WASHINGTON – The use of the experimental drug sofosbuvir in combination with ribavirin successfully reduced hepatitis C virus infection recurrence in 77% of posttransplant patients 4 weeks after treatment ended, based on the initial results of an ongoing large, prospective multicenter study.
HCV recurrence is the most common cause of mortality and graft loss following transplantation, and 10%-50% of those with a recurrent infection progress to cirrhosis within 5 years, Dr. Michael R. Charlton, professor of medicine at the Mayo Clinic, Rochester, Minn., said at the annual meeting of the American Association for the Study of Liver Diseases.
Alicia Ault/IMNG Medical Media
Dr. Michael R. Charlton
Sofosbuvir, manufactured by Gilead Sciences, is a nucleotide analogue inhibitor of the NS5B polymerase enzyme, which plays an important role in HCV replication. The compound is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6.
There are no approved treatments currently in the United States to prevent posttransplant HCV recurrence.
Dr. Charlton reported results for 40 patients in an ongoing open-label interferon-free study. Their mean age was 59 years, with a range of 49-75 years; 78% were male, 85% were white, 8% were black, and 3% were Hispanic. Thirty-five patients (88%) had been previously treated, with 9 of the 40 having been previously treated with protease inhibitors. The study enrollees had a mean baseline HCV RNA of 6.55 log10 IU/mL. Sixteen patients (40%) had cirrhosis. The predominant genotype was 1a, found in 22 patients (55%); 11 had genotype 1b, 6 had genotype 3, and 1 had genotype 4.
In the study, posttransplant patients with recurrent HCV infection of any genotype were included. The transplant had to have occurred between 6 and 150 months prior to enrollment. Patients had to have an absence of rejection and were excluded if they took more than 5 mg of prednisone daily. Study participants were given up to 24 weeks of sofosbuvir in a daily dose of 400 mg and ribavirin starting at 400 mg daily. The ribavirin dose was increased up to 1,200 mg daily, depending on the patient’s hemoglobin levels.
At week 4 of the study, all 40 patients were HCV RNA negative. At the end of treatment, 39 of the patients who were still in the trial were HCV negative. Four weeks post treatment, 27 of 35 were negative.
Of the nine patients who relapsed post treatment, eight were male, five were genotype 1a, three were genotype 1b, and one was genotype 4. Eight of the nine had prior treatment. And five had bridging fibrosis or cirrhosis.
There were no episodes of rejection, and there were no interactions that required adjustment of immunosuppressive therapy.
The most common side effects were fatigue, arthralgia, headache, and diarrhea. Six patients had a serious adverse event. Two patients withdrew as a result of a serious adverse event, but the events were not related to sofosbuvir, said Dr. Charlton.
In late October, the Food and Drug Administration’s Antiviral Drugs Advisory Committee unanimously recommended the approval of sofosbuvir for two indications: in combination with pegylated interferon and ribavirin, for treatment-naive adults with genotype 1 and 4 infections and in combination with ribavirin, for adults with genotype 2 and 3 infections.
If approved, as is expected, the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland, and Turkey, according to Gilead.
Dr. Charlton disclosed that he has received research support and consulting fees from a variety of companies, including AbbeVie, Biotest, Bristol Myers-Squibb, Gilead, Novartis, and Vertex.
The study was funded by Gilead Sciences.
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