Laird Harrison

November 20, 2015

SAN FRANCISCO — A fixed-dose combination of sofosbuvir plus velpatasvir is highly effective for patients with hepatitis C genotypes 1, 2, 4, 5, and 6, according to the ASTRAL-1 trial.

"The major advantage of this is the pangenotypic coverage with a simple 12-week regimen," said Jordan Feld, MD, MPH, from the Toronto Western Hospital Liver Clinic.

The trial results were presented here at the Liver Meeting 2015 and published online simultaneously in the New England Journal of Medicine.

There are highly effective treatments already on the market, but when choosing which combination of drugs to prescribe, clinicians must take into account the patient's treatment history, virus type and subtype, stage of fibrosis, and possible antiviral resistance, Dr Feld explained.

And many existing combinations include ribavirin, which can cause serious adverse events.

Dr Feld and his colleagues wanted to know if the combination of sofosbuvir, which inhibits the hepatitis C virus NS5B polymerase, and the experimental drug velpatasvir, which inhibits the NS5A polymerase, could simplify these treatments.

Data from two phase 2 trials, published earlier this month, showed that the two-drug combination is well tolerated and effective, as reported by Medscape Medical News.

The investigators evaluated patients treated at 81 sites in Canada, Europe, Hong Kong, and the United States from July to December 2014.

In the double-blind study, 624 patients were randomized to the once-daily single-tablet combination of sofosbuvir 400 mg plus velpatasvir 100 mg, and 116 patients were randomized to placebo.

There were no major differences between the two groups at baseline, and both groups included patients with compensated cirrhosis. In the combination group, 37% of patients were from the United States, 79% were white, and none were infected with HIV. Because of the low prevalence of patients infected with hepatitis C genotype 5, all were treated with the combination.

Overall, 99% of patients in the combination group achieved a sustained virologic response at 12 weeks, defined as a hepatitis C RNA count below 15 IU/mL. No one in the placebo group achieved that level of viral load at any timepoint.

Table. Sustained Virologic Response Rate at 12 Weeks

Hepatitis C Genotype Sustained Virologic Response (%)
1a 98
1b 99
2 100
4 100
5 97
6 100

 

After treatment, 99% of patients with cirrhosis achieved a sustained virologic response, as did 99% of previously treated patients.

Two patients experienced virologic failure. One was a 56-year-old white man without cirrhosis who had not been previously treated for his genotype 1a infection. The other was a 58-year-old black man with cirrhosis who had a persistently detectable hepatitis C RNA level during previous treatment with peginterferon and ribavirin for his genotype 1b infection.

Both men had undetectable levels of hepatitis C RNA after 4 weeks of treatment, but relapsed after that. Both had NS5A-resistant variants of the virus at baseline and at the time of relapse.

However, the other 255 patients in the combination group with NS5A-resistant variants all achieved a sustained virologic response, as did all 54 patients with NS5B-resistant variants.

Of the four patients in the combination group who did not achieve a sustained virologic response, two were lost to follow-up, and one discontinued treatment because of an anxiety attack. In addition, one died in his sleep during follow-up, but the investigators do not think the death was related to the treatment.

The rate of hematologic abnormalities was low in both the combination and placebo groups (1% vs 0%). There was no significant difference in the rate of any adverse events between the two groups.

"Very Impressive" Results

These results are "very impressive," said session moderator Ronald Sokol, MD, from the University of Colorado School of Medicine and Children's Hospital Colorado in Denver.

"There are some who believe that the future is a one-size-fits-all single pill, such that a primary care doctor could prescribe it without having to be concerned about genotype, viral load, or complications," he explained.

"This study seems to show that for most patients, this combination could be used for any genotype except genotype 3."

Because genotype 3 is the hardest to treat and often requires a combination of more than two drugs, it is now studied in separate trials, he said.

In fact, results from ASTRAL-2 and ASTRAL-3 were published online this week in the New England Journal of Medicine.

ASTRAL-3, an open-label study of patients with genotype 3 infection, showed that sustained virologic response was better with 24 weeks of sofosbuvir plus velpatasvir than with 24 weeks of sofosbuvir plus ribavirin (95% vs 80%).

ASTRAL-2, an open-label study of patients with genotype 2 infection, showed that sustained virologic response was better with 12 weeks of sofosbuvir plus velpatasvir than with 12 weeks of sofosbuvir plus ribavirin (99% vs 94%).

Results from ASTRAL-4, an open-label trial of patients with genotype 1a, 1b, 2, 3, 4, or 6 infection and decompensated cirrhosis, who were excluded from the ASTRAL-1 trial, were also published online this week in the New England Journal of Medicine. A competing combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir is contraindicated this population, as reported by Medscape Medical News.

ASTRAL-4 showed that sustained virologic response was worse with 12 weeks of sofosbuvir plus velpatasvir than with 24 weeks of sofosbuvir plus velpatasvir and 12 weeks of sofosbuvir plus velpatasvir plus ribavirin (83% vs 86% vs 94%).

Early improvements in hepatic function were seen in many patients, the ASTRAL-4 investigators report. The rate of adverse events was similar in the three groups, and included fatigue, nausea, and headache. The nine people who died were evenly distributed among the three groups, but the investigators did not attribute these deaths to the treatments.

The studies were funded by Gilead Sciences. Dr Feld reports relationships to Gilead Sciences, Aptalis, Bayer, and Bristol-Myers Squibb. Dr Sokol reports relationships to Gilead Sciences and AbbVie.

The Liver Meeting 2015: American Association for the Study of Liver Diseases (AASLD). Abstract LB-4. Presented November 16, 2015

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