Treatment with sofosbuvir results in a rapid and sustained virologic response in patients with hepatitis C virus (HCV), report investigators.

The nucleotide analogue that inhibits HCV replication is showing promise when given together with ribavirin or in addition to pegylated interferon (peginterferon) alfa-2a for a variety of genotypes and in different patient populations, new studies show.

"Interferon is always a challenging therapy and depending on the genotype we're treating, patients are going to require 6 months to a year of treatment," Eric Lawitz, MD, from the University of Texas Health Science Center in San Antonio, told Medscape Medical News.

"With sofosbuvir, patients with genotype 1 hepatitis C virus are only going to need 12 weeks of interferon, and in patients with genotype 2 and 3," Dr. Lawitz explained, "we can eliminate interferon completely so sofosbuvir offers a higher efficacy rate, a more favorable safety profile, and either a reduction in the time on interferon or its elimination entirely, which is a significant paradigm shift in the management of hepatitis C."

 
…a significant paradigm shift in the management of hepatitis C. Dr. Eric Lawitz
 

Results from several studies involving sofosbuvir will be presented this week at the International Liver Congress 2013 in Amsterdam, the Netherlands. The findings are published online April 23 in the New England Journal of Medicine in advance of the meeting.

NEUTRINO Trial

In the NEUTRINO open-label study, 327 patients infected with HCV genotypes 1, 4, 5, or 6 received sofosbuvir, ribavirin, and peginterferon alfa-2a for 12 weeks.

Sofosbuvir was given orally at a dose of 400 mg, once a day, along with ribavirin, also given orally in a dose based on weight. Patients who weighed less than 75 kg received 1000 mg/d, and heavier patients received 1200 mg/d. Patients received peginterferon alfa-2a subcutaneously once a week at a dose of 180 μg.

"Most of the patients who were included in the study had hepatitis C genotype1," the authors point out. Only 9% had genotype 4 and 2% had genotype 5 or 6.

In this single-group study, investigators report a sustained virologic response in 90% of patients (95% confidence interval [CI], 87% - 93%).

FISSION Trial

In the noninferiority study known as the FISSION trial, patients with hepatitis C genotype 2 or 3 were randomly assigned to 12 weeks of treatment with sofosbuvir plus ribavirin or to 24 weeks of treatment with peginterferon alfa-2a plus ribavirin. For the peginterferon-ribavirin group, the ribavirin dose was 800 mg/d given in 2 divided doses, in accordance with product labeling.

The sofosbuvir-based regimen was successful in 97% of patients with genotype 2 infection and 56% successful in those with genotype 3 infection compared with 78% and 63% in the standard peginterferon alfa-2a plus ribavirin group.

All patients receiving sofosbuvir in the 2 studies had rapid and substantial decreases in serum HCV RNA levels, the authors report. Further, the magnitude of the decrease during treatment was not substantially different between the various genotypes being treated, they point out.

By the second week after enrollment, 91% of sofosbuvir-treated patients with genotype 1, 4, 5, or 6 infection had an RNA level less than 25 IU/mL.

By week 4, this proportion had increased to almost 100%, and sustained virologic responses were maintained to study endpoint. Patients who achieve a sustained virologic response after 12 weeks of treatment are considered to be cured of hepatitis C.

Twenty-eight patients in the NEUTRINO study and 74 patients in the FISSION study who received treatment with sofosbuvir relapsed after achieving a virologic response at the end of treatment.

However, none of the RNA samples collected after therapy showed any sign of resistance-associated variants, confirming that sofosbuvir has a high barrier to resistance.

Adverse Events

Investigators report that discontinuation rates due to adverse effects were low among patients receiving sofosbuvir-containing regimens.

Among NEUTRINO patients, 2% of those receiving 12 weeks of sofosbuvir plus ribavirin with peginterferon discontinued treatment. In FISSION, just 1% of patients receiving 12 weeks of sofosbuvir plus ribavirin discontinued therapy. However, a higher rate — 11% — of patients who received 24 weeks of peginterferon plus ribavirin stopped treatment.

The most common adverse events in all groups were fatigue, headache, nausea, and insomnia. However, investigators report, influenza-like symptoms and fever, as well as depression, occurred much more frequently in patients receiving peginterferon than in those receiving sofosbuvir.

"These data demonstrate that sofosbuvir plus ribavirin will offer a significant improvement in therapy as the combination eliminates the need for interferon and it has the potential to halve treatment duration for patients with genotypes 2 and 3, which means patients could achieve cure in as little as 3 months," Dr. Lawitz said. "Should the FDA [US Food and Drug Administration] approve sofosbuvir for the treatment of hepatitis C, it could be used in all genotypes either with or without interferon and in treatment-naive, treatment-experienced and interferon-intolerant patients."

In a second paper published in the New England Journal of Medicine and scheduled to be presented at the International Liver Congress this week, researchers led by Ira Jacobson, MD, from Weill Cornell Medical College in New York unveil the findings from 2 new clinical trials of sofosbuvir.

POSITRON Trial

In 1 study, known as the POSITRON trial, patients who could not take peginterferon received sofosbuvir and ribavirin or placebo.

The primary endpoint for the trial was virologic response at 12 weeks. Investigators report that the rate of sustained virologic response was 78% (95% CI, 72% - 83%) among patients receiving sofosbuvir and ribavirin, compared with 0% among those receiving placebo (P < .001).

There was reportedly complete concordance (100%) between rates of sustained virologic response at 12 weeks and at 24 weeks among patients who received sofosbuvir and ribavirin; none of the 153 patients who could be evaluated had virologic relapse after week 12.

FUSION Trial

In the second study, known as the FUSION trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 or 16 weeks.

The rates of sustained virologic response achieved with sofosbuvir and ribavirin in the population of patients with prior treatment were superior to the historical control rate of 25%, with rates of 50% (95% CI, 40% - 60%) in the 12-week group and 73% (95% CI, 63% - 81%) in the 16-week group (P < .001).

The secondary analysis comparing rates of sustained virologic response between the groups showed that patients receiving 16 weeks of treatment had a significantly higher rate of sustained virologic response than patients receiving 12 weeks of treatment (difference, –23 percentage points; 95% CI, –35 to –11 percentage points; P < .001).

"In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection," report investigators. Among patients with genotype 3 infection, response rates were lower among those with cirrhosis.

The most common adverse events were again headache, fatigue, nausea, and insomnia, but the overall discontinuation rate was low at 1% to 2%.

In an accompanying editorial, Joost Drenth, MD, from Radboud University Nijmegen Medical Center in the Netherlands, cautioned that only 3 of 4 of the published sofosbuvir studies were randomized and only 1 was placebo-controlled.

 
[A] radical change in clinical practice is imminent. Dr. Joost Drenth
 

Dr. Drenth also suggested that there may be a worrisome loss of response to sofosbuvir over time that is not seen with interferon-based regimens. On the other hand, he pointed out, the NEUTRINO study involving patients with primarily genotype 1 infection, but also genotype 4, 5, and 6 HCV all responded to 12 weeks of treatment, with a collective rate of sustained virologic response of 90%.

"Sofosbuvir has ungenotypic activity, whereas other drugs target only genotype 1," Dr. Drenth told Medscape Medical News. "We can also treat these patients for a shorter period of time with sofosbuvir and there is less need for interferon. So this is all positive news and data from the sofosbuvir trials suggest that a radical change in clinical practice is imminent."

Gilead Sciences recently submitted a New Drug Application to the FDA for approval of once-daily sofosbuvir for the treatment of hepatitis C. Gilead also plans to file for regulatory approval in other countries, including in the European Union, in the second quarter of 2013.

The studies were funded by Gilead Sciences. Dr. Lawitz reports he has received research grants from multiple pharmaceutical companies.

N Engl J Med. Published online April 23, 2013. Lawitz study full text   Jacobson study full text   Editorial

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