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Consensus Statement |

Antiretroviral Drug Resistance Testing in Adult HIV-1 Infection Recommendations of an International AIDS Society–USA Panel

Martin S. Hirsch, MD; Françoise Brun-Vézinet, MD; Richard T. D'Aquila, MD; Scott M. Hammer, MD; Victoria A. Johnson, MD; Daniel R. Kuritzkes, MD; Clive Loveday, MD, PhD; John W. Mellors, MD; Bonaventura Clotet, MD, PhD; Brian Conway, MD; Lisa M. Demeter, MD; Stefano Vella, MD; Donna M. Jacobsen; Douglas D. Richman, MD
JAMA. 2000;283(18):2417-2426. doi:10.1001/jama.283.18.2417.
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Objective Assays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society–USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing.

Participants An International AIDS Society–USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing.

Evidence and Consensus Process The full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available.

Conclusions Emerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.

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Figure. Most Common Mutations in HIV-1 Genes Conferring Drug Resistance
Graphic Jump Location
For each amino acid residue, the letter above indicates the amino acid associated with wild-type virus; the italicized letters below, substitutions that confer viral resistance. Primary mutations (black bars) generally cause decreased inhibitor binding and are the first mutations selected. Secondary mutations (white bars) also contribute to drug resistance and should be considered as evidence of resistance, although they may have less direct effect on inhibitor binding in vitro than primary mutations. The mutation selected in vitro (black-and-white bar) is rarely seen in patients having treatment failure. For indinavir, the mutations listed as primary may not be the first mutations selected, but they are selected in most patient isolates in combination with other mutations. For zalcitabine, all mutations are listed as primary because of inadequate clinical data to determine the most frequent initial mutation. Amino acid abbreviations are: A, alanine; C, cysteine; D, aspartate; E, glutamate; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine. Multinucleoside resistance mutational patterns A and B each cause resistance to zidovudine, stavudine, lamivudine, didanosine, zalcitabine, and abacavir. Current listings are also available at http://www.iasusa.org/.
*Mutations selected by protease inhibitors in gag cleavage sites are not listed because their contribution to resistance is not fully defined.
† A preliminary report identifies mutations E44D and V118I as conferring moderately reduced (about 10-fold) susceptibility to lamivudine with uncertain clinical significance.22 This contrasts with the greater than 100-fold reduced susceptibility to lamivudine conferred by M184V or M184I, which is associated with virologic rebound.1416
‡ The mutations listed for zidovudine above contribute to reduced susceptibility to abacavir in vitro and in vivo and are listed as secondary, even though they may be present before abacavir is introduced.23,24 They have also been reported to be uncommonly selected by stavudine plus didanosine even in the absence of prior zidovudine exposure.2527 Phenotypic resistance of these mutations to stavudine or didanosine in vitro was not identified. The clinical significance of these mutations and of V75T on in vivo response to stavudine is not known.
§ Several insertions of 2 amino acids have been reported following T69S (or rarely T69A), including Ser-Ser; Ser-Gly; Ser-Ala; Glu-Ala; and Thr-Ser.28,29
∥ For nevirapine or delavirdine, each mutation can occur as an initial or subsequent mutation and affect inhibitor binding.3032



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