part of the study, 50 subjects with all stages of liver fibrosis were randomized to receive 400 mg of sofosbuvir with either weight-based or low-dose (600 mg/d) ribavirin for 24 weeks (25 in each group).
Twenty-four subjects in each group (96%) achieved viral suppression by week four. Four discontinued the study drug by week eight due to nonadherence. One patient declined to continue past week 12, but his viral load remained undetectable 24 weeks after stopping treatment.
Seven subjects (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after completing treatment, leading to SVR24 rates of 68% and 48%, respectively.
“To see a cure rate of about 70% in a difficult-to-treat patient population with an all oral regimen that does not contain interferon is wonderful news,” Dr. Michael Babich, program director of gastroenterology and hepatology at Allegheny General Hospital in Pittsburgh, Pennsylvania, who wasn’t involved in the study, told Reuters Health.
“This is not by any means a cure-all. There are going to continue to be treatment failures. But I think this is good news particularly for patients who have failed interferon-based regimens previously or for patients who can’t take interferon,” Dr. Babich said.
The study team identified three baseline factors associated with relapse: male sex, advanced liver disease, and high baseline HCV RNA levels. “These are the same poor predictors we’ve known about for years,” Dr. Babich said.
A pharmacokinetic-viral kinetic substudy in 20 subjects showed a slower rate of loss of infectious virus in relapsers than in participants who achieved SVR.
Dr. Osinusi and colleagues say the sofosbuvir/ribavirin combination was safe and well tolerated with no deaths or discontinuation of treatment due to adverse events. The most frequent adverse events were headache, anemia, fatigue, and nausea, the severity of which ranged from mild to moderate. There were seven grade three events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis.
“Because treatment of HCV is evolving from an interferon-based combination therapy to an all-oral, interferon-free directly acting antiviral agent regimen, these results are encouraging and provide important information regarding the expected treatment responses in a population representative of the U.S. epidemic,” the investigators say.
Dr. Babich noted that treatment regimens for chronic hepatitis C “have always included interferon and it has remained an integral part of all genotypes. The problem is it has side effects and it’s an injectable drug.”
“The pot of gold at the end of the rainbow,” he said, is an all oral agent regimen that will not include interferon. “In the last two years roughly, we started to see data from preliminary studies investigating new drugs that have the potential for eliminating the need for interferon as part of the treatment regimen. We are probably closer to this becoming a reality with genotype 2 and 3 infections. It’s quite likely that by the end of the year we will have our first option for interferon-free treatment for the genotype 2 and 3 patients.”
“Patients who are infected with genotype 1,” Dr. Babich noted, “have always had lower cure rates than genotype 2 and 3 patients irrespective of the treatment regimen. We are seeing the same phenomenon with interferon-free regimens in genotype 1, we are seeing lower cure rates than they are achieving with the same all oral regimens in the genotype 2 and 3 patients.”
“However, even with the lower cure rates, the cure rates are nothing to be scoffed at,” he said. “The cure rates that these studies are reporting, such as this one in JAMA, several years ago we would have considered these cure rates miraculous. They aren’t superior to the regimens we have available for genotype 1 now that include interferon but with the sacrifice of a small chance of cure we gain easier regimens, without injections, that will probably prove to be shorter in duration for many patients, with fairly comparable cure rates with lower side effects.”
The study was supported by the National Institutes of Health and by the German Research Foundation. Pharmasset Pharmaceuticals and subsequently Gilead Sciences provided sofosbuvir and scientific advice. Some of the investigators have financial relationships with Gilead and other drug companies. A complete list is available with the original article. Dr. Babich has no relevant disclosures.