Laird Harrison

November 16, 2015

SAN FRANCISCO — The combination of ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with or without ribavirin, appears to be safe and effective in patients with compensated cirrhosis caused by genotype 1 hepatitis C infection, researchers report.

This news will reassure clinicians and patients, because the US Food and Drug Administration (FDA) recently warned that the drug combination, marketed as Viekira Pak by AbbVie, can increase the risk for serious liver injury in patients with advanced liver disease.

"If you're using it in the appropriate populations, this is a very safe and effective option," Nancy Reau, MD, from the Rush University Medical Center in Chicago, told Medscape Medical News.

The phase 3b TOPAZ-II trial was designed to follow patients being treated with the combination regimen for 5 years to evaluate safety and efficacy. It is being conducted at about 50 sites around the United States.

Dr Reau presented preliminary results from the trial here at the Liver Meeting 2015.

The 650 patients enrolled in TOPAZ-II were 18 years and older, had chronic genotype 1 hepatitis C infection, and were either treatment-naïve or had been treated with pegylated interferon plus ribavirin.

TOPAZ-II

The genetic subtype of the virus and the condition of the patient's liver dictated the treatment regimen.

For patients with subtype 1a infection without cirrhosis and those with subtype 1b infection with cirrhosis, the 12-week regimen consisted of a daily combination of ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, twice-daily dasabuvir 250 mg, and twice-daily ribavirin (total weight-based dosing of 1000 mg or 1200 mg).

Patients with subtype 1a infection with cirrhosis and patients whose genotype was not identified took the same regimen for 24 weeks, although some took it for only for 12 weeks because of their history.

Patients with subtype 1b infection without cirrhosis took the same regimen, although without ribavirin, for 12 weeks.

In the intention-to-treat population, 95.3% of patients achieved a sustained virologic response after 12 weeks of treatment. This level of response is close to a cure and has been shown to reduce the risk for cirrhosis, decompensation, liver-related death, and all-cause mortality.

All treatment groups experienced high rates of sustained virologic response, regardless of previous treatment, hepatitis C subtype, baseline hepatitis C RNA level, IL28B genotype, or fibrosis stage.

Table. Sustained Virologic Response at 12 Weeks

Patient Group n Percent
All patients 615 95
Treatment-naïve 437 96
Treatment-experienced 178 93
Subtype 1a 452 95
Subtype 1b 163 98
Hepatitis C RNA level    
   <800,000 IU/mL 134 98
   ≥800,000 IU/mL 481 95
IL288 genotype    
   CC 146 97
   non-CC 467 95
Fibrosis stage    
   0 or 1 304 96
   2 88 96
   3 108 96
   4 115 92

 

Of the 29 patients (4.7%) who did not achieve a sustained virologic response, five had virologic breakthrough and 11 relapsed; of these, 14 had resistance-associated variant viruses.

The only predictor of the likelihood of virologic failure was a high baseline level of hepatitis C RNA, the researchers report. But even this variable had limited influence; 95% of those with a level of hepatitis C RNA of at least 800,000 IU/mL achieved a sustained virologic response.

Eighty percent of the patients experienced adverse events. Of these, 12% led to a modification of ribavirin, 4% were considered serious, and 1% led to study withdrawal. Ten percent of the adverse events were considered to be treatment-emergent, including fatigue, nausea, headache, pruritus. and insomnia.

One patient died of metastatic pancreatic adenocarcinoma, but the researchers did not consider this to be related to treatment.

FDA Warning

The study puts the FDA direction that Viekira Pak is contraindicated in patients with severe hepatic impairment into context for clinicians, said Dr Reau.

"In yet another population that included compensated cirrhosis, there were no significant side effects, and that, I think, is important with the label change," she explained.

Still, the drug should not be used in patients with decompensated cirrhosis, she said.

 
Anyone using these drugs in patients with cirrhosis needs to be absolutely clear that those patients are hepatically intact.
 

The study provides "a confirmation of the success and of the efficacy of these regimens, and the safety of these regimens as well," said Raymond Chung, MD, from the Massachusetts General Hospital in Boston.

"Perhaps it provides reassurance that fully cirrhotic patients can be treated safely," he told Medscape Medical News.

But Dr Chung cautioned that patients in clinical trials are often monitored more closely than patients in practice. Anyone using these drugs in patients with cirrhosis "needs to be absolutely clear that those patients are hepatically intact, as measured by clinical signs and symptoms and laboratory panels," he said. "And even with that, those cirrhotic patients need to be followed carefully."

This study was funded by AbbVie. Dr Reau reports relationships with AbbVie, Gilead, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, and Janssen. Dr Chung reports relationships with AbbVie, Idenix, Gilead, Mass Biologics, and Tranzyme.

The Liver Meeting 2015: American Association for the Study of Liver Diseases (AASLD). Abstract 1065. Presented November 15, 2015.

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