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Consensus Statement |

Antiretroviral Drug Resistance Testing in Adults With HIV Infection:  Implications for Clinical Management

Martin S. Hirsch, MD; Brian Conway, MD; Richard T. D'Aquila, MD; Victoria A. Johnson, MD; Françoise Brun-Vézinet, MD; Bonaventura Clotet, MD, PhD; Lisa M. Demeter, MD; Scott M. Hammer, MD; Donna M. Jacobsen; Daniel R. Kuritzkes, MD; Clive Loveday, MD, PhD; John W. Mellors, MD; Stefano Vella, MD; Douglas D. Richman, MD; for the International AIDS Society–USA Panel
JAMA. 1998;279(24):1984-1991. doi:10.1001/jama.279.24.1984.
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Objectives.— To review current knowledge of the biology and clinical implications of human immunodeficiency virus (HIV) resistance to antiretroviral drugs, describe assays for measuring resistance, and assess their use in clinical practice.

Participants.— The International AIDS Society-USA assembled a panel of 13 physicians with expertise in basic science, clinical research, and patient care relevant to HIV resistance to antiretroviral drugs.

Evidence.— We reviewed available data from published reports and presented at national and international research conferences. Basic science research, clinical trial results, and expert opinions were used to form the basis of this report. Data on methods for and characteristics of specific genotypic and phenotypic assays were obtained from manufacturers and service providers.

Consensus Process.— The panel met regularly between October 1997 and April 1998. Panel subgroups developed and discussed different sections of the report before discussing them with the entire panel. Conclusions and suggested approaches to the use of resistance testing were determined by group consensus.

Conclusions.— Plasma HIV RNA level and CD4+ cell count are the primary values that should be used to guide the initiation of antiretroviral therapy and subsequent changes in therapy. Possible causes of treatment failure other than development of drug resistance that should be considered are adherence, drug potency, and pharmacokinetic issues. Genotypic and phenotypic testing for HIV resistance to antiretroviral drugs may prove useful for individual patient management. Assays under development need validation, standardization, and a clearer definition of their clinical roles. Possible current roles of resistance testing for choosing an initial regimen or changing antiretroviral therapy, as well as possible implications of the presence or absence of phenotypic resistance and genotypic changes, are discussed.

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Figure 1.—The most common human immunodeficiency virus 1 mutations selected by protease inhibitors (A), and nucleoside and nonnucleoside reverse transcriptase inhibitors (B).31 For each amino acid residue listed, the letter above the listing indicates the amino acid associated with the wild-type virus. The italicized letter below the residue indicates the substitution that confers drug resistance. The drug-selected mutations are categorized as "primary" (black bars) or "secondary" (white bars). (The black-and-white bar indicates a mutation selected in vitro, but rarely seen in specimens from patients in whom therapy fails.) Primary mutations generally decrease inhibitor binding and are the first mutations selected. For indinavir, the mutations listed as primary may not be the first mutations selected, but they are selected in most patients' isolates in combination with other mutations. For zalcitabine, all mutations are listed as secondary because of inadequate clinical data to determine a common initial mutation. For nevirapine and delavirdine, each mutation can occur as either an initial or subsequent mutation and affect inhibitor binding. The asterisk indicates that the mutation has been reported in vitro, but relevance for clinical drug failure is uncertain. Amino acid abbreviations are as follows: 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 viruses have phenotypic resistance to most nucleoside reverse transcriptase inhibitors. Current listings are also available at http://hiv-web.lanl.gov/ or at http://www.viral-resistance.com.
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Figure 2.—Schematic representation of a recombinant phenotypic assay. Total RNA is extracted from a small volume of plasma that generally contains at least 1000 copies/mL of human immunodeficiency virus (HIV) RNA. After complementary DNA (cDNA) synthesis using reverse transcriptase (RT) in vitro, the viral protease and reverse transcriptase genes are amplified by polymerase chain reaction (PCR). The resulting amplicons are either cloned or recombined into an HIV vector plasmid, from which the protease and/or RT gene have been deleted. Stocks of recombinant virus are assayed for drug susceptibility.
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Figure 3.—Factors that contribute to antiretroviral drug failure due to resistance. Ongoing viral replication leads to the emergence of resistant virus, and ultimately to drug failure. The existence or emergence of resistant virus, the lack of drug levels adequate to inhibit viral replication, and host immune function each play a role. CTLs indicates cytotoxic T lymphocytes.

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