AASLD 2013: Black Hepatitis C Patients Do Well on Sofosbuvir Oral Regimens

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Interferon-free treatment using a single daily combination pill containing sofosbuvir plus ledipasvir demonstrated potent anti-HCV activity and was generally well-tolerated in a primarily African-American inner city population with genotype 1a hepatitis C, researchers reported at the recent AASLD Liver Meeting in Washington, DC. Adding a third drug resulted in high early post-treatment response rates with shorter treatment.

Combining direct-acting antiviral agents (DAAs) that target different steps of the hepatitis C virus (HCV) lifecycle allows for effective treatment without the prolonged duration and side effects associated with the former standard of care, pegylated interferon plus ribavirin.

Most clinical trials of next-generation HCV drugs have been sponsored by pharmaceutical companies. In parallel, the National Institute of Allergy and Infectious Diseases (NIAID) has conducted studies in underserved populations with the aim of finding simple, brief, and well-tolerated treatment for patients prone to difficulties with poor adherence and side effects.

In the previous SPARE study, Anu Osinusi from the National Institutes of Health Clinical Center and colleagues tested a simple 2-drug regimen of Gilead Science's nucleotide HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus either standard weight-based or low-dose ribavirin in primarily African-American, treatment-naive, genotype 1 hepatitis C patients in inner-city neighborhoods of Washington, DC. Because ribavirin can cause anemia, especially in black patients, they assessed whether starting with a lower dose could reduce side effects without compromising effectiveness.

As previously reported at prior conferences and in the August 28, 2013, Journal of the American Medical Association, treatment was generally safe and well-tolerated, with 24-week posted-treatment sustained virological response (SVR24) rates of 68% for the weight-based ribavirin arm, falling to 48% for the low-dose arm. While these rates compare favorably to pegylated interferon plus ribavirin for difficult-to-treat patients, numerous studies have since shown that much better response rates are possible with DAA combination regimens.

In the NIAID SYNERGY study, described in a poster at the Liver Meeting, Osinusi, Anita Kohli from Science Applications International, and colleagues evaluated ribavirin-free oral DAA regimens using a fixed-dose coformulation containing sofosbuvir and the NS5A inhibitor ledipasvir (GS-5885).

This Phase 2 study included 60 previously untreated genotype 1 chronic hepatitis C patients. Most (88%) were African-American, 72% were men, 70% had harder-to-treat HCV subtype 1a, 80% had unfavorable non-CC IL28B gene patterns, 23% had advanced liver fibrosis (stage F3), and 3 people had cirrhosis (stage F4); people with hepatitis B or HIV coinfection were excluded. People of African descent were traditionally regarded as poor responders to interferon-based therapy, but it is now known that this is largely due to a low frequency of the favorable IL28B CC variant associated with good interferon responsiveness.

Participants were consecutively enrolled into 3 arms. Arm A received the once-daily sofosbuvir/ledipasvir coformulation (400 mg/90 mg) alone for 12 weeks, Arm B received sofosbuvir/ledipasvir plus the non-nucleoside polymerase inhibitor GS-9669 (500 mg/day) for 6 weeks, and Arm C received sofosbuvir/ledipasvir plus the HCV protease inhibitor GS-9451 (80 mg/day) for 6 weeks. Patients with cirrhosis were only included in Arm A.

Results

"Subjects with poor prognostic factors for traditional interferon-based therapy can be effectively treated with interferon- and ribavirin-free DAA-only regimens," the researchers concluded.

"The single combination pill of [sofosbuvir/ledipasvir fixed-dose combination] for 12 weeks is an effective regimen to treat HCV in this population," they continued. This study provided "proof of concept that multiple DAAs targeting various stages of the HCV lifecycle in combination can effectively reduce HCV treatment durations, with high rates of SVR4, which will need to be confirmed with follow-up (SVR12) and in larger clinical trials."

11/21/13

Reference

A Kohli, Z Sims, M Marti, et al. Combination Oral, Ribavirin Free, Antiviral Therapy to Optimize Treatment Outcomes for Hepatitis C Treatment Naive Patients: Interim Results from the NIAID SYNERGY Trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract LB-8.