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13th International Drug Resistance Workshop8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain |
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Plenary Abstract Abstract 1, Page S1 |
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| P1 | INTRACELLULAR RESISTANCE TO HIV REPLICATION Antiviral Therapy 2004;9:S1 NR Landau When the virus infects new target cells and initiates reverse transcription, the encapsidated enzyme attacks the minus-strand of the reverse transcripts, modifying cytosines to uracil and resulting in G→A hypermutation on the subsequently synthesized plus-strands. APOBEC3G-induced G→A mutation has molded the HIV-1 genome over evolution resulting in an enrichment for A nucleotides. In cells infected with wild-type virus Vif induces the degradation of APOBEC3G, preserving the integrity of the viral genome. Most recently, studies aimed at understanding the resistance of primate cells to HIV-1 led to the identification of Trim5-α. Primate, but not human Trim5-alpha blocks HIV infection at reverse transcription by a mechanism that is not yet known. Current understanding of these host factors will be discussed with an emphasis on APOBEC3G.  Download Session 1 PDF: Abstracts 1 to 18
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| P2 | MONKEY BUSINESS: INSIGHTS INTO AIDS VIRUS PATHOGENESIS FROM P2 STUDIES IN NON-HUMAN PRIMATES Antiviral Therapy 2004;9:S2 JD Lifson Model systems presented will include observational natural history studies, as well as interventional studies, such as a model of transient ART during primary infection and therapeutic vaccination regimens in chronically infected macaques. Additional systems showing promise for the study of resistance to antiretroviral drugs in vivo in non-human primates may also be presented. Download Session 1 PDF: Abstracts 1 to 18
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Session 1: Resistance to New Antiretroviral Agents Abstract 2 thru 27, Pages S5 to S22 |
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| 1 | A MOLECULAR MODEL OF HIV-1 INTEGRASE INHIBITOR RESISTANCE Antiviral Therapy 2004;9:S5 D Hazuda and the Merck HIV-1 Integrase Discovery Team Like the DKA mutations, the napthyridine mutations also localize to the integrase active site, however, residues associated with DKA and napthyridine resistance map to discrete regions of the active site and define remarkably distinct ligand binding surfaces, which extend in opposing directions distal to the metal binding residues. This observation together with molecular modelling studies of these inhibitors suggest a molecular basis for their discordant resistance profiles, and the role of N155 in mediating cross class resistance and maintaining the architecture of the integrase active site. The proposed model also provides a rationale for developing integrase inhibitors with complementary resistance profiles. Download Session 1 PDF: Abstracts 1 to 18
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| 2 | NOVEL SMALL-MOLECULE COMPOUNDS WHICH INHIBIT STRAND TRANSFER 2 ACTIVITY OF HIV-1 INTEGRASE Antiviral Therapy 2004;9:S6 H Yan1, T Chiba1, Y Kitamura2, M Nishizawa1, M Fujino1, N Yamamoto1 and W Sugiura1 We have successfully found novel small-molecule IN inhibitory compounds carbazole derivatives. Though their strong cytotoxicity may limit carbazole derivatives to be used in clinical at this moment, it can be the lead compound for developing novel IN inhibitors. In addition, analysing IN inhibitory mechanisms of carbazole may give more detailed information of HIV-1 IN structure and function. Download Session 1 PDF: Abstracts 1 to 18
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| 3 | IN VITRO DEVELOPMENT OF RESISTANCE AGAINST STYRYLQUINOLINES OF HIV-1 BY EMERGENCE OF INTEGRASE MUTATIONS Antiviral Therapy 2004;9:S7 S Bonnenfant1,2, F Zouhiri1, A Chéret1 and H Leh1,3 Selection of resistance FZ41 is associated with the emergence of mutations at three residues within HIV-1 integrase, that have been previously involved for two of them with integrase non-catalytic function or drug interaction. With an in vitro resistance pattern different from those of diketo analogues, SQLs represent a new family of integrase inhibitors. Download Session 1 PDF: Abstracts 1 to 18
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| 4 | SELECTION FOR AND CHARACTERIZATION OF HIV-1 ISOLATES RESISTANT TO THE MATURATION INHIBITOR PA-457 Antiviral Therapy 2004;9:S8 K Salzwedel1, R Goila-Gaur2, C Adamson2, F Li1, A Castillo1, N Kilgore1, M Reddick1, C Matallana1, D Zoumplis1, D Martin1, G Allaway1, E Freed2 and C Wild1 These results support and extend previous observations that PA-457 is a specific inhibitor of CA-SP1 cleavage, with no activity against other Gag processing events. Characterizing the determinants of PA-457 activity is the first step in defining the molecular target for this novel HIV maturation inhibitor. Download Session 1 PDF: Abstracts 1 to 18
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| 5 | IN VITRO RESISTANCE PROFILE OF SMALL MOLECULE HIV ATTACHMENT INHIBITORS Antiviral Therapy 2004;9:S9 L Fan, NN Zhou, YF Gong, HT Ho, H Fang, B Eggers, J Fang, CB Li, D Langley, J Kadow and PF Lin The cumulative data strongly suggest that compound binding affects the residues in the CD4 pocket of gp120. Also, viral susceptibility to HIV-1 attachment inhibitors can be attributed to multiple interactions between various regions of gp120 and gp41, parallel to that observed for viral resistance to neutralization antibodies. Download Session 1 PDF: Abstracts 1 to 18
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| 6 | IN VITRO ESCAPE OF R5 PRIMARY ISOLATES FROM THE CCR5 ANTAGONIST, UK-427,857, IS DIFFICULT AND INVOLVES CONTINUED USE OF THE CCR5 RECEPTOR Antiviral Therapy 2004;9:S10 M Westby1, C Smith-Burchnell1, J Mori1, M Lewis1, R Mansfield1, J Whitcomb2, CJ Petropoulos2 and M Perros1 Resistance to UK-427,857 was either slow to emerge or did not develop during this study, suggesting there is considerable selective advantage in vitro for continued use of the CCR5 co-receptor in a UK-427,857-sensitive manner. Furthermore, our results indicate that gp160 mutations associated with UK-427,857 resistance may be strain-specific, suggesting that the context of the V3 loop is crucial for CCR5 recognition. These results offer promise for the efficacy and durability of UK-427,857-containing HAART. Download Session 1 PDF: Abstracts 1 to 18
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| 7 | SUPPRESSION OF X4- AND DUAL-TROPIC HIV-1 VARIANTS DURING A SHORT COURSE OF MONOTHERAPY WITH THE CXCR4 ANTAGONIST AMD3100 Antiviral Therapy 2004;9:S11 S Fransen1, W Huang1, J Toma1, G Bridger2, G Calandra1, JM Whitcomb1 and CJ Petropoulos1 During a short course of monotherapy with AMD3100, X4- and dual-tropic variants were suppressed, accompanied by a concomitant increase in the proportion of R5-tropic variants in the viral population. The suppression of dual-tropic variants merits additional investigation as this observation could have significant implications for the use of CXCR4 inhibitors in the clinic. Shifts in co-receptor tropism, both on and off treatment most likely result from selection of pre-existing variants from within the baseline quasispecies. Download Session 1 PDF: Abstracts 1 to 18
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| 8 | WITHDRAWAL OF FUSION INHIBITORS FROM A FAILING ANTIRETROVIRAL REGIMEN RESULTS IN REVERSION TO ENFUVIRTIDE SUSCEPTIBILITY Antiviral Therapy 2004;9:S12 GD Miralles1, T Melby1, R DeMasi1, Y Zhang1, G Heilek-Snyder2 and M Greenberg1 Following chronic enfuvirtide treatment, interruption of FI resulted in replacement of FIresistant populations by more susceptible ones. These findings extend earlier observations that fitness disadvantages observed in ENF-resistant viruses in vitro result in parallel fitness disadvantages in vivo. Download Session 1 PDF: Abstracts 1 to 18
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| 9 | A HUMAN MONOCLONAL ANTIBODY BLOCKS HIV ENTRY BY A T20-LIKE MECHANISM Antiviral Therapy 2004;9:S13 MD Miller and R Geleziunas for the HIV Antibody Discovery Team This study marks the first time that a synthetic antigen has been used to select a broadly-neutralizing monoclonal antibody. Discovery of D5 provides proof-ofconcept that the gp41 HR1 region is accessible to human IgG, that an IgG directed at HR1 can block HIV entry, and that it is possible to design synthetic antigens bearing an HR1-derived neutralizing epitope. Collectively, these observations lay the foundation for identification of therapeutic mAbs directed at HR1 and for design of immunogens capable of eliciting antibodies in vaccinees. Download Session 1 PDF: Abstracts 1 to 18
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| 10 | CROSS-RESISTANCE PROFILE OF THE NOVEL LYSINE-CONTAINING HIV-1 PROTEASE INHIBITOR PL-100 Antiviral Therapy 2004;9:S14 G Sévigny1, BR Stranix1, N Parkin2, Y Lie2 and J Yelle1 PL-100 has potent anti-protease and antiviral activity against wild-type HIV-1, and has a favourable cross-resistance profile as compared to the PIs tested in this study. Download Session 1 PDF: Abstracts 1 to 18
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| 11 | PHENOTYPIC AND GENOTYPIC RESISTANCE TO A NEW PROTEASE INHIBITOR, 640385, IN HIV-1 VIRUS SAMPLES FROM SUBJECTS FAILING AMPRENAVIR Antiviral Therapy 2004;9:S15 A Florance1, R Elston2, M Johnson1, W Spreen1 and M St Clair1 In a panel of HIV-1 isolates specifically selected for presence of amprenavir resistance, there was minimal evidence for cross-resistance between 640385 and amprenavir despite their chemical similarity. Although I54L/M+I84V mutations may contribute to decreased 640385 susceptibility, I54L/M mutations in the absence of I84V, and conversely I84V mutations in the absence of I54L/M and V32I+I47V do not appear to be associated with 640385 resistance. Similarly, the I50V mutation did not appear associated with 640385 resistance. Download Session 1 PDF: Abstracts 1 to 18
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| 12 | IN VITRO SELECTION AND CHARACTERIZATION OF RESISTANCE TO THE NEW HIV PROTEASE INHIBITOR GW640385 Antiviral Therapy 2004;9:S16 P Yates1, R Hazen3, M St Clair2, L Boone3 and R Elston1 The in vitro passage of HXB2 in the presence of GW640385 has identified amino acids associated with decreased susceptibility to GW640385. High pressure passage has led to the selection of the A28S protease mutation which was associated with a dramatic reduction in replicative capacity of the virus. Download Session 1 PDF: Abstracts 1 to 18
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| 13 | ANTIVIRAL ACTIVITY AND RESISTANCE PROFILE OF AG-001859, A NOVEL HIV-1 PROTEASE INHIBITOR WITH POTENT ACTIVITY AGAINST PROTEASE INHIBITOR-RESISTANT STRAINS OF HIV Antiviral Therapy 2004;9:S17 J Hammond, L Jackson, J Graham, S Knowles, J Digits, J Tatlock, T Jewell, S Canan-Koch and AK Patick AG-001859 is one compound in a series of novel allophenylnorstatin-containing HIV-1 PIs which demonstrates potent antiviral activity against strains of HIV resistant to the currently approved PIs. The pharmacokinetics and safety of several compounds from this series are currently being evaluated in Phase I studies. Download Session 1 PDF: Abstracts 1 to 18
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| 14 | HIGHLY POTENT HIV PROTEASE INHIBITORS WITH BROAD ACTIVITY AGAINST MDR STRAINS Antiviral Therapy 2004;9:S18 SV Gulnik, EI Afonina, B Yu, M Eissenstat, T Guerassina, AM Silva and JW Erickson SPI inhibitors are highly active against WT and MDR HIV isolates, and have the potential for further development. Download Session 1 PDF: Abstracts 1 to 18
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| 15 | ANALYSIS OF TIME OF FAILURE GENOTYPE AND PHENOTYPE FROM NNRTI-EXPERIENCED PATIENTS TREATED WITH CAPRAVIRINE Antiviral Therapy 2004;9:S19 J Hammond, R Pesano, P Hawley and AK Patick NNRTI-experienced patients treated with capravirine as part of a HAART regimen can achieve long-term suppression of viraemia. Results from the present study support previous in vitro and in vivo findings demonstrating that a single mutation conferring high-level resistance does not rapidly emerge during capravirine therapy. Rather, varied patterns of substitutions slowly emerge, indicating a high genetic barrier to resistance. Phase 2b studies evaluating capravirine in NNRTI-experienced patients are currently underway. Download Session 1 PDF: Abstracts 1 to 18
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| 16 | IN VITRO RESISTANCE DEVELOPMENT FOR A SECOND-GENERATION NNRTI: TMC125 Antiviral Therapy 2004;9:S20 JE Brillant, K Klumpp, S Swallow, N Cammack and G Heilek-Snyder TMC125 lost susceptibility with mutants: V179F, Y181C, L214F and M230L. In combination,these mutations conferred a >800 shift in susceptibility. The mutation patterns selected conferred cross-resistance to EFV, CPV and GSW678248. Download Session 1 PDF: Abstracts 1 to 18
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| 17 | DIOXOLANE-THYMINE NUCLEOSIDE (DOT) AGAINST DRUG-RESISTANT HIV-1 MUTANTS AND ITS MOLECULAR MECHANISM Antiviral Therapy 2004;9:S21 CK Chu1, YH Chong1 and RF Schinazi2 DOT is significantly active against nucleoside-resistant HIV-1 mutants. Thus, additional biological studies are warranted to determine the full potential of DOT as a potential anti-HIV agent (Supported by NIH AI32351, AI25899 and Veterans Affairs). Download Session 1 PDF: Abstracts 1 to 18
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| 18 | IMPACT OF RESIDUE 50 SUBSTITUTIONS ON PHENOTYPIC SUSCEPTIBILITY TO PROTEASE INHIBITORS Antiviral Therapy 2004;9:S22 DW Seekins1, NT Parkin2, C Chappey2, SL Hodder1, SM Schnittman3 and RJ Colonno3 These data indicate that the I50L substitution confers ATV-specific reductions in phenotypic susceptibility without cross-resistance to other marketed PIs. In contrast, APV-selected PI substitutions reduce phenotypic susceptibility to other PIs, in some cases, including LPV/r. Early use of ATV may preserve future treatment options. Download Session 1 PDF: Abstracts 1 to 18
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Session 2: Mechanisms of HIV Drug Resistance Abstracts 19 thru 43, Pages S25 to S49 |
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| 19 | RESISTANCE TO HIV-1 ENTRY INHIBITORS MAY OCCUR BY MULTIPLE MOLECULAR MECHANISMS Antiviral Therapy 2004;9:S25 CJ Petropoulos1, W Huang1, J Toma1, S Fransen1, S Bonhoeffer2 and JM Whitcomb1 Resistance to entry inhibitors can occur by multiple molecular mechanisms that may be dependent on the mode of inhibition. Our preliminary data suggest that escape from inhibitors that block receptor or co-receptor binding may occur by acquiring the ability to bind and utilize receptor–inhibitor complexes. Download Session 2 PDF: Abstracts 19 to 43
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| 20 | MUTATIONS IN HIV-1 RNASE H DOMAIN CONFER HIGH-LEVEL RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS AND PROVIDE NOVEL INSIGHTS INTO THE MECHANISM OF NUCLEOTIDE EXCISION-MEDIATED DRUG RESISTANCE Antiviral Therapy 2004;9:S26 GN Nikolenko1, S Palmer1, F Maldarelli1, JW Mellors2, JM Coffin1 and VK Pathak1 These results support our proposed mechanism for NRTI-mediated abrogation of HIV-1 replication and indicate that mutations in that RNase H domain can confer a high level of resistance to AZT and d4T. Our results strongly suggest that mutations in RNase H could be selected during antiviral therapy and significantly contribute to drug resistance either alone or in combination with NRTI resistance mutations in RT. Download Session 2 PDF: Abstracts 19 to 43
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| 21 | MISINCORPORATION OF THYMIDINE ANALOGUES CAN INCREASE DRUG SUSCEPTIBILITY Antiviral Therapy 2004;9:S27 B Marchand and M Götte Our biochemical data suggest that thymidine analogue RT inhibitors can be misincorporated, provided that the concentration of the nucleoside triphosphate is sufficiently high. The finding that TAMs-containing mutant enzymes are unable to remove mispaired d4T-MP may help to explain why the increase in phenotypic resistance to d4T is only minimal when measured in cell-based assays. Download Session 2 PDF: Abstracts 19 to 43
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| 22 | EFFECTS OF MUTATIONS ASSOCIATED WITH SUPPRESSION OF ZIDOVUDINE RESISTANCE IN HIV-1 REVERSE TRANSCRIPTASE ON REMOVAL OF TENOFOVIR FROM BLOCKED PRIMER/TEMPLATE Antiviral Therapy 2004;9:S28 N Hassani Espili1, T Bergroth1, A Pavlova1, X-W Shao2, P Mc Kenna3, A Sönnerborg1, J Lennerstrand1 The M184V mutation seems to reduce the ATP mediated excision of incorporated tenofovir both in a background of wild-type and multiple thymidine analogue-associated mutations. Furthermore, significant suppression of tenofovir resistance was found for both M184V and Y181C in the presence of T69S-SG insertion together with thymidine analogue-associated mutations. Thus, our biochemical data is consistent with cell culture data. This indicates that there would possibly be a benefit with tenofovir therapy, combined with therapy rendering suppression mutations, and these findings should therefore be taken into account in genotyping interpretations. Download Session 2 PDF: Abstracts 19 to 43
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| 23 | KINETIC MECHANISM OF HIV-1 REVERSE TRANSCRIPTASE CATALYSED AZT EXCISION Antiviral Therapy 2004;9:S29 N Sluis-Cremer and MA Parniak The absence of any observed phosphorothiate elemental effects in RT-catalysed incorporation of AZTTP and AZTTPaS is consistent with the hypothesis that the chemistry step is not rate-limiting during nucleotide incorporation. However, the large phosphorothioate elemental effects observed for the excision of both Rp and Sp isomers of AZTTPaS by wt and mutant RT indicates that the rate-limiting step of the phosphorolytic reaction is the chemistry step. The difference in rate-limiting steps for RT catalysed DNA synthesis and phosphorolytic excision suggests that inhibitors selective for the excision process may be possible. Download Session 2 PDF: Abstracts 19 to 43
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| 24 | SELECTIVE PRIMER UNBLOCKING OF CARBOVIR, LAMIVUDINE, TENOFOVIR AND ZIDOVUDINE BY WILD-TYPE HIV REVERSE TRANSCRIPTASE WITH NUCLEOTIDE AND DEOXYNUCLEOTIDE TRIPHOSPHATES Antiviral Therapy 2004;9:S30 P Gerondelis, MR Underwood and ER Lanier These studies suggest that NRTIs/ NtRTIs have different capacities to maintain chaintermination of wt RT catalysed DNA-dependent DNA polymerization under different experimental conditions, dependent in part upon the structure of the pyrophosphate donor. Generally, the PUB activity of wt RT appears to be dependent upon the nucleophile, the NRTI/NtRTI and the primer-template. Future studies of the PUB activity of both wt and resistant RT should take into consideration the selective PUB by nucleophiles other than ATP, as well as the dependence of this activity on specific primer-template sequence. Download Session 2 PDF: Abstracts 19 to 43
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| 25 | THE SELECTIVE ADVANTAGE OF AZT-RESISTANCE MUTATIONS CAN BE DEMONSTRATED IN VITRO BUT IS SUPPRESSED AT HIGH LEVELS OF PPi Antiviral Therapy 2004;9:S31 AJ Smith, PR Meyer, and WA Scott The most significant biochemical alteration in RTAZT in comparison with RTWT is enhanced excision activity, yet this difference is not manifested in a setting where the PPi-dependent reaction is greater than 35 µM. This suggests that the selection of AZT resistance occurs when PPi concentrations are low, such as in unstimulated CD4+ T cells or macrophages, or under conditions that restrict the ability of PPi to participate in the excision reaction at the site of reverse transcription. Download Session 2 PDF: Abstracts 19 to 43
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| 26 | BISPHOSPHONATE INHIBITORS OF NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR EXCISION Antiviral Therapy 2004;9:S32 MA Parniak1, S McBurney1, E Oldfield2 and JW Mellors1 In the presence of 50 µM BPH-218, the antiviral activity of AZT against TAM-HIV is dramatically increased (EC50≈0.05 µM), suggesting that BPH-218 restores activity of AZT against this virus. BPH-218 also enhances activity of AZT against wild-type HIV-1, implying that NRTI excision is a factor in replication of wild-type virus in the presence of NRTI. Molecular modeling suggests that BPH-218 may compete with ATP and/or PPi for binding to RT. BPH may represent a new class of antiviral adjuvant agents with potential clinical utility for the treatment of NRTI-resistant HIV infection. Download Session 2 PDF: Abstracts 19 to 43
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| 27 | IMPAIRED RESCUE OF CHAIN-TERMINATED DNA SYNTHESIS ASSOCIATED WITH THE L74V MUTATION IN HIV-1 REVERSE TRANSCRIPTASE Antiviral Therapy 2004;9:S33 F Frankel, D Turner, B Brenner, Y Quan and MA Wainberg These findings add to the evidence that K65R, L74V and M184V should be regarded as a group with regard to shared mechanisms of resistance to NRTIs and their consequences on RT enzymatic function. Download Session 2 PDF: Abstracts 19 to 43
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| 28 | THERMODYNAMIC ANALYSIS OF CAPRAVIRINE BINDING TO HIV REVERSE TRANSCRIPTASE AND INHIBITION OF DNA POLYMERASE AND RNASE H ACTIVITIES Antiviral Therapy 2004;9:S34 S Rajendran, JQ Hang, Y Yang, Y Li, S Tsing, J Barnett, N Cammack, A Ahene and K Klumpp The thermodynamic binding parameters for capravirine binding were consistent with different protein interactions in wild-type and mutant proteins. The inhibitory potency of capravirine on RNase H and polymerase activity was highest with wild-type protein and reduced with mutant proteins. However, there was no direct correlation between the effect of resistance mutations on protein binding, polymerase and RNase H inhibition. Download Session 2 PDF: Abstracts 19 to 43
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| 29 | NOVEL MECHANISMS INVOLVED IN NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) RESISTANCE OF BOTH THE SUBTYPE D HIV-1 ISOLATE AND REVERSE TRANSCRIPTASE DERIVED FROM A DRUG-NAÏVE UGANDAN Antiviral Therapy 2004;9:S35 H Baird1, Y Gao1, E Paxinos2, J Galovich2, M Abreha1, P Mugyenyi3, C Petropoulos2 and EJ Arts1 Native sequences responsible for this NNRTI resistance (L135, V139, and T245) were extremely rare in any HIV-1 subtype but nonetheless stable considering wild-type fitness. Since nevirapine is ARV of choice for blocking perinatal transmission and for combination therapy in Uganda, any NNRTI resistance in the drug-naïve population is quite alarming. Download Session 2 PDF: Abstracts 19 to 43
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| 30 | STRUCTURAL STUDIES OF BENZOPHENONE/HIV-1 RT COMPLEXES: INSIGHTS INTO THE POTENCY OF THE NEXT GENERATION NNRTIS AGAINST WT AND MUTANT HIV-1 Antiviral Therapy 2004;9:S36 DK Stammers1, DI Stuart1, J Ren1, PP Chamberlain1, K Weaver2, S Short2, C Andrews2, K Romines2, L Boone2, L Schaller2, A Freeman2 and J Chan2 The potency of the benzophenones against WT and mutant RTs is accomplished by a wide range of contacts with the protein as well as the stabilizing effect of hydrogen bond formation within the compound itself. The minimal contacts with Tyr181 and the relative flexibility of these compounds that allow subtle rearrangements are factors that contribute to the remarkable resilience of the benzophenone series to such a wide range of resistance mutations. Download Session 2 PDF: Abstracts 19 to 43
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| 31 | DINUCLEOSIDE POLYPHOSPHATES ARE NOVEL INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE WITH INCREASED POTENCY AGAINST ENZYMES CONTAINING AZT-RESISTANCE MUTATIONS Antiviral Therapy 2004;9:S37 P Meyer, A Smith, S Matsuura and W Scott AZT resistance mutations, alone or in combination with a 69-dipeptide insertion, conferred an increased susceptibility to inhibition by dinucleoside polyphosphates containing chain-terminating nucleoside analogues. Dinucleoside polyphosphates served as substrates for DNA polymerization by HIV- 1 RT and were incorporated much more readily by HIV-1 RT containing AZT resistance mutations. These results are very encouraging for development of novel, specific inhibitors of HIV-1 RT with increased efficacy against AZT-resistant RT which could be used to suppress the appearance of AZT-resistance mutations. Download Session 2 PDF: Abstracts 19 to 43
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| 32 | NATURAL RESISTANCE OF HIV-2 TO ZIDOVUDINE Antiviral Therapy 2004;9:S38 P Reid, H MacInnes, M Cong, W Heneine and JG García-Lerma Our results demonstrate that the activity of zidovudine on HIV-2 is lower than previously thought. The poor antiviral activity of zidovudine and the fact that most non-nucleoside RT inhibitors are not effective against HIV-2 emphasize the need for novel antiretroviral drugs for HIV-2. Download Session 2 PDF: Abstracts 19 to 43
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| 33 | POTENTIAL REVERSION PATHWAYS OF TYR 215 TO THR IN HIV-1 REVERSE TRANSCRIPTASES HAVING A DIPEPTIDE INSERTION BETWEEN CODONS 69 AND 70: CONSEQUENCES FOR ZIDOVUDINE AND STAVUDINE RESISTANCE Antiviral Therapy 2004;9:S39 T Matamoros1, S Franco2, BM Vázquez-Álvarez1, A Mas1, MA Martínez2 and L Menéndez-Arias1 Tyr-215 plays a critical role in ATP-dependent nucleotide excision, when a Ser-Ser insertion is present in the viral RT. Our data reveal that one-nucleotide changes at position 215 are sufficient to abrogate thymidine analogue resistance in isolates carrying the Ser-Ser insertion, thereby facilitating zidovudine and stavudine sensitization. Download Session 2 PDF: Abstracts 19 to 43
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| 34 | THE HIV-1 RT MUTATION H208Y COMBINED WITH T215Y CAUSES HYPERSUSCEPTIBILITY TO EFAVIRENZ Antiviral Therapy 2004;9:S40 SA Clark1, NS Shulman2, R Bosch3 and JW Mellors1 NNRTI HS to efavirenz can be demonstrated in vitro with as few as two codon changes in RT: H208Y + T215Y. This will facilitate investigation of the biochemical and structural basis of hypersusceptibility to NNRTIs. Download Session 2 PDF: Abstracts 19 to 43
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| 35 | EFFECT OF CELL CYCLE ARREST ON HIV SUSCEPTIBILITY TO RT INHIBITORS Antiviral Therapy 2004;9:S41 S Wurtzer, AJ Hance and F Clavel Cell cycle arrrest in S/G2 has marked effects on HIV susceptibility to nucleoside analogues, notably AZT. These results emphasize the importance of cellular proliferation in HIV drug susceptibility and underscore the need to evaluate HIV resistance in natural target cells under physiological conditions of activation and proliferation. Download Session 2 PDF: Abstracts 19 to 43
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| 36 | NOVEL HIV DRUG RESISTANCE MECHANISM LEADING TO PROTEASE INHIBITOR (PI) RESISTANCE IN RESPONSE TO A HIGH GENETIC BARRIER PI IN VITRO Antiviral Therapy 2004;9:S42 M Nijhuis1, NM van Maarseveen1, P Schipper1, IW Goedegebuure1, G Heilek-Snyder2, N Cammack2 and CAB Boucher1 In vitro selection experiments using the HGB protease inhibitor Ro-033-4649 resulted in the selection of a viral population displaying six–to eightfold PI resistance without mutations in the viral protease. This clearly demonstrates that a novel alternative drug resistance mechanism was identified. Interestingly, reproducible nucleotide changes in the region coding for the ribosomal frameshift site, the TFP and protease cleavage sites were observed that may be responsible for the reduced drug susceptibility. Download Session 2 PDF: Abstracts 19 to 43
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| 37 | ‘WIDE OPEN’ 1.3 Å STRUCTURE OF THE MULTIDRUG-RESISTANT HIV-1 PROTEASE REPRESENTS A NOVEL DRUG TARGET Antiviral Therapy 2004;9:S43 LC Kovari1, JF Vickrey1, P Martin1, G Proteasa1, E Hales1, K Kondapalli1, Y Jimenez1, J Martinez2, R MacArthur2, Z Wawrzak3, MA Winters4 and TC Merigan4 A series of HIV-1 MDR protease crystal structures reveal a domino effect of structural changes with multiple mutations altering the shape of the highly mutated HIV-1 protease. The crystal structures of the ‘wide open’ MDR HIV-1 protease represent a new ensemble of targets for the design of novel protease inhibitors. Download Session 2 PDF: Abstracts 19 to 43
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| 38 | SUSCEPTIBILITY TO SAQUINAVIR AND ATAZANAVIR IN HIGHLY PROTEASE INHIBITOR (PI) RESISTANT HIV-1 IS CAUSED BY LOPINAVIR-INDUCED DRUG RESISTANCE MUTATION L76V Antiviral Therapy 2004;9:S44 SM Mueller1, M Daeumer2, R Kaiser2, H Walter1, R Colonno3 and K Korn1 L76V was not seen previously in clinical samples and seems to revert resistance to saquinavir and atazanavir in viruses with high level PI resistance. The mutation was mainly selected by lopinavir and was detected in 7% of patients in the lopinavir arm of BMS 045 study. Resensitization was highly clinically relevant in all three cases with followup. Therefore, the presence of L76V provides unexpected salvage therapy options. Further studies are needed to investigate high level resistance to atazanavir and saquinavir despite the presence of L76V. Download Session 2 PDF: Abstracts 19 to 43
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| 39 | RESISTANCE-RELATED POLYMORPHISMS IN HIV-1 NON-B SUBTYPE PROTEASE INFLUENCE THE RESISTANCE PATHWAY AND AMPLIFY RESISTANCE TO PROTEASE INHIBITORS Antiviral Therapy 2004;9:S45 SH Qari, D Pieniazek and W Heneine Diverse combinations of known and novel mutations confer resistance to PI in HIV-1F and HIV-1CRF02 isolates indicating the need for improved algorithms for interpreting resistance test results. The L10V, M36I and V77I affect the genetic pathway of resistance in HIV-1CRF02 likely by modulating the fitness and resistance of the selected mutants. Both V77I and L10V amplify PI resistance and thus may play a role in the rapid emergence of high levels of clinical PI resistance. Download Session 2 PDF: Abstracts 19 to 43
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| 40 | PREDICTORS OF SELECTION OF K65R: TENOFOVIR USE AND LACK OF TAMs Antiviral Therapy 2004;9:S46 L Valer, L Martín-Carbonero, A Corral, C de Mendoza and V Soriano The selection of K65R is significantly associated with the use of TDF. However, other nucleoside combinations including d4T, ddI and/or ABC, may favour its selection as well, although more rarely. Reciprocal exclusion of K65R and TAMs may reflect that they represent divergent and antagonistic pathways driving to nucleoside analogue resistance. The frequent selection of M184V along with K65R result in a novel multi-nucleoside resistance genotype. Download Session 2 PDF: Abstracts 19 to 43
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| 41 | IN VITRO ANTIVIRAL INTERACTIONS AMONG TENOFOVIR, ABACAVIR, LAMIVUDINE AND DIDANOSINE Antiviral Therapy 2004;9:S47 CL Tremblay1,2, F Giguel1, H Dong3, TC Chou3 and MS Hirsch1 Utilizing a clinical wild-type HIV-1 isolate, in vitro antiviral drug interactions between tenofovir, abacavir, didanosine and lamivudine are favourable, and cannot explain the diminished efficacy observed in the clinical setting. Other mechanisms such as the low genetic barrier for the emergence of the K65R and M184V mutations need to be explored. Download Session 2 PDF: Abstracts 19 to 43
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| 42 | PREVALENCE OF HIV-1 GAG CLEAVAGE SITE MUTATIONS IN PATIENTS FAILING PROTEASE INHIBITORS IN THE GART STUDY (CPCRA 046) Antiviral Therapy 2004;9:S48 JD Baxter1, RE Leduc2, A DuChene2, H Leong3, MR Furtado4, OV Petrauskene4 and the CPCRA 046 Study team for the Terry Beirn Community Programs for Clinical Research on AIDS GAG cleavage site mutations and insertions were common in HIV-1 from patients failing protease inhibitor therapy. This analysis demonstrates associations between the presence of GAG cleavage site mutations and recognized protease mutations. Download Session 2 PDF: Abstracts 19 to 43
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| 43 | NO EVIDENCE FOR STAVUDINE RESISTANCE DUE TO NEVIRAPINE-SELECTED MUTATION Y181C IN HIV-1 REVERSE TRANSCRIPTASE IN A LARGE GENOTYPE/PHENOTYPE DATABASE Antiviral Therapy 2004;9:S49 K Korn, B Schmidt and H Walter In our data set, we cannot find any evidence for D4T resistance conferred by the Y181C mutation in HIV-1 RT. Therefore, we conclude that there is no reason to withhold stavudine from patients because of Y181C viruses, that interpretation systems for stavudine do not have to be changed and that there is no particular risk of failure with treatment regimens containing both stavudine and nevirapine. Download Session 2 PDF: Abstracts 19 to 43
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Session 3: HIV Pathogenesis, Fitness and Resistance Abstracts 44 thru 75, Pages S53 to S84 |
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| 44 | HIGH RATES OF HIV-1 RECOMBINATION IN T CELLS Antiviral Therapy 2004;9:S53 T Rhodes, O Nikolaitchik, J Chen and W-S Hu Our results illustrated the power of genetic recombination in generating variation of the viral population as markers separated by 100 bp can reach 12% of the maximum measurable recombination rate in one round of HIV-1 replication. These high rates of recombination also predict rapid assortment of mutations in the HIV-1 genome in vivo. Download Session 3 PDF: Abstracts 44 to 75
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| 45 | HIV-1 POPULATIONS ARE LARGE, HIGHLY DIVERSE, AND CHARACTERIZED BY FREQUENT RECOMBINATION IN DRUG-NAÏVE AND DRUG-RESISTANT INDIVIDUALS Antiviral Therapy 2004;9:S54 F Maldarelli1, M Kearney1, S Palmer1, M Polis2, J Mican2, R Stephens3, D Rock4, J Mellors5 and J Coffin1 Recombination among HIV-1 genomes in vivo is very frequent, implying a large, well-mixed population and frequent double infection. Download Session 3 PDF: Abstracts 44 to 75
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| 46 | COMPLEX PATTERNS OF RESISTANCE MUTATIONS DISTRIBUTED ON INDIVIDUAL HIV-1 GENOMES COMPRISING PREDOMINANT PLASMA POPULATIONS CIRCULATING IN TREATED INDIVIDUALS Antiviral Therapy 2004;9:S55 DD Huang1, DJ Brambilla2, MA Ussery3 and JW Bremer1 The data suggest that studies of replication capacity should take into account possible interaction between complex populations of virions whose genomes contain different combinations of resistance mutations. Studies may need to address the activity of mutations that work in trans as well as in cis. Download Session 3 PDF: Abstracts 44 to 75
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| 47 | EVIDENCE OF DIFFERENTIAL SELECTION OF HIV-1 VARIANTS CARRYING DRUG-RESISTANT MUTATIONS IN SEROCONVERTERS Antiviral Therapy 2004;9:S56 C Balotta1, S Corvasce1, L Romano2, M Violin1, F Razzolini2, I Vicenti2, A Marconi2, C Macchiesi2, S Machetti2, A Galli1, P Duca3 and M Zazzi2 HIV-1 variants carrying specific drug-resistant mutations seem to have a selective advantage in establishing new infections, as evaluated by odds ratio analysis and a binomial probability model. The analysis of larger databases may further investigate the transmission efficiency of low prevalent mutations. Download Session 3 PDF: Abstracts 44 to 75
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| 48 | EVOLUTION OF RESISTANCE MUTATIONS ACQUIRED AT TIME OF PRIMARY INFECTION: PERSISTENCE IN CIRCULATING AND ARCHIVED HIV STRAINS Antiviral Therapy 2004;9:S57 J Ghosn1, I Pellegrin2, C Deveau3, J Galimand1, M Harzic4, C Tamalet5, JP Viard1, C Goujard6, L Meyer3, C Rouzioux1 and ML Chaix1 HIV-resistant variants acquired at time of PHI may establish themselves as the dominant viral population, and are archived in the latent cellular reservoir. The absence of genotypic changes in circulating and archived viruses in a drug-free environment further supports the concept of expansion of a monoclonal resistant population. In such patients, classical triple-combination may be sub-optimal, thus promoting the accumulation of drug-resistance mutations and jeopardizing the already limited therapeutic options. Download Session 3 PDF: Abstracts 44 to 75
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| 49 | TRANSMITTED NNRTI DRUG RESISTANCE IS ASSOCIATED WITH HIGHER STEADY-STATE VIRAL LOAD MEASURES IN UNTREATED SUBJECTS WITH PRIMARY HIV INFECTION Antiviral Therapy 2004;9:S58 SJ Little1, RM Grant2,3, ES Daar4, M Markowitz5, FM Hecht3, V Johnson6, T Allen7, LM Frenkel8, C Benson9, JP Routy10, B Conway11, X Sun1, DD Richman1,12 and SDW Frost1 Lower viral loads associated with resistance to NRTIs and PIs are consistent with a fitness cost of resistance mutations to these drugs. The mechanism by which NNRTIs result in higher viral loads is unknown, but is not associated with a higher replicative capacity. Higher viral loads associated with NNRTI resistance may contribute to the high frequency of transmitted NNRTI resistance. Download Session 3 PDF: Abstracts 44 to 75
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| 50 | DISTINCT PATTERNS OF SELECTION AND FADING OF K103N AND Y181C ARE SEEN IN WOMEN WITH SUBTYPE A VS D HIV-1 AFTER SINGLE DOSE NEVIRAPINE: HIVNET 012 Antiviral Therapy 2004;9:S59 SH Eshleman1, J Wang2, LA Guay1, SP Cunningham1, A Mwatha2, ER Brown3, P Musoke4, F Mmiro4 and JB Jackson1 HIV-1 subtype influences selection and fading of NVPR mutations after single-dose NVP. Different patterns of selection and fading were observed for K103N and Y181C in women with subtypes A vs D. This suggests that HIV-1 subtype influences how specific drug resistance mutations impact viral replication in the presence and absence of antiretroviral drugs. Download Session 3 PDF: Abstracts 44 to 75
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| 51 | MECHANISMS OF PERSISTENCE OF NNRTI-RESISTANT VARIANTS AFTER DISCONTINUATION OF NNRTI-CONTAINING REGIMENS Antiviral Therapy 2004;9:S60 S Palmer1, V Boltz1, F Maldarelli1, M Kearney1, E Halvas2, J Mican3, J Mellors2 and J Coffin1 Neither the persistence of K103N after treatment cessation, nor the appearance of the alternative triplets that encode it were necessarily due to linkage to other mutations for drug resistance. However, the switches in codon frequency observed in two patients were associated with linkage to specific mutations arising as a result of changes in therapy. Download Session 3 PDF: Abstracts 44 to 75
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| 52 | WILD-TYPE FITNESS OF SUBTYPE C HIV-1 ISOLATES CONTAINING MULTIPLE DRUG-RESISTANT MUTATIONS IN REVERSE TRANSCRIPTASE IS DUE TO COMPENSATION AT THE VIRAL ENTRY STEP Antiviral Therapy 2004;9:S61 A Abraha1, I Nankya1, T Wrin2, C Petropoulos2, R Johnson3, D Katzenstein3 and EJ Arts1 Efficiency of host cell entry was almost perfect match to the fitness of primary HIV-1 isolates of subtype C and other group M subtypes, regardless of ARV resistance or sensitivity. Thus, it appears that the env gene had evolved to a more fit form and compensated for reduced PR-RT fitness. If this finding is restricted to subtype C or applies to all ARV-resistant HIV-1 isolates has yet to be studied. Download Session 3 PDF: Abstracts 44 to 75
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| 53 | A NOVEL METHOD BASED ON RECOMBINANT VIRUSES EXPRESSING GREEN (EGFP) OR RED (DSRED) FLUORESCENT PROTEINS TO STUDY REPLICATIVE FITNESS EVOLUTION OF NELFINAVIR-RESISTANT HIV-1 HARBOURING D30N AND L90M MUTATIONS IN THE PROTEASE GENE Antiviral Therapy 2004;9:S62 J Weber1, J Weberova1, P Kiser1, P Kazanjian2 and ME Quiñones-Mateu1 In this study, we have developed a new recombinant system based in growth-competition experiments that allows a more accurate quantification of HIV-1 replicative fitness associated to mutations in the pol gene. We are currently developing a similar model that will allow the cloning of pol and env genes in the same virus, which could be used to study viral strains from patients treated simultaneously with PI, RTI and entry inhibitors. Download Session 3 PDF: Abstracts 44 to 75
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| 54 | RELATIONSHIP BETWEEN LOW REPLICATION CAPACITY AND PROTEASE INHIBITOR HYPERSUSCEPTIBILITY IN >3000 CLINICAL SAMPLES LACKING PROTEASE INHIBITOR RESISTANCE MUTATIONS Antiviral Therapy 2004;9:S63 NT Parkin, M Bates, C Chappey, K Limoli and CJ Petropoulos While there was a significant correlation between RC and PI susceptibility, 9–11% of samples had either high RC and PI HS, or vice versa. The strength of the correlation was different for the various PIs, and reduction in the quantity of infectious virus had no impact on PI susceptibility, strongly indicating that PI HS is not simply a surrogate for impaired RC or a global effect of reduction in the infectivity titre. Structural and biochemical studies are required to fully understand the mechanisms of PI HS in PI wild-type viruses. Download Session 3 PDF: Abstracts 44 to 75
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| 55 | REPLICATION CAPACITY EXPLAINS THE PERSISTENCE OF DRUG-RESISTANT PROTEASE MUTANTS IN VIVO AFTER TRANSMISSION OR PARTIAL TREATMENT INTERRUPTION Antiviral Therapy 2004;9:S64 NM van Maarseveen, D de Jong, CAB Boucher and M Nijhuis We used an in vitro model system to mimic viral evolution in absence of drugs. We demonstrated that viral RC determines the evolution of protease mutants in absence of drugs. We observed that viral variants with the highest replication efficiencies (close to or better than wild-type) showed no evolution in the protease gene, despite the presence of up to five amino-acid substitutions. Viral variants with lower replication efficiencies increased their RC, either by losing their primary resistance mutations or by acquiring additional compensatory mutations. This analysis explains why some protease-resistant viruses acquire or lose mutations and other viruses persist in vivo in absence of therapy. Download Session 3 PDF: Abstracts 44 to 75
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| 56 | IMPACT OF NELFINAVIR RESISTANCE MUTATIONS ON IN VITRO PHENOTYPE, FITNESS AND REPLICATION CAPACITY OF HIV-1 WITH SUBTYPE B AND C PROTEASES Antiviral Therapy 2004;9:S65 LMF Gonzalez, RM Brindeiro, RS Aguiar, HS Pereira, CM Abreu, MA Soares and A Tanuri The reported uneven distribution of D30N and L90M PR mutations in B and C subtype strains can be explained by the drastic impairment of subtype C viruses harbouring D30N. Different resistance pathways assumed by the two subtypes may impact on subtype-specific drug resistance interpretation algorithms and account for clinical decision over NFV usage in antiretroviral therapy in developing countries where subtype C prevails. Download Session 3 PDF: Abstracts 44 to 75
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| 57 | REPLICATIVE FITNESS EVOLUTION OF A NELFINAVIR-RESISTANT HIV-1 STRAIN IN THE PRESENCE OF DIFFERENT PROTEASE INHIBITORS Antiviral Therapy 2004;9:S66 J Weber1, J Weberova1, P Kiser1, S Seaver2 and ME Quiñones-Mateu1 Elevated doses of nelfinavir further reduced the replicative fitness of the D30N virus. This virus was hypersusceptible to amprenavir in the absence of the N88S mutation. in vivo studies with 250 mg of nelfinavir added to a second PI regimen will aid to understand how to preserve these replicative impaired viruses, and their potential correlation with atypical responses to antiretroviral therapy. Download Session 3 PDF: Abstracts 44 to 75
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| 58 | EFFECT OF RT RESISTANCE MUTATIONS ON VIRAL REPLICATION IN HYDROXYUREA-PRETREATED CELLS Antiviral Therapy 2004;9:S67 E Dam1, F Bouchonnet2, F Clavel2 and AJ Hance2 Replication of many, but not all viruses carrying RT resistance mutations is sensitive to moderate depletion of dATP pools. This test may be a useful surrogate marker for testing the impact of these mutations on viral fitness. Download Session 3 PDF: Abstracts 44 to 75
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| 59 | FITNESS OF T215Y VERSUS T215F MUTANTS IN HIV-1 RT: COMPARISON OF SPECIFIC THYMIDINE ANALOGUE RESISTANCE MUTATION PATTERNS Antiviral Therapy 2004;9:S68 ZX Hu, P Reid, H Hatano, J Lu and DR Kuritzkes The relative fitness of these mutants is summarized as follows: 215Y >> 215F, 41L/215Y >> 41L/215F, 41L/210W/215Y >> 41L/210W/215F, 41L/ 67N/210W/215Y >> 41L/67N/210W/215F; 41L/215F >> 41L/210W/215F, 41L/215Y >> 41L/210W/215Y. Results of these experiments show that the combination of 215F together with 41L and 210W is highly unfavourable, and helps explain why this combination is rarely observed in clinical isolates from ZDV-treated patients. Download Session 3 PDF: Abstracts 44 to 75
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| 60 | THE Q207D REVERSE TRANSCRIPTASE MUTATION DECREASES ZIDOVUDINE SUSCEPTIBILITY AND INCREASES RELATIVE FITNESS OF ZIDOVUDINE-RESISTANT HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 Antiviral Therapy 2004;9:S69 J Lu1, J Whitcomb2 and DR Kuritzkes1 Data presented here suggest that the 207D mutation contributes to increased ZDV resistance and fitness of HIV-1 in the appropriate genetic background and under selective conditions. The finding that the 207D mutation altered ZDV susceptibility only in a viral genetic background containing multiple TAMs suggests that the mechanism by which this mutation contributes to ZDV resistance must depend on interactions made possible by alterations in the RT structure caused by the TAMs. It will be interesting to determine the biochemical and structural mechanisms by which this mutation exerts its effect. Download Session 3 PDF: Abstracts 44 to 75
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| 61 | REPLICATIVE FITNESS OF HIV-1 STRAINS WITH REDUCED SUSCEPTIBILITY TO PROTEASE-, REVERSE TRANSCRIPTASE- AND ENTRY (ENFUVIRTIDE)-INHIBITORS Antiviral Therapy 2004;9:S70 B Chakraborty, J Weber and ME Quiñones-Mateu We have analysed the replicative fitness of multidrug-resistant HIV-1 variants to multiple targets (i.e. pol and/or env genes). Enfuvirtide-resistant viruses seem to select different mutations according to their baseline genetic background. Pre-existent ‘compensatory’ mutations within the env gene appear to guarantee a minimal effect on viral fitness. Research performed at the Cleveland Clinic Foundation (M.E.Q-M) was supported by research grants: NIH-HL-67610, NIH-DE-015510, and NIHAI- 36219 (Center for AIDS Research at Case Western Reserve University). Download Session 3 PDF: Abstracts 44 to 75
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| 62 | REDUCED HIV REPLICATION CAPACITY IS ASSOCIATED WITH IMPROVED CD4 RECONSTITUTION FOLLOWING SUPPRESSIVE HAART Antiviral Therapy 2004;9:S71 C Hicks These data suggest that pre-treatment patient and viral characteristics determine the magnitude of CD4 reconstitution following suppressive HAART. If confirmed in larger populations, these findings could allow individualization of treatment initiation timing based on measurable parameters that predict CD4 reconstitution. Download Session 3 PDF: Abstracts 44 to 75
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| 63 | VERY LOW LEVELS OF PLASMA HIV-1 VIRAEMIA IN SUBJECTS WITH SUSTAINED SUPPRESSION OF VIRAEMIA <50 COPIES/ML CAN INFLUENCE THE RECOVERY OF CD4 CELL COUNTS AFTER INITIATING HAART PROMOTING THE OCCURRENCE OF TRANSIENT VIRAEMIC EPISODES Antiviral Therapy 2004;9:S72 AG Marcelin1, V Martinez2, JP Morini2, J Deleuze2, A Krivine2, I Gorin2, L Perrin3, G Peytavin4, S Yerly3, N Dupin2 and V Calvez1 These results suggest that transient viraemic episodes may be markers of ongoing viraemia below 50 copies/ml and can impair the CD4 cell count recovery. The impairment of CD4 cell count recovery seems to be affected by the occurrence of blips rather than by the level of viraemia below 50 copies/ml itself. Download Session 3 PDF: Abstracts 44 to 75
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| 64 | CD8 T CELL RECOGNITION OF HIV-1 RT MUTATIONS INDUCED BY THERAPY WITH RT INHIBITORS IN HIV-INFECTED PATIENTS WITH PERSISTENT LOW VIRAL LOAD Antiviral Therapy 2004;9:S73 A Samri1, P Jeannin1, AG Marcelin3, D Costagliola2, N Alatrakchi1, A Biligui4, R Agher4, V Calvez3, C Duvivier4, C Katlama4 and B Autran1 Presence of drug-resistance mutations in HIV-1-RT do not alter the immune recognition of corresponding CD8 epitopes and are frequently recognized by CD8 T cells from patients treated and harbouring these mutations. Patients with LVL recognized frequently both WT and mutated RT sequences while patients with VF did not suggest a possible benefit of this cross-recognition in the viral immune control. Download Session 3 PDF: Abstracts 44 to 75
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| 65 | CD8+ T CELL ACTIVATION LEVELS MAY BE PREDICTED BY POL REPLICATION CAPACITY OF DRUG-RESISTANT AND WILD-TYPE HIV-1 Antiviral Therapy 2004;9:S74 JD Barbour1,2, E Sinclair2, T Wrin3, MS Bates3, MR Segal2, RM Grant1,2, BM Bredt2, JN Martin2 and SG Deeks2 Viral pol replication capacity may directly determine immune activation levels, and therefore influence disease progression in a manner independent of its influence on plasma viral load. Download Session 3 PDF: Abstracts 44 to 75
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| 66 | SELECTION PRESSURE BY NEUTRALIZING ANTIBODIES RESULTS IN HIGHER ADAPTIVE MUTATION RATES IN GP120 Antiviral Therapy 2004;9:S75 B Joos1, A Trkola1, H Kuster1, M Fischer1, JK Wong2, J Böni3, C Leemann1, B Hirschel4, R Weber1, HF Günthard1 and the Swiss HIV Cohort Study These findings suggest that autologous neutralizing antibodies contribute to control of viraemia in a fraction of patients during chronic HIV-infection. Download Session 3 PDF: Abstracts 44 to 75
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| 67 | EVOLUTION OF NRTI RESISTANCE PATTERNS IN HEAVILY PRE-TREATED HIV-1-INFECTED PATIENTS UNDERGOING TREATMENT INTERRUPTION Antiviral Therapy 2004;9:S76 M Balduin1, S Sierra1, M Däumer1, JK Rockstroh2, M Oette3, G Fätkenheuer1, N Beerenwinkel4, D Hoffmann5, J Selbig6, H Pfister1 and R Kaiser1 The results of this study indicate that the disappearance of TAMs during TI follows a distinct pattern, similarly to the AZT mutational pathway (Boucher et al., 1992; Beerenwinkel et al., 2004), but in a reverse direction. The initial mutation in the AZT resistance pathway is the K70R, which also remains or occurs during TI. From this starting point a virus can follow a different branch of the resistance pathway under a new selective pressure even though a crossresistant virus probably persists as a minor variant. Download Session 3 PDF: Abstracts 44 to 75
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| 68 | TARGETING RESERVOIRS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION: INDUCING LATENT VIRAL EXPRESSION WITHOUT HOST CELL ACTIVATION Antiviral Therapy 2004;9:S77 DM Margolis1,2, G Lehrman1, NM Archin1, L Ylisastigui1, MB Kvanli2, D Turner2, J Wagner2, H Wise2 and RJ Bosch3 Practical strategies that disrupt latency but do not enhance new infection may be of use as antiretroviral therapy improves. VPA and IL7 are capable of inducing expression of quiescent provirus without fully activating cells or enhancing de novo infection. VPA and IL7 induce outgrowth of HIV from the resting CD4+ cells of aviraemic patients at concentrations achievable in vivo as frequently as mitogen stimulation; SB203580 achieves this effect less efficiently. Download Session 3 PDF: Abstracts 44 to 75
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| 69 | EXPRESSION OF APOBEC3G VARIES ACROSS INDIVIDUALS, IN DIFFERENT HIV HOST CELLS, AND WITH IMMUNOLOGICAL ACTIVATION Antiviral Therapy 2004;9:S78 MP De Pasquale, T Allos, L Sutton, N Madison, A Shintani, SM Grill, D Unutmaz and RT D’Aquila APOBEC3G expression varies across CD4+ T lymphocytes from uninfected individuals and is expressed at a higher level in CD4+ T lymphocytes than PBMCs. Activation of cells by mitogen, IL4 and TCR stimulation up-regulates APOBEC3G expression. APOBEC3G activity against HIV may vary across individuals, cell types and with cellular activation status. Download Session 3 PDF: Abstracts 44 to 75
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| 70 | ISOLATED LOPINAVIR RESISTANCE AFTER VIROLOGICAL REBOUND OF A LOPINAVIR/RITONAVIR-BASED REGIMEN Antiviral Therapy 2004;9:S79 NT Parkin1, CJ Petropoulos1, C Chappey1, J Friend2, T Liegler2, JN Martin2 and SG Deeks2 Although primary resistance to lopinavir is difficult to generate in vivo, it is not impossible. The preferred pathway for lopinavir resistance may involve V32I and I47A. The lack of isolated lopinavir resistance in the other I47A-containing samples described here likely reflects the emergence of this mutation when lopinavir was used in PI-experienced patients. Continued phenotypic/genotypic analysis in patients receiving lopinavir as their first-line PI will be needed to confirm these results. Download Session 3 PDF: Abstracts 44 to 75
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| 71 | SURVEILLANCE OF RESISTANCE IN KZN SOUTH AFRICA, INCLUDING MOTHER-INFANT PAIRS 6 WEEKS AFTER SINGLE-DOSE NVP Antiviral Therapy 2004;9:S80 M Gordon1, N Graham1, R Bland2, N Rollins2, T De Oliveira1, B Monosi1, K Van Laethem3, A Vandamme3 and S Cassol1,2 Taken together, these findings suggest that the pattern of resistance in African patients will be similar to that observed for the treatment of subtype B infection. However, given the high rate of resistance in mothers and infants after single-dose NVP, the search for safer regimens to prevent MTCT should be intensified. Download Session 3 PDF: Abstracts 44 to 75
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| 72 | A NOVEL 5 AMINO ACID INSERTION IN THE β3-β4 LOOP OF HIV-1 RT CONFERRING ONLY LOW-LEVEL MULTIDRUG RESISTANCE Antiviral Therapy 2004;9:S81 MCDG Huigen1, L de Graaf1, D Eggink1, R Schuurman1, V Müller2, CAB Boucher1 and M Nijhuis1 To our knowledge, this is the first patient isolate with an insertion in the ß3-ß4 loop of HIV-1 reverse transcriptase that does not result in highlevel resistance to multiple nucleoside analogues, probably due to a lack of accompanying TAMs. The described variant had an in vivo fitness advantage of 2–3% and persisted in the patient. Apparently, this small fitness advantage under drug pressure was sufficient enough for selection and persistence of this insertion in vivo. Download Session 3 PDF: Abstracts 44 to 75
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| 73 | PHYLOGENY AND RESISTANCE PROFILE OF HIV-1 POL SEQUENCES OBTAINED FROM RECTAL BIOPSIES AND BLOOD Antiviral Therapy 2004;9:S82 AB Petersen1, M Storgaard2, N Obel3, SF Jensen2, LB Jørgensen1, TV Madsen1 and C Nielsen1 Phylogeny and the mutation pattern of sequences obtained from rectal biopsies and blood suggest that the PBMCs and the rectal mucosa harbour HIV-1 from several timepoints of the infection, and that resistance mutations from earlier treatment regimen can be found in both compartments. Download Session 3 PDF: Abstracts 44 to 75
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| 74 | EVOLUTION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 VARIANTS RESISTANT TO PROTEASE INHIBITORS AFTER A PROTEASE INHIBITOR-SPARING REGIMEN Antiviral Therapy 2004;9:S83 N Gianotti1, E Seminari1, A Lazzarin1, E Boeri2, M Clementi1,2, A Danise1, S Salpietro1, G Fusetti1 and A Castagna1 In highly PI-experienced patients, under a PI-sparing regimen PI mutations can reduce, remain stable or even increase. In the majority of cases the reduction is negligible. It may be hypothesized that the selective pressure exerted by RTIs can maintain PI mutations with low influence on virus fitness in the predominant plasma viral quasispecies. Download Session 3 PDF: Abstracts 44 to 75
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| 75 | IMPACT OF THE M184V/I ON PROTEASE INHIBITOR SUSCEPTIBILITIES IN PROTEASE INHIBITOR-NAÏVE PATIENTS Antiviral Therapy 2004;9:S84 NS Shulman, RJ Bosch, M Albrecht, N Hellmann and DA Katzenstein for the ACTG 364 team M184V/I, which generally reduces viral replicative capacity was associated with lower fold-changes in susceptibility to selected PIs. The observed lower PI fold-change in the presence of M184V may be due to lower replication capacity in these viruses. Download Session 3 PDF: Abstracts 44 to 75
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Session 4: New Resistance Technologies and Interpretations Abstracts 76 thru 106, Pages S87 to S117 |
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| 76 | REAL-TIME PCR ASSAYS IDENTIFY TRANSMITTED DRUG-RESISTANT HIV-1 PREVIOUSLY UNDETECTED BY CONVENTIONAL NUCLEOTIDE SEQUENCING Antiviral Therapy 2004;9:S87 JA Johnson1, J-F Li1, D Bennett1, M Cong1, T Spira1, RW Shafer2, T Gleeson3, P Sandstrom3 and W Heneine1 We report the development of sensitive real-time point mutation assays and demonstrate their ability to detect low levels of transmitted drug resistant HIV-1 which conventional sequence analysis failed to identify. Given the high-throughput capability and greater sensitivity over conventional testing, these assays will be useful in screening for drug resistant mutants. Download Session 4 PDF: Abstracts 76 to 106
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| 77 | ESTIMATING RESISTANCE IN DRUG EXPERIENCED PATIENTS IN THE UK Antiviral Therapy 2004;9:S88 D Pillay1, H Green2, B Gazzard3,6, A Pozniak3,6, R Matthias2, M Johnson4, D Churchill5, M Fisher5, T Hill1, AM Geretti4, J Clarke5, P Cane7, C Loveday8, G Scullard6, P Easterbrook9, K Porter2, I Williams1, R Gilson1, C Sabin1,4, A Phillips1,4 and D Dunn2, on behalf of the UK Collaborative Group on HIV Drug Resistance and UK Collaborative HIV Cohort Study (UK CHIC) Single time point analysis indicates triple class resistance remains stable over time. In contrast, consideration of multiple tests showed a steady rise in the proportion of treated patients with triple class resistance. The latter analysis is more relevant for understanding the level of drug resistance at the population level, although absolute values are underestimated due to low rate of testing at treatment failure. Download Session 4 PDF: Abstracts 76 to 106
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| 78 | PREVALENCE OF MULTIPLE-CLASS ANTIRETROVIRAL DRUG RESISTANCE IN HIV-1-TREATED PATIENTS Antiviral Therapy 2004;9:S89 B Masquelier1, D Costagliola2, A Schmuck3, J Cottalorda4, V Schneider5, J Izopet7, D Descamps7, C Poggi8, F Brun-Vézinet7 and the ANRS Resistance Study Group We did not observe increase in the prevalence of multiple class resistant viruses in patients followed in French hospitals between 2001 and 2002. A combination of two PIs was still possible in 68% of patients. Such surveillance is required to determine the proportion of treated patients who need access to new drugs directed against new viral targets. Download Session 4 PDF: Abstracts 76 to 106
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| 79 | PREDICTED PHENOTYPIC RESISTANCE IN ROUTINE CLINICAL SAMPLES BETWEEN 1998 AND 2003 Antiviral Therapy 2004;9:S90 AR Rinehart1, P Lecocq2, P McKenna2, T Pattery2, B Wasikowski3 and LT Bacheler1 Among isolates with resistance, the prevalence of resistance to NNRTIs increased, while resistance to NRTIs and PIs declined. However, the magnitude of resistance to some PIs increased since 2001. These trends are consistent with changing treatment practices and resistance testing utilization between 1998 and 2003. Download Session 4 PDF: Abstracts 76 to 106
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| 80 | CHANGES IN PREVALENCE OF NRTI RESISTANCE ASSOCIATED MUTATIONS AMONG CLINICAL ISOLATES FROM 1999–2003 Antiviral Therapy 2004;9:S91 H Faruki1, J Sebastian1, J Scott2, J Stamp2 and ER Lanier2 The prevalence of some key mutations associated with ART resistance has changed significantly over the past five years. Prescribing patterns and regimen efficacies may be key factors in these changes, although further studies are required to establish causes for these effects. Download Session 4 PDF: Abstracts 76 to 106
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| 81 | LARGE SCALE CLUSTER ANALYSIS OF HIV-1 PROTEASE MUTATIONS IN A CLINICAL DATABASE Antiviral Therapy 2004;9:S92 R Kagan1, M Winters2, T Merigan2 and P Heseltine1 Although the incidence of PI resistance has been declining, the number of PR codons associated with resistance has increased over a fiveyear period. We have identified 11 novel PR residues in a clinical data set that are consistently associated with resistance. Cluster analysis has demonstrated significant covariation of PR mutations. Phenotypic and clinical studies are needed to assess the role of these novel PR mutations found in these clusters. Download Session 4 PDF: Abstracts 76 to 106
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| 82 | THE CHANGING PREVALENCE OF HIV-1 PROTEASE (PR) AND REVERSE TRANSCRIPTASE (RT) POLYMORPHISMS IN PRIMARY HIV INFECTION (PHI), CHRONIC-NAÏVE, AND FOLLOWING EXPOSURE TO ANTIRETROVIRAL THERAPY (ART) Antiviral Therapy 2004;9:S93 C Loveday1, E MacRae1, MA Johnson2 and on behalf of the ICVC Collaborative Research Group1 Certain polymorphisms confer biological advantages to HIV during early evolution in the host and following ART. Genetic homogeneity at infection is followed by significant genetic expansion in the polymorphic repertoire of chronic-naïve patients. Drug pressure showed the polymorphic repertoire altered and implies that although these polymorphisms may not confer resistance alone, they provide a background to facilitate resistance in the presence of recognized mutations. Download Session 4 PDF: Abstracts 76 to 106
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| 83 | THE ASSOCIATION OF K65R WITH Q151M COMPLEX AND THE RELATIONSHIP TO ANTIRETROVIRAL TREATMENT: RESULTS FROM A NORTHERN CALIFORNIA CLINIC POPULATION Antiviral Therapy 2004;9:S94 AR Zolopa1, SY Rhee1, D Shin1, L Hurley2, WJ Fessel2 and RW Shafer1 The association of Q151M complex with K65R appears to occur in heavily NRTI–treated patients who received long-term ddI (often as monotherapy). The association does not appear to be as strongly related to use of TDF and appears to be waning. K65R does not appear to occur prior to development of the Q151M complex. Download Session 4 PDF: Abstracts 76 to 106
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| 84 | HIV DRUG RESISTANCE AND TREATMENT FAILURE: CONTRASTING MORTALITY AND VIRAL LOAD ENDPOINTS Antiviral Therapy 2004;9:S95 ZL Brumme, M Rescky, B Wynhoven, W Dong, K Chan, B Yip, B Sattha, J Montaner, R Hogg, and PR Harrigan A very high proportion of individuals with virological failure had some detectable resistance. Of particular interest, only a low prevalence of broad antiretroviral resistance was observed in individuals who died, indicating that an exhaustion of treatment options due to drug resistance was not the primary driver of mortality in this cohort. Download Session 4 PDF: Abstracts 76 to 106
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| 85 | A SCREENING ALGORITHM FOR SURVEILLANCE OF ANTIRETROVIRAL DRUG RESISTANCE AMONG INDIVIDUALS NEWLY DIAGNOSED WITH HIV IN THE US Antiviral Therapy 2004;9:S96 DE Bennett1, B Byers1, L McCormick1, J Johnson1 ,T Gleeson2, V Simon3, AJ Smith1, C Archibald2, G Jayaraman2, P Sandstrom2 and W Heneine1 This study suggests that RT-PCR or other point mutation assays could be used to screen 10 positions in the HIV genome as an initial low-cost ARVDR surveillance tool in the US. Full genotyping would be performed only on strains for which screening revealed an ‘indicator’. Validated laboratory tests and prospective comparisons against genotyping in a variety of geographic areas would be required to confirm the utility of this approach. Regular review of the algorithm would be needed as ARV drug usage patterns change. Download Session 4 PDF: Abstracts 76 to 106
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| 86 | VALIDATION OF MOLECULAR INDICATORS OF RESISTANCE TRANSMISSION (MIRTS) FOR EPIDEMIOLOGICAL STUDIES OF DRUG RESISTANCE TRANSMISSION IN HIV Antiviral Therapy 2004;9:S97 D van de Vijver1, B Brenner2, D Turner2, P Sandstrom3, D Dunn4, H Green4, D Bennett5, W Heneine5, R Shafer6, T Leitner7, D Costagliola8, A-M Vandamme9, M Wainberg2, C Boucher1 and R Schuurman1 A validated algorithm for epidemiological determination of transmission of drug resistant HIV is now available, and can be applied for standardized analysis, and comparison of studies. MIRTs is validated for subtype B. Validation for other subtypes will be performed with the availability of large datasets of non-B subtypes. Download Session 4 PDF: Abstracts 76 to 106
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| 87 | THE CALCULATED GENETIC BARRIER FOR DRUG RESISTANCE MUTATIONS IN SIX DIFFERENT NON-B SUBTYPES AND TWO CRFS IN A LARGE EUROPEAN DATASET IS LARGELY SIMILAR TO SUBTYPE B Antiviral Therapy 2004;9:S98 DAMC van de Vijver1, AMJ Wensing1,2, G Angarano3, B Åsjö4, C Balotta5, E Boeris6, R Camacho7, M-L Chaix8, D Costagliola9, E Op de Coul10, A de Luca11, I Maljkovic12, C de Mendoza13, I Derdelinckx14, Z Grossman15, O Hamouda16, A Hatzakis17, IM Hoepelman2, R Hemmer18, A Horban19, K Korn20, C Kücherer16, T Leitner21, C Loveday22, E MacRae22, L Meyer23, C Nielsen24, V Ormaasen25, L Perrin26, D Paraskevis17, E Puchhammer-Stöckl27, L Ruiz28, M Salminen29, JCC Schmit18, F Schneider18, R Schuurman1, V Soriano13, G Stanczak19, M Stanojevic30, A-M Vandamme14, K Van Laethem14, M Violin5, K Wilbe12, S Yerly26, M Zazzi31 and CAB Boucher1 on behalf of the SPREAD Programme In a large dataset of European HIV-1 sequences (including more than 600 non-B) we found no major difference between subtypes in the calculated genetic barrier for drug resistance mutations at major positions defined by the IAS. Download Session 4 PDF: Abstracts 76 to 106
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| 88 | NUCLEOTIDE AND AMINO ACID POLYMORPHISMS AT DRUG RESISTANCE SITES IN NON-B SUBTYPE HIV-1 VARIANTS Antiviral Therapy 2004;9:S99 D Turner1, B Brenner1, D Moisi1, M Detorio1, T Kurimura2, M Essex3 and MA Wainberg1 These substitutions and polymorphisms reflect different patterns of codon usage among viruses of different subtypes. However, the existence of different subtypes may only rarely affect patterns of drug resistance-associated mutations. Download Session 4 PDF: Abstracts 76 to 106
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| 89 | HIV DRUG RESISTANCE AMONG HIV+ INJECTION DRUG USERS: RISK BEHAVIOUR AND PATIENTS’ BELIEFS ON THE TRANSMISSIBILITY OF HIV Antiviral Therapy 2004;9:S100 M Kozal1, KR Amico2, J Chiarella1, J Fisher2, D Cornman2, W Fisher3 and G Friedland1 A small proportion of active IDU carry resistant HIV and engage in risk behaviour but, because of multiple event related sharing partners, expose a substantial number of partners during unsafe needle/works sharing events. The majority of IDU in care with and without resistant HIV believe that sharing needles will put partners at risk for contracting HIV yet many still engage in IDU risk behaviour, demonstrating the complexities of resistance and risk behaviour and the challenges in reducing drug resistant HIV transmission. Download Session 4 PDF: Abstracts 76 to 106
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| 90 | NATURAL HISTORY OF TRANSMITTED DRUG RESISTANT AND WILD-TYPE INFECTIONS AND SUPERINFECTION IN THE MONTREAL PRIMARY HIV-1 INFECTION (PHI) COHORT Antiviral Therapy 2004;9:S101 BG Brenner, D Turner, JP Routy, D Moisi, M Oliveira and MA Wainberg These findings indicate that recently infected persons harbour a single dominant circulating viral species in their plasma and PBMCs that persists for 2–6 years. Download Session 4 PDF: Abstracts 76 to 106
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| 91 | SLOWER SEROLOGICAL EVOLUTION IN PRIMARY HIV-1 DRUG RESISTANCE Antiviral Therapy 2004;9:S102 HM Truong1,2, FM Hecht2, JD Barbour1,2, MP Busch3, T Liegler1 and RM Grant1,2 Our findings suggest acquisition of a major primary resistance mutation results in a lower average OD/CO at time of HIV diagnosis and a slower subsequent increase in OD/CO. The relationship between OD/CO and primary resistance prevalence is mainly attributable to delayed evolution of serological responses rather than loss of primary resistance overtime. Delayed serological responses may reflect underlying differences in B-cell activation or viral antigen presentation during drug-resistant infections. Download Session 4 PDF: Abstracts 76 to 106
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| 92 | DETERMINATION OF TRANSMISSION RATE DIFFERENCES OF VARIOUS HIV-1 DRUG-RESISTANT MUTATIONS WITH META-ANALYSIS Antiviral Therapy 2004;9:S103 MD de B Edwardes1, J-P Routy2, D Turner3, V Simon4, B Brenner3 and MA Wainberg3 A new approach for random-effects meta-analysis works well for this application of rare correlated events. Results suggest that the presence of TAMs or T215 may be associated with a greater risk of transmission of HIV-1. At the same time, the results for M184V/I may partly reflect the diminished replicative capacity of viruses that possess this mutation. Download Session 4 PDF: Abstracts 76 to 106
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| 93 | CLUSTERS AND TRENDS IN PRIMARY RESISTANCE IN SAN FRANCISCO, 2001–2003 Antiviral Therapy 2004;9:S104 RM Grant1,2, TI Liegler1 and FM Hecht2 Decreasing trends in primary resistance prevalence in San Francisco may reflect decreasing treatment in early infection, greater treatment success with more potent regimens, or alterations in epidemiological core groups. Drug-resistant HIV-1 is being transmitted in clusters of recently infected persons, which may represent the main opportunity for transmission of these impaired viruses. The clusters that appeared in 2002 did not persist in 2003, suggesting sporadic occurrence or detection rather than epidemic expansion of transmission-adapted drug-resistant HIV-1. Download Session 4 PDF: Abstracts 76 to 106
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| 94 | HIV DRUG RESISTANCE AMONG FOREIGN-BORN PERSONS NEWLY DIAGNOSED WITH HIV IN THE US Antiviral Therapy 2004;9:S105 DE Bennett, I Zaidi, AJ Smith and L McCormick HIVDR epidemiology among newly diagnosed FB persons in this US study differs from that in Europe. FB persons contributed nearly 20% of new diagnoses; the prevalence of resistance among them was similar to that among persons born in the US. Explanations could include a widespread access to HIV drugs in some Latin American and Caribbean countries contributing highly to US immigration, or many FB persons diagnosed with HIV in the US could have been infected here. US clinicians treating FB patients should not assume baseline susceptibility to all HIV drugs. Download Session 4 PDF: Abstracts 76 to 106
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| 95 | SURVEILLANCE OF HIV ANTIRETROVIRAL DRUG RESISTANCE AND SUBTYPES IN NEWLY DIAGNOSED HIV-INFECTED PATIENTS IN SPAIN IN 2003 Antiviral Therapy 2004;9:S106 C Gutiérrez1, C Mendoza2, I Erkicia3, M Leal4, P Domingo5, MJ Galindo6, JD Pedreira7, A Guelar8, A Masabeu9, J Iribarren10, JL Blanco11, JM Llibre12, N Margall4, S Pérez-Elías1, S Gutierrez4, JF Baldoví6, X Camino10, T Pumarola11, S Moreno1, B Clotet3, V Soriano2 and L Ruiz3 on behalf of the Maraton TV3 Study Group The prevalence of primary RT and PI-genotypic resistance in Spain is close to 10%. There is no evidence of an increase in the risk of being infected with drug-resistance mutations during the last 3 years. HIV-1 non-B subtypes were detected in 10% of the patients suggesting an increase of non-B subtypes according to previous studies. Surveillance for antiretroviral drug resistance in HIV-naïve patients and for non-B subtypes is warranted in Spain. Download Session 4 PDF: Abstracts 76 to 106
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| 96 | PREVALENCE OF REDUCED DRUG SUSCEPTIBILITY IN TREATMENT-NAÏVE PATIENTS IN THE UK Antiviral Therapy 2004;9:S107 DT Dunn1, H Green1, R Matthias1, P Woodburn1, R Gifford2, I Chrystie3, M Zuckerman3, AM Geretti4, C Loveday5, J Clark6, D Pillay2, P Cane7, D Churchill8, A Pozniak9 on behalf of the UK HIV Collaborative Group on HIV Drug Resistance Although the prevalence of transmitted drug resistance was 18.0% based on the presence of one or more major mutations, in only half of these samples (8.9%) were the mutations significant enough for the virus to be ascribed as having markedly reduced drug susceptibility. Current methods for defining transmitted resistance may be inadequate. Download Session 4 PDF: Abstracts 76 to 106
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| 97 | THE PREVALENCE OF DRUG RESISTANCE IN A POPULATION OF INDIVIDUALS TESTING POSITIVE FOR HIV INFECTION IN CANADA FROM 2000–2003 Antiviral Therapy 2004;9:S108 T Gleeson1, CP Archibald1, GC Jayaraman1 and P Sandstrom1 for the Canadian HIV Strain and Drug Resistance Surveillance Program2 The laboratory arm of CHSDRSP has aided in providing unique information to help improve the understanding of the evolving HIV epidemic in Canada. The data suggests that the prevalence of primary HIV drug resistance and variability of subtype may be increasing in Canada and that there also appears to be a shift in drug class prevalence. Download Session 4 PDF: Abstracts 76 to 106
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| 98 | CHANGES IN PREVALENCE AND PATTERNS OF DRUG RESISTANT MUTATIONS IN JAPAN - SUMMARY OF NATIONWIDE HIV-1 DRUG RESISTANCE SURVEILLANCE STUDY (1996 TO 2003) IN JAPAN Antiviral Therapy 2004;9:S109 W Sugiura1, M Matsuda1, T Chiba1, J Kakizawa1, M Nishizawa1, H Miura1, M Hamatake1, T Ueda1, M Fujino1, K Yamada2 and N Yamamoto1 Our data demonstrates significant increase of HIV drug resistance in these 7 years. Further continuation of the surveillance is necessary not only to understand epidemiological status, but also to find effective strategy to overcome the HIV drug resistance issue. Download Session 4 PDF: Abstracts 76 to 106
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| 99 | TRANSMISSION OF ANTIRETROVIRAL DRUG RESISTANT HIV STRAINS BETWEEN 1996 AND 2003 IN VICTORIA, AUSTRALIA, AND THEIR SUBSEQUENT EVOLUTION IN UNTREATED INDIVIDUALS Antiviral Therapy 2004;9:S110 T Middleton1, R Taqi1, J Russelll, N Roth2, N Medland3 and C Birch1 Over the last 8 years transmission of drug resistant virus was approximately 13% in recently infected individuals in Victoria, Australia. Individuals who had primary HIV infection with resistant virus did poorly in terms of their virological and immunological response compared to individuals infected with wildtype virus. This suggests that decreased replicative fitness often associated with resistant virus may not imply a slower rate of progression. Download Session 4 PDF: Abstracts 76 to 106
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| 100 | GENOTYPIC HIV-DRUG RESISTANCE AMONG NEWLY DIAGNOSED, NEVER TREATED PERSONS IN MEXICO Antiviral Therapy 2004;9:S111 L Fuentes-Romero1, RA Rodriguez-Diaz1, M Viveros-Rogel1, S Bertagnolio2, E Leon3, G Ruiz-Palacios1, D Sutherland2, LE Soto-Ramirez1 and the Global Resistance Network from the World Health Organization Frequency of resistance in newly diagnosed patients in Mexico is similar to that reported in some US cities and European countries in recently infected persons. The most frequent mutation associated with transmitted resistance is M41L, probably in relation to the extensive use of AZT as low dose monotherapy and in Mexico. This findings support the development of strategies to perform HIV-resistance surveillance in countries with history of inadequate use of antiretrovirals and starting universal coverage programmes. Download Session 4 PDF: Abstracts 76 to 106
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| 101 | PREVALENCE OF MUTATIONS ASSOCIATED WITH ANTIRETROVIRAL DRUG RESISTANCE (ARVDR) IN A COHORT OF TREATED INDIVIDUALS IN FOUR US CITIES Antiviral Therapy 2004;9:S112 AJ Smith1, H Wang1, D Bennett1, E Teshale1, S Buskin2, A Morse3, A Wohl4, D Swerdlow1, P Sullivan1 and M Wolfe1 In a large US cohort of HIV-infected individuals prescribed ART in 2001–2003, four out of five of those tested had HIV resistant to at least one antiretroviral drug. For the high proportion of persons with HIV resistant to two or three drug classes, treatment options are limited. New drug classes are becoming available, but regimens must be carefully chosen and adherence monitored so that options do not become further restricted. These data suggest also that a high proportion of persons receiving ART in some settings could potentially transmit drug-resistant HIV. Interventions that minimize high-risk behaviours among persons in treatment will also minimize the transmission of resistant HIV. Download Session 4 PDF: Abstracts 76 to 106
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| 102 | ANALYSIS OF PTAP DUPLICATIONS IN THE GAG P6 REGION OF SUBTYPE C HIV-1 Antiviral Therapy 2004;9:S113 SH Eshleman1, N Marlowe2, J Hackett3, Jr M Schumaker2, V Holzmayer3, P Hay4, SP Cunningham, SG Devare3, JB Jackson1 and T Flys1 PTAP duplications are more common in subtype C than other HIV-1 strains. Further studies are needed to determine whether these duplications influence viral replication capacity, antiretroviral drug susceptibility, or other phenotypic properties of subtype C isolates. Download Session 4 PDF: Abstracts 76 to 106
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| 103 | NELFINAVIR RESISTANCE IN HIV-1 SUBTYPE B AND G INFECTED PATIENTS: EVIDENCE FOR DIFFERENT PATHWAYS AND NOVEL MUTATIONS ASSOCIATED WITH FAILURE OF NELFINAVIR BASED REGIMENS Antiviral Therapy 2004;9:S114 R Camacho1, K Deforche2, ME Valadas3, K Van Laethem2, MJ Águas4, J Vera5,L Rosado6, T Batista7, V Bezerra8, I Soares9, T Branco10, A Mouzinho11, E Teófilo12, T Faria13, A Abecasis1, P Gomes1, AP Carvalho1 and A-M Vandamme2 Bayesian Networks were very informative for subtype-dependent nelfinavir resistance pathways. We found different frequencies of mutations in patients failing nelfinavir when comparing subtype B and G, while some new mutations were identified. Whether these differences are only dependent on the genetic background or whether the clinical differences observed are relevant needs to be further investigated. Download Session 4 PDF: Abstracts 76 to 106
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| 104 | EFFECT OF HIV-1 SUBTYPE ON DEVELOPMENT OF NNRTI RESISTANCE MUTATIONS IN PATIENTS FAILING FIRST LINE THERAPY Antiviral Therapy 2004;9:S115 PA Cane1, H Osman2 and E Smit2 With the exception of V106M, which occurred exclusively in this dataset in subtype C virus in patients treated with efavirenz, all the major NNRTI mutations were observed in all the subtypes. However, the relative frequency of mutations at codons 103 and 190 varied significantly between the subtypes. These observations may be of importance for the development of rapid tests for the detection of NNRTI resistance in the developing world. |