ABSTRACT
BACKGROUND: Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy. METHODS: Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia. RESULTS: Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing. CONCLUSIONS: RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure.
Subject(s)
Antiviral Agents/therapeutic use , Drug Resistance, Viral/genetics , Genetic Variation , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Indoles/therapeutic use , Peptide Hydrolases , Adolescent , Adult , Aged , Amino Acid Substitution , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Cyclopropanes , Double-Blind Method , Drug Therapy, Combination , Female , Genotype , Hepacivirus/classification , Hepacivirus/genetics , Hepatitis C, Chronic/virology , Humans , Indoles/administration & dosage , Indoles/pharmacology , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Male , Middle Aged , Peptide Hydrolases/genetics , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacology , Polyethylene Glycols/therapeutic use , Proline/analogs & derivatives , RNA, Viral/genetics , Ribavirin/administration & dosage , Ribavirin/pharmacology , Ribavirin/therapeutic use , Sulfonamides , Treatment Failure , Treatment Outcome , Viremia/drug therapy , Viremia/virology , Young AdultABSTRACT
Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in biochemical assays (IC(50)=0.045 µM, HIV RT RNase H; 13 µM, HIV RT-polymerase; 24 µM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC(50)=0.19 µM) with a modest window with respect to cytotoxicity (CC(50)=3.3 µM).
