Sofosbuvir Plus Ribavirin Effective in Multiple Hepatitis Genotypes

According to study results presented at The Liver Meeting 2012, combination treatment with ribavirin and the uridine nucleotide analog sofosbuvir achieved high rates of sustained viral response in a range of patients with hepatitis C.

The uridine nucleotide analog sofosbuvir, in combination with ribavirin, induces rapid decline in viral load in most hepatitis C patients infected with genotypes 1, 2 or 3, according to data presented at The Liver Meeting, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Adding a third drug GS-5885, which inhibits replication through another mechanism, appears to increase efficacy.

The results presented are part of a larger trial, called ELECTRON, testing the efficacy of sofosbuvir (formerly GS-7977) in hepatitis C. “Sofosbuvir is a potent nucleotide chain terminator,” explained lead investigator Edward Gane, MD, of Auckland City Hospital in New Zealand. “It is taken once daily, is very well tolerated, and has a very high barrier to the development of resistance,” a key feature for therapies against rapidly mutating viruses.

Previous trials have shown the ability of patients taking the drug, in combination with ribavirin, to achieve sustained viral reduction (SVR), but the rate of SVR is reduced when either ribavirin is reduced or treatment is shortened.“We hypothesized that adding a second potent directing acting antiviral would enhance the response,” said Gane. That second agent is GS-5885.

Patients in the five arms of the ELECTRON trial presented here displayed a cross-section of viral genotypes and previous therapy experience. The first three arms enrolled patients who were either genotype 1 and treatment naïve, genotype 1 and unresponsive to standard therapy (ribavirin plus peginterferon), or genotype 2 or 3 with some response to previous therapy. Patients in all three of these arms received 12 weeks of daily sofosbuvir plus ribavirin.

Patients in the 4th and 5th arms were genotype 2 or 3 and treatment-naïve. Those in arm 4 received an 8-week course of the two drugs, while those in arm 5 received 12 weeks of sofosbuvir with a reduced dose of ribavirin (800 mg).

A subset of patients with genotype 1 also received GS-5885.

In all arms, there was a very rapid fall in viral load during treatment. The highest rate of viral suppression at 12 weeks after treatment cessation (SVR12) was 84%, for the arm 1, treatment-naïve patients with genotype 1. Results in the other arms were 10%, 68%, 64%, and 60%, for arms 2 through 5, respectively. Genotype 1 null responders (arm 2) are typically the hardest patients to treat.

In the small group of patients receiving GS-5885 as well, 3 of 3 null responders achieved SVR4 (control of virus 4 weeks after stopping treatment), with studies ongoing of their more prolonged response. “The addition of GS-5885 appears to increase the efficacy of this regime,” Gane said.

Adverse events were generally mild and well tolerated, with no patients discontinuing because of side effects of the drugs. There were no serious adverse events attributed to sofosbuvir. Headache, fatigue, nausea, and upper respiratory tract infection were the most common events.

The combination of these treatments “is both a safe and effective regimen for both treatment naïve and treatment-experienced patients, but reducing the dose or duration of ribavirin may reduce its effect,” said Gane.

Gilead Sciences, which sponsored the trial, is moving forward with a Phase III trial of the combination of sofosbuvir and GS-5885.