Sensitivity of Phenotypic Susceptibility Analyses for Nonthymidine Nucleoside Analogues Conferred by K65R or M184V in Mixtures with Wild-Type HIV-1

Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy. Consistent with this notion were (1) the pr...

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Bibliographic Details
Published in:The Journal of infectious diseases 2009-01, Vol.199 (1), p.84-88
Main Authors: Underwood, Mark R., Ross, Lisa L., Irlbeck, David M., Gerondelis, Peter, Rouse, Elizabeth, St. Clair, Marty H., Trinh, Lan, Parkin, Neil, Lanier, E. Randall
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - therapeutic use
Anti-HIV Agents - therapeutic use
Antivirals
Biological and medical sciences
Didanosine - therapeutic use
Dideoxynucleosides - therapeutic use
Drug Therapy, Combination
Fundamental and applied biological sciences. Psychology
Genetic mutation
Genetic Predisposition to Disease
Genotype
HIV
HIV 1
HIV Infections - drug therapy
HIV-1 - genetics
HIV/AIDS
Human immunodeficiency virus 1
Human immunodeficiency virus 2
Humans
Infectious diseases
Lamivudine - therapeutic use
Medical sciences
Microbiology
Miscellaneous
Nucleosides
Organophosphonates - therapeutic use
Phenotype
Plasmids
Sequencing
Tenofovir
Viral Load
Virology
Viruses
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Summary:Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy. Consistent with this notion were (1) the presence of low-level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose-dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus. These findings underscore the limitations of stand-alone phenotypic susceptibility measures and emphasize the importance of complementary and/or more sensitive techniques. (ClinicalTrials.gov identifier:NCT00053638.)
ISSN:0022-1899
1537-6613
DOI:10.1086/595296