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 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.
Underwood
Mark R
MR
GlaxoSmithKline, Inc., Research Triangle Park, North Carolina 27709-3398, USA. mark.r.underwood@gsk.com
Ross
Lisa L
LL
Irlbeck
David M
DM
Gerondelis
Peter
P
Rouse
Elizabeth
E
St  Clair
Marty H
MH
Trinh
Lan
L
Parkin
Neil
N
Lanier
E  Randall
E
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D016049:Didanosine / Q000627:therapeutic use; D015224:Dideoxynucleosides / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use; D010641:Phenotype; D010957:Plasmids; D000068698:Tenofovir; D019562:Viral Load; D000099227:Abacavir
D000225:Adenine; D019380:Anti-HIV Agents; D016049:Didanosine; D015224:Dideoxynucleosides; D019259:Lamivudine; D063065:Organophosphonates; D000068698:Tenofovir; D000099227:Abacavir