William E Delaney

..The efficacy of adefovir dipivoxil in treating lamivudine-resistant HBV and the delayed emergence of adefovir resistance are key factors contributing to the durable response achieved in broad groups of chronic hepatitis B patients...

..Here we review the basis of drug resistance in HBV, with emphasis on aspects that are likely to affect drug choice in future...

..Together, these results suggest that rtV173L is a compensatory mutation that is selected in lamivudine-resistant patients due to an enhanced replication phenotype...

..There was no evidence of cytotoxicity with any of the drugs when used alone or in combination at the tested doses...

..Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV...

..The rtA181T mutation has also been observed at low frequency, alone or in combination with rtN236T...

..In conclusion, the PC stop codon mutation appears to increase the replication efficacy of lamivudine-resistant virus but does not affect in vitro drug sensitivity...

..In conclusion, no adefovir resistance mutations were identified in a large group of chronic hepatitis B patients treated with ADV for 48 weeks...

..Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys...

..In conclusion, these results, although based on a limited number of patients, suggest that treatment with ADV does not lead to the emergence of resistant virus after up to 60 weeks of therapy...

..The vector described here enables the efficient phenotypic analysis of full-length HBV isolates from patients and will be useful in future studies including resistance surveillance, cross-resistance analyses, and novel drug-discovery...

..Overall, the antiviral and metabolic profile of tenofovir supports its development for the treatment of chronic hepatitis B...

..Specific protocols are provided for screening 1a replicons that encode the Renilla luciferase gene and for replicons that do not encode exogenous reporter genes, both in 96-well (manual) and in 384-well (high-throughput) formats...

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..Overall, the efficient production of infectious 1b/2a virus particles will facilitate the discovery and characterization of inhibitors targeting steps that involve the structural genes of genotype 1b HCV...

..These new reagents will enhance drug discovery efforts targeting genotype 1a and facilitate the profiling of compound activity among different HCV genotypes and subtypes...

..This adapted virus will facilitate further studies of the HCV life cycle, virus structure, and high-throughput drug screening...

..The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth...

..These insights into RNA virus quasispecies structure provide guidance for selecting clinical drug concentrations and selecting antiviral drug combinations most likely to suppress resistance...

..The syntheses and preliminary biological evaluation of these phosphinic acids is described...

..Importantly, we observed a significant correlation (p<0.0001) in antiviral potency between the 2a replicon and 2a infectious virus for all classes of compounds tested...

..40 +/- 0.92 micro M, respectively, compared to 0.064 +/- 0.020 micro M lamivudine. There were no significant differences in sensitivity between wild-type and nucleoside analogue-resistant (rtL180M, rtM204I, and rtL180M + rtM204V) HBV...

..The final protocol describes how to determine the reversibility of inhibitor binding to the enzyme, an important parameter that can affect the pharmacodynamic properties of a compound...

..The syntheses and preliminary biological evaluation of this phosphonate class of inhibitor are described...

..The challenge is how to best use these drugs long-term to minimize antiviral resistance and maintain maximal antiviral suppression, which is anticipated to make the greatest impact on limiting advanced complications of CHB...

..In conclusion, nucleos(t)ide analogues can target initial plus-strand DNA repair and reduce but not completely block HBV infection...

..We concluded that the rtM204I mutation generates a polymerase that is not only resistant to lamivudine but also replicates nucleic acids to lower levels in vitro...

..Following drug withdrawal there was prompt recrudescence of WHV viremia to pretreatment levels. It was concluded that oral administration of TDF for 4 weeks was safe and effective in the woodchuck model of chronic HBV infection...

..The results demonstrate that supplemental adefovir dipivoxil treatment is effective in suppressing replication of lamivudine-resistant B-domain mutants in the woodchuck model of hepatitis B virus infection...

..Long-term ADV therapy significantly decreased cccDNA levels by a primarily noncytolytic mechanism...