This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a nonnucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection. (Funded by Abbott; ClinicalTrials.gov number, NCT01306617.).

The majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated.

No abstract

bThe 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 among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A 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, respectively. 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 coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log 10 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 genotype 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. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.) H epatitis 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, including cirrhosis, liver failure, and hepatocellular carcinoma. There are 7 major HCV genotypes, which differ in their geographic distribution, disease progression, and response to therapy (3). In the United States, Europe, and Japan, genotype 1 is the most prevalent genotype, and globally it accounts for approximately 60% of HCV infections (4).Therapy for those infected with HCV genotype 1 improved with the approval of the NS3/4A protease inhibitors (PIs) telaprevir, boceprevir, and, more recently, simeprevir (5-10). Although the addition of a PI to pegylated interferon (pegIFN) and ribavirin (RBV) therapy significantly improved sustained virologic response (SVR) rates compared to those with pegIFN/RBV therapy alone, IFN-based therapies are associated with treatment-limiting toxicities (11). In addition, there are many patients who are ineligible for IFN-based treatment due to comorbidities such as depression (12). Early clinical trials with these PIs also demonstrated that drug resistance developed within days after initiation of treatment (13-15). The rapid selection of resistant variants is facilitated by a high rate of virus production and the infidelity of the HCV RNA polymerase (16). Thus, there is a need for effective treatme...

The authors describe the drug–drug interaction profile of the he patitis C direct‐acting antiviral agents ABT‐450, ombitasvir, and dasabuvir with cyclosporine A and tacrolimus, and use pha rmacokinetic simulations to develop recommendations for reduced doses of cyclosporine A and tacrolimus in posttransplant patients with recurrent hepatitis C infection.