Laird Harrison

November 19, 2015

SAN FRANCISCO — For patients with hepatitis C genotype 3 infection, a virtual cure is achieved by most patients treated with the combination of daclatasvir, sofosbuvir, and ribavirin, a new study shows.

"We can say that daclatasvir plus sofosbuvir plus ribavirin for 12 or 16 weeks is a highly efficacious therapy for genotype 3–infected patients with advanced fibrosis or compensated cirrhosis, a population in urgent need of treatment," said Vincent Leroy, MD, PhD, from the University of Grenoble in Saint-Martin d'Hères, France.

He presented findings from the ALLY-3+ trial here at the Liver Meeting 2015.

Genotype 3 is considered the hardest of the hepatitis C genotypes to treat, and patients with cirrhosis pose a particular challenge, Dr Leroy said.

In the previous ALLY-3 trial, 96% of patients without cirrhosis treated with 12 weeks of daclatasvir, an NS5A inhibitor, plus sofosbuvir, a nucleoside NS5B inhibitor, achieved a sustained virologic response. However, only 63% of patients with cirrhosis achieved a sustained response.

Dr Leroy and his colleagues wanted to see how well these two drugs would work in patients with compensated advanced fibrosis or cirrhosis when combined with ribavirin.

In their open-label phase 3b study, the investigators treated 48 patients with a regimen of daclatasvir 60 mg, sofosbuvir 400 mg, and a weight-based dose of ribavirin. Half the patients were randomized to 12 weeks of treatment and half were randomized to 16 weeks of treatment.

Patients were excluded if they had evidence of hepatic decompensation, were pregnant, or were not using contraception.

In the study cohort, 80% of patients were men, 98% were white, and 74% had been previously treated, including 10% who had relapsed on sofosbuvir. In addition, 28% had a fibrosis score of 3, indicating advanced fibrosis, and 72% had a fibrosis score of 4, indicating compensated cirrhosis.

The hepatitis C RNA count was at least 6 million IU/mL in 52% of the patients.

There were no virologic breakthroughs with the 12-week or 16-week treatment.

Table. Outcomes 12 Weeks After Treatment

Outcome Sustained Virologic Response, n Relapse, n Death, n
Treatment regimen      
   12 weeks (n = 24) 21 2 1
   16 weeks (n = 26) 24 2 0
   Overall (n = 50) 45 4 1
Patient characteristic      
   Cirrhosis (n = 36) 31 4 1
   Advanced fibrosis (n = 14) 14 0 0
   Previously treated (n = 37) 33 3 0

 

Eight patients had resistance-associated variants of the virus at baseline, but seven of them achieved a sustained virologic response. The exception was a patient with the NS5A–Y93Y/H variant.

At the time of failure, all four patients who relapsed had the resistance-associated variant NS5A–Y93H. The researchers did not find any sofosbuvir-associated resistance-associated variants in NS5B at baseline or at relapse.

The most common adverse events were insomnia (30%), fatigue (26%), and headache (24%). One patient had a grade 3 hemoglobin reduction, but none of the patients discontinued treatment because of adverse events.

Dr Leroy concluded that the 12-week and 16-week courses of treatment were comparable.

 
Genotype 3 generally does not respond to two-drug combinations.
 

This study is "headed in the right direction," said session moderator Ronald Sokol, MD, from the University of Colorado School of Medicine and Children's Hospital Colorado in Denver.

"Something's different about genotype 3," he said. "In every study with direct-acting antivirals, it's the hardest to treat. That's why there are now always separate clinical trials, and they either have longer duration or they add another drug. Genotype 3 generally does not respond to two-drug combinations."

The response was not as impressive in patients with cirrhosis as it was in the other groups, Dr Sokol pointed out.

The study was funded by Bristol-Myers Squibb. Dr Leroy reports financial relationships with many companies, including Bristol-Myers Squibb. Dr Sokol reports relationships with Gilead Sciences and AbbVie.

The Liver Meeting 2015: American Association for the Study of Liver Diseases (AASLD). Abstract LB-3. Presented November 16, 2015.

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