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The Body PRO Covers: The 8th Conference on Retroviruses and Opportunistic Infections

Diagnostics

February 5, 2001

  • Determination of a Clinically Relevant Phenotypic Resistance "Cutoff" for Abacavir Using the PhenoSense Assay (Poster 254)
    Authored by E. R. Lanier, N. Hellmann, J. Scott, M. Ait-Khaled, T. Melby, E. Paxinos, H. Werhane, C. Petropoulos, E. Kusaba, M. St. Clair, L. Smiley, and S. Lafon
    View the original abstract


Early in our understanding of HIV drug resistance, we believed that resistance was all or nothing; sort of like being pregnant. A greater appreciation of the complexities of drug resistance has fortunately prevailed. A troubling issue for many HIV treaters is the relationship between drug resistance mutations and the likelihood of treatment failure. Most of the data about which mutations are associated with resistance come from in vitro monotherapy studies; the clinical relevance of individual mutations or set of mutations is often difficult to glean from multi-drug clinical trials. Deciding on what level of mutations or reduction in susceptibility leads to treatment failure is important, particularly for clinicians trying to optimize treatment regimens for patients after initial HAART failure.

Initial attempts in studies to determine a phenotypic breakpoint for susceptibility relied simply on maximum variation (or variance) of the test in the laboratory on a day-to-day basis. For some drugs, however, the level of resistance needed for clinical failure was greater than the 2.5- or 4-fold variance of the commercial tests. Defining the clinically relevant breakpoint would require analysis of clinical viral isolates.

Previous studies showed that mutations associated with reduced susceptibility to zidovudine (ZDV), d4T, and/or lamivudine (3TC) were associated with resistance to abacavir (ABC). In this study, Lanier and collaborators from GlaxoSmithKline and Virologic analyzed virus samples from 140 treatment-experienced research subjects for whom ABC was added to current therapy as a single agent. Duplicate samples of virus were analyzed for genotype by Visible Genetics assay and for phenotype using the Virologic PhenoSense assay. These viral genotypes and phenotypes were then compared to the virologic responses to therapy (defined as viral load <400 copies/mL or >0.5 log change in viral load) at 8-24 weeks of treatment. Examination of the effect of reverse transcriptase (RT) mutations on viral load showed that the response to ABC is reduced when four or more nucleoside RT inhibitor (NRTI) mutations were present at baseline. Importantly, there was no significant effect of the 3TC-resistance mutation at codon 184 when only one or two other NRTI mutations were present. There was no relationship between baseline viral load, baseline CD4 count, and duration of prior antiretroviral therapy with the likelihood of response to ABC. Analysis of the phenotypic profiles of viral isolates showed that viral RNA response was significantly reduced if the baseline ABC sensitivity was greater than 4.5-fold that of wild-type virus. (See chart.) No patients with greater than 7-fold loss of susceptibility had a virologic response.

These data are of immediate relevance for the treatment community. There is a growing use of abacavir as a component of second or subsequent rounds of antiretroviral treatment. Many (if not most) of these patients will have had prior treatment with ZDV, d4T, or 3TC. The data presented here should improve the clinical utility of drug susceptibility testing for abacavir. We should expect similar data in the near future about other antiretroviral drugs, including boosted protease inhibitors.


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This article was provided by TheBodyPRO.com. It is a part of the publication The 8th Conference on Retroviruses and Opportunistic Infections.
 



Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.
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