Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1clinical, phenotypic and genotypic correlates
作者:
Jeannette Whitcomb,
Wei Huang,
Kay Limoli,
Ellen Paxinos,
Terri Wrin,
Gail Skowron,
Steven Deeks,
Michael Bates,
Nicholas Hellmann,
Christos Petropoulos,
期刊:
AIDS
(OVID Available online 2002)
卷期:
Volume 16,
issue 15
页码: 41-47
ISSN:0269-9370
年代: 2002
出版商: OVID
关键词: HIV-1;non-nucleoside reverse transcriptase inhibitor;hypersusceptibility;phenotype;genotype
数据来源: OVID
摘要:
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.
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