Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates.
OBJECTIVE
The routine use of phenotypic drug resistance testing in patient management has revealed that many HIV-1 strains possess significantly increased drug sensitivity, or 'hypersusceptibility' compared with wild-type viruses. This study describes hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) and was designed to determine the prevalence of and viral characteristics associated with NNRTI hypersusceptibility in patient-derived viruses.


METHODS
Retrospective analyses were performed on a large clinical laboratory dataset containing phenotypic drug susceptibility and genotypic sequence results from HIV-1 patient isolates. Genetically engineered viruses were used to confirm the role of certain nucleoside reverse transcriptase inhibitor (NRTI)-resistance mutations in NNRTI hypersusceptibility.


RESULTS
Hypersusceptibility to delavirdine, efavirenz and nevirapine was detected in 10.7, 10.8 and 8.0% of more than 17,000 consecutive plasma samples submitted for phenotypic susceptibility testing. In analyses limited to a subset of viruses derived from patients with known treatment histories, NNRTI hypersusceptibility was observed significantly more frequently among viruses from NRTI experienced/NNRTI-naive patients compared with viruses from NRTI/NNRTI-naive patients. Significant inverse correlations between NRTI and NNRTI susceptibility exist among the viruses from NRTI-experienced patients. Analyses of viruses classified according to their NNRTI susceptibility identified 18 positions in reverse transcriptase where substitutions were significantly associated with NNRTI hypersusceptibility.


CONCLUSIONS
NNRTI hypersusceptibility is common among patient HIV-1 isolates, especially in NRTI-resistant viruses. Genotypic correlates of hypersusceptibility are complex and not easily defined by a simple analysis of NRTI-associated resistance mutations. NNRTI hypersusceptibility may provide an explanation for the superior virologic response to NNRTI-containing salvage regimens observed in NRTI-experienced patients in several clinical trials.
Whitcomb
Jeannette M
JM
ViroLogic Inc, South San Francisco, California 94080, USA.
Huang
Wei
W
Limoli
Kay
K
Paxinos
Ellen
E
Wrin
Terri
T
Skowron
Gail
G
Deeks
Steven G
SG
Bates
Michael
M
Hellmann
Nicholas S
NS
Petropoulos
Christos J
CJ
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D015995:Prevalence; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase