Triple directing-acting combination treats decompensated liver disease

A combination of simeprevir, sofosbuvir and daclatasvir has the potential to become a short-duration, ribavirin-free alternative regimen for the treatment of difficult-to-cure hepatitis C virus (HCV) GT1-infected patients, according to a new study.

“HCV treatment continues to improve. High sustained virologic response (SVR) rates can be achieved even in patents with very advanced disease and other characteristics historically associated with poor treatment outcomes,” Eric Lawitz, MD, clinical professor of medicine at the University of Texas Health Science Center in San Antonio, Texas, told Medical Economics.

The researchers published their results in the April 2017 Journal of Viral Hepatitis.

Chronic HCV infection is associated with the development of cirrhosis, and patients who develop decompensated cirrhosis have decreased survival rates compared with those who have compensated cirrhosis. Despite availability of treatment for HCV infection in patients with decompensated liver disease, treatment options must be carefully considered in this patient group due to the severity of their underlying disease, said Lawitz.

Next: Study details

The Phase II IMPACT study evaluated the efficacy, safety and tolerability of the combination of three potent direct-acting antiviral (DAA) agents: simeprevir, an HCV NS3/4A protease inhibitor; sofosbuvir, a pangenotypic nucleotide HCV NS5B polymerase inhibitor; and daclatasvir, a pangenotypic HCV NS5A replication complex inhibitor. All three have different mechanisms of action, non-overlapping resistance profiles and are approved for the treatment of HCV infection.

The study enrolled 40 HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease. “The hypothesis of the study was that the addition of a third compound would increase the regimen's potency in this particularly challenging population,” said Lawitz.

All patients cleared HCV after only 12 weeks of therapy, confirming that eradication of the infection is possible even in very advanced stages.

“All 40 of the treatment-naïve and treatment-experienced patients with cirrhosis and portal hypertension (Child Pugh A) or decompensation (Child Pugh B) achieved SVR12 and SVR24 after the end of treatment, regardless of the presence of simeprevir and/or daclatasvir resistance-associated variants at baseline,” said Lawitz.

Overall, the triple DAA regimen was well tolerated. Grade 1/2 adverse events occurred in two-thirds of patients. There were no discontinuations due to adverse events, and only one on-treatment Grade 3 adverse event (gastrointestinal hemorrhage in a Child Pugh B patient) was reported, but this was not related to study treatment, he said.

Lawitz acknowledged that larger trials would be required to confirm the study's results, and noted that currently the use of a protease inhibitor in patients with decompensated liver disease is not recommended. Simeprevir is not indicated for Child Pugh B and C and no dose recommendation can be given for that patient population, he said.

“Nonetheless, a very important take away from IMPACT is that combination of three mechanisms of action can enhance response rates over what could be delivered by a combination of just two of the drugs alone,” said Lawitz. “This proof of concept supports, by the enhanced potency of the combination of three mechanisms of action, the consideration of the possibility of further shortening treatment in patients without cirrhosis.”