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, ICAAC, 2003). In addition, the in whom the drug is failing; (4) correlation fovir. This effect may be overcome by an K65R mutation can confer cross-resistance studies between genotype at baseline and accumulation of NAMs or other mutations. to emtricitabine and lamivudine (Miller et al, virologic response in patients exposed to The clinical significance of this effect is not ICAAC, 2003; Miller et al, Antivir Ther, 2003; the drug. Drugs that have been approved by known. Miller et al, 10th CROI, 2003; Parikh et al, the US Food and Drug Administration (FDA) 4. Data on revertant mutations in codon 215 Antivir Ther, 2003; Ruane et al, Antivir Ther, or are available through expanded access indicate that the T215D/C/S/E/N/A/V substi- 2003; McArthur et al, Antivir Ther, 2003). protocols are included. Additional informa- tutions confer increased risk of virologic fail- Additional mutations that confer resistance tion on the mutations is provided, where ure of zidovudine and stavudine in antiretro- or cross-resistance to emtricitabine are pos- necessary, in these user notes. viral-naive adults starting therapy with these sible, but are yet to be described. 1. The 69 insertion complex, consisting of a drugs (Riva et al, Antivir Ther, 2002). In vitro 11. The accumulation of NAMs (M41L, mutation at codon 69 (typically T69S) and studies and preliminary clinical studies sug- D67N, K70R, L210W, T215Y/F, K219Q/E followed by an insertion of 2 or more amino gest that the T215Y mutant may emerge [note: data here do not include E44D and acids (S-S, S-A, S-G, or others), is associated quickly from these mutations in the pres- V118I]) increases resistance to tenofovir. with resistance to all FDA-approved nRTIs. ence of zidovudine or stavudine (Garcia- Mutations M41L and L210W contribute The 69 insertion complex is often accompa- Lerma et al, Proc Natl Acad Sci U S A, 2001; more than others. Therefore, the number nied by mutations at other sites. Some other Lanier et al, Antivir Ther, 2002; Riva et al, and type of NAMs will determine the degree amino acid changes from the wild-type T in Antivir Ther, 2002). of reduced response. T69D/N/S may also codon 69 without the insertion may also be 5. Mutations at codon 75 (V75T/M/S/A) have contribute to a reduced response to teno- associated with broad nRTI resistance. been observed in vitro and may confer a fovir (Miller et al, Antivir Ther, 2002; Lu et al, 2. The nRTI-associated mutations (NAMs), low-level change in susceptibility to stavu- Antivir Ther, 2002; Masquelier et al, Antivir including M41L, E44D, D67N, K70R, V118I, dine (Lacey et al, Antimicrob Agents Ther, 2002). L210W, T215Y/F, and K219Q/E, are associat- Chemother, 1994). ed with cross-resistance to nRTIs and are 12. The K103N or Y188L mutation alone represented by vertical pink lines. 6. The K65R mutation or the L74V muta- can substantially reduce the clinical utility of Zidovudine and stavudine select for these tion, alone or in combination with the all currently approved NNRTIs. mutations, and as such, the positions and NAMs or T69D/N can lead to didanosine mutations are indicated on the bars along resistance. 13. The V106M mutation confers high-level with the pink lines. For other nRTIs, the 7. Based on preliminary, yet-unpublished resistance in vitro to nevirapine, delavirdine, NAMs are not commonly selected by those data, the M184V mutation does not appear and efavirenz (Brenner et al, AIDS, 2003). drugs, but the presence of the NAMs confers to have a negative impact on in vivo This mutation has been observed only in cross-resistance to the drugs. This is repre- responses to didanosine, even though the HIV clade C clinical isolates, although site- sented by pink lines only at the positions. mutation reduces susceptibility in vitro directed mutagenesis indicates that V106M The E44D and V118I mutations are listed (Winters et al, Antivir Ther, 2002; Eron et al, confers cross-resistance to all NNRTIs in HIV as NAMs. In a recent study, the E44D and Antivir Ther, 2002; Pozniak et al, Antivir clade B virus. V118I mutations were more common in Ther, 2002). virus from patients who had been on 14. Accumulation of 2 or more of these zidovudine and lamivudine, and were asso- 8. When present with NAMs, the M184V mutations substantially reduces the clinical ciated with higher-level resistance to zidovu- mutation contributes to reduced susceptibil- utility of all of the currently approved dine (Stoeckli et al, Antimicrob Agents ity to abacavir and is associated with NNRTIs. Chemother, 2002). When present together impaired response in vivo. However, when with other NAMs, the E44D and V118I present alone, the M184V mutation does 15. The prevalence of the Y318F mutation mutations confer resistance to lamivudine. not appear to be associated with a reduced in clinical isolates along with mutations Analysis from the AIDS Clinical Trials Group virologic response to abacavir in vivo K103N, Y181C, or P236L was approximate- (ACTG) study 136 has shown that the V118I (Harrigan et al, J Infect Dis, 2000). ly 5%, 2%, and 15%, respectively (Kemp et mutation is commonly selected by a zidovu- al, Antivir Ther, 2001). In vitro this mutation dine/didanosine regimen (Shafer et al, J 9. The E44D and V118I mutations were confers resistance to nevirapine, delavirdine, Infect Dis, 1995). Findings from ACTG study reported to confer low-level resistance to and efavirenz.

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

16. The Y181C/I mutation is not selected by clinical effectiveness of lopinavir/ritonavir. It tions conferring enfuvirtide resistance. efavirenz, but its presence contributes to is reasonable to consider phenotyping to Testing to detect only the depicted HR1 low-level cross-resistance to the drug. assess this in individual cases. mutations may not be adequate for clinical Clinical impact of this mutation may be management of suspected failure of regi- overcome with a fully active antiretroviral 22. Protease mutation L63P is common in mens including enfuvirtide and must be combination regimen, although no clinical viruses that have never been exposed to PIs interpreted in the context of resistance test- trial data yet address this question. (Kozal et al, Nat Med, 1996) and may be ing results for all other components of the more prevalent in viruses from patients in regimen. 17. V108I and P225H each contribute to whom a PI-containing regimen has failed. efavirenz resistance when present in However, by itself, L63P does not cause any combination with other NNRTI-associated appreciable increase in the IC for any PI. Key. For each amino acid residue, the letter 50 above the bar indicates the amino acid associat- mutations. Although V108I or P225H alone L63P is listed for lopinavir/ritonavir (and not ed with wild-type virus and the letter(s) below does not confer measurable resistance in any other PI) because studies have shown indicate the substitution(s) that confer viral resis- laboratory strains of HIV-1, their presence in that this mutation, when present with multi- tance. The number shows the position of the a clinical isolate may indicate prior selection ple other mutations, is associated with clini- mutation in the protein. Mutations selected by for efavirenz-resistant variants. cal failure. protease inhibitors in Gag cleavage sites are not listed because their contribution to resistance is 18. Resistance mutations in the protease 23. When administered to patients as the not yet fully defined. HR1 indicates first heptad gene are classified as either “major” or initial PI, atazanavir selects for the muta- repeat; NAMs indicates nRTI-associated muta- “minor” (if known). tions I50L and A71V (Colonno et al, Antivir tions; nRTI indicates nucleoside reverse transcrip- Major: In general, major mutations are Ther, 2002). When used as a subsequent PI tase inhibitor; NNRTI indicates nonnucleoside reverse transcriptase inhibitor; PI indicates pro- either (1) selected first in the presence of in combination with saquinavir, atazanavir tease inhibitor. The figures were last published in the drug; or (2) shown at the biochemi- selects for I54L and I84V (Colonno et al, Topics in HIV Medicine in May/June 2003. cal or virologic level to lead to an alter- Antivir Ther, 2002). In vitro, atazanavir ation in drug binding or an inhibition of selects for V32I, M46I, I84V, and N88S Amino acid abbreviations: A, alanine; C, cys- viral activity or viral replication. By (Gong et al, Antimicrob Agents Chemother, teine; D, aspartate; E, glutamate; F, phenylala- themselves, major mutations have an 2000). Although other mutations, such as nine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; effect on phenotype. In general, these V82A and L90M, have not been selected for P, proline; Q, glutamine; R, arginine; S, serine; T, by atazanavir either in vitro or in vivo, these mutations tend to be the major contact threonine; V, valine; W, tryptophan; Y, tyrosine. residues for drug binding. mutations have been shown to confer cross- resistance to atazanavir, particularly when Minor: In general, minor mutations present in combination with each other or appear later than major mutations, and with other known PI resistance mutations by themselves do not have a significant The IAS–USA Drug Resistance (Colonno et al, Antivir Ther, 2000). effect on phenotype. In some cases, Mutations Group their effect may be to improve replica- 24. Tipranavir/ritonavir is currently available tive fitness of virus carrying major In June 2003, as part of a regular rotation of through an expanded access protocol and is mutations. the members and roles of the group, Victoria not approved by the FDA. A. Johnson, MD, was named Chair of the 19. Accumulation of 4 or more of these IAS–USA Drug Resistance Mutations Group. mutations is likely to cause multi-PI resis- 25. To date, resistance mutations in the Deenan Pillay, MD, PhD, and Amalio Telenti, tance (Palmer et al, AIDS, 1999; Shafer et al, gp41 envelope gene have been identified MD, PhD, were newly appointed to the Ann Intern Med, 1998). primarily at positions 36 to 45 of the first group. Robert M. Grant, MD, MPH, from the heptad repeat (HR1) region. These muta- Gladstone Institute of Virology and Im- 20. For indinavir, the mutations listed as tions have been identified in viruses from munology in San Francisco, Clive Loveday, major may not be the first mutations select- patients having been on enfuvirtide and MD, PhD, from the International Clinical ed, but they are present in most clinical iso- have been shown to confer resistance or Virology Centre in Buckinghamshire, lates in combination with other mutations. reduced susceptibility (Wei et al, Antimicrob England, and Robert W. Shafer, MD, from Agents Chemother, 2002; Sista et al, Antivir the Stanford University School of Medicine, 21. Major and minor mutations have not Ther, 2002; Mink et al, Antivir Ther, 2002). have completed their terms on the project, and have rotated off. The group is grateful been designated for lopinavir/ritonavir-asso- It is important to note that wild-type viruses for their participation during the last few ciated resistance since currently there are lacking any mutations in the depicted HR1 years. no clear data defining degrees of influence region vary 500-fold in susceptibility and The IAS–USA Drug Resistance Mutations with this drug combination. The accumula- such pretreatment susceptibility differences Group was originally a subgroup of the tion of 6 or more of these mutations is asso- were not associated with differences in clin- IAS–USA HIV Resistance Testing Panel. In ciated with a diminished response to ical response (Labrosse et al, J Virol, 2003; 2000, the Drug Resistance Mutation Group lopinavir/ritonavir. The product information Greenberg et al, 10th CROI, 2003). Further- became an independent entity. The group states that accumulation of 7 or 8 mutations more, it is possible that mutations and/or has forged a collaborative process designed confers resistance to the drug. However, polymorphisms in other regions in the enve- to identify key HIV-1 drug resistance muta- recent data suggest as few as 4 mutations lope, yet to be identified, as well as corecep- tions through independent and unbiased can be associated with such high-level resis- tor usage and density may affect suscepti- consensus, and seeks to rapidly deliver tance (Prado et al, AIDS, 2002). Further clin- bility to enfuvirtide (Reeves et al, PNAS, emerging information on resistance to clini- ical experience and research are needed to 2002). Further research is needed to define cal practitioners. better define the mutations that affect the the full spectrum of clinically relevant muta-

219 International AIDS Society–USA Topics in HIV Medicine

References with selection of the K65R mutation: a retro- through phenotype correlations: novel muta- spective chart review. Antivir Ther. 2003;8: tion patterns and amprenavir cross-resistance. 1. Descamps D, Flandre P, Calvez V, et al. S835. AIDS. 2003;17: 955-961. Mechanisms of virologic failure in previously untreated HIV-1 infected patients from a trial of 13. Shafer RW, Hsu P, Patick AK, Craig C, 24. Rice H, Nadler J, Schaenman J, et al. induction-maintenance therapy. Trilege (Agence Brendel V. Identification of biased amino acid Genotypic predictors of response to Nationale de Recherches sur le SIDA 072) Study substitution patterns in human immunodefi- lopinavir/ritonavir in clinical practice. Antivir Team. JAMA. 2000;283: 205-211. ciency virus type 1 isolates from patients treat- Ther. 2003;8:S169. ed with protease inhibitors. J Virol. 2. Havlir DV, Hellmann NS, Petropoulos CJ, et al. 1999;73:6197-6202. 25. Kagan RM, Shenderovich M, Ramnarayan Drug susceptibility in HIV infection after viral K, Heseltine PNR. Emergence of a novel rebound in patients receiving indinavir-contain- 14. Maguire M, Shortino D, Klein A, et al. lopinavir resistance mutation at codon 47 cor- ing regimens. JAMA. 2000;283:229-234. Emergence of resistance to protease inhibitor relates with ARV utilization. Antivir Ther. amprenavir in human immunodeficiency virus 2003;8:S54. 3. Maguire M, Gartland M, Moore S, et al. type 1-infected patients: selection of four alter- Absence of zidovudine resistance in antiretrovi- native viral protease genotypes and influence 26. Labrosse B, Labernardiere JL, Dam E, et al. ral-naive patients following zidovudine/lamivu- of viral susceptibility to coadministered reverse Baseline susceptibility of primary human dine/protease inhibitor combination therapy: transcriptase nucleoside inhibitors. Antimicrob immunodeficiency virus type 1 to entry virological evaluation of the AVANTI 2 and Agents Chemother. 2002;46:731-738. inhibitors. J Virol. 2003;77: 1610-1613. AVANTI 3 studies. AIDS. 2000;14:1195-1201. 15. Carrillo A, Stewart KD, Sham HL, et al. In 27. Greenberg ML, Melby T, Sista P, et al. 4. Gallego O, Ruiz L, Vallejo A, et al. Changes in vitro selection and characterization of human Baseline and on-treatment susceptibility to the rate of genotypic resistance to antiretroviral immunodeficiency virus type 1 variants with enfuvirtide seen in TORO 1 and TORO 2 to 24 drugs in Spain. AIDS. 2001;15:1894-1896. increased resistance to ABT-378, a novel pro- weeks. [Abstract 141.] 10th Conference on tease inhibitor. J Virol. 1998;72:7532-7541. 5. Walmsley S, Bernstein B, King M, et al. Retroviruses and Opportunistic Infections. February 10-14, 2003; Boston, Mass. Lopinavir-ritonavir versus nelfinavir for the ini- 16. Gong YF, Robinson BS, Rose RE, et al. In tial treatment of HIV infection. N Engl J Med. vitro resistance profile of the human immunod- 2002;346:2039-2046. eficiency virus type 1 protease inhibitor BMS- 28. Reeves JD, Gallo SA, Ahmad N, et al. 232632. Antimicrob Agents Chemother. 2000;44: Sensitivity of HIV-1 to entry inhibitors corre- 6. Hirsch MS, Brun-Vézinet F, Clotet B, et al. 2319-2326. lates with envelope/coreceptor affinity, receptor Antiretroviral drug resistance testing in adults density, and fusion kinetics. Proc Natl Acad Sci infected with human immunodeficiency virus 17. Wu TD, Schiffer CA, Gonzales MJ, et al. U S A. 2002; 99:16249-16254. type I: 2003 recommendations of the Mutation patterns and structural correlates in International AIDS Society–USA panel. Clin human immunodeficiency virus type 1 pro- Infect Dis. 2003;37:113-128. tease following different protease inhibitor Acknowledgements treatments. J Virol. 2003;77:4836-4847. 7. Quinn JB, Borroto-Esoda K, Hinkle J, Shaw A, The IAS–USA Drug Resistance Muta- Harris J, Rousseau F. Overview of the genotypic 18. Mo H, Parkin N, Stewart KD, et al. I84A and tions Group thanks Jennifer Ham, MPH, findings from emtricitabine-treated HIV+ I84C mutations in protease confer high-level for managing the efforts of the group, patients. [Abstract H-908.] 43rd Interscience resistance to protease inhibitors and impair Conference on Antimicrobial Agents and replication capacity. Antivir Ther. 2003;8:S56. and Neil Parkin, PhD, of ViroLogic Inc. Chemotherapy. September 14-17, 2003. for responding to panel questions and 19. McCallister S, Kohlbrenner V, Squires K, et providing information. 8. Miller MD, Margot NA, McColl DJ, Coakley DF, al. Characterization of the impact of genotype, Cheng AK. Characterization of virologic failure phenotype, and inhibitory quotient on antiviral Comments? through 96 weeks among treatment-naive activity of tipranavir in highly treatment-experi- patient taking tenofovir DF (TDF) or stavudine enced patients. Antivir Ther. 2003;8: S15. The IAS–USA Drug Resistance Mut- (d4T) in combination with lamivudine (3TC) and efavirenz (EFV). Antivir Ther. 2003;8: S553. 20. Hall D, McCallister S, Neubacher D, Kraft M, ations Group welcomes comments on Mayers DL. Characterization of treatment- the mutations figures and user notes. 9. Miller MD, White KL, Petropoulos CJ, Parkin emergent resistance mutations in two Phase II Please send your evidence-based com- NT. Decreased replication capacity of HIV-1 clin- studies of tipranavir. Antivir Ther. 2003;8:S16. ments, including relevant reference cita- ical isolates containing K65R or M184V RT tions, to the IAS–USA at resistance@ mutations. [Abstract P616.] 10th Conference on 21. Colonno RJ, Thiry A, Limoli K, Parkin N. Retroviruses and Opportunistic Infections. Activities of atazanavir (BMS-232632) against a iasusa.org or by fax at (415) 544-9401. February 10-14, 2003; Boston, Mass. large panel of human immunodeficiency virus Please include your name and institu- type 1 clinical isolates resistant to one or more tion. 10. Parikh U, Koontz D, Hammond J, et al. approved protease inhibitors. Antimicrob Agents K65R: a muti-nucleoside resistance mutation of Chemother. 2003;47: 1324-1333. Financial Disclosures: The authors disclose the low but increasing frequency. Antivir Ther. following affiliations with commercial supporters 2003;8:S152. 22. Monno L, Saracino A, Scudeller L, et al. HIV- that may have interests related to the content of 1 phenotypic susceptibility to lopinavir (LPV) this article: 11. Ruane P, Luber A, Akil B, et al. Factors influ- and genotypic analysis in LPV/r-naive subjects encing selection of K65R mutation among with prior protease inhibitor experience. J Dr Brun-Vézinet has received grant support from patients receiving tenofovir (TDF) containing Acquir Immune Defic Syndr. 2003;33:439-447. bioMérieux, Bristol-Myers Squibb, GlaxoSmith- regimens. Antivir Ther. 2003;8:S42. Kline, PE Biosystems, and Visible Genetics and 12. McArthur RD, Crane LR, Alvarez D, Fairfax 23. Parkin NT, Chappey C, Petropoulos CJ. has served as a consultant to GlaxoSmithKline M, Richmond D, Curtis G. Factors associated Improving lopinavir genotype algorithm and Visible Genetics; Dr Clotet has received grant

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

support from Bristol-Myers Squibb, Gilead, Roche, Squibb and as a speaker or on a speakers bureau GlaxoSmithKline, Gilead, Bristol-Myers Squibb, and Visible Genetics; Dr Conway has received for Abbott, Boehringer Ingelheim/Roxanne, Roche, and Tibotech-Virco; Dr Richman has research support from Boehringer Ingelheim and Bristol-Myers Squibb, Chiron, GlaxoSmithKline, served as a consultant to Abbott, Achillion, research funding from Abbott, Agouron, Bristol- Merck, Roche, Vertex, and ViroLogic; she has Bristol-Myers Squibb, Chiron, Gilead, Myers Squibb, Schering, and Triangle; Dr D’Aquila received grant support from Boehringer GlaxoSmithKline, Merck, Novirio, Pfizer, Roche, has served as a speaker or on a speakers bureau Ingelheim, Bristol-Myers Squibb, GlaxoSmith- Tibotec-Virco, Triangle, and ViroLogic; Dr for Agouron, Bristol-Myers Squibb, Gilead, Kline, and Visible Genetic; Dr Kuritzkes has Schapiro has served as a scientific advisor to ViroLogic, and Visible Genetics and as a consul- served as a consultant to Abbott, Bayer, Roche and Visible Genetics and on the speakers tant to Bristol-Myers Squibb and GlaxoSmith- Boehringer Ingelheim, Bristol-Myers Squibb, bureau for Abbott, Bristol-Myers Squibb, and Kline; he also receives research grant support Gilead, GlaxoSmithKline, Ortho Biotech, Roche, Roche; he has received other financial support from Bristol-Myers Squibb; Dr Demeter has Shire, Trimeris, and ViroLogic; he has received from GlaxoSmithKline and Virology Education; served on the speakers bureau and scientific advi- honoraria from Abbott, Bristol-Myers Squibb, Dr Telenti has no affiliations to disclose. sory committee for Glaxo SmithKline and has Gilead, GlaxoSmithKline, Roche, and ViroLogic received research support from Applied and grant support from Abbott, Bayer, Bristol- Biosystems, Bristol-Myers Squibb/DuPont Merck, Myers Squibb, GlaxoSmithKline, Roche, and Top HIV Med. 2003;11(6):215-221 and Visible Genetics; Dr Johnson has served as a Tanox; Dr Pillay has served as a consultant to, Copyright  2003 International AIDS Society–USA consultant to GlaxoSmithKline and Bristol-Myers and has received research grants from

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