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Coverage provided by Brian A. Boyle, M.D., J.D.

July 10, 2001

• Genetic Correlates of Phenotypic Hypersusceptibility to Efavirenz (EFV) in Highly Nucleoside-Experienced Subjects in ACTG 364 (Poster 594)
  Authored by Katzenstein, D.; Shulman, N.; Bosch, R.; Liou, S.; Whitcomb, J.; Hellmann, N.; Albrecht, M.; Stanford University, Stanford, CA, USA

The issue of non-nucleoside hypersusceptibility (HS) has been discussed for sometime. Some reports have indicated that HIV-infected patients with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) have phenotypic assays that demonstrate non-nucleoside hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTIs) which is proportional to zidovudine (ZDV) resistance and may be the result of specific mutations in the reverse transcriptase (RT) gene.

Investigators from Stanford University evaluated NRTI-experienced patients enrolled in the ACTG 364 study to determine if specific RT mutations were associated with NNRTI HS. Genotypic and phenotypic profiles for RT and six licensed NRTIs and three NNRTIs were obtained from 130 samples in subjects with more than four years of ZDV and other NRTI experience, but who were naive to NNRTIs.

The researchers found that 37% of the patients demonstrated hypersusceptibility to efavirenz (EFV) which was defined by a fold change in susceptibility less than 0.4 relative to wild type (i.e., a more than 2.5 fold increase in susceptibility relative to wild-type).

A negative correlation was found between the fold-change in susceptibility to ZDV and EFV, such that as ZDV sensitivity decreased, EFV sensitivity increased (p<0.01). Examination of 200 RT codons demonstrated that this finding was associated with the nucleoside analog mutations T215Y/F, R211K, L210W, M41L, and D67N (p < 0.01). Further, while mutations at 215 were found to be present in 94% of HS isolates this mutation alone did not cause hypersusceptibility, but the most common associations with hypersusceptibility were 215 in combination with either 67 or 211.

These data indicate that NNRTI hypersusceptibility was present to some degree in 37% of viral isolates from NRTI-experienced patients. As discussed above, this hypersusceptibility appeared to correlate with ZDV phenotypic resistance, a history of ZDV use, and the presence of certain ZDV-related mutations.

It should be noted that these findings contradict several other studies that have failed to find hypersusceptibility and confirm several that did. Meanwhile, the clinical significance and utility of hypersusceptibility remains highly speculative. The authors suggest a clinical trial evaluating "the continued use of NRTI drugs to maintain hypersusceptibility in salvage regimens utilizing EFV," but one would have to weigh carefully the potential risks and benefits of continuing ZDV -- including the possibility that doing so may lead to the development of additional ZDV-related mutations -- which may cause the development of, or an increase in, resistance to other NRTIs.

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