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XI International HIV Drug Resistance Workshop: Basic Principles and Clinical ImplicationsSeville, Spain, 2–5 July 2002 |
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Session 1: New antiretrovirals Abstracts 1 thru 23, Pages S3 to S25 |
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| 1 | A NOVEL HIV-1 INTEGRASE INHIBITOR MEDIATES SUSTAINED SUPPRESSION OF VIRAL REPLICATION AND CD4 DEPLETION IN A SHIV RHESUS MACAQUE MODEL OF INFECTION Antivir Ther. 2002;7(Suppl 1):S3 D Hazuda and the HIV-1 Integrase Inhibitor Discovery Team We, therefore, evaluated a representative integrase inhibitor from this series in a pre-clinical efficacy study using a rhesus macaque infection model with SHIV 89.6P. Oral administration of the compound as a single agent effectively inhibited viral replication (1 to 3 log decrease in vRNA) and preserved CD4 levels. Viral inhibition was sustained throughout the 75-day course of compound administration. These observations provide the first demonstration of biological activity for an inhibitor of HIV-1 integrase in vivo.  Download Abstracts
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| 2 | DISCOVERY OF A POTENT ANTIVIRAL HIV INTEGRASE INHIBITOR WITH POTENTIAL CLINICAL UTILITY Antivir Ther. 2002;7(Suppl 1):S4 SD Young and the HIV Integrase Inhibitor Discovery Team The leading compound from this new series has good pharmacokinetics in rats, dogs and rhesus macaques. Its absolute oral bioavailability and half-life in these species, along with its stability in isolated human hepatocytes, suggests a high potential for good pharmacokinetics in humans. Following preliminary safety assessment studies, this compound has moved into Phase I clinical trials for evaluation in healthy volunteers. Download Abstracts
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| 3 | MIV-310 REDUCES MARKEDLY VIRAL LOAD IN PATIENTS WITH VIROLOGICAL FAILURE DESPITE MULTIPLE-DRUG THERAPY: RESULTS FROM A 4-WEEK PHASE II STUDY Antivir Ther. 2002;7(Suppl 1):S4 V Calvez1, R Tubiana2, J Ghosn2, M Wirden1, AG Marcelin1, C Westling3, H Shoen2, J Harmenberg3, G Mårdh3, B Öberg3 and C Katlama2 MIV-310 at 7.5 mg/day efficiently reduced viral load in patients with virological failure despite multiple resistance to NRTI. Further studies are being planned. Download Abstracts
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| 4 | IDENTIFICATION OF AMINO ACID SUBSTITUTIONS CORRELATED WITH REDUCED ATAZANAVIR SUSCEPTIBILITY IN PATIENTS TREATED WITH ATAZANAVIR CONTAINING REGIMENS Antivir Ther. 2002;7(Suppl 1):S4 RJ Colonno1, J Friborg1, RE Rose1, E Lam2 and N Parkin2 PT and GT analysis of isolates from patients treated with regimens containing atazanavir suggest that the emergence of the amino acid substitutions I50L and A71V in treatment-naïve patients may result in selective resistance to atazanavir. Download Abstracts
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| 5 | IN VITRO SELECTION EXPERIMENTS DEMONSTRATE AN INCREASED GENETIC BARRIER TO RESISTANCE DEVELOPMENT TO TMC114 AS COMPARED WITH CURRENTLY LICENSED PROTEASE INHIBITORS Antivir Ther. 2002;7(Suppl 1):S5 S De Meyer, H Azijn, M Van Ginderen, I De Baere, R Pauwels and M-P de Béthune In a standardized protocol, in vitro selection of resistant HIV was much slower with TMC114 as compared to amprenavir, nelfinavir or lopinavir. While virus capable of replicating in micromolar levels of amprenavir, nelfinavir or lopinavir was readily selected, the selection concentration of TMC114 could not be raised above 100 nM. Viruses isolated in the presence of 100 nM TMC114 showed low replication capacity and only a 10-fold change in susceptibility to the inhibitor. Little or no cross-resistance to current PIs, except to saquinavir, was observed with these viruses. These results suggest an increased genetic barrier to the development of resistance to TMC114. Download Abstracts
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| 6 | GENERATION AND CHARACTERIZATION OF HIV-1 VARIANTS RESISTANT TO BMS-806, A NOVEL HIV-1 ENTRY INHIBITOR Antivir Ther. 2002;7(Suppl 1):S6 P-F Lin, YF Gong, B Rose, W Blair, N Zhou, Q Guo, H-T Ho, C Li, D Langley, H Wang, T Spicer, G Demers, T Wang, J Friborg, B Robinson and RJ Colonno Genotypic and phenotypic analysis of the BMS-806 selected HIV-1 variants confirmed the results of biochemical studies showing that the binding target of this novel inhibitor is the HIV-1 envelope glycoprotein gp120. The lack of cross-resistance between BMS-806 and other classes of inhibitors suggests the potential utility of this compound class in HIV drug combination therapy. Download Abstracts
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| 7 | INCIDENCE OF RESISTANCE AFTER TREATMENT FOR TWO YEARS WITH EMTRICITABINE IN PATIENTS CHRONICALLY INFECTED WITH HEPATITIS B VIRUS Antivir Ther. 2002;7(Suppl 1):S7 K Borroto-Esoda, H Mommeja-Marin, A Snow, E Mondou, A Rigney, C Wakeford and F Rousseau Emtricitabine produced a sustained virological response (41% <LOD at 2 years). At 2 years the overall incidence of L526M±M550V/I associated resistance was 25% and lower among patients receiving 200 mg for the duration of the study (19%), suggesting that more viral suppression with emtricitabine limits the emergence of resistant variants. This observation is consistent with results from an HIV clinical trial where the incidence of developing the M184V mutation after treatment with emtricitabine was low (21%). This profile could be especially interesting among patients co-infected with HBV and HIV. Download Abstracts
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| 8 | THE USE OF α-BORANOPHOSPHATE NUCLEOSIDE ANALOGUES TO SUPPRESS HIV-MEDIATED MULTI-DRUG RESISTANCE TO LAMIVUDINE, DIDEOXYNUCLEOSIDES, AND ZIDOVUDINE Antivir Ther. 2002;7(Suppl 1):S8 J Deval1, B Selmi1, B Schneider2, P Meyer3, J Boretto1, S Sarfati3, D Deville- Bonne2, C Guerreiro3, J Janin3, M Véron2 and B Canard1 Knowledge of the exact mechanism of drug resistance and suppression will guide design of novel nucleotide analogues, such as PMPA, for which both the K65R substitution and the borano substitution might prove very relevant in future therapies. Download Abstracts
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| 9 | TMC125 CAN SUPPRESS THE SELECTION OF RESISTANT HIV FROM A VIRUS POPULATION CARRYING THE K103N OR THE Y181C MUTATION Antivir Ther. 2002;7(Suppl 1):S8 J Vingerhoets1, H Azijn1, E Fransen1, K Andries2, R Pauwels1 and M-P de Béthune1 In a standardized in vitro selection protocol, NNRTI-resistant mutants carrying the K103N or the Y181C mutation behaved similarly to wild-type HIV-1, that is, no virus breakthrough was observed in the presence of 1 µM TMC125. Selection of TMC125 resistant strains from the double K103N/Y181C mutant was comparable to the profiles observed with first generation NNRTIs when using wild-type HIV-1. These data confirm the existence of an increased genetic barrier to the development of resistance against TMC125. Download Abstracts
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| 10 | IN VITRO SUSCEPTIBILITY OF HIV-1 TO TIPRANAVIR Antivir Ther. 2002;7(Suppl 1):S9 L Doyon, S Tremblay, M Cartier and MG Cordingley The development of decreased susceptibility to tipranavir in vitro is slow and complex, involving the sequential accumulation of multiple mutations in the viral protease. Acquisition of a similar constellation of mutations appears to influence susceptibility to tipranavir in the context of both the wild-type and multi-PI resistant protease. Download Abstracts
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| 11 | HIV-1 RESISTANCE TO THE GP41-DEPENDENT FUSION INHIBITOR C-34 Antivir Ther. 2002;7(Suppl 1):S10 M Armand-Ugón, A Gutiérrez, B Clotet and JA Esté We describe for the first time a mutation L33S outside of the GIV (positions 36–38) motif that generates resistance to known peptidic fusion inhibitors. Mutations at position 38 that modify sensitivity to DP178 may also affect the sensitivity of HIV-1 to inhibitory peptides that contain amino acids W117, W120, I124. HIV-1 becomes resistant to gp41 inhibitors if the peptide includes residues that are placed C-terminus from those that project into the cavity (W117, W120, I124). The design of new inhibitors of gp41-mediated fusion should be directed to the residues that form the hydrophobic cavity. Download Abstracts
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| 12 | IN VITRO ANTIVIRAL ACTIVITY OF T-1249 A SECOND GENERATION FUSION INHIBITOR Antivir Ther. 2002;7(Suppl 1):S10 ML Greenberg1, D Davison1, L Jin1, S Mosier1, T Melby1, P Sista1, R Demasi1, D Miralles1, N Cammack2 and TJ Matthews1 T-1249 exhibited potent in vitro activity against enfuvirtide-naïve clinical isolates. The activity of T1249 was independent of resistance to existing classes of antiretrovirals. Clinical isolates and site-directed mutants of pNL4-3 bearing enfuvirtide resistance associated substitutions in gp41 amino acids 36-45 remained largely sensitive to T-1249. These findings suggest that the gp41 target and mechanism of action of T-1249 and enfuvirtide, though similar and perhaps overlapping, are not identical. Download Abstracts
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| 13 | NOVEL MUTATIONS IN A HIGHLY CONSERVED REGION OF HIV-1 GP41 ARE ASSOCIATED WITH T-20 TREATMENT Antivir Ther. 2002;7(Suppl 1):S11 SD Kemp1, L Ruiz2, AM Lucas1, A Bonjoch2, J Martinez-Picado2, BA Larder1 and B Clotet2 This study identified both novel mutations and those that have been previously identified as either associated or not associated with decreased sensitivity to T-20. These mutations occurred in a highly conserved region of HIV-1 gp41 isolated from patients treated with T-20. Further research is required to establish the precise role of these mutations in T-20 susceptibility and treatment response. Download Abstracts
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| 14 | MULTIVARIATE ANALYSES OF ANTIVIRAL RESPONSE TO TENOFOVIR DF THERAPY IN ANTIRETROVIRAL-EXPERIENCED PATIENTS Antivir Ther. 2002;7(Suppl 1):S12 MD Miller, L Zhong, S Chen, NA Margot and M Wulfsohn Multivariate regression analyses and in vitro susceptibility results confirm that the infrequent K65R mutation or multiple mutations in the 41-210-215 TAM pathway are associated with reduced responses to tenofovir DF therapy. Prior accumulation of ≥5 TAMs within this pathway is associated with the highest levels of resistance. Continued thymidine analogue therapy in the presence of replicating HIV probably results in progression of this resistance pathway. Download Abstracts
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| 15 | AZIDE GROUP CONTAINING 3-ARYL-1, 3-DIKETO ACID DERIVATIVES ARE POTENT INHIBITORS OF HIV-1 REPLICATION Antivir Ther. 2002;7(Suppl 1):S13 ES Svarovskaia1, R Barr1, X Zhang2, GCG Pais2, C Marchand3, Y Pommier3, TR Burke Jr2 and VK Pathak1 These results indicate that diketo acid derivatives containing azide groups are potent inhibitors of HIV-1 integrase and viral replication. Download Abstracts
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| 16 | MINIMAL VARIATION IN THE T-20 BINDING DOMAIN OF DIFFERENT HIV-1 SUBTYPES FROM ANTIRETROVIRAL-NAÏVE AND -EXPERIENCED PATIENTS Antivir Ther. 2002;7(Suppl 1):S13 Li Xu, S Hue, D Ratcliffe, J Workman, S Jackson, P Cane and D Pillay This is the first report on sequence analysis of the HR-1 domain of different subtypes of HIV-1 in T-20-naïve patients. Despite the genetic variability among subtypes, our data suggests that the 'GIV' motif within the HR1 region is highly conserved, and natural variants may only rarely occur in the absence of specific selective pressure. Download Abstracts
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| 17 | RESISTANCE INDUCTION STUDIES WITH INHIBITORS OF HIV-1 NUCLEOCAPSID ZINC FINGER PROTEIN Antivir Ther. 2002;7(Suppl 1):S14 M Huang, M Deshpande and WG Rice (1) The data are consistent with an antiviral action elicited by selective targeting of the HIV NC zinc fingers. (2) NC inhibitors are active against HIV-1 strains resistant to other drugs. (3) In vitro induction of virus strains resistant to NC inhibitors has thus far proved unsuccessful, as predicted from the essential and conserved nature of NC zinc fingers. (4) NC zinc finger inhibitors may be a valuable addition to current therapies and may help curb the rapid emergence of viral resistance. Download Abstracts
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| 18 | NEW MUTATIONS AT RESIDUE POSITIONS CRITICAL FOR T-20 RESISTANCE IN T-20-NAÏVE PATIENTS INFECTED WITH CLADE B HIV-1 ISOLATES Antivir Ther. 2002;7(Suppl 1):S14 F Roman1, D Gonzalez2, R Boulme2, C Lambert1, S Deroo1, A Fischer1, T Baurith1, T Staub1, V Arendt1, F Schneider1, R Hemmer1 and JC Schmit1 No classical resistance-associated mutations to T-20 were identified in B or non-B isolates in our study. However, we identified two new mutations in B isolates in a region critical for T-20 activity: I37V and Q39R. The impact of these mutations on T-20 sensitivity has not been determined in vitro. These findings emphasize the need to develop phenotypic resistance testing for fusion inhibitors. Download Abstracts
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| 19 | D-FDOC: A DIOXOLANE PYRIMIDINE NUCLEOSIDE WITH ACTIVITY AGAINST COMMON NUCLEOSIDE-RESISTANT HIV-1 Antivir Ther. 2002;7(Suppl 1):S15 RF Schinazi1, J Mellors2, S Erickson–Viitanen4, J Mathew1, U Parikh2, P Sharma1, M Otto4, Z Yang3, CK Chu3 and DC Liotta1 In Swiss mice treated for 5 days at 3.3 to 100 mg/kg (once-a-day, intraperitoneally), no overt toxicity was apparent at any dose. Taken together, the potent and selective activity of D-FDOC against M184V and zidovudine-resistant HIV-1 variants suggest that advanced pharmacological and toxicological studies of this compound should be pursued. Download Abstracts
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| 20 | THE DRUG RESISTANCE PROFILE OF TENOFOVIR: A STORY OF RESISTANCE AND RESENSITIZATION Antivir Ther. 2002;7(Suppl 1):S16 K Wolf1, H Walter1, T Schnell1, W Keulen2, N Beerenwinkel3, J Selbig4, A-M Vandamme5, K Korn1 and B Schmidt1 Tenofovir resistance is associated with insertions between RT 67–70 as well as K65R in the presence of Q151M. Zidovudine mutations – in particular 41 and 215 – confer cross-resistance to tenofovir, which can be in part resensitized by M184V. This supports the conclusion that the parallel administration of tenofovir and lamivudine may be of clinical benefit in zidovudine-experienced patients. Download Abstracts
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| 21 | CHARACTERIZATION OF BASELINE AND TREATMENT-EMERGENT RESISTANCE TO T-20 (ENFUVIRTIDE) OBSERVED IN PHASE II CLINICAL TRIALS: SUBSTITUTIONS IN GP41 AMINO ACIDS 36–45 AND ENFUVIRTIDE SUSCEPTIBILITY OF VIRUS ISOLATES Antivir Ther. 2002;7(Suppl 1):S16 P Sista1, T Melby1, ML Greenberg1, D Davison1, L Jin1, S Mosier1, M Mink1, E Nelson1, L Fang1, N Cammack2, M Salgo3 and TJ Matthews1 Both the low incidence of substitutions in the gp41 aa 36–45 region at baseline, and the correlation between changes in this region on treatment and reduced susceptibility to enfuvirtide, support its importance as a principal determinant of enfuvirtide resistance. The majority of patients failing on treatment exhibited amino acid substitutions in gp41 aa 36–45 and PBMC virus isolates with reduced susceptibility to enfuvirtide also exhibited substitutions in this region. The role of other gp41 loci in determining resistance to enfuvirtide is unknown at present and is the subject of ongoing research. Download Abstracts
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| 22 | IMPACT OF HIV-1 GP41 AMINO ACID SUBSTITUTIONS (POSITIONS 36–45) ON SUSCEPTIBILITY TO T-20 (ENFUVIRTIDE) IN VITRO: ANALYSIS OF PRIMARY VIRUS ISOLATES RECOVERED FROM PATIENTS DURING CHRONIC ENFUVIRTIDE TREATMENT AND SITE-DIRECTED MUTANTS IN NL4-3 Antivir Ther. 2002;7(Suppl 1):S17 M Mink1, M Greenberg1, S Mosier1, S Janumpalli1, D Davison1, L Jin1, T Melby1, P Sista1, D Lambert1, N Cammack2, M Salgo3 and T Matthews1 Specific substitutions in gp41 amino acids 36–45 observed in plasma virus or clinical isolates during enfuvirtide treatment conferred decreased susceptibility to enfuvirtide in vitro in the modified NL4-3 virus and/or in primary clinical isolates. These results support the premise that this region of gp41 is a primary target for enfuvirtide and a principal locus for emergence of enfuvirtide resistance. Further study will be needed to characterize possible contributions of HIV-1 gp41 residues outside of aa 36–45 on enfuvirtide susceptibility. Download Abstracts
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| 23 | IN VITRO EFFECTS OF MIV-310 (ALOVUDINE, 3´-FLUORODEOXY THYMIDINE, FLT) AGAINST HIV MUTANTS Antivir Ther. 2002;7(Suppl 1):S18 L Vrang1, H Zhang1, S Palmer2, E-Y Kim3, T Merigan3 and B Oberg1,4 A highly potent effect of MIV-310 was observed against most HIV mutants with resistance to other nucleoside analogues. This corresponds well to the lack of resistance development in cell culture where no resistance was observed in the pressure of MIV-310 under conditions when resistance developed in the presence of zidovudine, zalcitabine and lamivudine. The potent effect of MIV-310 against MDR has promoted a clinic trial in HIV patients failing present therapy. Download Abstracts
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Session 2: Mechanisms of HIV drug resistance Abstract 24 thru 45, Pages S29 to S50 |
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| 24 | MUTATIONS IN HIV-1 PROTEASE ASSOCIATED WITH RESISTANCE TO AMPRENAVIR CONTRIBUTE TOWARDS PHENOTYPIC RESISTANCE TO LOPINAVIR Antivir Ther. 2002;7(Suppl 1):S23 NT Parkin, C Chappey and CJ Petropoulos Cross-resistance between lopinavir and amprenavir is under appreciated. Existing genotypic interpretation algorithms are not sensitive enough for identification of viruses with reduced lopinavir and/or amprenavir susceptibility. This finding has implications for the use of lopinavir-based salvage therapy after failure of amprenavir-based regimens, or vice versa. Download Abstracts
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| 25 | CRYSTAL STRUCTURES OF HIV-1 REVERSE TRANSCRIPTASE MUTATED AT CODONS 100, 106 AND 108 SHOW NEVIRAPINE RESISTANCE IS MEDIATED VIA PERTURBATION OF INTERACTIONS WITH TYR181 OR TYR188 Antivir Ther. 2002;7(Suppl 1):S23 DK Stammers1, J Ren1, CE Nichols1, PP Chamberlain1, KL Weaver2, SA Short2 and DI Stuart1 For all three mutants nevirapine resistance appears to be induced indirectly via perturbation of the inhibitor’s interactions with either Y181 and/or Y188. This mechanism could provide a general explanation of why second generation compounds, which are less dependent on aromatic ring stacking with Y181 and Y188 than nevirapine, are more resilient to a range of mutations in the NNRTI binding site. Download Abstracts
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| 26 | THE V118I MUTATION IN THE REVERSE TRANSCRIPTASE OF HIV-1 DIMINISHES THE INCORPORATION OF MULTIPLE NUCLEOSIDE ANALOGUE INHIBITORS Antivir Ther. 2002;7(Suppl 1):S24 M Girouard1,2, K Diallo1,2, B Marchand1,2, S McCormick1, MA Wainberg1,2,3 and M Götte1,2,3 Our data make clear that resistance to zidovudine is associated with at least two different mechanisms. A single amino acid substitution (that is, V118I) determines whether decreased rates of nucleotide incorporation or increased rates of excision of the chain-terminator is dominant in this regard. As for the Q151M mutation, the V118I substitution may decrease susceptibility to multiple nucleoside analogues. Download Abstracts
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| 27 | MECHANISMS OF NUCLEOSIDE ANALOGUE RESISTANCE Antivir Ther. 2002;7(Suppl 1):S25 PL Boyer1, SG Sarafianos2, E Arnold2 and SH Hughes1 The structures of HIV-1 RT in complex with a DNA with an zidovudine-MP terminated primer at either the N or the P site have allowed us to refine our model for zidovudine excision. The long azido group does not block the translocation of an zidovudine-MP terminated primer to the P site, but does interfere with the formation of the closed complex. In contrast to the classic zidovudine resistance mutations, which are quite selective for zidovudine- MP excision, the fingers insertions (together with T215Y) show enhanced excision with a number of nucleoside analogues. This is due, at least in part, to an overall decrease in the stability of the closed complex, which gives the end of the primer better access to the N site, favouring excision. Download Abstracts
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| 28 | MECHANISM OF ANTI-HIV ACTIVITY OF D4-NUCLEOSIDE ANALOGUES AGAINST ZIDOVUDINE- AND LAMIVUDINE-RESISTANT HIV-1 MUTANTS: MOLECULAR MODELLING STUDIES Antivir Ther. 2002;7(Suppl 1):S25 Y Chong1, H Choo1, RF Schinazi2 and CK Chu1 In contrast, the M184V did not affect the binding affinity of the natural D-configured d4N such as D-2´-Fd4C- TP, which may be one of the reasons for the potent antiviral activity of D-2´-F-d4C-TP against the lamivudine-resistant RT. However, the isosteric replacement of 4´-oxygen of D-2´-F-d4CTP to 4´-sulfur provided cross-resistance with M184V RT. In comparison to D-2´-F-d4CTP, the large van der Waals radius of the 4´-sulfur atom as well as longer C-S bond length of D-2´-F-4´-Sd4CTP results in a steric hindrance with Val184, which destabilized the resulting complex. Download Abstracts
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| 29 | MOLECULAR MODELLING APPROACH TO EXPLAIN THE SUSCEPTIBILITY OF PMPA FOR DRUG-RESISTANT HIV-1 REVERSE TRANSCRIPTASE: K65R, Q151M AND M184V Antivir Ther. 2002;7(Suppl 1):S26 J Courcambeck1, G Pepe1,2 and P Halfon1,3 A novel Tridimensional molecular modelling method was developed to explain and partially predict HIV-1 RT drug resistance. This constitutes an interesting alternative and complementary way to the genotypic and phenotypic assays. Further works are in process to extend these first data to other RT mutations like TAMs and others INRTIs. Download Abstracts
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| 30 | NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR-ASSOCIATED RESISTANCE SUBSTITUTIONS AND SUSCEPTIBILITY TO ABACAVIR, DIDANOSINE AND STAVUDINE Antivir Ther. 2002;7(Suppl 1):S27 C Craig1, C-Q Zhu2, M Ait-Khaled2 and M Tisdale1 Despite extensive genotypic resistance mutation, only abacavir exceeded the assay biological cut-off, and this was observed only with ≥4 TAMs when 184V or 74V were included. Didanosine and stavudine susceptibilities remained below the biological cut-off with up to seven substitutions, despite statistically significant increases in foldresistance relative to samples without TAMs in the case of stavudine. Therefore, phenotype may have limited utility for detection of clinically significant resistance particularly to stavudine and didanosine. Download Abstracts
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| 31 | IN VITRO SELECTION OF THE T215Y AND K65R MUTATIONS BY STAVUDINE AND DEMONSTRATION OF HIGH-LEVEL RESISTANCE TO STAVUDINE Antivir Ther. 2002;7(Suppl 1):S28 G García-Lerma1, H MacInnes1, S Nidtha1, D Bennett2, H Weinstock2 and W Heneine1 We show that 215Y is selected by stavudine in vitro, confirming a selective advantage for this mutation in the presence of this drug. We also show that K65R is frequently selected by stavudine, supporting a primary role for this mutation in stavudine resistance. The high level of stavudine resistance associated with K65R suggests that K65R may compromise the treatment efficacy of this drug. Similarly, the ability of HIV-1215D and HIV-1215C to rapidly select 215Y in vitro implies that patients infected with these viruses and treated with stavudine may be at increased risk for acquiring 215Y. The detection of stavudine resistance by an enzymatic assay and not by culture-based assays has important implications for phenotypic resistance testing for stavudine. Download Abstracts
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| 32 | PHENOTYPIC IDENTIFICATION OF HIV-2 PROTEASE RESISTANCE MUTATIONS BY RECOMBINANT VIRAL ASSAY Antivir Ther. 2002;7(Suppl 1):S28 J Goncalves1, S Coelho1, F Antunes2 and J Moniz-Pereira1 HIV-2 can develop alterations in the protease gene that confer resistance to indinavir and saquinavir. Moreover, the indinavir and saquinavir resistance mutations pattern in HIV-2 protease are not similar to HIV-1. Similarly, HIV-1 resistance mutations to these drugs are not interchangeable with HIV-2. Download Abstracts
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| 33 | SPECTRUM OF HIV-1 REVERSE TRANSCRIPTASE MUTATIONS SELECTED BY NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR TREATMENT IS GREATER THAN PREVIOUSLY REPORTED Antivir Ther. 2002;7(Suppl 1):S29 MJ Gonzales1, T Wu2, J Taylor3, I Belitskaya3, R Kantor1, D Israelski1, S Chou4, AR Zolopa1, J Fessel5 and RW Shafer1 Besides the 18 known NRTI-resistance mutations, mutations at nine additional RT positions are strongly associated with NRTI therapy. These mutations appear to be accessory because they occur almost exclusively together with known drugresistance mutations. Download Abstracts
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| 34 | D30N IS NOT THE PREFERRED RESISTANCE PATHWAY IN SUBTYPE C PATIENTS TREATED WITH NELFINAVIR Antivir Ther. 2002;7(Suppl 1):S30 Z Grossman1,2, E Paxinos3, D Auerbuch1, S Maayan1, N Parkin3, D Engelhard1, M Lorber1, E Kedem1, F Mileguir1, N Vardinon1, Z Bentwich1, C Petropoulos3 and JM Schapiro1 Although the same major protease mutations develop in subtype B and C pts failing PI therapy, the rates at which mutational pathways develop differ for certain drugs. This may be due to the impact of baseline polymorphisms on resistance and fitness when mutations develop. Knowledge of these differences may have important clinical ramifications, as in treatment with nelfinavir where D30N should not be expected to develop, and to preserve future options, in the majority of cases. Download Abstracts
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| 35 | EXPANSION OF THE HIV-1 PROTEASE ACTIVE SITE CORRELATES WITH CLINICAL PROGRESSION TO MULTIDRUG RESISTANCE Antivir Ther. 2002;7(Suppl 1):Sxx LC Kovari1, JF Vickrey1, B Logsdon1, G Proteasa1, M Winters2 and TC Merigan2 Regions of active site expansion include the protease S1 and S1´ subsites. The practical implication of active site expansion is the possibility of designing larger drugs with increased P1 and P1´ groups that fit into the enlarged HIV protease active site. Download Abstracts
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| 36 | RATE OF EMERGENCE OF THYMIDINE ANALOGUE RESISTANCE MUTATIONS IN HIV-1 REVERSE TRANSCRIPTASE SELECTED BY STAVUDINE OR ZIDOVUDINE-BASED REGIMENS IN TREATMENT-NAÏVE PATIENTS Antivir Ther. 2002;7(Suppl 1):S31 DR Kuritzkes1, RL Bassett2, RK Young3, H Barrett3, JL Koel4, JD Hazelwood4, and VA Johnson4 for ACTG 306 and 370 Protocol Teams Thymidine analogue mutations emerged at comparable rates in HIV-1 during zidovudine- or stavudine-based therapy. However, there was a trend towards a greater risk of developing ≥2 TAMs in the zidovudine/lamivudine arm, perhaps due to more frequent emergence of M41L in this group. Download Abstracts
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| 37 | ANALYSING THE GENOTYPIC BASIS OF HYPERSUSCEPTIBILITY TO AMPRENAVIR IN HIV FROM ANTIRETROVIRAL-NAÏVE PATIENTS Antivir Ther. 2002;7(Suppl 1):S32 AJ Leigh Brown1,2, B Good1, SD Frost1, AC Collier3, E Connick4, B Conway5, E Daar6, M Kilby7, JP Routy8, JB Margolick9, M Markowitz10, K Dawson11, N Hellmann11, DD Richman1 and SJ Little1 Several different methods of analysis indicate that hypersusceptibility to amprenavir in ARV-naïve patients is not due to rare mutations at primary resistance-associated sites but is conferred by combinations of polymorphic amino acids. Alternative amino acids at some of the identified sites have been identified as ‘secondary mutations’ in the acquisition of drug resistance, indicating the algorithms are correctly identifying sites with effects on protease function. Download Abstracts
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| 38 | CROSS-RESISTANCE PATTERNS FOR HIV-1 MULTI-NUCLEOSIDE RESISTANT MUTANTS WITH MUTATIONS ASSOCIATED WITH RE-SENSITIZATION TO ZIDOVUDINE Antivir Ther. 2002;7(Suppl 1):S33 J Lennerstrand1, T Bergroth1, X-W Shao2, A Van Cauwenberge3, P Mc Kenna3 and A Sönnerborg1 The 184 mutation reduced the resistance towards zidovudine, stavudine, abacavir and tenofovir on the 69S-SG complex mutant. The biochemical mechanism of tenofovir resistance for the 69S-SG complex mutant seems to be an ATP dependent primer unblocking. Although the 184 mutation in the 69S-SG complex reduced the levels of zidovudine, stavudine, abacavir and tenofovir resistance, the biochemical mechanism of this reduction in resistance remains to be clarified. Download Abstracts
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| 39 | INTERPLAY OF DRUGS AND DRUG-RESISTANT REVERSE TRANSCRIPTASE ON HIV-1 MUTANT FREQUENCIES Antivir Ther. 2002;7(Suppl 1):S34 LM Mansky and LC Gajary This observation indicates that HIV-1 can mutate at a significantly higher rate when drug-resistant virus replicates in the presence of drug. These increased mutant frequencies could have important implications for drug therapy regimes as well as HIV-1 population dynamics and evolution. Download Abstracts
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| 40 | SELECTION OF THYMIDINE ANALOGUE MUTATIONS BY NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS OCCURS STEP BY STEP AND THROUGH TWO DIFFERENT PATHWAYS Antivir Ther. 2002;7(Suppl 1):S34 AG Marcelin1, M Wirden1, C Delaugerre1, P Viegas1, A Simon2, C Katlama3 and V Calvez1 These results suggest that there are two distinct pathways to develop TAMs and that the first step may drive the development of the kind of mutation patterns. Among the two major TAMs profiles, the profile initiated by the development of the mutations 41L or 215Y seems to be mainly observed. These results could have some consequences for the choice of the nucleosides or nucleotides used in the first or second lines of treatment. Download Abstracts
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| 41 | Q145M, A NOVEL HIV-1 REVERSE TRANSCRIPTASE MUTATION CONFERRING RESISTANCE TO NUCLEOSIDE AND NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Antivir Ther. 2002;7(Suppl 1):S35 S Paolucci1, F Baldanti1, M Tinelli2, N Labo1, E Cattaneo1, G Maga3 and G Gerna1 A new mutation in HIV-1 RT conferring resistance to all RT inhibitors was identified. The proximity of Q145M to the reported multidrug resistance associated mutation Q151M suggests that this RT region might be crucial for drug recognition and processing. Download Abstracts
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| 42 | AN HIV-1 ISOLATE WITH THE MUTATION G190E AND AN INSERTION BETWEEN CODONS 100–105 OF REVERSE TRANSCRIPTASE: PHENOTYPIC RESISTANCE IMPLICATIONS Antivir Ther. 2002;7(Suppl 1):S35 N Desire1, C Amiel3, V Schneider1, N Delphin1, E Dam2, F Clavel3, JC Nicolas1 and W Rozenbaum4 The combination of an insertion in the 100–105 region and the mutation G190E may increase the activity of the RT compared to the activity of RT carrying these changes individually. Download Abstracts
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| 43 | DRUG RESISTANCE AND SUBSTRATE RECOGNITION IN HIV-1 PROTEASE Antivir Ther. 2002;7(Suppl 1):S36 MM Prabu-Jeyabalan, NM King, E Nalivaika, WRP Scott and CA Schiffer The ensemble of structures of the substrates sequences that HIV protease recognizes provide a unique template for the design of inhibitors, which may be less susceptible to drug resistance. Each of the substrates, when bound to the symmetric homodimeric HIV protease, adopts an asymmetric shape in contrast with the relatively symmetric shape of the currently prescribed inhibitors. This is important in terms of understanding drug resistance, as in the case of the drug-resistant mutation V82A, as most of the substrates do not make extensive contact with Val 82 while most of the currently used designed inhibitors do. Download Abstracts
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| 44 | HIV-1 REVERSE TRANSCRIPTASE MUTATIONS IDENTIFIED BY IN VITRO SELECTION WITH TENOFOVIR (TDF) ± ABACAVIR AND TENOFOVIR ± LAMIVUDINE Antivir Ther. 2002;7(Suppl 1):S37 C Stone1, M Ait-Khaled2, C Craig1 and M Tisdale1 Mutational patterns differed depending on the drug combination examined. Interestingly, with wild-type virus both abacavir/tenofovir and lamivudine/tenofovir in vitro selected for the K65R mutation. With NRTI-resistant variants, the M184V was deselected with tenofovir alone but this was prevented by the addition of abacavir. Thus there is a balance of selection pressures for M184V in the presence of abacavir or lamivudine and tenofovir. The relevance of these in vitro findings to the clinic remains to be determined. Download Abstracts
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| 45 | STATISTICAL ANALYSIS FOR LINKAGE AMONG HIV-1 PROTEASE SEQUENCES Antivir Ther. 2002;7(Suppl 1):S37 N Hoffman1, C Schiffer2 and R Swanstrom1 Statistical linkage (both positive and negative) was revealed between pairs of sites in protease sequences from both untreated and treated subjects, including two clusters of positions distal to the active site. While some of the interactions may reflect fortuitous linkage in heavily treated subjects with many resistance mutations, others will likely represent important co-operative interactions that are amenable to experimental validation. Download Abstracts
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Session 3: HIV pathogenesis, fitness and resistance Abstract 46 thru 83, Pages S53 to S90 |
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| 46 | TRANSMISSION OF DRUG RESISTANT HIV-1 EXHIBITING LOWER REPLICATION CAPACITY IS ASSOCIATED WITH HIGHER CD4 CELL COUNTS Antivir Ther. 2002;7(Suppl 1):S41 RM Grant1,2, JD Barbour2, T Wrin3, M Warmerdam1, NS Hellmann3, JO Kahn2, CJ Petropoulos3 and FR Hecht2 CD4 T-cell counts were higher in drug-naïve subjects recently infected with drug resistant HIV-1 exhibiting decreased replication capacity, especially if PI resistance was evident. The wide variation in replication capacity of recombinant viruses containing PR-RT segments derived from recently transmitted HIV-1 may reflect the diversity of quasispecies capable of establishing new infections, or bottlenecks in the virus population as a result of poorly understood selective pressures exerted during virus transmission. Download Abstracts
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| 47 | PRODUCTIVE INFECTION MAINTAINS A DYNAMIC STEADY-STATE OF RESIDUAL VIRAEMIA IN HIV-1 INFECTED PERSONS TREATED WITH SUPPRESSIVE ANTIRETROVIRAL THERAPY FOR 5 YEARS Antivir Ther. 2002;7(Suppl 1):S41 D Havlir1, M Strain1, M Clerici2, D Trabattoni2, P Ferrante2 and J Wong1 In patients treated with efavirenz + indinavir, levels of residual viraemia were established by 9 months, were predicted by baseline proviral DNA and remained constant for 5 years. Even after years of highly suppressive therapy, HIV RNA levels declined rapidly after the addition of abacavir suggesting that productive infection contribute to residual viraemia and can be inhibited with therapy intensification. Download Abstracts
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| 48 | CO-EVOLUTION AND COMPETITION OF VIRAL POPULATIONS WITH DISTINCT RESISTANCE GENOTYPES IN PATIENTS FAILING TREATMENT WITH PROTEASE INHIBITORS Antivir Ther. 2002;7(Suppl 1):S42 C Charpentier, DE Dwyer, D Lecossier, F Clavel and AJ Hance In patients experiencing virological treatment failure, the re-inforcement of resistance does not result from a linear accumulation of PI resistance mutations in a single lineage of viruses. Multiple quasispecies with distinct resistance genotypes usually coexist at any given time, and some initially minority populations, with or without additional changes, can subsequently emerge as majority populations. Thus, the characterization of the resistance profile of the majority population only underestimates extent of the drugresistance capital of the total population, and its ability to rapidly generate novel genotypes. Download Abstracts
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| 49 | HIV SPECIFIC IMMUNITY, T-CELL ACTIVATION AND REPLICATIVE CAPACITY IN ANTIRETROVIRAL TREATED ADULTS EXPERIENCING INTERMITTENT VERSUS PERSISTENT LOW-LEVEL VIRAL REPLICATION Antivir Ther. 2002;7(Suppl 1):S43 AC Karlsson1, P Hunt2, E Sinclair2, SR Younger1, E Hagos2, T Wrin3, C Petropoulos3, J Martin2, DF Nixon1 and SG Deeks2 The antigenic threshold required to induce generalized T-cell activation may be higher than that for the generation of HIV-specific immune responses. Durable maintenance of low-level viraemia (<1000 copies/ml) is associated with emergence of a replication-deficient drug-resistant variant, enhanced HIV-specific immunity and generalized T-cell activation. Download Abstracts
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| 50 | GENETICS OF HIV-1 POPULATIONS IN ACUTE AND CHRONIC INFECTION Antivir Ther. 2002;7(Suppl 1):S43 S Palmer1, M Kearney1, F Maldarelli1, S Kottilil2, D Lucey3, J Metcalf2, D Rock2, M VanHoutte4, L Michels4, K Hertogs4, J Mellors5 and J Coffin1 Limiting-dilution PCR-based sequencing provides a new level of sensitivity for understanding the evolution of viral populations. Although significant levels of genetic diversity accumulate in the target region in long-term infected individuals, HIV populations present in the three patients analysed up to 9 weeks after infection were virtually monomorphic. Download Abstracts
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| 51 | A NEW REVERSE TRANSCRIPTASE-SHIV TO STUDY HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR-RESISTANCE IN PIGTAILED MACAQUES Antivir Ther. 2002;7(Suppl 1):Sxx Z Ambrose, SH Hughes and VN KewalRamani RT-SHIVmne should be useful for preclinical trials of NNRTIs in macaques and for understanding the development of in vivo drug resistance. Significantly, RT-SHIVmne could be used for infection of pigtailed macaques (Macaca nemestrina), which are currently in greater abundance than rhesus macaques. The RT-SHIVmne infection model also could be used to evaluate the relative fitness of wild-type and mutant HIV-1 RT under non-selective and selective conditions in vivo. Download Abstracts
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| 52 | BIOLOGICAL PHENOTYPE, REPLICATIVE CAPACITY AND DRUG RESISTANCE OF HIV STRAINS ISOLATED FROM PATIENTS FAILING ANTIRETROVIRAL THERAPY Antivir Ther. 2002;7(Suppl 1):S45 E Nicastri2, L Sarmati1, G d’Ettorre4, L Palmisano5, SG Parisi3, I Uccella1, E Concia3, V Vullo4, S Vella5 and M Andreoni1 In patients failing highly active antiretroviral therapy (HAART) the detection of HIV isolates with R5 biological phenotype correlates with high CD4+ cell count, an impaired replicative capacity, and a high number of drug-resistance mutations. These results could contribute to explain the presence of relatively high CD4 cell count in heavily pretreated patients despite a virological failure during HAART. Download Abstracts
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| 53 | PREVALENCE OF ATYPICAL MUTATIONS AT CODON 215 OF HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 2002;7(Suppl 1):S46 P Cane1, Y Rehman2, K Porter3 and D Pillay1 Changes at codon 215 of RT are associated with transmission of drug resistance in a significant minority of cases, and such changes or derivatives of them may be long-lived in the absence of treatment. The presence of atypical mutations at codon 215 in heavily treated patients showing multiple other nucleoside reverse transcriptase inhibitor mutations may also represent changes associated with improvement of viral fitness. Download Abstracts
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| 54 | HIV-1 RESISTANCE PATTERN MAY BE FREQUENTLY DIFFERENT THAN IN BLOOD IN THE MALE GENITAL COMPARTMENT OF PATIENTS WITH THERAPEUTIC FAILURE Antivir Ther. 2002;7(Suppl 1):S46 J Ghosn1–6, JP Viard2, M De Almeida3, L Aaron2, C Goujard4, D Salmon5, C Katlama6, R Tubiana6, M Leruez-Ville1, C Rouzioux1 and ML Chaix1 Resistant HIV-1 viral strains are very frequent (63%) in the male genital tract of heavily pretreated patients, with genetic resistance pattern diversity confirming HIV compartmentalization. In the issue of sexual transmission, we also show that semen cells and seminal plamsa may be differently involved in the spread of HIV-resistant viral strains. Download Abstracts
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| 55 | EVALUATING HIV-1 SUPERINFECTION IN CELL CULTURE, THE SCID-HU THY/LIV MODEL AND HIV-INFECTED INDIVIDUALS WITH HIGH RISK FF RE-EXPOSURE TO THE VIRUS Antivir Ther. 2002;7(Suppl 1):S47 B Chakraborty1, L Valer2, HR Rangel1, J Weber1, CA Stoddart3, MM Lederman4, V Soriano2 and ME Quiñones-Mateu1 Based on our cell culture and SCIDhu Thy/Liv results, we could assume that HIV-1 superinfection may occur in vivo and it may well correlate with viral fitness. If true, superinfection with a drugresistant HIV-1 strain could jeopardize antiviral treatment in a patient originally infected with a wild-type HIV-1 variant. We are currently screening samples from the ACTU/CWRU cohort to identify HIV-infected individuals who suddenly experimented treatment failure, despite admitting good compliance with its medication. These results will aid to evaluate the role of viral fitness in HIV-superinfection and if re-infection with HIV-1 drug resistant variants could be responsible for antiretroviral therapy failures. Download Abstracts
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| 56 | EVIDENCE OF THYMIC FUNCTION IN HEAVILY ANTIRETROVIRAL TREATED HIV-1-INFECTED ADULTS ON LONG-TERM VIROLOGICAL FAILURE Antivir Ther. 2002;7(Suppl 1):S48 J Delgado1, E Ruiz-Mateos1, A Vallejo1, A Rubio1,2, M Leal1, S Molina1, M Martinez- Moya1 and E Lissen1 This study found clear evidences that the thymus of heavily antiretroviral treated HIV-1 infected adults on long-term virological failure is actively engaged in thymopoiesis, generating new naïve T cells to the peripheral lymphocyte pool. Download Abstracts
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| 57 | GENETIC EVOLUTION OF THE HIV REVERSE TRANSCRIPTASE GENE IN PATIENTS UNDERGOING A SIMPLIFICATION REGIMEN WITH DIDANOSINE PLUS HYDROXIUREA FOR 12 MONTHS AND DRUG DISCONTINUATION THEREAFTER Antivir Ther. 2002;7(Suppl 1):S49 C de Mendoza, N Camino, P Barreiro, E Valencia, M Núñez and V Soriano Didanosine+HU may be a satisfactory option for HIV positive individuals on successful triple antiretroviral therapies willing to simplify their therapy. However, virus evolution takes place in most subjects showing persistent low-levels of viraemia. In a significant proportion of them, didanosine drives the selection of RT mutations (mainly L74V), which seem to compromise viral fitness in a great extent. These variants with impaired replication capacity may explain the apparent long-term benefit of didanosine+ HU. Rescue interventions are relatively well preserved for those subjects. In contrast, others may select NAMs on didanosine+HU, which could affect the response to future salvage therapies. Download Abstracts
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| 58 | SHIFTS IN CELL ASSOCIATED HIV-1 RNA BUT NOT IN EPISOMAL HIV-1 DNA CORRELATE WITH NEW CYCLES OF HIV-1 INFECTION IN VIVO Antivir Ther. 2002;7(Suppl 1):S50 M Fischer1, A Trkola1, B Joos1, R Hafner1, H Joller2, MA Muesing3, DR Kaufman3, E Berli1, B Hirschel4, R Weber1 and HF Günthard1 for the Swiss HIV-1 Cohort Study5 Absence of significant shifts in late- DNA levels during short STIs indicated that transient rebounding viraemia did not suffice to increase the pool size of infected cells in the periphery and thus resembles a stage of limited HIV replication. Levels of 2-LTR circles did not reflect rapid changes in HIV-1 replication. In contrast, expression of HIV-UsRNAPBMC increased with rebounding plasma viraemia and consequently provides a more sensitive, albeit not absolute marker of ongoing HIV-1 replication at the cellular level. Download Abstracts
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| 59 | PERSISTENT HIV-1 TRANSCRIPTION IN LYMPHOID TISSUE OF PATIENTS ON LONG-TERM HIGHLY ACTIVE ANTIRETROVIRAL THERAPY DOES NOT RESULT IN VIRION PRODUCTION Antivir Ther. 2002;7(Suppl 1):S50 M Fischer1, B Joos1, J Wong2, M Opravil1, R Weber1 and H Günthard1 for the Swiss HIV-1 Cohort Study3 In viraemic pt, HIV-RNA levels were highly correlated with the numbers of infected cells but not with plasma viraemia, implying that the expression of HIV-RNA as well as the production and the trapping of virions in lymphoid tissue may be locally restricted. On HAART, the expression of virionencapsidated HIV-UsRNA and of intracellular HIVMsRNA was depleted and production of intracellular HIV-UsRNA per infected cell was significantly lowered. Thus, HIV-infected cells persisting in lymphoid tissue on HAART show attenuated patterns of HIVRNA expression, which may allow their escape from eradication by immunological mechanisms. Download Abstracts
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| 60 | NO SELECTION OF HIV-1 RESISTANT STRAINS AFTER EIGHT CYCLES OF STRUCTURED TREATMENT INTERRUPTION IN A CONTROLLED, RANDOMIZED CLINICAL TRIAL (RIGHT 901) Antivir Ther. 2002;7(Suppl 1):S51 A Foli1, S Paolucci2, R Maserati3, L Tomasoni4, M Migliorino5, F Maggiolo6, A Pan7, F Baldanti2, J Lisziewicz1 and F Lori1 Our results indicate that STI does not increase the chance of developing resistance compared to continuous HAART. However, our trial is still limited by small subject numbers, so rare resistance emergence cannot be excluded. Earlier, small STI studies that used different drugs did report development of new resistance mutations selected by lamivudine or a non-nucleoside reverse transcriptase inhibitor. This difference is consistent with the hypothesis that these drugs may more readily select resistance mutations than the drugs used in our study, perhaps because they have a lower genetic barrier to resistance and/or a longer intracellular half-life than the other drugs in the regimen. Selection of appropriate drugs might represent a strategy to minimize onset of resistance during STI. Download Abstracts
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| 61 | CHARACTERIZING THE PROGRESSION OF VIRAL MUTATIONS OVER TIME Antivir Ther. 2002;7(Suppl 1):S52 AS Foulkes1 and V DeGruttola2 Our methods identify the order of accumulation of mutations and estimate the rates at which patterns of mutations develop. Incorporation of minority species into analyses reduces estimated rates of reversion to more sensitive states and therefore may provide a more realistic picture of how viral populations progress. Download Abstracts
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| 62 | QUANTIFICATION OF THE EFFECT OF RESISTANCE MUTATIONS ON REVERSE TRANSCRIPTASE ACTIVITY BY EVALUATION OF THE KINETICS OF RETROTRANSCRIPTION IN INFECTED CELLS Antivir Ther. 2002;7(Suppl 1):S52 AJ Hance, F Bouchonnet, F Mammano and F Clavel Real time PCR can be used to quantify the kinetics of HIV DNA synthesis in synchronously infected cells, revealing clear defects in RT function for viruses carrying resistance mutations. In some cases these defects can be relatively subtle, and are only apparent when the kinetics of DNA synthesis is evaluated in cells in which dNTP metabolism has been modified by hydroxyurea. This finding is consistent with the possibility that the replication of mutant viruses may be selectively impaired in cell populations with relatively low deoxynucleotide pools. Download Abstracts
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| 63 | MODELLING THE EFFECT OF HIV REPLICATION CAPACITY ON TREATMENT OUTCOMES Antivir Ther. 2002;7(Suppl 1):S53 NS Hellmann1, T Wrin1, M Bates1, R Grant2, C Hicks3, R Haubrich4 and CJ Petropoulos1 Assessment of viral replication capacity may be useful in patient management at all HIV disease stages, for making treatment decisions to delay, start, stop, continue, or change antiretroviral therapy. The current model suggests that despite increasing rates of drug resistance, associated reductions in RC may provide continuing clinical benefits comparable to partially suppressive antiretroviral therapy. Download Abstracts
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| 64 | DIVERSE OUTCOME OF GENOTYPIC RESISTANCE ANALYSIS OVER TIME IN TWO PATIENTS WITH TRANSMITTED REVERSE TRANSCRIPTASE INHIBITOR AND PROTEASE INHIBITOR RESISTANCE MUTATIONS AT PRIMARY INFECTION Antivir Ther. 2002;7(Suppl 1):S54 KK Koelsch1, S Little1,2, CC Ignacio1, DD Richman1,2 and JK Wong1,2 Evolution of transmitted resistance to antiretroviral agents can be characterized using Dye Primer sequencing. Resistant variants can persist for more than one year after primary infection, despite the absence of antiretroviral therapy. These results from patient two are consistent with either superinfection from a second donor after primary infection or co-infection with distinct variants during primary infection from the same donor followed by the outgrowth of the second strain in response to evolutionary pressures. Envelope sequencing of the two divergent genotypes from patient two is in progress to investigate these possibilities. Download Abstracts
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| 65 | PHYLOGENETIC ANALYSIS OF HIV-1 FROM AN AIDS DEMENTIA PATIENT SUGGESTS COMPARTMENTALIZED EVOLUTION IN THE MID FRONTAL GYRUS OF THE BRAIN Antivir Ther. 2002;7(Suppl 1):S55 D Irlbeck1, MJ Stanhope2, C Douady2, HM Amrine2, T Melby3, DR McClernon1 and ER Lanier1 The monophyly of MFG sequences suggests independent evolution of HIV-1 in the MFG of CNA3001 patient 345. This monophyletic distribution, combined with the absence of resistance mutations, and lack of evidence for positive selection, suggests the possibility of incomplete drug penetration in the MFG of this individual. Clearly, this surmise needs to be substantiated with data from other similarly sampled patients. Download Abstracts
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| 66 | DIVERGENT EVOLUTION OF PHENOTYPIC ANTIRETROVIRAL SUSCEPTIBILITY OF HIV ISOLATED FROM CEREBROSPINAL FLUID AND PLASMA Antivir Ther. 2002;7(Suppl 1):S55 SL Letendre1, E Paxinos2, J Wong1, C Petropoulos2, J Whitcomb2, J Galovich2, N Hellmann2, JA McCutchan1 and RJ Ellis1 Antiretroviral therapy susceptibility of HIV strains isolated from plasma and CSF can diverge during TI and may predict subsequent therapeutic response. In CSF, HIV replication returned more slowly but, paradoxically, reversion to strains with wildtype susceptibility occurred more quickly. Emergence of a monophyletic, fully susceptible strain in CSF, but not in plasma, suggests derivation from an archived CNS source. CNS-specific selection pressures may favour replication of such wild-type strains, which may explain why HIV replication is more readily suppressed there. By suppressing HIV replication in the CNS even when it fails in plasma, ARV therapy may have neuroprotective benefits in patients with few treatment options. Download Abstracts
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| 67 | FITNESS OF HIV-1 CLINICAL ISOLATES RESISTANT TO T-20 (ENFUVIRTIDE) Antivir Ther. 2002;7(Suppl 1):S56 J Lu1, P Sista2, N Cammack3 and D Kuritzkes4 These results extend our previous observations and confirm that enfuvirtide resistance mutations in HR-1 mutations identified in patient isolates obtained after treatment with enfuvirtide confer a significant growth disadvantage in the absence of drug as compared to wild-type. Further studies are needed to determine whether this relative loss of viral fitness contributes to the sustained antiviral activity of enfuvirtide. Download Abstracts
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| 68 | DETAILED ANALYSIS OF GENETIC VARIATION IN VIVO SUGGESTS HIV EFFECTIVE POPULATION SIZE IS LARGE Antivir Ther. 2002;7(Suppl 1):S57 F Maldarelli1, M Kearney1, S Palmer1, D Rock2, J Falloon3, J Mican3, S Liu2, A Pau4, M VanHoutte5, L Michels5, K Hurtogs5, J Metcalf2, R Stephens6, J Mellors7 and J Coffin1 HIV infection proceeds with a high rate of replication, mutation, and recombination, yielding a genetically diverse, yet surprisingly stable population. Our data showing that the stability of the fine structure of HIV populations even after 100-fold declines in viral load suggests that the effective population size of HIV is relatively large. Download Abstracts
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| 69 | HOST FACTORS THAT DOWN REGULATE HIV LTR EXPRESSION MAY ESTABLISH OR MAINTAIN QUIESCENT INFECTION IN T CELLS Antivir Ther. 2002;7(Suppl 1):S58 DM Margolis1,3, L Ylisastigui1, A Wozniakowski1, H Johnson1, V Rucker2, P Dervan2 and D Sodora1 Studies of resting T cells from viraemic patients suggested that exposure of resting T cells to specific polyamides induced outgrowth of HIV from the latent reservoir of infected cells (Margolis et al., Scottsdale, USA, 2001). Studies of resting cells obtained by leukopheresis of aviraemic donors are ongoing. Taken together, our findings suggest that host factors play an ongoing, active role in the maintenance of viral latency. Therapeutics that modulate the activity of these host factors may allow targeting of the stable, persistent reservoir of HIV infection. Download Abstracts
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| 70 | VIROLOGICAL CHARACTERIZATION OF PATIENTS THROUGH 48 WEEKS IN T20-205 WHO ACQUIRED T-20 (ENFUVIRTIDE) RESISTANCE-ASSOCIATED MUTATIONS DURING PRIOR SHORT-TERM ENFUVIRTIDE MONOTHERAPY Antivir Ther. 2002;7(Suppl 1):S58 T Melby1, P Sista1, E Nelson1, S Mosier1, M Mink1, M Greenberg1, L Fang1, N Cammack2, M Salgo3 and T Matthews1 Enfuvirtide resistance-associated substitutions observed in TRI-003 did not persist in plasma after a mean of 4 months without selective pressure from enfuvirtide. The group of patients with prior enfuvirtide resistance in TRI-003 did not acquire enfuvirtide resistance-associated substitutions more frequently than other TRI-003 patients in T20-205 and viral load responses during T20-205 were similar for both groups of patients. The absence of substitutions associated with resistance to enfuvirtide at baseline in T20-205 is consistent with the idea of reduced replicative fitness for viruses harbouring enfuvirtide resistance-associated substitutions. Download Abstracts
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| 71 | SELECTION OF THE 184V/I MUTATIONS DURING STRATEGIC TREATMENT INTERRUPTION (SWISS SPANISH INTERMITTENT TREATMENT TRIAL-SSITT) Antivir Ther. 2002;7(Suppl 1):S59 L Perrin1, S Yerly1, C Fagard2, M Le Braz2, HF Günthard3, B Hirschel2 and the Swiss HIV Cohort Study (SHCS) Overall, these data indicate that strategic treatment interruptions within the SSITT are not associated with frequent selection of detectable drug-resistance mutations, the only exception being mutations at the 184 codon. Selection of this mutation is associated with high viraemia during the first rebound (high level of replication) and occurs relatively early. Download Abstracts
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| 72 | REVERSE TRANSCRIPTASE MUTATIONS THAT CONFER NON-NUCLOSIDE REVERSE TRANCSRIPTASE INHIBITOR RESISTANCE MAY ALSO IMPAIR REPLICATION CAPACITY Antivir Ther. 2002;7(Suppl 1):S60 W Huang, T Wrin, A Gamarnik, J Beauchaine, JM Whitcomb and CJ Petropoulos Not all NNRTI resistance mutations preserve HIV-1 replication capacity. Although several common NNRTI resistance mutations do not alter replication capacity, others can impair replication capacity to varying degrees. Furthermore, different amino acid substitutions at the same position can result in dramatic differences in replication capacity and NNRTI susceptibility. The replication capacity of viruses containing more than one NNRTI mutation cannot be predicted by assessing the replication capacity of each of the single mutants. These finding may have important implications for the management of patients harbouring NNRTI resistant viruses. Download Abstracts
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| 73 | THEORETICAL RATIONALE FOR THE USE OF SINGLE DRUG SEQUENTIAL ANTIRETROVIRAL THERAPY REGIMENS Antivir Ther. 2002;7(Suppl 1):S61 AN Phillips, MS Youle, F Lampe, MA Johnson, CA Sabin, A Cozzi Lepri and C Loveday It is unclear whether we yet (or will ever) have enough drugs with high enough cost of resistance. However, these results provide a theoretical rationale for studying (with as many ‘different’ drugs as possible) the use of sequential regimens in appropriately controlled conditions as a potential ‘resistance-proof’ strategy, initially in those with multidrug-resistant virus. Download Abstracts
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| 74 | EMERGENCE OF RESISTANCE MUTATIONS IN CHILDREN TREATED WITH DIDANOSINE PLUS STAVUDINE AFTER TREATMENT TO PREVENT MOTHER-TO-CHILD TRANSMISSION Antivir Ther. 2002;7(Suppl 1):S61 C Pillay1, G Gray2, G Stevens3, B Jivkov2, A Violari2, W Stevens3, J McIntyre2 and L Morris1 These data indicate that HIV-1 infection in infants is not due to the transmission of drug resistant virus following short-course therapy with didanosine, stavudine or zidovudine. However continued therapy with didanosine plus stavudine was associated with resistance in half the infants. Download Abstracts
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| 75 | CHARACTERIZATION OF MULTIDRUG RESISTANT HIV-1 ISOLATES Antivir Ther. 2002;7(Suppl 1):S62 V Simon, J Vanderhoeven, N Padte, D Murray, P Balfe and M Markowitz Multidrug resistant HIV-1 isolates that replicate, in the absence of drugs, to levels similar to or higher than fully susceptible variants do exist. Introduction of the regions encoding drug resistance into a wild-type background results in pronounced replication defects that were only partially rescued by complementation with the isogeneic gag. However, these defects were not seen in the primary MDR isolates described herein, suggesting the presence of compensatory changes outside of the cloned region. Further studies are needed to elucidate the adaptive mechanisms that confer replication capacity despite the presence of a MDR phenotype. Download Abstracts
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| 76 | DISPROPORTIONATE RETENTION OF WILD-TYPE HIV-1 IN CELLULAR RESERVOIRS OF HIV REFLECTS THE INHERENT STABILITY OF ARCHIVAL SEQUENCES Antivir Ther. 2002;7(Suppl 1):S63 DM Smith1, CC Ignacio1, MC Strain1,3, DV Havlir1,2, R Lam1, T Macaranas1, DD Richman1,4 and JK Wong1,4 The disproportionate retention of wild-type HIV-1 in latent cellular reservoirs is related to greater intrinsic stability (regarding longer half-life) of archival sequences rather than the effects of ongoing replication or of replication in sanctuary sites. These results support a model of memory lymphocyte turnover with complex subexponential decay characteristics over the standard model of a homogeneous population with exponential decay. Download Abstracts
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| 77 | HIV-1 GAG CLEAVAGE SITE MUTATIONS AND NON-CLEAVAGE SITE MUTATIONS ARE CLOSELY RELATED IN VIRAL FITNESS RECOVERY PROCESS Antivir Ther. 2002;7(Suppl 1):S63 L Myint1, M Matsuda1, Z Matsuda1, Y Yokomaku1, T Chiba1, A Okano1, K Yamada2, and W Sugiura1 Mutations related to the protease inhibitor resistance emerge within protease, its cognitive Gag cleavage sites as well as Gag non-cleavage sites. These mutations are tightly linked each other and co-existence of these mutations is necessary for the full recovery of virus fitness. Download Abstracts
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| 78 | COMPARISON OF RETROSPECTIVE AND RECENT REVERSE TRANSCRIPTASE AND PROTEASE SEQUENCES FROM TREATMENT-NAÏVE PATIENTS IN KWAZULU-NATAL AND CAPE TOWN, SOUTH AFRICA Antivir Ther. 2002;7(Suppl 1):S64 M Tarin, T De Oliveira, K Bishop and S Cassol This study provides important data on the evolving HIV epidemic in South Africa. The limited evolution of C viruses may reflect the fact that these viruses achieved optimal fitness early in the HIV-1 epidemic in South Africa. None of the naturally occurring RT and PR substitutions in our isolates have been previously shown to confer primary resistance to the currently available antiretroviral drugs. Download Abstracts
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| 79 | DISCORDANT HIV-1 DRUG RESISTANCE MUTATIONS BETWEEN PLASMA AND VAGINAL SECRETIONS IN PUERTO RICAN FEMALES UNDER HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2002;7(Suppl 1):S65 G Tirado1, GR Jove1 and Y Yamamura1 1) Drug resistance mutations emerged independently in each compartment. Seven of nine females showed discordant mutation patterns between vaginal and plasma HIV-1. 2) Low homology in ‘discordant’ females suggests genital HIV-1 represents a distinct lineage from that in plasma. 3) ‘Discordant’ females showed either delayed emergence or clearance of resistant mutants in vaginal HIV-1 population. Vaginal tract thus seems to be a fairly separated compartment. 4) Vaginal tract has potential to serve as reservoir for relapse with drugresistant mutants after control of plasma viraemia. Download Abstracts
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| 80 | DIFFERENTIAL CD4-CELL RESPONSE IN PATIENTS USING A PROTEASE INHIBITOR BASED OR NEVIRAPINE BASED FIRST LINE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY REGIMEN Antivir Ther. 2002;7(Suppl 1):S66 F van Leth, F Wit, F de Wolf and J Lange for the ATHENA cohort study The increase in CD4-cells during first line nevirapine use was smaller compared to both first line PI-containing ART and first line indinavir use. The clinical relevance remains to be elucidated since this difference did not result in a difference in disease progression or therapy failure. Download Abstracts
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| 81 | DEVELOPMENT OF VIRAL QUASISPECIES AND RESISTANCE MUTATIONS IN LYMPH NODES OF HIV-INFECTED PATIENTS WITH SUSTAINED CONTROL OF VIRAEMIA DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2002;7(Suppl 1):S66 J van Lunzen1, B Zöllner1, HJ Stellbrink1, I Stahmer1, C Schneider1, L Ruiz3, B Clotet3, P Racz2 and K Tenner-Racz2 Development of viral quasispecies and resistance mutations may occur in LN during HAART despite sustained control of viraemia. However, no resistance mutations could be detected in LN of patients who responded well to potent HAART regimens in this compartment. Download Abstracts
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| 82 | AMPLIFICATION OF MULTIDRUG-RESISTANT VIRUS BY SINGLE DRUGS IN MIXED MULTIDRUG-RESISTANT:WILDTYPE COCULTURE Antivir Ther. 2002;7(Suppl 1):S67 B Brenner, JP Routy, B Spira, D Moisi, M Oliveira, M deTorio, and MA Wainberg A single antiviral drug can amplify mutations related to both PR and RT indicating the linkage of these mutations on a single viral backbone. Comparative fitness was K103N > WT> dual-class MDR>> triple class MDR in the absence of drug pressure. Despite impairments in replicative fitness, MDR viruses persist as minor proportions (<2%) of mixed MDR:WT infections. Under conditions of NRTI, NNRTI, or PI drug pressure, outgrowth of minor MDR species can occur. These findings have implications in the management of MDR infections by treatment interruption in the settings of PHI and highly active antiretroviral therapy failure. Download Abstracts
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| 83 | VIROLOGICAL BENEFIT OF M184V IN ASSOCIATION WITH MULTIDRUG RESISTANCE Antivir Ther. 2002;7(Suppl 1):S68x M Wainberg, B Brenner, M Petrella, M Gotte and D Moisi Our findings substantiate the notion that 184V can compromise viral fitness despite evoking lamivudine resistance. The118I multi-NRTI resistance pathway arising from stavudine, didanosine, and abacavir regimens can offset the virological benefits of 184V. Download Abstracts
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Session 4: New resistance technologies and interpretations Abstract 84 thru 120, Pages S93 to S129 |
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| 84 | COLLABORATIVE HIV RESISTANCE-RESPONSE DATABASE INITIATIVES: SAMPLE SIZE FOR DETECTION OF RELATIONSHIPS BETWEEN HIV-1 GENOTYPE AND HIV-1 RNA RESPONSE USING A NON-PARAMETRIC APPROACH Antivir Ther. 2002;7(Suppl 1):S71 G DiRienzo and V DeGruttola Sample sizes between 2000 and 4000 for any specific regimen (or groups of regimens with similar genotype profiles) are required to detect moderate effects on HIV-1 RNA associated with particular patterns of mutations, assuming prevalences comparable to those observed in DiRienzo et al. (2001). Download Abstracts
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| 85 | CONSTRUCTION, TRAINING AND CLINICAL VALIDATION OF AN INFERENTIAL INTERPRETATION SYSTEM FOR GENOTYPIC HIV-1 DRUG RESISTANCE BASED ON FUZZY RULES LEARNING FROM VIROLOGICAL OUTCOMES Antivir Ther. 2002;7(Suppl 1):S71 A De Luca1, M Vendittoli2, F Baldini1, S Di Giambenedetto1, MG Rizzo1, MP Trotta3, A Cingolani1, F Forbici3, CF Perno3, A Antinori3 and G Ulivi4 Using a fuzzy logic approach in a virological outcomes training system to implement a rule-based algorithm we obtained significant improvements of outcomes prediction. The resulting algorithm showed independent adjunctive correlation with outcomes over two rule-based interpretation algorithms. Although the system was trained and validated on a limited number of cases, this approach deserves further evaluation. Download Abstracts
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| 86 | GENETIC CORRELATES OF INCREASED SUSCEPTIBILITY TO PROTEASE INHIBITORS IN WILD-TYPE VIRUSES Antivir Ther. 2002;7(Suppl 1):S72 NT Parkin, E Paxinos, C Chappey, T Wrin, A Gamarnik and CJ Petropoulos Several mutations were identified for each PI, which are associated with HS. Since many of these mutations were shared by several PIs, it is unlikely that PI HS is related only to inter-assay variability. The association between replication capacity and PI HS is being investigated. Download Abstracts
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| 87 | DETECTION OF MINOR POPULATIONS OF DRUG-RESISTANT VIRUSES IN PATIENTS UNDERGOING STRUCTURED TREATMENT INTERRUPTIONS Antivir Ther. 2002;7(Suppl 1):S73 KJ Metzner1,a, S Bonhoeffer2, M Fischer3, R Karanicolas1,b, R Weber3, B Hirschel4, LG Kostrikis1,c, HF Günthard3, for the Swiss HIV Cohort Study Our results indicate that STI can lead to the development of drug-resistant HIV-1 variants. Minor virus populations with mutations at L90M and M184V were detected in several patients undergoing STI suggesting that such variants can emerge during periods of increased HIV-1 replication, when drug concentrations may be waning (suboptimal). The appearance and disapperance of these variants at different times during the treatment cycles suggests that the timing of STI and re-initiation of antiretroviral therapy may be critical, and may vary with each patient. Download Abstracts
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| 88 | QUANTITATIVE PHENOTYPE PREDICTION BY SUPPORT VECTOR MACHINES Antivir Ther. 2002;7(Suppl 1):S74 N Beerenwinkel1, B Schmidt2, H Walter2, R Kaiser3, T Lengauer1, D Hoffmann4, K Korn2 and J Selbig5 SVM models allow for reliable predictions of phenotypes from genotypes. Contrary to methods that rely on selecting specific sequence position (either on a rational basis like, for example, decision tree classifiers or by human experts), SVM models attach a weight to each point mutation. Thus, they can capture resistance phenomena that are not linked to a few prominent sequence positions, but depend on the overall sequence background. The SVM models have been integrated into the geno2pheno prediction system and can be used online (http://cartan.gmd.de/geno2pheno.html). Download Abstracts
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| 89 | GENO2PHENO IS PREDICTIVE OF SHORT-TERM VIROLOGICAL RESPONSE Antivir Ther. 2002;7(Suppl 1):S74 N Beerenwinkel1, M Däumer2, S Sierra2, B Schmidt3, H Walter3, K Korn3, M Oette4, G Fätkenheuer5, J Rockstroh6, T Lengauer1, D Hoffmann7, R Kaiser2 and J Selbig8 Predicting phenotypic resistance with the geno2pheno system can be beneficial for the selection of new antiretroviral regimens. Drug combinations with three or more drugs scored as active have an increased probability of reducing viral load by at least 2 logs within the first 5 weeks of therapy. Download Abstracts
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| 90 | NEW RT-PCR PRIMERS IMPROVE NON-B CLADE DETECTION BY THE TRUGENETM HIV-1 GENOTYPING TEST Antivir Ther. 2002;7(Suppl 1):S75 A Burke1, R Camacho2, AP Carvalho2, B Larder1, S Kemp1 and A De La Rosa3 In this group of patients with non-B (mainly clade G) HIV-1 infection, the substitution of the current TRUGENE v1.0 RT-PCR primers with an alternative prototype primer mix (v1.5) produced a clear improvement in sequencing and the production of resistance reports. Download Abstracts
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| 91 | TREATMENT HISTORY ADDS LITTLE OR NO PREDICTIVE VALUE TO HIV-1 GENOTYPIC RESISTANCE INTERPRETATION DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY FAILURE FOR SUBSEQUENT VIROLOGICAL OUTCOME: DIFFERENT VALUE ACCORDING TO INTERPRETATION SYSTEM AND SALVAGE TREATMENT Antivir Ther. 2002;7(Suppl 1):S76 A De Luca1, S Di Giambenedetto1, F Baldini1, MG Rizzo1, A Cingolani1, MP Trotta2, S Giannella2, P Narciso2, CF Perno2, G Ulivi3 and A Antinori2 In multi-experienced patients history of prior virological failures added little or no useful additional information for outcomes prediction to interpretation of genotypic resistance at failure, in particular when GSS of IS showed stronger outcomes prediction. Results require cautious interpretation because drugs with previous treatment failure might have been avoided in the salvage regimens. Download Abstracts
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| 92 | POOR PREDICTION OF VIROLOGICAL OUTCOMES BY THE INTERPRETATION OF HIV-1 RESISTANCE TO DIDANOSINE AND ABACAVIR USING 11 AVAILABLE RULE-BASED ALGORITHMS Antivir Ther. 2002;7(Suppl 1):S76 S Di Giambenedetto1, F Baldini1, C Cori2, MG Rizzo1, A Cingolani1, G Liuzzi2, CF Perno2, A De Luca1 and A Antinori2 The interpretation of genotypic resistance to didanosine and abacavir is extremely heterogeneous among tested IS. Abacavir scores from a single IS and didanosine scores from three of 11 analysed IS correctly discriminate virological outcomes of salvage regimens containing these agents. Download Abstracts
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| 93 | PREDICTIVE VALUE OF DIFFERENT DRUG RESISTANCE INTERPRETATION SYSTEMS IN THERAPY MANAGEMENT OF HIV-INFECTED PATIENTS IN DAILY ROUTINE Antivir Ther. 2002;7(Suppl 1):S77 P Braun1, M Helm2, R Ehret1, B Schmidt3, KH Stürner1, H Walter3, C Hoehn1, K Korn3 and H Knechten1 Our analysis shows, a good correlation between prognosis of interpretation systems and virological outcome in daily clinical routine. Virological success and therapy failure is predicted correctly with a similar percentage. Therapy failure or success does not only depend on drug resistance, but is caused by multiple factors. New drugs, for example, lopinavir were not discussed in each system (here: Geno2Pheno). Lopinavir, however, was given to 35 patients, which could explain that slightly lower performance of Geno2Pheno in this comparison. It is clearly shown that permanent updates and expansion of data bases are necessary to ensure the best interpretation for clinical routine. These data should be confirmed by further analysis with a larger number of patients. Download Abstracts
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| 94 | ENZYMATIC BIOASSAY FOR THERAPEUTIC DRUG MONITORING OF HIV PROTEASE INHIBITORS Antivir Ther. 2002;7(Suppl 1):S78 S Gulnik1, B Yu1, M Markowitz2 and JW Erickson1 The PI-TDM is a novel, fast, reliable and economical enzyme-based bioassay for measuring total HIV PI potential in serum samples. Download Abstracts
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| 95 | SELECTION OF EFFECTIVE DRUG REGIMEN AFTER VIROLOGICAL FAILURE: IMPACT OF GENOTYPIC RESISTANCE TESTING OVER PHYSICIAN EXPERIENCE Antivir Ther. 2002;7(Suppl 1):S79 S Haupts1, B Ledergerber1, J Boni2, J Schupbach2, K Rentsch3 R Weber1 and HF Gunthard1 Treatments based on genotype and Retrogram® interpretation were slightly superior than regimens based on drug history only, but not always acceptable to patients. A better (lower) resistance score of the consensus ART translated into significant virological benefit. A high VL at time of virological failure was associated with decreased response to new ART, thus favouring early treatment changes after recognition of treatment failure. Download Abstracts
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| 96 | DETECTION LIMIT OF DIFFERENT DNA SEQUENCING-BASED METHODS FOR A MINOR NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR-RESISTANT VARIANT (K103N) Antivir Ther. 2002;7(Suppl 1):S80 E Halvas1 and J Mellors1 Using mixtures of viruses derived from molecular clones that differ only by a single nucleotide, mutant frequencies as low as 10% could be reliably detected by cycle sequencing of RT-PCR product. Lower detection sensitivity might be expected using patient samples that are more polymorphic or have lower viral loads. Cloning and sequencing of clones derived from RT-PCR product has the advantage of definitively detecting mutant codons (as compared with detecting minor peaks on elecropherograms) but the higher variability in frequency estimates is probably because of practical limitations on the number of clones that can be analysed, which results in sampling bias. More sensitive technologies are needed to detect and quantify minor drug-resistant variants. The well-characterized panel of viral mixtures we have created can be used for blinded evaluations of new technologies and can be provided to interested investigators. Download Abstracts
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| 97 | PERFORMANCE OF RE_CALL SEQ BASECALLING SOFTWARE FOR HIGH-THROUGHPUT HIV DRUG-RESISTANCE BASECALLING USING ‘IN-HOUSE’ METHODS Antivir Ther. 2002;7(Suppl 1):S80 W Dong1, B Wynhoven1, T Mo1, T Hall2, R Galli1 and PR Harrigan1 RE_Call software provides accurate sequence base-calling with greatly reduced operator intervention compared with other commercially available software, resulting in improved HIV drug-resistance testing throughput and turnaround time. Download Abstracts
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| 98 | PREDICTIVE POWER OF SINGLE MUTATIONS, MUTATION SCORE AND CMIN LEVELS FOR RESPONSE TO A RITONAVIR BOOSTED SAQUINAVIR SALVAGE THERAPY Antivir Ther. 2002;7(Suppl 1):S81 L Valer, A Hill, D Gonzalez de Requena, and V Soriano, on behalf of the Fortogene Spanish Team Both saquinavir mutation score and Cmin drug levels may be useful to predict which heavily pretreated subjects could benefit from this intervention. Saquinavir Cmin levels under 100 ng/ml may partly be a marker of poor adherence. Analyses correlating response with phenotypic resistance are in progress. Download Abstracts
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| 99 | ASSESSING RESISTANCE COSTS OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY VIA MEASURES OF FUTURE DRUG OPTIONS Antivir Ther. 2002;7(Suppl 1):S82 H Jiang1, D Kuritzkes2, S Deeks3, D Katzenstein4, M Albrecht5 and V DeGruttola1 Study endpoints that quantify the preservation of future therapeutic options can be used to compare the resistance costs induced by different treatment strategies. With variance comparable to that of change in HIV-1 RNA from baseline, modest sized studies can detect clinically meaningful randomized effects on development of resistance. Download Abstracts
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| 100 | USING CLASSIFICATION TREES TO EXPLORE RELATIONSHIPS BETWEEN VIRAL GENOTYPE AND RESPONSE TO LOPINAVIR/RITONAVIR-BASED REGIMENS Antivir Ther. 2002;7(Suppl 1):S82 M King1, D Kempf1, J Isaacson1, R Rode1, S Brun1, B Bernstein1, V Calvez2, I Cohen-Codar3, E Guillevic3, JP Chauvin3 and E Sun1 Classification trees may provide insights into the relationship between viral genotype and response to LPV/r-based therapy that are difficult to discern using more traditional statistical methods such as logistic regression, and their interpretability may simplify the communication of such relationships. In this analysis, mutation score was more strongly associated with response than any individual PI mutation. Other factors, such as adherence, are also likely to be associated with response. Download Abstracts
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| 101 | SUSCEPTIBILITY OF PRIMARY VIRUSES TO ENTRY INHIBITORS Antivir Ther. 2002;7(Suppl 1):S83 B Labrosse1, J-L Labernardière2, E Dam2, V Trouplin2, F Clavel1 and F Mammano1 Our recombinant assay allows rapid and simple determination of HIV susceptibility to entry inhibitors, together with independent testing of the R5 and X4 component of the plasma virus population. Consistent with previous observations, primary viruses display a wide range of IC50 values to T-20 and to inhibitors targeting co-receptors. This suggests that phenotypic testing for HIV susceptibility to entry inhibitors may be useful not only for the monitoring of resistance in treated patients, but also for the optimization of therapy in patients naïve of this class of drugs. Download Abstracts
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| 102 | THE INTERNATIONAL HIV RESISTANCE RESPONSE DATABASE INITIATIVE: A NEW GLOBAL COLLABORATIVE APPROACH TO RELATING VIRAL GENOTYPE AND TREATMENT TO CLINICAL OUTCOME Antivir Ther. 2002;7(Suppl 1):S84 BA Larder, V DeGruttola, S Hammer, R Harrigan, S Wegner, D Winslow and M Zazzi, on behalf of the HIV Resistance Response Database Initiative (RDI) By combining data, expertise and resources on a global basis, the RDI has the potential to provide a mechanism by which individual genotypes can be used to predict response to different antiretroviral drug combinations with a high degree of confidence. It is intended to make the database widely accessible to scientists and clinicians via the internet. Download Abstracts
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| 103 | SIMULTANEOUS GENOTYPIC AND PHENOTYPIC HIV-RESISTANCE TESTING AND INFLUENCE ON TREATMENT SELECTION IN THE CPCRA 064 (MDR) STUDY Antivir Ther. 2002;7(Suppl 1):S85 J Lawrence1, D Mayers2, K Huppler Hullsiek3, B Schmetter4, D Abrams1, and J Baxter5 for the CPCRA 064 Study Team of the Terry Beirn Community Programs for Clinical Research on AIDS In this clinical trial of patients with MDR virus, differences were found between simultaneous GART and PART drug susceptibility results. Sensitivity on PART appears to be an influencing factor on provider prescribing patterns for certain drugs. The clinical response to regimens selected in this manner, preceded by a STI or not, will be examined upon further completion of this trial. Download Abstracts
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| 104 | A NOVEL AND RAPID PHENOTYPIC ASSAY FOR MONITORING VIRAL SUSCEPTIBILITY TO ENTRY INHIBITORS |