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Update of the Drug Resistance Mutations in HIV-1: Fall 2006

Victoria A. Johnson, MD, Françoise Brun-Vézinet, MD, PhD, Bonaventura Clotet, MD, PhD, Daniel R. Kuritzkes, MD, Deenan Pillay, MD, PhD, Jonathan M. Schapiro, MD, and Douglas D. Richman, MD

The International AIDS Society–USA the regimen (in this setting, resistance or more of the NNRTI mutations depict- (IAS–USA) Drug Resistance Mutations most commonly develops to lamivu- ed on these bars may lead to poorer Group is marking 6 years as an inde- dine or the nonnucleoside reverse tran- long-term virologic response (see user pendent volunteer panel of experts scriptase inhibitors [NNRTIs]).2-6 The note 12). focused on identifying key HIV-1 drug absence of detectable drug resistance Protease Inhibitors resistance mutations. The goal of the following treatment failure may result effort is to quickly deliver accurate and from the presence of drug-resistant In the protease inhibitor (PI) category, unbiased information on these muta- minority viral populations, patient the ritonavir bar has been removed tions to HIV clinical practitioners. medication nonadherence, laboratory because ritonavir is now used only for This version of the IAS–USA Drug error, drug-drug interactions leading to pharmacologic purposes, not as Resistance Mutations Figures replaces subtherapeutic drug levels, and possi- monotherapy, as discussed in user the version published in this journal in bly compartmental issues, indicating note 15. The “/ritonavir” designation October/November 2005.1 The IAS–USA that drugs may not reach optimal levels has been added to atazanavir, fosam- Drug Resistance Mutations Figures are in specific cellular or tissue reservoirs. prenavir, darunavir, indinavir, and designed for use in identifying muta- saquinavir to indicate boosting with low-dose ritonavir. User note 16 pro- tions associated with viral resistance to Revisions to the Figures for the antiretroviral drugs and in making vides an update on how HIV-1 Gag August/September 2006 Update therapeutic decisions. Care should be cleavage site changes can cause PI taken when using this list of mutations resistance in vitro. for surveillance or epidemiologic stud- Nucleoside (or Nucleotide) Reverse Based on new data (see user note 17), ies of transmission of drug-resistant Transcriptase Inhibitors the following minor mutations have virus. A number of amino acid substi- Among the changes in the August/ been added to atazanavir with or with tutions, particularly minor mutations, September 2006 version of the figures out ritonavir: L10C, K20T/V, E34Q, represent polymorphisms that in isola- and user notes, user note 1 has updates F53L/Y, I54A, I64L/M/V, V82F/I, and tion may not reflect prior drug about NNRTI hypersusceptibility. On I93M. A darunavir/ritonavir bar has selective pressure or reduced drug the nucleoside (or nucleotide) reverse been added for the fully approved susceptibility. transcriptase inhibitor (nRTI) bars, the drug formerly known as TMC-114 (see In the context of making clinical K70E mutation has been added to teno- user note 18). The darunavir/ritonavir decisions regarding antiretroviral ther- fovir. User note 4 discusses mutations major mutations on the bar are I50V, apy, evaluating the results of HIV geno- outside of the reverse transcriptase I54M, L76V, and I84V and the minor typic testing includes: (1) assessing gene region depicted on the figure bars. mutations are V11I, V32I, L33F, I47V, whether the pattern or absence of a These mutations may prove to be I54L, G73S, and L89V. Minor muta- pattern in the mutations is consistent important for HIV drug resistance. Also tions added to saquinavir/ritonavir with the patient’s antiretroviral history; on the nRTI bars, the E44D and V118I are: L24I, I62V, and V82F/T/S. (2) recognizing that in the absence of mutations have been removed from drug (selection pressure), resistant stavudine and zidovudine because the Comments? strains may be present at levels below significance of E44D or V118I when the limit of detection of the test (ana- each occurs in isolation is unknown The IAS–USA Drug Resistance Mut- lyzing stored samples, collected under (see user note 5). selection pressure, could be useful in ations Group welcomes comments on this setting); and (3) recognizing that Nonnucleoside Reverse Transcriptase the mutations figures and user notes. virologic failure of the first regimen Inhibitors typically involves HIV-1 isolates with The multi-NNRTI resistance bars have resistance to only 1 or 2 of the drugs in been removed because the presence of 2 (continued, page 130)

Author Affiliations: Dr Johnson (Group Chair), Birmingham Veterans Affairs Medical Center 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 Kuritzkes, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Dr Pillay, Royal Free and University College Medical School, London, England; Dr Schapiro, National Hemophilia Center, Sheba Medical Center, Tel Aviv, Israel; Dr Richman (Group Vice Chair), Veterans Affairs San Diego Healthcare System and the University of California San Diego, La Jolla, CA.

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MUTATIONS IN THE REVERSE TRANSCRIPTASE GENE ASSOCIATED WITH RESISTANCE TO REVERSE TRANSCRIPTASE INHIBITORS Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (nRTIs)1

Multi-nRTI Resistance: 69 Insertion Complex2 (affects all nRTIs currently approved by the US FDA) M A ▼ K LTK 41 62 69 70 210 215 219 L V Insert R WY Q FE

Multi-nRTI Resistance: 151 Complex3 (affects all nRTIs currently approved by the US FDA except tenofovir) AVF FQ 62 75 77 116 151 VILYM

Multi-nRTI Resistance: Thymidine Analogue-associated Mutations4,5 (TAMs; affect all nRTIs currently approved by the US FDA) M DK LTK 41 67 70 210 215 219 L NR WY Q FE

KL Y M Abacavir6 65 74 115 184 RV F V

KL Didanosine7,8 65 74 RV

K M Emtricitabine 65 184 R V I

K M Lamivudine 65 184 R V I

MDK LTK Stavudine4,5,9,10 41 67 70 210 215 219 LNR WY Q FE

K K Tenofovir11 65 70 RE

4,5,9,10 MDK LTK Zidovudine 41 67 70 210 215 219 LNR WY Q FE

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)1,12 KV Y Y P Delavirdine 103 106 181 188 236 NM C L L

LKVV Y YG P Efavirenz 100 103 106 108 181 188 190 225 INMI C LS H IA

LKVV Y YG Nevirapine 100 103 106 108 181 188 190 INAI C CA MIL H

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Special Contribution – Resistance Mutations Volume 14 Issue 3 August/September 2006 Date of Revision: August 2006 MUTATIONS IN THE PROTEASE GENE ASSOCIATED WITH RESISTANCE TO PROTEASE INHIBITORS 13,14,15,16

Atazanavir LGKL V LEM M G I F I DIIAG V IINLI +/-ritonavir17 10 16 20 24 32 33 34 36 46 48 50 53 54 60 62 64 71 73 82 84 85 88 90 93 IERI I IQI I V LLL EVLVC A VVSML FM FL L YV MIST M VI VV M VTTF CT TLAI V A

Fosamprenavir/ LV MIIIGVIL ritonavir 10 32 46 47 50 54 73 82 84 90 FI IVVLSAVM ILVF R MS V T

Darunavir/ VVLIIIGLIL ritonavir18 11 32 33 47 50 54 73 76 84 89 IIFVVMSVVV L

Indinavir/ LKL V M M I AGVVI L ritonavir 10 20 24 32 36 46 54 71 73 77 82 84 90 IMI I I I V VSIAV M RR L TAF V T

Lopinavir/ LKL VL MI IFI LAGVI L ritonavir19 10 20 24 32 33 46 47 50 53 54 63 71 73 82 84 90 FMI IF IV VLV PVSAV M IR LA L T F R AT V MS T S

LDM M AVVINL Nelfinavir20 10 30 36 46 71 77 82 84 88 90 FN I I VIAVDM ILTFS T S

Saquinavir/ LL G IIAGVVIL ritonavir 10 24 48 54 62 71 73 77 82 84 90 II V VVVSIAVM R LTF V T S

Tipranavir/ LI K L EM K M I I Q H T VN I L ritonavir21 10 13 2 0 33 35 36 43 46 47 54 58 69 74 82 83 84 90 VV M F G I T L V A E K P L D V M R MT V

MUTATIONS IN THE GP41 ENVELOPE GENE ASSOCIATED WITH RESISTANCE TO ENTRY INHIBITORS

Enfuvirtide22

GIVQ QNN 36 37 38 39 40 42 43 First heptad repeat (HR1) region DVA R HT D SM E

Amino acid abbreviations: A, alanine; C, cysteine; MUTATIONS D, aspartate; E, glutamate; F, phenylalanine; G, Insertion glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; Amino acid, wild-type L ▼ M, methionine; N, asparagine; P, proline; Q, glu- Amino acid position 90 54 tamine; R, arginine; S, serine; T, threonine; V, valine; Major (boldface type; protease only)14 M W, tryptophan; Y, tyrosine. Amino acid substitution conferring resistance Minor (lightface type; protease only)14

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The International AIDS Society–USA Drug Resistance Mutations Group reviews new data Mutations at this level could modulate on HIV drug resistance in order to maintain a current list of mutations associated with NNRTI resistance by affecting dimerization clinical resistance to HIV. This list includes mutations that may contribute to a reduced of p66/p51 heterodimers (Gupta et al. virologic response to a drug. Antivir Ther, 2006). The clinical relevance of these mutations has not been assessed. The mutations listed have been identified by 1 or more of the following criteria: (1) in vitro passage experiments or validation of contribution to resistance by using site-direct- 5. The E44D and the V118I mutations ed mutagenesis; (2) susceptibility testing of laboratory or clinical isolates; (3) genetic increase the level of resistance to zidovu- sequencing of viruses from patients in whom the drug is failing; (4) correlation studies dine and stavudine in the setting of TAMs, between genotype at baseline and virologic response in patients exposed to the drug. In and correspondingly increase cross-resis- addition, the group only reviews data that have been published or have been presented tance to the other nRTIs. The significance of at a scientific conference. Drugs that have been approved by the US Food and Drug E44D or V118I when each occurs in isola- Administration (FDA) are included (listed in alphabetical order by drug class). User notes tion is unknown (Romano et al, J Infect Dis, provide additional information as necessary. Although the Drug Resistance Mutations 2002; Walter et al, Antimicrob Agents Group works to maintain a complete and current list of these mutations, it cannot be Chemother, 2002; Girouard et al, Antivir assumed that the list presented here is exhaustive. Readers are encouraged to consult Ther, 2002). the literature and experts in the field for clarification or more information about specif- ic mutations and their clinical impact. 6. The M184V mutation alone does not appear to be associated with a reduced User Notes virologic response to abacavir in vivo (Harrigan et al, J Infect Dis, 2000; Lanier et 1. Numerous nucleoside (or nucleotide) J Infect Dis, 2004). al, Antivir Ther, 2004). When present with reverse transcriptase inhibitor (nRTI) muta- 4. Multi-nRTI resistance mutations, also 2 or 3 TAMs, M184V contributes to reduced tions, such as the M41L, L210W, and T215Y known as nucleoside analogue-associated susceptibility to abacavir and is associated mutations, may lead to viral hypersuscepti- mutations (NAMs), are associated with with impaired virologic response in vivo bility to the nonnucleoside reverse tran- resistance to numerous nRTIs. The M41L, (Lanier et al, Antivir Ther, 2004). The scriptase inhibitors (NNRTIs) in nRTI-treat- D67N, K70R, L210W, T215Y/F, and M184V plus 4 or more TAMs resulted in no ed individuals. The presence of these K219Q/E are known as TAMs. TAMs are a virologic response to abacavir in vivo mutations may improve subsequent viro- subset of NAMs that are selected by the (Lanier et al, Antivir Ther, 2004). logic response to NNRTI-containing regi- thymidine analogues zidovudine and stavu- mens in NNRTI treatment-naive individuals dine and are associated with cross-resis- 7. The K65R mutation may be selected (Shulman et al, AIDS, 2004; Demeter et al, tance to all nRTIs currently approved by the 11th CROI, 2004; Haubrich et al, AIDS, by didanosine and is associated in vitro 2002; Tozzi, J Infect Dis, 2004; Katzenstein US FDA (Larder et al, Science, 1989; Kellam with decreased susceptibility to the et al, AIDS, 2003). NNRTI hypersusceptibil- et al, Proc Natl Acad Sci USA, 1992; Calvez drug (Winters et al, Antimicrob Agents ity can be conferred by 2 distinct pheno- et al, Antivir Ther, 2002; Kuritzkes et al, J Chemother, 1997). The impact of the K65R types: increased enzyme susceptibility to Acquir Immune Defic Syndr, 2004). mutation in vivo is unclear. NNRTI (eg, V118I/T215Y) or decreased viri- Mutations at the C-terminal reverse tran- on associated levels of reverse transcriptase scriptase domains (amino acids 293–560) 8. The presence of 3 of the following—M41L, (eg, H208Y/T215Y and V118I/H208Y/T215Y). outside of regions depicted on the figure D67N, L210W, T215Y/F, and K219Q/E—has The viruses that contained less reverse tran- bars may prove to be important for HIV been associated with resistance to didano- scriptase replicated less efficiently than drug resistance. Mutations in the connec- sine (Marcelin et al, Antimicrob Agents those with wild-type levels of reverse tran- tion (A371V) and RNase H (Q509L) Chemother, 2005). The K70R and M184V scriptase. (Clark et al, Antivir Ther, 2006). domains of reverse transcriptase are co- mutations are not associated with a The clinical relevance of all these mutations selected on the same genome as TAMs and decreased virologic response to didanosine in has not been assessed. increase significantly zidovudine resistance vivo (Molina et al, J Infect Dis, 2005). when combined with TAMs. They also 2. The 69 insertion complex consists of a increase, although to a much lesser extent, 9. The presence of the M184V mutation substitution at codon 69 (typically T69S) cross-resistance to lamivudine, abacavir, appears to delay or prevent emergence of and an insertion of 2 or more amino acids and tenofovir but not to stavudine or TAMs (Kuritzkes et al, AIDS, 1996). This effect (S-S, S-A, S-G, or others). The 69 insertion didanosine (Brehm et al. Antiviral Ther, may be overcome by an accumulation of complex is associated with resistance to all 2006). In zidovudine-exerienced patients, it TAMs or other mutations. The clinical signifi- nRTIs currently approved by the US FDA when present with 1 or more thymidine has been shown by drug susceptibility test- cance of this effect of M184V is not known. analogue-associated mutations (TAMs) at ing that, in the C-terminal domain, the codons 41, 210, or 215 (Miller et al, J Infect mutations G335C, N348I, and A360I 10. The T215A/C/D/E/G/H/I/L/N/S/V substitu- Dis, 2004). Some other amino acid changes exhibited 30-, 35-, and 30-fold increases tions are revertant mutations at codon 215, from the wild-type T at codon 69 without in zidovudine resistance, respectively. conferring increased risk of virologic failure the insertion may also be associated with (Nikolenko et al, Antiviral Ther, 2006.) of zidovudine or stavudine in antiretroviral- broad nRTI resistance. Three mutations (N348I, T369I, and naive patients (Riva et al, Antivir Ther, 2002; E399D) in the reverse transcriptase C-ter- Chappey et al, Antivir Ther, 2003; Violin et 3. Tenofovir retains activity against the minus are associated with the increased al, AIDS, 2004). In vitro studies and prelim- Q151M complex of mutations (Miller et al, resistance to zidovudine and to NNRTIs. inary clinical studies suggest that the T215Y

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mutant may emerge quickly from one of effect on phenotype. In some cases, correlated with baseline susceptibility and these mutations in the presence of zidovu- their effect may be to improve replica- the presence of multiple specific PI muta- dine or stavudine (Garcia-Lerma et al, J Virol, tive fitness of the virus containing tions. Reductions in response were associ- 2004; Lanier et al, Antivir Ther, 2002; Riva major mutations. However, some ated with increasing numbers of the et al, Antivir Ther, 2002). minor mutations are present as com- mutations indicated in the bar. Some of mon polymorphic changes in HIV-1 these mutations appear to have a greater 11. The K65R mutation is associated with a nonsubtype B clades, such as K20I/R effect on susceptibility than others (eg, reduced virologic response to tenofovir in and M36I in protease. I50V versus V11I). Further study and analy- vivo (Miller et al, J Infect Dis, 2004). A sis in other populations are required to reduced response occurs in the presence of 15. Ritonavir is not listed separately as it is refine and validate these findings. 3 or more TAMs inclusive of either M41L or currently used at therapeutic doses as a L210W (Miller et al, J Infect Dis, 2004). pharmacologic booster of other PIs. At high- 19. In PI-experienced patients, the accumu- Slightly increased treatment responses to er doses tested previously in humans, riton- lation of 6 or more of the mutations tenofovir in vivo were observed if M184V avir administered as monotherapy produces indicated on the bar is associated was present (Miller et al, J Infect Dis, 2004). mutations similar to those produced by indi- with a reduced virologic response to navir (Molla, Nature Med, 1996). lopinavir/ritonavir (Masquelier et al, 12. The long-term virologic response to Antimicrob Agents Chemother, 2002; Kempf sequential NNRTI use is poor, particularly 16. HIV-1 Gag cleavage site changes can et al, J Virol, 2001). The product informa- when 2 or more mutations are present cause PI resistance in vitro. It has been tion states that accumulation of 7 or 8 (Antinori et al, AIDS Res Hum Retroviruses, observed that mutations in the N-terminal mutations confers resistance to the drug. In 2002; Lecossier et al, J Acquir Immune Defic part of gag (MA: E40K; L75R; K113E and CA: contrast, in those in whom lopinavir/riton- Syndr, 2005). The K103N or Y188L muta- M200I; A224A/V), outside the cleavage site, avir is their first PI used, resistance to this tion alone prevents the clinical utility of all contribute directly to PI resistance by enhanc- drug at the time of virologic rebound is rare. NNRTIs currently approved by the US FDA ing the overall Gag processing by wild-type However, there is emerging evidence that (Antinori et al, AIDS Res Human Retroviruses, protease. (Nijhuis et al. Antivir Ther, 2006). specific mutations, most notably I47A (and 2002). The V106M mutation is more com- The clinical relevance of these mutations possibly I47V) and V32I are associated with mon in HIV-1 subtype C than in subtype B, has not been assessed. high-level resistance (Mo et al, J Virol, 2005; and confers cross-resistance to all currently Friend et al, AIDS 2004; Kagan et al, Protein approved NNRTIs (Brenner et al, AIDS, 2003; 17. In most patients in whom an ataz- Sci, 2005). Cane et al, J Clin Micro, 2001). anavir/ritonavir-containing regimen was fail- ing virologically, accumulations of the follow- 20. In some nonsubtype-B HIV-1, D30N is 13. The same mutations usually emerge ing 13 mutations were found (L10F/I/V, selected less frequently than other PI muta- whether or not PIs are boosted with low- G16E, L33F/I/V, M46I/L, I54L/V/M/T, D60E, tions (Gonzalez et al, Antivir Ther, 2004). dose ritonavir, although the relative fre- I62V, A71I/T/L, V82A/T, I84V, I85V, L90M, quency of mutations may differ. Data on and I93L). Seven mutations were retained in 21. Accumulation of more than 2 mutations the selection of mutations in antiretroviral- an atazanavir score (L10F/I/V, G16E, at positions 33, 82, 84, and 90 corre- naive patients in whom a boosted PI is fail- L33F/I/V, M46I/L, D60E, I84V, I85V); the late with reduced virologic response to ing are very limited. Numerous mutations presence of 3 or more of these mutations tipranavir/ritonavir, although an independent are often necessary to significantly impact predicts a reduced virologic response at 3 role for L90M was not found. Detailed analy- virologic response to a boosted PI. Although months, particularly when L90M was pre- ses of data from phase II and III trials in PI- numbers vary for the different drugs, 3 or sent (Vora, et al, Antivir Ther, 2005). A differ- experienced patients identified mutations more mutations are often required. ent report (Bertoli et al, Antivir Ther, 2006) associated with reduced susceptibility or found that the presence of 0, 1, 2, or greater virologic response. These include: L10V, 14. Resistance mutations in the protease than or equal to 3 of the following mutations I13V, K20M/R, L33F, E35G, M36I, K43T, gene are classified as either “major” or were associated with 92%, 93%, 75%, and M46L, I47V, I54A/M/V, Q58E, H69K, T74P, “minor,” if data are available. 0% virologic response to atazanavir/riton- V82L/T, N83D, and I84V. Accumulation of avir: L10C/I/V, V32I, E34Q, M46I/L, F53L, these mutations is associated with reduced Major mutations in the protease gene I54A/M/V, V82A/F/I/T, I84V; presence response. Subsequent genotype-phenotype are defined in general either as those of I15E/G/L/V, H69K/M/N/Q/R/T/Y, and and genotype-virologic response analyses selected first in the presence of the I72M/T/V improved the chances of response. determined some mutations have a greater drug; or those shown at the biochemi- For unboosted atazanavir, the presence of 0, effect than others (eg, I84V versus I54M). cal or virologic level to lead to an alter- 1, 2, or greater than or equal to 3 of the Refinement and clinical validation of these ation in drug binding or an inhibition following mutations was associated with findings are pending (Schapiro et al, CROI, of viral activity or viral replication. 83%, 67%, 6%, and 0% response rates: 2005; Kohlbrenner et al, DART, 2004; Major mutations have an effect on G16E, V32I, K20I/M/R/T/V, L33F/I/V, F53L/Y, Mayers et al, Antivir Ther, 2004; Hall et al, drug susceptibility phenotype. In gen- I64L/M/V, A71I/T/V, I85V, I93L/M. Antivir Ther, 2003; McCallister et al, Antivir eral, these mutations tend to be the Ther, 2003; Parkin et al, CROI, 2006; primary contact residues for drug 18. Darunavir (formerly TMC-114), boost- Bacheler et al, European HIV Drug binding. ed with ritonavir, was approved by the US Resistance Workshop, 2006). Minor mutations generally emerge FDA in June 2006. Resistance data are later than major mutations, and by therefore still preliminary and limited. 22. Although resistance to enfuvirtide is themselves do not have a significant HIV RNA response to boosted darunavir associated primarily with mutations in the

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first heptad repeat (HR1) region of the posed adaptation. In order to ensure Merck, Monogram Biosciences, Panacos, gp41 envelope gene, wild-type viruses in the integrity of the mutations figures, Pfizer, Roche/Trimeris, and VirXsys, and the depicted HR1 region vary 500-fold in it is the policy of the IAS–USA to grant grant support from Bayer, Boehringer susceptibility. Such pretreatment suscepti- permission for only minor preap- Ingelheim, Bristol-Myers Squibb, Glaxo- bility differences were not associated with proved adaptations of the figures (eg, SmithKline, Human Genome Sciences, differences in clinical responses (Labrosse an adjustment in size). Minimal adap- Merck, Roche/Trimeris, Schering-Plough, et al, J Virol, 2003). Furthermore, muta- tations only will be considered; no and Tibotec; Dr Pillay has served as a con- tions or polymorphisms in other regions in alterations of the content of the fig- sultant to and has received research grants the envelope (eg, the HR2 region or those from GlaxoSmithKline, Gilead, Bristol- yet to be identified) as well as coreceptor ures or user notes will be permitted. Myers Squibb, Roche, and Tibotec-Virco; Dr usage and density may affect susceptibility Please note that permission will be to enfuvirtide (Reeves et al, Proc Natl Acad granted only for requests to reprint or Richman has served as a consultant to Sci USA, 2002; Reeves et al, J Virol, 2004; adapt the most current version of the Achillion, Anadys, Bristol-Myers Squibb, Xu et al, Antimicrob Agents Chemother, mutations figures as they are posted Gilead, GlaxoSmithKline, Idinex, Merck, 2005). Thus, testing to detect only the on the Web site (www.iasusa.org). Monogram, Pfizer, Roche, and Tibotec; Dr depicted HR1 mutations may not be ade- Because scientific understanding of Schapiro has served as a scientific advisor quate for clinical management of suspect- HIV drug resistance is evolving quick- to Bayer and Roche and on the speakers ed failure (Reeves et al, J Virol, 2004; ly and the goal of the Drug Resistance bureau for Abbott, Bristol-Myers Squibb, Menzo et al, Antimicrob Agents Chemother, Mutations Group is to maintain the and Roche, and has received other financial 2004; Poveda et al, J Med Virol, 2004; Sista most up-to-date compilation of muta- support from GlaxoSmithKline and Virology et al, AIDS, 2004; Su, Antivir Ther, 2004). tions for HIV clinicians and Education. researchers, the publication of out-of- Funding/Support: This work was funded by (continued from page 125) date figures is counterproductive. If you have any questions about reprints IAS–USA. No private sector or government or adaptations, please contact us. funding contributed to this effort. Panel Please send your evidence-based members are not compensated. comments, including relevant refer- ence citations, to the IAS–USA at Financial Disclosures: The authors disclose resistance2006“at”iasusa.org or by the following affiliations with commercial References fax at 415-544-9401. Please include organizations that may have interests relat- your name and institution. ed to the content of this article: Dr Brun- Vézinet has received grant support from 1. Johnson VA, Brun-Vézinet F, Clotet B, et al. Update of the Drug Resistance Mutations in Bayer, bioMérieux, Bristol-Myers Squibb, Reprint Requests HIV-1: Fall 2005. Top HIV Med. 2005;13:125- GlaxoSmithKline, and PE Biosystems and 131. has served as a consultant to Abbott, Bayer, The Drug Resistance Mutations Group Boehringer Ingelheim, GlaxoSmithKline, 2. Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic failure in previously welcomes interest in the mutations Gilead, Roche, and Tibotec; Dr Clotet has untreated HIV-infected patients from a trial of figures as an educational resource for served as a consultant and received grant practitioners and encourages dissem- induction-maintenance therapy. Trilege support from Abbott, Boehringer Ingelheim, (Agence Nationale de Recherches sur le SIDA ination of the material to as broad an Bristol-Myers Squibb, Gilead Sciences, 072) Study Team. JAMA. 2000;283:205-211. audience as possible. However, we GlaxoSmithKline, Pfizer, and Roche; Dr 3. Havlir DV, Hellmann NS, Petropoulos CJ, et require that permission to reprint the Johnson has served as a consultant to figures be obtained and that no alter- al. Drug susceptibility in HIV infection after viral GlaxoSmithKline, Bristol-Myers Squibb, rebound in patients receiving indinavir-contain- nations in the content be made. If Virco, and ViroLogic and as a speaker or on ing regimens. JAMA. 2000;283:229-234. you wish to reprint the mutations fig- a speakers bureau for Abbott, Bayer, Boeh- 4. Maguire M, Gartland M, Moore S, et al. ures, please send your request to the ringer Ingelheim/Roxanne, Bristol-Myers IAS–USA via e-mail (see above) or Absence of zidovudine resistance in antiretro- Squibb, Chiron, GlaxoSmithKline, Merck, viral-naive patients following zidovudine/ fax. Requests to reprint the material Roche, Vertex, and ViroLogic, and has lamivudine/protease inhibitor combination should include the name of the pub- received grant support from Boehringer therapy: virological evaluation of the AVANTI 2 lisher or sponsor, the name or a Ingelheim, Bristol-Myers Squibb, Glaxo- and AVANTI 3 studies. AIDS. 2000;14:1195- description of the publication in SmithKline, and Bayer; Dr Kuritzkes has 1201. which you wish to reprint the materi- served as a consultant to Abbott, Anormed, 5. Gallego O, Ruiz L, Vallejo A, et al. Changes in al, the funding organization(s), if Avexa, Bayer, Boehringer Ingelheim, Bristol- the rate of genotypic resistance to antiretrovi- applicable, and the intended audi- Myers Squibb, Chiron, Gilead, Glaxo- ral drugs in Spain. AIDS. 2001;15:1894-1896. ence of the publication. Requests to SmithKline, Merck, Monogram Biosciences, 6. Walmsley S, Bernstein B, King M, et al. make any minimal adaptations of the Panacos, Pfizer, Roche/Trimeris, Schering- Lopinavir-ritonavir versus nelfinavir for the material should include the former, Plough, Tanox, Tibotec, and VirXsys, and initial treatment of HIV infection. N Engl J plus a detailed explanation of has received honoraria from Abbott, Med. 2002;346:2039-2046. how the adapted version will be Anormed, Avexa, Bayer, Boehringer changed from the original version Ingelheim, Bristol-Myers Squibb, Gilead, Top HIV Med. 2006;14(3):125-130 and, if possible, a copy of the pro- GlaxoSmithKline, Human Genome Sciences, Copyright 2006, International AIDS Society–USA

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