Two-drug direct-acting antiviral combination treats advanced liver disease

August 8, 2018

Ledipasvir/sofosbuvir is safe and effective for hepatitis C virus patients who fail on simeprevir/ sofosbuvir.

Real–world experience supports the use of a fixed–dose combination with ledipasvir/sofosbuvir as a safe, well–tolerated and efficacious treatment option in hepatitis C virus (HCV) patients who fail prior therapy with simeprevir/ sofosbuvir, including patients with decompensated cirrhosis and liver transplant recipients, according to a new study. The addition of ribavirin may help achieve an optimal virologic response, particularly in those who receive 12 weeks of therapy.

Combination therapy of the nonstructural protein 3/4A protease inhibitor simeprevir with the nonstructural protein 5B nucleotide analogue polymerase inhibitor sofosbuvir has been approved for hepatitis C genotype 1, with overall sustained virologic response rates at 12 weeks (SVR12) of 85 to 95 percent. The single tablet fixed–dose combination of the nonstructural protein 5A inhibitor ledipasvir with sofosbuvir is also approved for genotype 1, with SVR12 rates of 95 percent and higher.

Since ledipasvir targets a different site in the HCV replication cycle, it was postulated that ledipasvir/sofosbuvir could be a retreatment option for simeprevir/sofosbuvir failures.

The researchers published their results in the May 2018 issue of Alimentary Pharmacology & Therapeutics.

A study of combined treatment from 2 hepatology centers included 30 patients previously treated with simeprevir/sofosbuvir, with or without ribavirin, for 12 weeks, but who failed to achieve SVR and then underwent retreatment with ledipasvir/sofosbuvir, with or without ribavirin.
The patients received ledipasvir/sofosbuvir, with or without ribavirin, for 12 to 24 weeks based on the discretion of the treating hepatologist. Three-quarters of the patients were Caucasian men. Most of them had genotype 1a and cirrhosis; two-thirds had decompensated, Child's class B or C cirrhosis. Three patients were liver transplant recipients with recurrent HCV.

“Our results with an overall SVR of 90 percent using ledipasvir/sofosbuvir with or without ribavirin for 12 to 24 weeks in those who have failed an initial 12–week course of simeprevir/sofosbuvir with or without ribavirin provide a promising option for such patients,” wrote the researchers, led by Apurva A. Modi, MD, of Baylor All Saints Medical Center in Fort Worth, Texas.

The cohort was notable for a large proportion with advanced liver disease, including 86 percent with cirrhosis and the majority with a history of clinical decompensation. Despite their advanced disease, 90 percent, 92 percent and 100 percent of patients with Child's class A, B, and C, respectively, achieved SVR.

The treatment was well tolerated, with 37 percent of patients reporting no adverse events. The most common adverse events were fatigue, headache, insomnia and nausea. Two patients with Child's B cirrhosis required hospitalization during treatment, one for variceal hemorrhage and one for abdominal pain. No treatment discontinuations or deaths occurred. As expected, the majority of patients who received ribavirin experienced anemia as a side effect.

“Based on our findings, a multi–direct-acting antiviral (DAA) regimen involving the use of 3 or more DAAs may not be required in the majority of cases of simeprevir/sofosbuvir failure especially in those with decompensated cirrhosis, and dual DAA therapy with ledipasvir/sofosbuvir could be considered a viable option,” the researchers wrote.