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. Erlotinib 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 Ponatinib concentration 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. Buspirone HCl 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).