3, 4 The HCV NS5B RNA-dependent RNA polymerase is a key enzyme involved in HCV replication, catalyzing the synthesis of the complementary minus-strand RNA and subsequent genomic plus-strand RNA from the minus-strand template and is also an ideal target for inhibiting HCV replication. Ixazomib nmr Direct-acting antiviral agents (DAAs) target the HCV-encoded proteins and when added to Peg-IFN/RBV have resulted in improved SVR rates compared to standard of care.5, 6 Telaprevir and boceprevir are two NS3/4a protease inhibitors for which phase 3 trials are nearing completion. In these trials,5-7 telaprevir and boceprevir are both added to Peg-IFN/RBV, with substantial improvement in SVR rates in both treatment-naive

patients and prior nonresponders. These agents are associated with additional side effects including anemia, skin rash, and gastrointestinal www.selleckchem.com/products/Roscovitine.html symptoms. Both telaprevir and boceprevir have been shown to cause rapid selection of resistance-associated variants when given as monotherapy, and neither DAA should be administered without Peg-IFN/RBV.8

Studies with both drugs have shown that optimal doses of RBV are needed to maximize SVR rates and minimize the development of resistance-associated variants. The resistance profile of triple therapy with boceprevir is similar to that of telaprevir in patients who fail to achieve SVR,5 and cross-resistance against other NS3 protease inhibitors may occur.8, 9 These resistant strains have been found to persist after withdrawal of therapy with telaprevir and boceprevir in combination with Peg-IFN/RBV and can persist up to 3 years.8, 9 The INFORM-1 (Interferon-Free regimen for the Management of HCV)

trial is the first randomized, double blind, placebo-controlled, dose escalation trial performed in six centers in New Zealand and Australia. This trial was designed to examine the safety of two new direct-acting antiviral drugs: RG7128 and danoprevir. RG7128 is a 3′5′-di-isobutyric acid ester prodrug of the cytosine nucleoside analogue β-D-2′-deoxy-2′-fluoro-2′C-methylcytidine. Thymidine kinase This compound’s triphosphate form inhibits HCV NS5b RNA polymerase. Danoprevir is a macrocyclic inhibitor of HCV NS3/4A protease, which differs from the linear protease inhibitors telaprevir and boceprevir. The addition of RG7128 to danoprevir is an important milestone as the combination of DAAs in the treatment of hepatitis C has the potential to reduce the emergence of resistant associated variants. Moreover, therapies that can be effective in patients with hepatitis C genotype 1 infection without Peg-IFN/RBV will make treatment possible for the many patients who have contraindications to Peg-IFN therapy. Eighty-eight genotype 1–infected Caucasian patients without cirrhosis who had a minimum HCV RNA of 105 IU/mL were randomized in the INFORM-1 trial, including both treatment-naïve (n = 66) and treatment-experienced patients (n = 22).