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Drug Resistance Mutations in HIV-1 Volume 11 Issue 6 November/December 2003

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Drug Resistance Mutations in HIV-1 Volume 11 Issue 6 November/December 2003 Special Contribution - Drug Resistance Mutations in HIV-1 Volume 11 Issue 6 November/December 2003 Drug Resistance Mutations in HIV-1 Victoria A. Johnson, MD, Françoise Brun-Vézinet, MD, PhD, Bonaventura Clotet, MD, PhD, Brian Conway, MD, Richard T. D'Aquila, MD, Lisa M. Demeter, MD, Daniel R. Kuritzkes, MD, Deenan Pillay, MD, PhD, Jonathan M. Schapiro, MD, Amalio Telenti, MD, PhD, and Douglas D. Richman, MD The International AIDS Society–USA pressure), resistant strains may be pre- V32I and the I84A/C have been added to (IAS–USA) Drug Resistance Mutations sent at levels below the limit of detec- the list of accumulated mutations con- Group is a volunteer panel of experts tion of the test; analyzing stored sam- ferring multi-PI resistance (see User that meets regularly to review and inter- ples (collected under selection pressure) Note 9).13-18 In addition, mutations have pret new data on HIV-1 resistance. The could be useful in this setting; and (3) been added for tipranavir/ritonavir, focus of the group is to identify muta- recognizing that virologic failure of the which is currently available through an tions associated with clinical resistance first regimen typically involves HIV-1 expanded access protocol and is not to HIV-1. These mutations have been isolates with resistance to only 1 or 2 of approved for use by the US FDA. A num- identified by 1 or more of the following the drugs in the regimen; in this setting, ber of major (L33I/F/V, V82L/T, I84V, and criteria: (1) in vitro passage experiments resistance most commonly develops to L90M) and minor (L10I/V, K20M/L/T, or validation of contribution to resis- lamivudine or the nonnucleoside re- M46I, and I54V) mutations were identi- tance by using site-directed mutagene- verse transcriptase inhibitors.1-5 This fied for tipranavir/ritonavir from data sis; (2) susceptibility testing of laboratory paradox may involve patient nonadher- presented at the XII International HIV or clinical isolates; (3) genetic sequenc- ence, laboratory error, drug-drug inter- Drug Resistance Workshop in Los Cabos, ing of viruses from patients in whom the actions leading to subtherapeutic drug Mexico.19,20 Based on data published by drug is failing; (4) correlation studies levels, and possibly compartmental Colonno and colleagues,21 7 minor muta- between genotype at baseline and viro- issues, indicating that drugs may not tions associated with resistance to logic response in patients exposed to the reach optimal levels in specific cellular atazanavir (L10I/F/V, K20R/M/I, L24I, drug. Drugs that have been approved by or tissue reservoirs. L33I/F/V, M36I/L/V, G48V, and G73C/ the US Food and Drug Administration Revised recommendations for S/T/A) have been added. For lopinavir/ (FDA) or are available through expanded antiretroviral resistance testing were ritonavir, the I54V/L mutation has been access protocols are included. recently published by the IAS–USA HIV expanded to I54V/L/A/M/T/S22-24 and the The IAS–USA Drug Resistance Muta- Resistance Testing Guidelines Panel6 and I47V mutation has been expanded to tions Figures are designed for use in can be found on the IAS–USA Web site I47V/A.15,25 In the fusion inhibitor catego- identifying mutations associated with at www.iasusa.org. ry, the discussion in User Note 25 has drug resistance and in making therapeu- been expanded to include current find- tic decisions. Care should be taken when Revisions to the Figures in this ings on issues that affect susceptibility to using this list of mutations for surveil- October 2003 Update enfuvirtide.26-28 lance or epidemiologic studies of trans- The group is currently summarizing In the nucleoside and nucleotide reverse mission of drug-resistant virus; a num- the HIV-1 resistance mutations that are transcriptase inhibitor (nRTI) category, ber of amino acid substitutions, particu- associated with non-subtype B virus and mutations for emtricitibine have been larly minor mutations, represent poly- plans to include it in the next update. added. Emtricitabine and lamivudine morphisms, which in isolation may not Data continues on HIV susceptibility to share a similar reverse transcriptase reflect prior drug selective pressure or antiretroviral drugs. (cont’d, pg 220) reduced drug susceptibility. M184V/I mutation pattern (see User In the context of making clinical deci- Note 10).7 In addition, the K65R muta- sions regarding antiretroviral therapy, tion has been added to stavudine, The IAS–USA Mutations Figures are evaluating the results of HIV genotypic lamivudine, and emtricitabine. Data available on a pocket-sized folding card. testing includes: (1) assessing whether presented at recent conferences indi- Copies of the card can be ordered by phone at the pattern or absence of a pattern in the cate that this mutation can confer resis- (415)544-9400, at www.iasusa.org/resis mutations is consistent with the patient’s tance to stavudine and cross-resistance tance_mutations/index.html, by mail, or by e- 8-12 antiretroviral regimen; (2) recognizing to lamivudine and emtricitabine. In mail at: resistance@iasusa. org. that in the absence of drug (selection the protease inhibitor (PI) category, the Author Affiliations: Dr Johnson (Group Chair), Veterans Affairs Medical Center, Birmingham, and the University of Alabama at Birmingham School of Medicine, Birmingham, AL; Dr Brun-Vézinet, Hôpital Bichat-Claude Bernard, Paris, France; Dr Clotet, Fundacio irsiCAIXA and HIV Unit, Hospital Universitari Germans Trias I Pujol, Barcelona, Spain; Dr Conway, University of British Columbia, Vancouver, BC; Dr D'Aquila, Vanderbilt University Medical Center, Nashville, Tenn; Dr Demeter, University of Rochester Medical Center, Rochester, NY; Dr Kuritzkes, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Dr Pillay, Royal Free and University College Medical School, London, England; Dr Schapiro, Stanford University School of Medicine, Palo Alto, Calif; Dr Telenti, University Hospital of Lausanne, Switzerland; Dr Richman (Group Vice Chair), Veterans Affairs San Diego Healthcare System, and the University of California San Diego, La Jolla, Calif. 215 International AIDS Society–USA Topics in HIV Medicine Date of Revision: October 2003 MUTATIONSMUTATIONS IN INTHE THE REVERSE REVERSE TRANSCRIPTASE TRANSCRIPTASE GENE GENE ASSOCIATED ASSOCIATED WITH WITH RESISTANCE RESISTANCE TO TO REVERSEREVERSE TRANSCRIPTASE TRANSCRIPTASE INHIBITORS INHIBITORS NucleosideNucleoside and and Nucleotide Nucleotide Reverse Reverse Transcriptase Transcriptase Inhibitors Inhibitors Multi-nRTI Resistance: 151 Complex Multi-nRTI Resistance: 69 Insertion Complex1 Multi-nRTI Resistance: 44 118 2 NAMs I E 3,4 Zidovudine 44 118 D I E 3–5 Stavudine 44 118 D I 6,7 Didanosine Zalcitabine Abacavir8 Lamivudine9,10 Emtricitabine10 Tenofovir3,11 NonnucleosideNonnucleoside Reverse Reverse Transcriptase Transcriptase Inhibitors Inhibitors Multi-NNRTI Resistance12,13 Multi-NNRTI Resistance: Accumulation of Mutations14 Nevirapine Delavirdine15 Efavirenz15-17 216 Special Contribution - Drug Resistance Mutations in HIV-1 Volume 11 Issue 6 November/December 2003 Date of Revision: October 2003 MUTATIONS IN THE PROTEASE GENE ASSOCIATED WITH RESISTANCE TO PROTEASE INHIBITORS Protease Inhibitors18 Multi-PI Resistance: Accumulation of Mutations19 C Indinavir20 Ritonavir Saquinavir Nelfinavir Amprenavir Lopinavir/ 21,22 Ritonavir Atazanavir23 C Tipranavir/ Ritonavir24 (expanded access) MUTATIONS IN THE GP41 ENVELOPE GENE ASSOCIATED WITH RESISTANCE TO ENTRY INHIBITORS Enfuvirtide25 HR1 Region MUTATIONS See User Note 21 Insertion Amino Acid, Wild-Type See User Note 22 Amino Acid Position Major (boldface type; protease only) Amino Acid, Substitution Vertical pink lines Minor (lightface type; indicate NAMs protease only) 217 International AIDS Society–USA Topics in HIV Medicine User Notes October 2003. 241 have shown that the E44D mutation is lamivudine when accompanied by several commonly selected by zidovudine/didano- other nRTI-associated mutations (M41L, The IAS–USA Drug Resistance Mutations sine (Hanna et al, J Infect Dis, 2002) and that D67N, L210W, T215Y/F, K219Q/E) in the Group reviews new data on HIV drug resis- the E44D mutation is associated with a sig- absence of a concurrent M184V mutation tance in order to maintain a current list of nificantly worse response to treatment with (Hertogs et al, Antimicrob Agents Chemother, mutations associated with clinical resistance zidovudine and didanosine, with or without 2000). Data presented but not yet published to HIV. This list includes mutations that may nevirapine (Precious et al, AIDS, 2000). The (D'Arminio-Monforte et al, 8th CROI, 2001), contribute to a reduced virologic response significance of E44D or V118I when each reported no association over the short term to a drug. These mutations have been iden- occurs in isolation is unknown (Romano et between E44D or V118I and virologic tified by 1 or more of the following criteria: al, J Infect Dis, 2002; Walter et al, Antimicrob response to a lamivudine-containing combi- (1) in vitro passage experiments or valida- Agents Chemother, 2002; Girouard et al, nation regimen. (See also User Note 2.) tion of contribution to resistance by using Antivir Ther, 2002). site-directed mutagenesis; (2) susceptibility 10. Emtricitabine and lamivudine have sim- testing of laboratory or clinical isolates; (3) 3. The M184V mutation may enhance sus- ilar reverse transcriptase M184V/I patterns genetic sequencing of viruses from patients ceptibility to zidovudine, stavudine, or teno- (Quinn et al,
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