Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).

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Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) replication in vitro and in vivo that is currently in clinical trials for the treatment of chronic HBV infections. A major limitation of the current HBV antiviral therapy, lamivudine (3TC), is the emergence of drug-resistant HBV in a majority of treated patients due to specific mutations in the nucleotide binding site of HBV DNA polymerase (HBV Pol). To determine the effects of 3TC resistance mutations on inhibition by ETV triphosphate (ETV-TP), a series of in vitro studies were performed. The inhibition of wild-type and 3TC-resistant HBV Pol by ETV-TP was measured using recombinant HBV nucleocapsids, and compared to that of 3TC-TP. These enzyme inhibition studies demonstrated that ETV-TP is a highly potent inhibitor of wild-type HBV Pol and is 100-to 300-fold more potent than 3TC-TP against 3TC-resistant HBV Pol. Cell culture assays were used to gauge the potential for antiviral cross-resistance of 3TC-resistant mutants to ETV. Results demonstrated that ETV inhibited the replication of 3TC-resistant HBV, but 20-to 30-fold higher concentrations were required. To gain further perspective regarding the potential therapeutic use of ETV, its phosphorylation was examined in hepatoma cells treated with extracellular concentrations representative of drug levels in plasma in ETV-treated patients. At these concentrations, intracellular ETV-TP accumulated to levels expected to inhibit the enzyme activity of both wild-type and 3TC-resistant HBV Pol. These findings are predictive of potent antiviral activity of ETV against both wild-type and 3TC-resistant HBV.Infection with hepatitis B virus (HBV) is a medical problem of global proportions. Despite the existence of a safe vaccine, approximately 5% of the world population is infected with HBV. Approved therapies for chronic HBV infection are treatment with alpha interferon or lamivudine (3TC). Drawbacks to treatment with alpha interferon include a low sustained response rate, undesirable side effects, the need for parenteral administration, and high cost. Therapy with 3TC is less costly and more convenient to use, but it also suffers from a low sustained response rate. Of more fundamental concern is that while initial treatment of patients with 3TC results in a rapid lowering of HBV DNA levels in the blood, its efficacy is severely compromised in most patients by the development of antiviral resistance after prolonged therapy.The inhibition of HBV replication by nucleoside analogs results from the recognition of nucleoside analog triphosphates (TPs) by the RNA-dependent DNA polymerase of HBV (HBV Pol). Clinical resistance to 3TC results from amino acid substitutions at position 550 (methionine [M]) in the highly conserved YMDD motif of HBV Pol (31). Variants with the double mutation M550V/L526M or the single mutation M550I predominate (reviewed in reference 14). Molecular modeling studies suggest that these mutations alter the nucleotide binding site of HBV Pol to cause steric hindrance of 3TC-TP ...

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