AT THE INTERNATIONAL LIVER CONGRESS 2015
VIENNA (FRONTLINE MEDICAL NEWS) – All-oral HCV therapy with grazoprevir and elbasvir plus sofosbuvir achieved high, sustained virologic response (SVR) rates at 12 weeks after only 6-8 weeks of therapy in a proof-of-concept phase II study.
“HCV therapy is evolving toward a once-daily, short duration, pan-genotypic, highly effective and safe regimen,” said Dr. Fred Poordad of the Texas Liver Institute, San Antonio, who reported the findings of the C-SWIFT study at the meeting sponsored by the European Association for the Study of the Liver.
“The aim of this study was to combine three highly potent direct-acting antivirals (DAAs) grazoprevir, elbasvir and sofosbuvir, each with a different mechanisms of action, to see if we could shorten therapy in two of the most difficult-to-cure populations, genotype 1 [GT1] and genotype 3 [GT3] with and without cirrhosis,” he said.
For inclusion, patients had to be treatment naive and older than 18 years of age. Cirrhosis had to be present, assessed either by liver biopsy or via noninvasive testing, and the minimum hemoglobin at enrollment needed to be 9.5 g/dL. Patients also had to be negative for HIV and the hepatitis B virus, and have liver enzyme below 350 IU/L.
Treatment consisted of a fixed-dose, once daily combination of grazoprevir 100 mg and elbasvir 50 mg plus additional sofosbuvir 400 mg, once daily. The duration of therapy depended on genotype and the presence or absence of cirrhosis.
A total of 102 patients with GT1 were enrolled, of whom 61 had no cirrhosis and were treated with the three-drug combination for a total of 4 (n = 31) or 6 (n = 30) weeks. Patients with GT1 and cirrhosis were treated with the regimen for 6 (n = 20) or 8 (n = 21) weeks.
There were 41 GT3 patients enrolled, of whom 29 had no cirrhosis and were treated for 8 (n = 15) or 12 weeks (n = 14). The 12 GT3 cirrhotic patients received 12 weeks of the regimen.
Dr. Poordad noted that the majority of patients studied were male, in their mid-50s, and of white ethnicity. The majority of the GT1 patients were subtype 1a.
Results showed that 33% of GT1 patients without cirrhosis achieved SVR12 with 4 weeks of treatment, and 87% with 6 weeks therapy. SVR12 was achieved in 80% and 94% of patients with GT1 and cirrhosis after 6 and 8 weeks of therapy, respectively.
No patient experienced breakthrough. Twenty of the noncirrhotic GT1 patients treated for 4 weeks relapsed, as did four who were treated for 6 weeks. Four relapses also occurred in cirrhotic GT1 patients treated for 6 weeks and one patient with cirrhosis relapsed after 8 weeks of treatment.
Dr. Poordad noted that patients relapsed most commonly if they had either wild-type virus or resistant-associated variants (RAV) already present at baseline.
In the GT3 arms, SVR12 was achieved by 93% and 100% of the noncirrhotic patients treated for 8 weeks and 12 weeks, respectively, and by 91% of those with cirrhosis who had 12 weeks of treatment. One patient discontinued treatment early for a reason other than virologic failure and two patients relapsed – one patient without cirrhosis in the 8-week treatment group and one in the cirrhotic group.
“All of the patients became ‘target not detected’ at the end of treatment,” Dr. Poordad observed. “The patient in the 8-week arm relapsed somewhere between SVR4 and SVR12, while the cirrhotic patient relapsed in the first 4 weeks of follow-up” he said.
Of the two GT3 patients with biologic failures, one did not have baseline RAVS and also had wild-type virus at relapse. The other patient had RAVs at baseline in NS3 and in NS5A at relapse.
There were “very few adverse events,” Dr. Poordad said, noting that there were no significant declines in hemoglobin or elevations in liver enzymes or bilirubin. The most common adverse events were headache, fatigue, and nausea, all of which occurred in fairly low numbers.
“This novel regimen of grazoprevir/elbasvir with sofosbuvir was able to shorten therapy duration to 8 weeks or less among patients who were cirrhotic and noncirrhotic with genotype 1,” Dr. Poordad said in summary.
Even GT3 patients were able to achieve high SVR12 rates with 8-12 weeks of therapy, including those who had cirrhosis.
“The concept of shortening therapy, even in the cirrhotic patients, has been demonstrated by this study,” he concluded.
He noted that retreatment of virologic failures was ongoing.
The study was sponsored by Merck & Co. Dr. Poordad has received grant/research support from Merck & Co. and numerous other pharmaceutical companies.
