More Direct-Acting Antiviralsfor Treatment of Hepatitis C
ABSTRACT & COMMENTARY
By Dean L. Winslow, MD
Clinical Professor of Medicine and Pediatrics Division of Infectious Diseases and Geographic Medicine Stanford University School of Medicine, Associate Editor of Infectious Disease Alert
Dr. Winslow is a consultant for Siemens Diagnostic.
SYNOPSIS: In a phase 2b, randomized, open-label trial, faldepravir+deleobuvir+ribavirin resulted in 52-69% rate of sustained virologic response (SVR) at 12 weeks in patients with HCV genotype 1 infection.
SOURCE: Zerzem S, et al. Faldepravir and deleobuvir for HCV genotype 1 infection. New Engl J Med 2013;369:630-9.
Faldepravir (a HCV protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor) were studied in a phase 2b randomized, open-label trial. 362 patients, all with previously untreated HCV genotype 1 infection were randomly assigned to 5 groups: Faldepravir (FDV) 120 mg daily plus deleobuvir (DBV) 600 mg three times daily plus ribavirin (RBV) for 16, 28, or 40 weeks (TID 16W, TID 28W, TID 40W), FDV 120 mg daily plus DBV 600 mg twice daily plus RBV for 28 weeks (BID 28W), or FDV 120 mg daily plus DBV 600 mg three times daily without RBV for 28 weeks (TID 28W-NR). The primary endpoint was sustained virologic response 12 weeks after completion of treatment.
SVR was attained in 59% TID 16W group, 59% in the TID 28W group, 52% in the TID 40W group, 69% BID 28W group, and 39% in the TID 28W-NR group. The rate of SVR did not differ significantly by protease inhibitor (PI) dose or duration in the ribavirin-containing arms. However the SVR rate was significantly higher in the TID 28W dose than in the TID 28W-NR arm. Rates of SVR were higher in patients with genotype 1b infection (56-85%) than they were in patients with genotype 1a infection (11-47%) and also tended to be higher in patients with IL28B CC genotype. Rash, photosensitivity, nausea, vomiting and diarrhea were seen in all arms but serious adverse events were recorded in only 7% of patients. Anemia was more prominent in patients treated with RBV-containing regimens.
We will soon have quite a few options for direct-acting antiviral (DAA) treatment of HCV infection which do not require the use of interferon. Faldepravir (like boceprevir and telaprevir) is inhibitor of the HCV NS3/4a serine protease. Deleobuvir is a non-nucleoside inhibitor of the NS5b polymerase. These drugs are only a bit behind a number of other DAA’s in the drug development pipeline. These other agents include sofosbuvir,1a nucleoside analogue NS5b polymerase inhibitor and ABT-333,2another NS3/4a protease inhibitor, both of which also demonstrated excellent activity in combination with RBV for treatment of HCV genotype 1 infections. However at this point it appears that RBV may still be necessary as part of these various combination therapy regimens.
1.Gane EJ, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. New Engl J Med 2013;368:34-44
2.Poordad F, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. New Engl J Med 2013;368:45-53.