Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Abstract

Three hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additivesynergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic. H epatitis C virus (HCV) is a positive-stranded RNA virus in theFlaviviridae family of enveloped virions which affects an estimated 170 million people worldwide and is the major cause of chronic hepatitis. Currently, approximately 50% of patients infected with genotype 1 (gt 1), the most prevalent form of the virus, fail to achieve a sustained reduction in viral load with therapy employing pegylated alpha interferon (IFN-␣) plus ribavirin (alfa/RBV) (52,54,56). A substantial fraction (20%) of chronically infected patients develop serious progressive liver disease, including cirrhosis or hepatocellular carcinoma. alfa/RBV treatment is associated with a high incidence (Ͼ30%) of adverse effects, some of which are of sufficient severity to cause patients to discontinue therapy (56). Despite the recent approval of two new direct-acting antiviral agents (DAAs), boceprevir and telaprevir, for use in combination with alfa/RBV (18, 47), their use may be limited by poor efficacy in some patient populations, inconvenient 3-times-daily dosing of the DAA, and association with side effects, including anemia, rash, and gastrointestinal effects, in addition to the well-documented spectrum of adverse effects associated with alfa/RBV. Although addition of these DAAs to the standard of care for HCV represents a significant i...

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