Miriam E. Tucker

April 14, 2014

LONDON — An interferon-free triple-combination antiviral regimen is highly effective in people with hepatitis C genotype 1 and cirrhosis, according to a new study.

"Safe and effective regimens are needed for patients with cirrhosis," which remains difficult to cure, even in the era of direct-acting antiviral therapy, said investigator Fred Poordad, MD, vice president of academic and clinical affairs at The Texas Liver Institute and a clinical professor of medicine at the San Antonio University of Texas Health Science Center.

The 78-center multinational randomized TURQUOISE II study is the first-ever trial of an all-oral antiviral regimen conducted exclusively in cirrhotic patients with hepatitis C genotype 1, said Dr. Poordad.

The combination, from AbbVie, consists of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir, and the non-nucleoside polymerase inhibitor dasabuvir and ribavirin. Sustained viral response at 12 weeks (SVR12) was 91.8% after 12 weeks of treatment and 95.9% after 24 weeks of treatment, and the combination was generally well tolerated.

The results were presented here at the European Association for the Study of the Liver International Liver Congress 2014 and simultaneously published online in the New England Journal of Medicine.

Two other trials of this 3D regimen presented at the meeting — SAPPHIRE I and SAPPHIRE II — showed SVR12 rates of about 96% in treatment-naïve and treatment-experienced noncirrhotic patients.

TURQUOISE II compared 12-week and 24-week 3D regimens in 380 treatment-naïve (40%) and treatment-experienced (60%) patients with Child-Pugh class A cirrhosis, some of whom had low platelet counts, low albumin, and radiographic evidence of ascites. Such patients are typically excluded from other trials, Dr. Poordad explained.

Genotype 1a Might Require Longer Treatment

Both the 12- and 24-week regimens were superior to historic SVR12 rates with current regimens, including direct-acting antivirals and pegylated interferon. However, rates were somewhat better for hepatitis C genotype 1b.

Table. Sustained Viral Response in Patients With Hepatitis C

Weeks of Treatment Genotype 1a, % Genotype 1b, %
12 88.6 98.5
24 94.2 100.0

 

In the group with genotype 1a, the difference was driven by previous null responders rather than by those who were treatment-naïve or partial responders at baseline, Dr. Poordad reported.

Relapse was significantly higher in the 12-week group than in the 24-week group (5.9% vs 0.6%). Of the 12 patients in 12-week group who relapsed, 7 were genotype 1a null responders, he noted.

High SVR12 rates were even achieved in patients with low platelet counts and low albumin levels. Of 17 patients who had virologic failure after 12 weeks of treatment, 15 were found to have at least 1 resistance-associated variant at the time of failure.

Safety

Adverse event rates were about 91% in each of the treatment groups. The most common events in the 12- and 24-week groups were fatigue (32.7% vs 46.5%), headache (27.9% vs 30.8), and nausea (in 17.8% vs 20.3%). Hemoglobin levels below 10 g/dL were less common in the 12-week than 24-week group (7.2% vs 11.0%), and were managed with a ribavirin dose reduction.

Most adverse events were mild to moderate. There were more serious adverse events in the 12-week than the 24-week group (6.2% vs 4.7%), which led to discontinuation in about 2% of each group. No specific pattern in adverse events was noted.

Clinical Judgment Needed

"This was a very good study," said session comoderator Jean-Michel Pawlotsky, MD, PhD, director of the French National Reference Centre for Viral Hepatitis. "It's a cirrhotic population, so it's an important trial."

"There are a lot of cirrhotic patients. The data are clear-cut, with an unexpectedly high SVR rate," he told Medscape Medical News.

"I think for genotype 1, a 24-week regimen is probably reasonable because of the lower SVR rates," he added.

"One has to use clinical judgment," explained Dr. Poordad. "If you can't determine whether or not a patient was a null responder, you might want to consider treatment for a little bit longer."

"There was no statistical difference between the 2 arms, but because there was a numerical difference, you might want to err on the side of treating a little bit longer. Patients certainly tolerate 24 weeks just as well," he said.

After his presentation, Dr. Poordad was asked about the tolerability of the ribavirin. "I was actually amazed that in this very large cohort of patients, they tolerated the ribavirin quite well," he said. "I would say it's probably more tolerable than we think, even in this population."

Other studies of the 3D regimen suggest that patients with hepatitis C genotype 1b might not need ribavirin. "I think we need further study in the 1a population. Although they still achieve high SVRs without ribavirin, to maximize SVR with this regimen in the 1a population, I would start with ribavirin," Dr. Poordad said.

Dr. Poordad reports financial relationships with AbbVie, Achillon Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Kadmon, Medarex, Medtronic, Merck, Novartis, Onyx/Bayer, Salix, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec/Janssen, Theravance, Vertex, and ZymoGenetics. Dr. Pawlotsky reports financial relationships with Abbott, AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Janssen, Merck, Novartis, and Roche.

European Association for the Study of the Liver (EASL) International Liver Congress 2014. Abstract 163. Presented April 12, 2014.

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