In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance amongmembers of the same drug class. ABT-450 is an efficacious inhibitor of HCVNS3/4A protease, with 50 % effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respec-tively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadmin-istered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. AmeanmaximumHCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in ge-notype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (StudyM11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.) Hepatitis C virus (HCV) infection is a global health problem,with 160 to 180 million individuals infected worldwide (1, 2). Chronic HCV infection can lead to serious liver disease, includin