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Double or Triple DAA Therapy for HCV-1 Yields 95-100% SVRs in 6 or 12 Weeks (SYNERGY Study)
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CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Six or 12 weeks of therapy with three oral direct-acting antivirals (DAAs) for HCV genotype 1 (HCV-1) infection yielded 95% or higher sustained virologic response rates 12 weeks after treatment ended in treatment-naive inner-city patients with hard-to-treat HCV infection [1]. Almost everyone had an undetectable HCV load at the end of 6 or 12 weeks of treatment with an assay that measures HCV RNA levels down to 12 IU/mL.
Researchers from the National Institutes of Health and collaborating centers in the Washington-Baltimore area proposed that their findings offer "a new paradigm of combination therapy to reduce HCV treatment duration, which may be vital to the treatment and eradication of HCV globally."
SYNGERY involved double- or triple-DAA combinations given for 6 or 12 weeks to treatment-naive HCV-1 patients consecutively enrolled in three arms of this phase 2 prospective cohort study. No one had HIV-1 infection. The base combination included sofosbuvir (a nucleotide NS5B polymerase inhibitor) and ledipasvir (an NS5A inhibitor) in a once-daily fixed-dose combination (FDC). Arm A participants took FDC for 12 weeks. Arm B participants took FDC plus GS-9669, a once-daily nonnucleoside NS5B inhibitor, for 6 weeks. Arm C enrollees took FDC plus GS-9451, a once-daily HCV NS3/4 protease inhibitor, for 6 weeks. Each arm had 20 participants. No one in arm B or C could have cirrhosis; arm A participants could have any fibrosis stage.
Most study participants (88%) were African American, men (72%), and infected with genotype 1a (70%). Most had an HCV load above 800,000 IU/mL (70%), and most had an IL28B non-CC genotype (82%), which is associated with lower chances of responding to interferon/ribavirin. Stage 3 or worse fibrosis affected 35% in arm A, 25% in arm B, and 25% in arm C. None of these variables differed significantly between arms.
In an intention-to-treat analysis, everyone in arm A, 75% in arm B, and 95% in arm C had an end-of-treatment viral load below 12 IU/mL. With an assay limit of 43 IU/mL, everyone in every arm had an undetectable HCV load at the end of treatment.
Everyone in arm A had a sustained virologic response for 12 weeks after completing therapy (SVR12), as did 95% in arm B and 100% in arm C. All told, 39 or 40 participants in this hard-to-treat population attained SVR12 after 6 weeks of treatment with triple-DAA therapy. Everyone taking two DAAs for 12 weeks reached SVR12. Viral decay was significantly faster with the triple combinations than with the double combinations.
No one stopped treatment, and there were no grade 4 adverse events or serious adverse events related to study medication. There were two grade 3 adverse events--pain related to post-treatment liver biopsy and vertigo in a patient with a history of severe intermittent vertigo. Alanine aminotransferase levels dropped to normal after 2 weeks of treatment in 90% in arm A, 100% in arm B, and 95% of arm C. Grade 3 abnormalities developed during treatment in 15% in arm A, 10% in arm B, and 20% in arm C.
The SYNERGY team concluded that, "in this inner city patient population addition of a third antiviral agent allowed successful eradication of HCV in 6 weeks in a difficult to treat patient population."
Reference
1. Kohli A, Sims Z, Nelson A, et al. Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: final results of the SYNERGY trial. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 27LB.
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