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Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates

Whitcomb, Jeannette Ma; Huang, Weia; Limoli, Kaya; Paxinos, Ellena; Wrin, Terria; Skowron, Gailc; Deeks, Steven Gb; Bates, Michaela; Hellmann, Nicholas Sa; Petropoulos, Christos Ja

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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.

From aViroLogic Inc., South San Francisco, bUniversity of California at San Francisco and San Francisco General Hospital, San Francisco, California and the cRoger Williams Medical Center/Brown University, Providence, Rhode Island, USA.

Requests for reprints to: Dr J. Whitcomb, ViroLogic Inc. 345 Oyster Point Boulevard, South San Francisco, California 94080, USA.

Received: 16 April 2002; revised: 13 June 2002; accepted: 3 July 2002.

© 2002 Lippincott Williams & Wilkins, Inc.