AASLD 2011: High Sustained Response Rates with PSI-7977 Plus Pegylated Interferon/Ribavirin


Adding the hepatitis C virus (HCV) polymerase inhibitor PSI-7977 to pegylated interferon plus ribavirin produced a 91% cure rate for previously untreated patients with hard-to-treat HCV genotype 1, according to results from the PROTON study presented this month at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) in San Francisco.

The advent of direct-acting antiviral agents (DAAs) that target different steps of the HCV lifecycle has ushered in a new paradigm in hepatitis C treatment. Trials of all-oral regimens are underway, but studies that are further along have mostly tested DAAs with pegylated interferon/ribavirin in an effort to increase response rates and shorten treatment duration.

The Phase 2b PROTON study evaluated the safety and efficacy of PSI-7977, Pharmasset's once-daily uridine nucleotide analog HCV polymerase inhibitor, added to pegylated interferon alfa-2a (Pegasys) and ribavirin.

At AASLD Eric Lawitz from Alamo Medical Research presented 12-week sustained virological response (SVR12) outcomes -- or continued undetectable HCV RNA 12 weeks after completion of treatment -- for patients with HCV genotype 1.

Data presented earlier this year showed that 96% of patients with easier-to-treat genotypes 2 or 3 achieved SVR12 using PSI-7977 plus pegylated interferon/ribavirin for 12 weeks.

The genotype 1 analysis included 121 treatment-naive patients. Approximately half were men, the median age was about 50 years, about 75% were white, 20% were black, and 10% were Hispanic. About 75% had HCV subtype 1a and about 40% had the favorable IL28B CC gene pattern; people with liver cirrhosis were excluded.

Participants were randomly assigned to receive 200 mg or 400 mg once-daily PSI-7977 plus pegylated interferon/ribavirin for 12 weeks, continuing on pegylated interferon/ribavirin alone for another 12 weeks. At that point, those with extended rapid virological response (eRVR) stopped treatment, while non-eRVR patients continued on a pegylated interferon/ribavirin "tail" through week 48. A control arm received pegylated interferon/ribavirin standard therapy for 48 weeks.


The researchers noted that the high SVR rate among HCV genotype 1 patients was independent of predictors of poor interferon response.

Lawitz elaborated that among the 13 PROTON participants with the unfavorable IL28B TT pattern, all had a "brisk response" and all achieved SVR12.

Another study presented at AASLD, called ELECTRON, showed that PSI-7977 plus ribavirin -- but without pegylated interferon -- produced a 100% SVR12 rate for genotype 2 and 3 patients. This regimen will be carried forward in further studies of patients with all genotypes.

Investigator affiliations: Alamo Medical Research, San Antonio, TX; Quest Clinical Research, San Francisco, CA; Southern California Liver Ctr, Coronado, CA; VMMC, Seattle, WA; Cedars Sinai Med Ctr, Los Angeles, CA; GI Specialists of Georgia, Marietta, GA; Beth Israel Deaconess, Boston, MA; North Shore University Hospital, Manhassett, NY; OIC, Orlando, FL; Kansas City Gantroenterology and Hepatology, LLCG, Kansas City, MO; University of Florida, Gainesville, FL; Mount Sinai, New York, NY; Cornell University, New York, NY; University of Chicago, Chicago, IL; Alabama Liver and Digestive Specialists, Montgomery, AL; University of North Carolina, Chapel Hill, NC; Fundacion de Investigacion De Diego, San Juan, Puerto Rico; University of Pennsylvania, Philadelphia, PA; Johns Hopkins University, Lutherville, MD; California Pacific Medical Center, San Francisco, CA; ACRI, Anaheim, CA; Columbia Gastroenterology, Columbia, SC; Pharmasset, Inc., Princeton, NJ.



E Lawitz, JP Lalezari, T Hassanein, et al. Once-Daily PSI-7977 Plus Peg/RBV in Treatment-naïve Patients with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-treatment. 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 225.