- Category: Experimental HCV Drugs
- Published on Tuesday, 04 March 2014 00:00
- Written by Liz Highleyman
Interferon- and ribavirin-free treatment using sofosbuvir, ledipasvir, and a third drug for as little as 6 weeks can cure a majority of previously untreated people with genotype 1 hepatitis C, including those with traditional predictors of poor response, according to results from the SYNERGY trial presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) this week in Boston.
The old standard-of-care hepatitis C treatment using pegylated interferon plus ribavirin lasts 12 to 24 weeks, requires weekly injections, causes difficult side effects, and fails to cure many patients. The advent of direct-acting antiviral agents (DAAs) now allows for interferon-free, all-oral treatment that is better tolerated and has higher sustained response rates.
While most clinical trials of next-generation hepatitis C drugs are sponsored by pharmaceutical companies, the National Institutes of Allergy and Infectious Diseases (NIAID) is conducting parallel studies in underserved populations, looking for simple, well-tolerated treatments for people prone to difficulties with poor adherence and side effects. Many people with hepatitis C belong to marginalized groups that have limited access to health care. In addition, many have a history of injection drug use, and people in recovery are often hesitant to undergo treatment that involves needles
In the NIAID SYNERGY study, Anita Kohlifrom the National Institutes of Health and colleagues evaluated brief interferon- and ribavirin-free oral DAA regimens using a fixed-dose coformulation of Gilead Science's recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi, formerly GS-7977) and NS5A inhibitor ledipasvir (formerly GS-5885).
Participants were randomly assigned to receive either dual therapy with sofosbuvir/ledipasvir alone for 12 weeks, or the coformulation plus a third direct-acting drug -- either the non-nucleoside HCV polymerase inhibitor GS-9669 or the HCV protease inhibitor GS-9451 -- for six weeks.
The previous NIAID SPARE study showed that 24 weeks of sofosbuvir plus weight-based or low-dose ribavirin (used in an effort to reduce anemia) was generally safe and well tolerated, with 24-week post-treatment sustained virological response (SVR24) rates of 68% and 48%, respectively. But recent trials have shown much higher cure rates with combinations of DAAs that target different steps of the HCV lifecycle.
SYNERGY enrolled 60 mostly low-income chronic hepatitis C patients in Washington, DC. Most had factors traditionally associated with poor treatment response: about 70% were men, around 90% were African-American, about 85% had unfavorable non-CC IL28B gene variants, and 70% had hard-to-treat HCV subtype 1a. About one-quarter had advanced liver fibrosis or cirrhosis (stage F3-F4), but people with cirrhosis were excluded from the six-week arms. People with hepatitis B or HIV coinfection were excluded.
"We believe this population is really reflective of the hepatitis C population in the U.S., which historically has been a difficult-to-treat population," Kohli said.Kohli reported 12-week post-treatment sustained virological response (SVR12) rates at CROI, following presentation of SVR4 rates at last year's AASLD Liver Meeting. Though relapse sometimes still occurs after SVR4, SVR12 is considered a cure.
- HCV viral load declined rapidly, yielding end-of-treatment response rates of 100% in all arms.
- SVR4 and SVR12 rates were the same:
o 100% for patients taking sofosbuvir/ledipasvir alone;
o 95% for those who took sofosbuvir/ledipasvir with GS-9669;
o 100% for those who took sofosbuvir/ledipasvir plus GS-9451.
- 1 patient in the GS-9669 arm relapsed after stopping therapy.
- 90%, 100%, and 95% of patients in the 3 arms, respectively, experienced alanine aminotransferase (ALT) normalization by day 14.
- All regimens were generally safe and well-tolerated.
- There were no serious adverse events or study discontinuations related to study drugs.
- The most common side effects were headache, fatigue, and diarrhea, the latter occurring more often in the arm using GS-9669.
"Hepatitis C can be successfully and safely treated in 6 weeks using 3 direct acting agents with different mechanisms of action," the researchers concluded. "This short duration, simple therapy for HCV may prove relevant for the global elimination of hepatitis C, where uncomplicated, well-tolerated therapy is required to ensure adherence and minimize health care expenditures."
Kohi explained that SYNERGY was designed as an 8-arm trial. Future arms will enroll people with cirrhosis to receive sofosbuvir/ledipasvir plus GS-9451. Researchers will also look at an even shorter triple regimen taken for only 4 weeks.
Session co-moderator Jürgen Rockstroh said that most treatment failures seen in oral DAA combination trials have been related to lack of adherence, which brief therapy could improve. But he cautioned that adding a third drug could increase the cost of treatment, even if it is taken for a shorter period.
A Kohli, Z Sims, A Nelson, et al. Combination Oral Hepatitis C Antiviral Therapy for 6 or 12 Weeks: Final Results of the SYNERGY Trial. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 27LB.