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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. Download Session 4 PDF: Abstracts 76 to 106
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| 105 | TEMPORAL CHARACTERIZATION OF FREQUENCY OF DRUG-RESISTANCE ASSOCIATED MUTATIONS IN THE HIV-1 PROTEASE AND REVERSE TRANSCRIPTASE Antiviral Therapy 2004;9:S116 F Ceccherini-Silberstein1, M Santoro1, V Svicher1, C Gori2, M Zaccarelli2, F Forbici2, R d’Arrigo2, MP Trotta2, MC Bellocchi2, U Visco-Comandini2, S Giannella2, A Bertoli1, A Antinori2 and CF Perno1,2 Data suggest that first resistance test is required by clinicians earlier in 2003 than 1999, and that the patterns of mutations associated to cross–resistance are sharply decreased (at the time of first test) over the years both for NRTI and for PI (probably due to the decrease of dual NRTI therapy, to an increased use of boosted-PI-regimens, and/or to an earlier definition of failure followed by therapeutic change). Overall results further support the extensive use of resistance test in clinical practice. Download Session 4 PDF: Abstracts 76 to 106
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| 106 | TRANSMISSION OF HIV-1 CONTAINING V118I IN REVERSE TRANSCRIPTASE DOES NOT COMPROMISE RESPONSE TO FIRST LINE THERAPY Antiviral Therapy 2004;9:S117 C Mihailidis1, D Dunn2, D Pillay3 and A Pozniak1 We found no evidence that transmission of virus with V118I compromised response to HAART containing two nucleoside analogues. While this does not exclude the possibility that V118I-containing transmitted viruses reflect previous drug selective pressure, our data suggests that this mutation alone should not be included within the definition of clinically significant transmitted drug resistance. Larger studies are required to explore the impact of polymorphisms/possible resistance mutations on therapy response. Download Session 4 PDF: Abstracts 76 to 106
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Session 5: New Resistance Technologies and Interpretations Abstracts 107 to 134, Pages S121 to S148 |
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| 107 | A FUZZY RELATIONAL SYSTEM TRAINED BY GENETIC ALGORITHMS AND HIV-1 RESISTANCE GENOTYPES/VIROLOGICAL RESPONSE DATA FROM PROSPECTIVE STUDIES USEFULLY PREDICTS TREATMENT OUTCOMES Antiviral Therapy 2004;9:S121 M Prosperi1,2, S Di Giambenedetto3, MP Trotta4, A Cingolani3, L Ruiz5, JD Baxter6, P Clevenbergh7, CF Perno4,8, R Cauda3, G Ulivi1, A Antinori4 and A De Luca3 Genetic algorithms with fuzzy operators showed a good learning capability from resistance genotype/virologic outcomes correlations with different regimens. The system informs, for each specific drug, on weight of mutations involved in the correlation with the VL response. Download Session 5 PDF: Abstracts 107 to 134
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| 108 | APPLICATION OF MULTIPLE LINEAR REGRESSION MODELLING TO THE QUANTITATIVE PREDICTION OF HIV-1 DRUG SUSCEPTIBILITY PHENOTYPE FROM VIRAL GENOTYPE Antiviral Therapy 2004;9:S122 H Vermeiren1, T Van den Bulcke1, H Van Marck2, P Lecocq1, M Van Houtte1 and L Bacheler3 Multiple linear regression on Virco’s correlative database yields reliable quantitative drug susceptibility predictions. Furthermore, this is a fully data driven technique that is promising for identification of resistance associated mutations, provided higher-order interactions are included. Download Session 5 PDF: Abstracts 107 to 134
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| 109 | PREVIOUS DRUG EXPOSURE DATA SIGNIFICANTLY INCREASE THE ACCURACY OF ARTIFICIAL NEURAL NETWORKS IN PREDICTING VIROLOGICAL RESPONSE TO COMBINATION THERAPY Antiviral Therapy 2004;9:S123 BA Larder1, D Wang1, A Revell2, R Harrigan3, J Montaner3 and C Lane4 The addition of historical AZT exposure data significantly improved the accuracy of ANN in predicting response to combination therapy including d4T, ABC or TDF, confirming that historical exposure to antiretroviral drugs can influence response to a new regimen. This study suggests that historical treatment information may act as a surrogate for the presence of minority mutant populations and can enable ANN to overcome this potential shortcoming of current genotyping. Download Session 5 PDF: Abstracts 107 to 134
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| 110 | PROBABILISTIC GRAPHICAL MODELS FOR PREDICTION OF HIV-1 DRUG RESISTANCE MUTATIONS BASED ON ANTIRETROVIRAL TREATMENT HISTORY Antiviral Therapy 2004;9:S124 J Ravela, R Raina, SY Rhee, JM Schapiro and RW Shafer A simple probabilistic graphical model predicts the presence of drug-resistance mutations with an accuracy of approximately 75%. Models that contain interactions among drugs and among mutations are under development. Algorithms based on these models may be used to supplement drug susceptibility results in persons with complicated treatment histories for whom susceptibility testing often underestimates the extent of resistance. Such algorithms may also be useful in parts of the world without access to drug susceptibility testing. Download Session 5 PDF: Abstracts 107 to 134
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| 111 | COMPUTING THE GENETIC BARRIER Antiviral Therapy 2004;9:S125 N Beerenwinkel1, T Sing1, M Däumer2, R Kaiser2 and T Lengauer1 Our definition of the genetic barrier relies on calculating the probability of mutational pathways and the level of resistance the resulting mutational patterns induce. This quantification of the concept allows for systematic evaluations of the genetic barrier as a predictive factor in clinical trials. Download Session 5 PDF: Abstracts 107 to 134
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| 112 | DISCORDANCES BETWEEN INTERPRETATION ALGORITHMS FOR GENOTYPIC RESISTANCE TO PROTEASE AND REVERSE TRANSCRIPTASE INHIBITORS ARE SUBTYPE DEPENDENT Antiviral Therapy 2004;9:S126 J Snoeck1, R Kantor2, RW Shafer2, K Van Laethem1, K Deforche1, AP Carvalho3, B Wynhoven4, MA Soares5, P Cane6, J Clarke7, C Pillay8, S Sirivichayakul9, K Ariyoshi10, A Holguin11, H Rudich12, R Rodrigues13, MB Bouzas14, F Brun-Vézinet15, C Reid16, P Cahn14, LF Brigido13, Z Grossman12, V Soriano11, W Sugiura10, P Phanuphak9, L Morris8, J Weber7, D Pillay6, A Tanuri5, PR Harrigan4, R Camacho3, JM Schapiro2, D Katzenstein2 and A-M Vandamme1 Overall, the different algorithms agreed well on the level of resistance scored. However we could attribute some of the discordances to specific (subtype-dependent) combinations of mutations. It is not yet know whether therapy response is subtypedependent, but the advice given to clinicians based on an interpretation algorithm can vary according to the subtype. Download Session 5 PDF: Abstracts 107 to 134
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| 113 | EVALUATION OF DIFFERENT APPROACHES FOR THE DEFINITION OF CLINICALLY RELEVANT BREAKPOINTS FOR PHENOTYPIC RESISTANCE DATA Antiviral Therapy 2004;9:S127 B Winters1, LT Bacheler2, D Nauwelaers1, A Rinehart2, M McGregor3, R Harrigan4, M Perez-Elias5, M Miller6, S Emery7, F van Leth8, D Hall9, JD Baxter10 and A Pozniak11 Definition 2 provides a broadly applicable description of the dependence of virological response on baseline resistance with the least dependence on the specific patient characteristics or treatment regimens studied. Both linear and logistic regression approaches provide consistent results for this definition. Download Session 5 PDF: Abstracts 107 to 134
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| 114 | COMPARISON OF ORIGINAL AND UPDATED GENOTYPIC AND PHENOTYPIC SUSCEPTIBILITY ALGORITHMS FOR TREATMENT-EXPERIENCED PATIENTS Antiviral Therapy 2004;9:S128 R DeMasi1, T Melby1, D Miralles1, M Bates2, N Parkin2, C Chappey2, G Heilek-Snyder3, M Greenberg1 and D Kuritzkes4 While a range of concordance between the original and updated GT/PT scores across ARVs was observed, there was overall good agreement between the original and updated GT/PT dichotomous scores. The effect of ENF+OB over OB as estimated using the updated GT/PT rules was similar to that based on the original rules, with minimal improvement in the prognostic values of updated GSS/PSS on virological response. Download Session 5 PDF: Abstracts 107 to 134
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Session 5: Epidemiology Abstracts 115 thru 132, Pages S129 to S146 |
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| 115 | A GENOTYPIC INHIBITORY QUOTIENT (GIQ) FOR FOSAMPRENAVIR/RTV (908/R) Antiviral Therapy 2004;9:S129 R Elston1, S White2, P Yates1, F Xu1, N Richards2, S Sharp2, MB Wire3 and M Tisdale1 The GIQs for 908/r BID were significantly associated with response at week 12 and week 24. GIQ offers a method of identifying subjects with the greatest potential to respond to 908/r BID in combination with N(t)RTIs. Download Session 5 PDF: Abstracts 107 to 134
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| 116 | EXPERTS SELECT DIFFERENT ANTIRETROVIRAL DRUG REGIMENS WHEN PRESENTED WITH RESISTANCE DATA IN THE FORM OF GENOTYPE, PHENOTYPE, OR COMBINED GENOTYPE PLUS PHENOTYPE Antiviral Therapy 2004;9:S130 AR Zolopa1, M Bates2 and N Parkin2 Expert clinicians/virologists make different regimen choices based on GT, PT, or PTGT. Since provision of PTGT results can lead to different ARV choice there is potential clinical value to having the combined results, at least in certain settings. We cannot determine if these differences in ARV choice lead to differences in clinical outcomes. Download Session 5 PDF: Abstracts 107 to 134
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| 117 | GENOTYPIC ALGORITHMS SPECIFIC TO LOPINAVIR/RITONAVIR OUTPERFORM NONSPECIFIC LISTS OF PI MUTATIONS IN PREDICTING VIROLOGICAL RESPONSE TO LOPINAVIR/RITONAVIR IN PI-EXPERIENCED PATIENTS Antiviral Therapy 2004;9:S131 M Norton, D Kempf, S Brun, J Omachi, P Cernohous and M King Mutation score algorithms that are LPV/r-specific and based on larger data sets were better predictors of virological response to a LPV/r-based regimen, compared to more general lists of PI-related mutations. Download Session 5 PDF: Abstracts 107 to 134
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| 118 | D4T VIRTUAL PHENOTYPE CAN PREDICT VIROLOGICAL RESPONSE TO D4T MONOTHERAPY AFTER AZT TREATMENT, BUT NOT AT THE CURRENT CUTOFF Antiviral Therapy 2004;9:S132 NS Shulman1, M Hughes2, MA Winters1, J Delgado1, TC Merigan1, DA Katzenstein1 d4T VPT can predict response to d4T monotherapy in AZT experienced patients, but the current cutoff of 1.8 is too high. A cutoff of 1.0 or greater was the most predictive in this cohort. Download Session 5 PDF: Abstracts 107 to 134
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| 119 | GENOTYPIC PREDICTORS OF A RESPONSE TO DIDANOSINE MONOTHERAPY IN ZIDOVUDINE-EXPERIENCED PATIENTS Antiviral Therapy 2004;9:S133 J Delgado1, M Hughes2, MA Winters1, K Smith1, TC Merigan1, DA Katzenstein1 and NS Shulman1 The presence of a 215Y/F was generally associated with non-response to ddI monotherapy. Download Session 5 PDF: Abstracts 107 to 134
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| 120 | AN ADDITIVE/SUBSTRACTIVE GENOTYPIC SCORE AS A DETERMINANT OF THE VIROLOGICAL RESPONSE TO DIDANOSINE (DDI)-CONTAINING REGIMENS IN NRTI-EXPERIENCED PATIENTS Antiviral Therapy 2004;9:S134 S Capdepont1, V Aurillac-Lavignolle2, M Faure1, M Dupon3, P Morlat3, JM Ragnaud3, G Chêne2, H Fleury1, B Masquelier1 and the GECSA We could define and validate a genotypic score predictive of the virological response to ddI-including regimens in NRTI-experienced patients. This additive/substractive model enabled us to take into account the negative or positive effects of RT substitutions on VR. Download Session 5 PDF: Abstracts 107 to 134
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| 121 | COMPARISON OF HIV-1 VIRAL LOAD AND RESISTANCE GENOTYPING BETWEEN FROZEN PLASMA AND A NOVEL DRIED PLASMA TRANSPORTATION MATRIX Antiviral Therapy 2004;9:S135 RM Lloyd Jr1, DA Burns1, AM Thompson1, RL Mathis1, M Holodniy2, JT Huong1, A De La Rosa3, B Yen-Lieberman4, W Armstrong4, A Taege4, DR McClernon5 and PM Feorino1 Viral load values for frozen and SampleTanker dry specimens are within acceptable ranges for clinical care or research purposes. Genotype accuracy and reproducibility for SampleTanker are comparable to published data in the TruGene™ product insert. Use of the SampleTanker plasma matrix gives adequate results for quantitative and qualitative clinical specimen testing. SampleTanker matrix is a useful replacement for frozen specimens and will significantly diminish transportation-associated costs for standard patient diagnostics and clinical trial studies worldwide. Download Session 5 PDF: Abstracts 107 to 134
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| 122 | DEVELOPMENT OF A DNA MICROARRAY TO DETECT HCV AND HIV DRUG RESISTANCE Antiviral Therapy 2004;9:S136 M Kozal and J Chiarella A microarray assay can determine the sequence of the HCV genotype 1a NS5A and NS5B genes and HIV-1 pol concurrently in a single hybridization microarray assay. This tool may greatly facilitate investigations into the genetic determinants of IFN and RBV resistance in HCV and the effect of HCV therapy on HIV genes in coinfected patients. Download Session 5 PDF: Abstracts 107 to 134
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| 123 | PERFORMANCE OF A COMMERCIAL GENOTYPING SYSTEM FOR ANALYSIS OF DIVERSE HIV-1 STRAINS Antiviral Therapy 2004;9:S137 N Marlowe1, J Hackett Jr3, SP Cunningham2, B Drews1, P Swanson3, C Brennan3, SG Devare3, L Zekeng4, L Kaptue5 and SH Eshleman2 The ViroSeq system can be used to analyse plasma samples with diverse HIV-1 strains. Availability of this genotyping system should facilitate studies of HIV-1 drug resistance in non-subtype B strains of HIV-1. Download Session 5 PDF: Abstracts 107 to 134
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| 124 | A PROPOSED APPROACH TO PROFICIENCY TESTING FOR HIV-1 DRUG RESISTANCE GENOTYPING Antiviral Therapy 2004;9:S138 JW Bremer1, DJ Brambilla2, S Granger2, DD Huang1 and MA Ussery3 Parameters and a scoring paradigm for evaluating HIV gene sequencing have been identified. We propose to evaluate laboratory performance, i.e. proficiency, by; 1) the total number of disagreements between bases of the submitted sequence and the CS; 2) the quality of a sequence excluding mixture disagreements and missing data; and 3) the total number of disagreements between amino acids at resistance- associated codons in the submitted sequence and the CS. Download Session 5 PDF: Abstracts 107 to 134
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| 125 | REPEATED CONTROL ASSESSMENTS FOR RESISTANCE GENOTYPING IMPROVE PERFORMANCES OF LABORATORIES Antiviral Therapy 2004;9:S139 A Ruffault1, ML Chaix2, B Masquelier3, J Izopet4, V Calvez5, D Descamps6, AG Marcelin5, C Tamalet7, S Yerly8, F Brun-Vèzinet6, D Costagliola9 and the ANRS Resistance Study Group Repeated quality control assessments increase genotyping performances of virology laboratories. Quality control assessments must include HIV negative control, specimens with low viral load, specimen in duplicate, samples with high number of resistance mutations and non-B subtypes, at least in countries with high prevalence of non-B subtype infections. Download Session 5 PDF: Abstracts 107 to 134
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| 126 | DETECTION AND CHARACTERIZATION OF RARE DRUG RESISTANT HIV-1 RT VARIANTS USING A SENSITIVE PHENOTYPIC ASSAY Antiviral Therapy 2004;9:S140 DV Nissley1,3, J Julias1,3, J Mellors2, S Hughes3 and J Strathern3 The TyHRT system is a sensitive phenotypic assay that detects known and novel HIV-1 RT variants that contribute to NNRTI resistance. The system can be used to characterize the phenotypes of unusual RT variants and may be useful for identifying alleles that contribute to hypersusceptibility. Download Session 5 PDF: Abstracts 107 to 134
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| 127 | TROPISM DETERMINATION AND PERFORMANCE OF PHENOSCRIPT™ HIV-1 ENTRY INHIBITOR ASSAY Antiviral Therapy 2004;9:S141 JL Labernardiere1,2, S Lebel-Binay1, JL Faudon1, A Holguin3, V Soriano3 and A Cheret1 Phenoscript™ Envelope assay is a useful tool for measuring the susceptibility of B and non-B HIV-1 viruses to entry inhibitors. Download Session 5 PDF: Abstracts 107 to 134
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| 128 | SIMULTANEOUSLY ASSESSING ASSOCIATION AMONG BASELINE FACTORS AND TIME TO VIROLOGICAL FAILURE AND OFF-TRACK IN ACTG 398 Antiviral Therapy 2004;9:S142 G DiRienzo1, V DeGruttola1, S Hammer2 and J Mellors3 Using valid statistical approaches for subgroup analyses with multiple endpoints, we identify baseline characteristics associated with better (subgroup (Y)) or worse (subgroups (C) and (O)) response to treatment regimens in ACTG 398; subgroup (C) responded favourably to an additional PI. These results also suggest that the empirically derived endpoint time to OT better correlates with known determinants of poor virological response than time to VF. Download Session 5 PDF: Abstracts 107 to 134
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| 129 | DEVELOPMENT OF A TIPRANAVIR MUTATION SCORE: ANALYSIS OF PROTEASE MUTATIONS ASSOCIATED WITH PHENOTYPIC DRUG SUSCEPTIBILITY AND ANTIVIRAL RESPONSE IN PHASE II CLINICAL TRIALS Antiviral Therapy 2004;9:S143 VM Kohlbrenner1, DB Hall1, J Schapiro2, J Baxter3, CA Boucher4, M Frank1, S McCallister1 and DL Mayers1 TPV requires the accumulation of multiple protease mutations among 17 codons to predict decreased phenotypic susceptibility or decreased antiviral responses. L90M does not appear to be related to decreased TPV susceptibility, but when combined with mutations at codons 82 or 84 it may be an indicator of multiple associated protease mutations. A TPV mutation score is being developed to relate protease mutations to decreased TPV susceptibility or reduced antiviral responses to TPV/r-containing regimens. Download Session 5 PDF: Abstracts 107 to 134
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| 130 | SENSITIVITY OF PHENOTYPIC ANALYSES FOR DETECTION OF K65R OR M184V IN MIXTURES WITH WILD-TYPE HIV-1 Antiviral Therapy 2004;9:S144 MR Underwood1, LL Ross1, DM Irlbeck1, P Gerondelis1, MH StClair1, L Trinh2, N Parkin2 and ER Lanier1 Phenotypic testing can be advantageous for identifying non-algorithmic resistance and identifying mutational interactions (e.g. M184V decreasing resistance to tenofovir, stavudine, and zidovudine). However, the level of tenofovir and lamivudine resistance may be underestimated when K65R and/or M184V are present as mixtures. For patients experiencing early tenofovir/lamivudine containing regimen failure, phenotypic information in the absence of accompanying genotypic data should be interpreted with caution. These data emphasize the value of combined genotypic and phenotypic analyses. Download Session 5 PDF: Abstracts 107 to 134
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| 131 | CHARACTERIZATION OF NEVIRAPINE RESISTANCE MUTATIONS USING RT-PCR AND DNA SEQUENCING METHODS IN A MOTHER-INFANT COHORT FOLLOWING SINGLE DOSE NEVIRAPINE Antiviral Therapy 2004;9:S145 S Loubser1, G Sherman2, C Chezzi1, S Jones2, S Cohen1, A Puren3 and L Morris1 The ‘in-house’ assay amplified 87.8% (n=189) of samples, including subtype A and C subtypes and showed improved sensitivity compared to Viroseq, probably due to the use of a nested PCR. The most common resistance mutations detected were K103N and Y181C. These data confirm earlier reports that single dose NVP is associated with the selection of high-level resistance mutations in HIV-1 subtype C infected populations. Download Session 5 PDF: Abstracts 107 to 134
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| 132 | NEW GENOTYPIC SCORE COMPRISING MUTATIONS IMPACTING NEGATIVELY AND POSITIVELY THE VIROLOGICAL RESPONSE TO DIDANOSINE IN TREATMENT-EXPERIENCED PATIENTS FROM THE RANDOMIZED DIDANOSINE ADD ON JAGUAR STUDY Antiviral Therapy 2004;9:S146 AG Marcelin1, P Flandre2, J Pavie3, N Schmidely4, M Wirden1, O Lada1, D Chiche4, MC Bernard4, JM Molina3 and V Calvez1 Genotypic score (M41L + L74V + D67N + K219Q/E + T215Y/F + T69D – K70R – M184V/I) is a better predictor than a score including only mutations impacting negatively the virological response to didanosine. Download Session 5 PDF: Abstracts 107 to 134
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| 133 | CHANGES IN GENOTYPIC RESISTANCE PATTERNS FOR SQV, LPV AND APV WITH RISING PHENOTYPIC CUT-OFF LEVELS: ANALYSIS OF TORO 1/2 DATABASE Antiviral Therapy 2004;9:S149 K Tsai, A Hill, P Ravindran, G Heilek-Snyder, C Su and S Chiu Using a large database of highly HAART experienced patients; statistical methods highlight amino acid positions in protease that appear at higher phenotypic changes (fold change of 10 or more) where loss of susceptibility to PIs has been observed in the clinic. Download Session 5 PDF: Abstracts 107 to 134
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| 134 | DEVELOPMENT OF A NEW GENOTYPIC RESISTANCE ASSAY INVOLVING THE ENTIRE GP41 SEQUENCE FOR EVALUATING RESISTANCE TO ENFUVIRTIDE Antiviral Therapy 2004;9:S150 SL Walmsley1, MR Loutfy2, JM Raboud1, R Saskin1, F Smaill3, D Rouleau4, JS Montaner5, B Trottier6, J Gill7, W Schlech8, K Gough1, A Rachlis1, B Cameron9, N Lapointe10 and PR Harrigan5 A new gp41 genotypic resistance assay assessing the entire AA sequence has been successfully developed. Conserved and polymorphic regions of gp41 with little clinical significance were determined. New gp41 mutations which are likely clinically relevant were identified. Download Session 5 PDF: Abstracts 107 to 134
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Session 6: Clinical Implications of Resistance Abstracts 135 thru 166, Pages S151 to S182 |
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| 135 | RISK OF DEVELOPMENT OF DRUG RESISTANCE IN PATIENTS STARTING ANTIRETROVIRAL THERAPY WITH THREE OR MORE DRUGS IN ROUTINE CLINICAL PRACTICE Antiviral Therapy 2004;9:S151 AN Phillips1, D Dunn2, C Sabin1, A Pozniak3, R Matthias2, AM Geretti4, J Clarke5, D Churchill6, I Williams1,7, T Hill1, H Green2, K Porter2, G Scullard5, M Johnson4, P Easterbrook8, R Gilson1,7, M Fisher6, C Loveday9, B Gazzard3 and D Pillay1, for the UK HIV Drug Resistance Database and UK CHIC Groups In routine practice, rates of virological failure and of resistance development in patients who started ART with three or more drugs are appreciable, emphasizing the need for new antiretrovirals over the coming years. Download Session 6 PDF: Abstracts 135 to 166
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| 136 | ABSENCE OF SELECTION OF RESISTANT VARIANTS DURING THE EARLY PHASE OF THERAPY WITH LOPINAVIR/RITONAVIR (LPV/R) AND EFAVIRENZ (EFV) (BIKS STUDY) Antiviral Therapy 2004;9:S152 V Ferré, C Allavena, E André-Garnier, C Rabreau, F Raffi and the BIKS Study Group Despite a low genetic barrier to resistance, EFV does not select NNRTI-resistance mutations in patients having a SVR on treatment with EFV and LPV/r. Download Session 6 PDF: Abstracts 135 to 166
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| 137 | KINETICS OF THE PLASMA VIRAL LOAD AND RESISTANCE MUTATIONS IN NAÏVE PATIENTS AFTER INITIATION OF NNRTI OR BOOSTED PI-CONTAINING HAART Antiviral Therapy 2004;9:S153 C Torti1, E Quiros-Roldan1, F Gargiulo2, N Manca2, F Moretti1, A Patroni1, V Tirelli1, P Nasta1, S Casari1 and G Carosi1 for the Si.S.Ther. Study Group of the MASTER Cohort In this pilot study, despite similar initial potency of the two regimens, resistance mutations were observed during the initial phase of the pVL decrement using sensitive method for minority subspecies. If de-novo emergence of these mutations is confirmed by more specific methods (e.g. real time PCR), their impact on the virological outcome needs to be ascertained over long-term follow-up. Download Session 6 PDF: Abstracts 135 to 166
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| 138 | ESTIMATION OF PHENOTYPIC CLINICAL CUTOFFS FOR VIRTUALPHENOTYPE™ THROUGH META ANALYSES OF CLINICAL TRIAL AND COHORT DATA Antiviral Therapy 2004;9:S154 LT Bacheler1, B Winters2, D Nauwelaers1, A Rinehart2, M McGregor3, R Harrigan4, M Perez-Elias5, M Miller6, S Emery7, F van Leth8, P Robinson9, JD Baxter10 and A Pozniak11 The assay-specific CCO defined in this study, although preliminary, apply a consistent approach to multiple drugs and a heterogeneous population of HAART treated subjects. Cutoff definitions based on fractions of the effect range are applicable to diverse patient populations. Download Session 6 PDF: Abstracts 135 to 166
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| 139 | DOES DRUG CLASS MULTI-RESISTANCE AFFECT SURVIVAL? ANALYSIS FROM A COHORT OF HIV PATIENTS WHO EXPERIENCED TREATMENT FAILURE Antiviral Therapy 2004;9:S155 M Zaccarelli, V Tozzi, P Lorenzini, F Forbici, MP Trotta, U Visco-Comandini, C Gori, E Boumis, MC Bellocci, R Bellagamba, R D’Arrigo, G Liuzzi, P Narciso, CF Perno and A Antinori Even in the era of highly effective antiretroviral treatments detection of drug class multi-resistance, if extended to ≥2 classes, is related to poorer clinical outcome, and represents a powerful risk-marker of disease progression and death. Download Session 6 PDF: Abstracts 135 to 166
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| 140 | PREVIOUSLY UNCLASSIFIED MUTATIONS AT POSITIONS ASSOCIATED WITH ANTIRETROVIRAL DRUG RESISTANCE Antiviral Therapy 2004;9:S156 SY Rhee1, L Hurley2, A Zolopa1, WJ Fessel2, DP Nguyen2, S Slome2, S Smith2, D Klein2, M Horberg2, J Flamm2, S Follansbee2 and RW Shafer1 Previously unclassified mutations at drug resistance positions occur frequently. Further studies are needed to determine whether the phenotypic impact of these mutations is similar to the known mutations at the same positions. Download Session 6 PDF: Abstracts 135 to 166
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| 141 | VIRAL LOAD IN PATIENTS FAILING THERAPY: IS IT THE TYPE OF MUTATION OR THE TOTAL NUMBER OF MUTATIONS THAT MATTER? Antiviral Therapy 2004;9:S157 N Machouf, B Trottier, R Thomas, JP Routy and MA Wainberg These results suggest that in addition to certain mutations such as M184V/I, K70R or D30N, the number of major mutations is an important determinant of VL in patients failing therapy. These findings have implications for switching or maintaining a suboptimal therapy in patients failing RT and protease inhibitor containing regimen. Download Session 6 PDF: Abstracts 135 to 166
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| 142 | RISK OF DEVELOPING SELECTED DE NOVO RESISTANCE MUTATIONS DURING STRUCTURED THERAPY INTERRUPTION (STI) IN CHRONIC HIV-1 INFECTION Antiviral Therapy 2004;9:S158 M Arnedo1, F García2, C Gil1, P Castro2, JL Blanco2, JM Miró2, T Pumarola1 and JM Gatell2 26% of patients participating in STI protocols selected resistance mutations that were already present before being recruited in about half of them. Among NNRTI and 3TC recipients the percentage was 23% and 50% and again, in both cases, selected mutations were already present before being recruited in about half of them. Download Session 6 PDF: Abstracts 135 to 166
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| 143 | BASELINE PREDICTORS AND VIROLOGICAL OUTCOME IN SUBJECTS DEVELOPING MUTATIONS DURING INTERMITTENT HAART Antiviral Therapy 2004;9:S159 L Palmisano1, M Giuliano1, MF Pirillo1, CM Galluzzo1, M Andreotti1, R Bucciardini1, E Nicastri2, V Fragola1, M Andreoni3 and S Vella1 1. The present results show that in subjects with ‘undetectable’ viraemia (measured with currently used assays), actual levels of HIV RNA, as well as the presence of mutations in proviral DNA, are predictors of resistance during STIs. 2. A correlation exists between actual levels of viraemia at baseline and presence of archived mutations. 3. Virological response to therapy reinstitution is jeopardized by the emergence of mutations during STI. Download Session 6 PDF: Abstracts 135 to 166
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| 144 | TREATMENT INTERRUPTION IN PATIENTS WITH MULTIPLE FAILURES TO ARV THERAPY: CAN THE CONTROVERSY BE SOLVED? Antiviral Therapy 2004;9:S160 D Costagliola1, C Duvivier1,2, V Calvez3, S Dominguez1,2, M Wirden3, J Ghosn1, C Delaugerre3, G Peytavin4 and C Katlama1,2 In the management of multiple failures, complete re-occurrence of wild-type viruses appears deleterious. TI should not be used unless HIV has kept some sensitivity to available drugs. Download Session 6 PDF: Abstracts 135 to 166
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| 145 | PATTERNS OF CD4 AND HIV-1 RNA CHANGE DURING STRUCTURED TREATMENT INTERRUPTION IN PATIENTS WITH MULTIDRUG-RESISTANT HIV (CPCRA 064 MDR-HIV STUDY) Antiviral Therapy 2004;9:S161 J Lawrence1, K Huppler Hullsiek2, D Abrams1, B Schmetter3, J Baxter4 and the CPCRA 064 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) Although most patients with MDRHIV show the typical response of CD4 decline and HIV RNA rebound during treatment interruption, discordant CD4 and HIV RNA responses are not uncommon. We identified a group of patients who had relatively stable CD4 counts during treatment interruption. These patients had significantly lower baseline CD4 counts and tended to have greater baseline resistance and less reversion of resistance compared with patients who had a rapid CD4 decline. Download Session 6 PDF: Abstracts 135 to 166
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| 146 | DETERMINANTS OF REPLICATION CAPACITY (RC) IN HIV-1 ISOLATES FROM ANTIRETROVIRAL (ART)-EXPERIENCED ADULTS FAILING A PI-BASED REGIMEN, AND RELATIONSHIP OF RC WITH HIV-1 RNA AND CD4 COUNTS Antiviral Therapy 2004;9:S162 R Haubrich1, J Hernandez2, M Bates3, M Thompson4, D Margolis5, K Pappa2, L Yau2 and R Schooley6 Phenotypic resistance (number of agents) and genotypic resistance (the M184V mutation, TAMs and PR mutations at 82) were associated with decreased RC in ARV-experienced subjects. RC was directly correlated with viral load and inversely correlated with CD4 counts, suggesting that decreased RC due to viral resistance may be associated with preservation of CD4 numbers. Download Session 6 PDF: Abstracts 135 to 166
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| 147 | IMPACT OF THREE OR FOUR PROTEASE MUTATIONS AT CODONS 33, 82, 84 AND 90 ON 2 WEEK VIROLOGICAL RESPONSES TO TIPRANAVIR, LOPINAVIR, AMPRENAVIR AND SAQUINAVIR ALL BOOSTED BY RITONAVIR IN PHASE 2B TRIAL BI 1182.51 Antiviral Therapy 2004;9:S163 DL Mayers1, J Leith1, H Valdez1, CA Boucher2, J Schapiro3, J Baxter4, S McCallister1, VM Kohlbrenner1, J Scherer1 and DB Hall1 In this randomized study of treatment experienced HIV-positive patients, the presence of three or four mutations at codons 33, 82, 84 and 90 was associated with median viral load responses of <0.5 log10 copies/ml for ritonavir-boosted LPV, APV and SQV. TPV/r remained the most active boosted PI with a median 2 week viral load reduction of 1.2 log10 copies/ml. Download Session 6 PDF: Abstracts 135 to 166
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| 148 | MINOR PROTEASE INHIBITOR RESISTANT VARIANTS, EVEN AT VERY LOW LEVEL, CAN DRIVE THE FAILURE RESISTANCE MUTATIONS PROFILES OF SUBSEQUENT PROTEASE INHIBITOR-BASED REGIMEN Antiviral Therapy 2004;9:S164 AG Marcelin, B Roquebert, I Malet, M Wirden, C Katlama and V Calvez At the time of nelfinavir failure, mutation D30N was rarely associated to other major PI resistance mutations. At the clonal level, the presence of minor species containing other PI resistance mutations, even at very low level, can explain the evolution of resistance pathways involved in the failures to subsequent other PI-based regimen. Download Session 6 PDF: Abstracts 135 to 166
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| 149 | VIROLOGICAL RESPONSE FOLLOWING SWITCH TO ATAZANAVIR/RITONAVIR IN RELATION TO BASELINE GENOTYPIC RESISTANCE PATTERN Antiviral Therapy 2004;9:S165 S Yerly, S Vora, H Günthard, P Vernazza, H Furrer, A Zinkernagel, B Hirschel, L Perrin and the Swiss HIV Cohort Study (SHCS) Despite mutations associated with ATV-resistance, we have observed significant virological response in protease inhibitor and nucleoside reverse transcriptase-experienced patients who were switched to a genotype guided optimised salvage regimen containing boosted ATV. Download Session 6 PDF: Abstracts 135 to 166
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| 150 | REVERSE TRANSCRIPTASE MUTATION M184V DELAYS THE SELECTION OF THYMIDINE-ANALOGUE MUTATIONS IN CHILDREN INFECTED WITH SUBTYPE-C HIV-1 Antiviral Therapy 2004;9:S166 D Averbuch1, JM Schapiro2, D Engelhard1, S Gradstein3, G Gottesman4, E Kedem5, M Einhorn6, G Grisaru-Soen7, M Ofir8, F Milguir9, H Rudich9, D Ram9 and Z Grossman9 In this subtype C paediatric population, a treatment strategy of initiating and maintaining a thymidine analogue + lamivudine based regimen (regardless of incomplete viral suppression), compared to other initial regimens and/or frequent drug changes, resulted in reduced accumulation of TAMs. This is likely due to enhancement of a TAM-sparing effect of M184V in subtype-C infection. In small children, with antiretroviral therapy initiated soon after birth and complete adherence difficult to achieve, a conservative regimen resulting in low rates of resistance merits further investigation. Download Session 6 PDF: Abstracts 135 to 166
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| 151 | GENOTYPIC REVERSE TRANSCRIPTASE EVOLUTION IN ANTIRETROVIRAL-EXPERIENCED PATIENTS RECEIVING TENOFOVIR DF-CONTAINING REGIMENS Antiviral Therapy 2004;9:S167 B Masquelier1, D Descamps2, L Bocket3, C Tamalet4, M Wirden5, B Montes6, J Izopet7, P Palmer8, V Schneider9, A Ruffault10, V Ferre11, G Peytavin2, A Trylesinski12, M Miller13, F Brun-Vezinet2, D Costagliola14 and the ANRS AC11 Resistance Study Group In antiretroviral-experienced patients receiving TDF-containing regimens, minimal RT genotypic changes were shown despite continuous HIV-1 replication. Cross-resistance mediated by the baseline NRTI resistance mutations appears to be responsible for enabling continued replication. Download Session 6 PDF: Abstracts 135 to 166
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| 152 | CLINICAL AND GENOTYPIC CORRELATES OF K65R MUTATION IN AN UNSELECTED COHORT OF HIV-INFECTED PERSONS NAÏVE FOR TENOFOVIR Antiviral Therapy 2004;9:S168 MP Trotta, S Bonfigli, F Ceccherini Silberstein, D Zinzi, R D'Arrigo, F Soldani, M Zaccarelli, P Marconi, U Visco Comandini, E Boumis, F Forbici, V Tozzi, P Narciso, CF Perno and A Antinori 1) In antiretroviral-experienced patients, selection and sequencing of the best nucleoside- backbone should be based on patients' clinical history and genotypic test; 2) caution should be used in starting TDF in patients who are failing an abacavircontaining regimen; 3) longer exposure to lamivudine and presence of M184V seems protective for K65R suggesting the utility to incorporate lamivudine in TDF-based regimens; 3) K65R was inversely associated with TAMs indicating that these patterns could represent antagonistic ways of viral evolution; 4) the strong association between K65R and Q151M-complex confirm the utility of performing systematically GRT in therapy failure before initiation of TDF; 3) since nucleoside and non-nucleoside inhibitors bind to different sites on reverse transcriptase in a non-exclusive way, cross-resistance should be further investigated. Download Session 6 PDF: Abstracts 135 to 166
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| 153 | SELECTION OF THE K65R MUTATION IN PLASMA AND PBMCS OF HIV-2-INFECTED PATIENTS RECEIVING TENOFOVIR-CONTAINING REGIMEN Antiviral Therapy 2004;9:S169 D Descamps1, F Damond1, S Matheron1, G Peytavin1, S Delarue1, P Campa1, G Collin1, S Pueyo2, G Chêne2, F Brun-Vézinet1 and the French ANRS HIV-2 Cohort Study Group As reported in HIV-1, K65R mutation emerges after a short TDF exposure in HIV-2- infected patients. The K65R substitution was not selected in the patient with virus harbouring thymidine analogues mutations at baseline, as also described in HIV-1. Phenotypic and clinical studies on a large number of patients are needed to determine the relevance of this substitution in HIV-2-treated patients. Download Session 6 PDF: Abstracts 135 to 166
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| 154 | DEVELOPMENT OF RESISTANCE MUTATIONS IN PATIENTS RECEIVING SALVAGE THERAPY WITH TENOFOVIR Antiviral Therapy 2004;9:S170 J Grebely, J Raffa and B Conway Virological response to TDF in salvage therapy was poorer in patients on single class regimens, and was associated with the development of K65R. Certain baseline mutation patterns at codons 67 and 70 may protect against its development and may help identify a subgroup of patients in whom TDF resistance may be slower to develop after its initiation in salvage therapy. Download Session 6 PDF: Abstracts 135 to 166
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| 155 | DYNAMIC OF SELECTION OF THE K65R AND M184V/I MUTATIONS IN PATIENTS ENROLLED IN TONUS TRIAL Antiviral Therapy 2004;9:S171 C Delaunay1, D Descamps1, R Landman1, G Peytavin1, P Flandre2, A Trylesinski3, G Collin1, A Benalycherif1, F Monchecourt3, F Brun-Vézinet1 and the Tonus Trial Study Group (IMEA 021) In this population of naïve patients receiving abacavir/lamivudine/tenofovir, M184V/I mutation was selected more frequently at W4 than K65R mutation. However, K65R mutation can also be detected early. These preliminary results did not show that these mutations are initially carried by the same genome. However, despite optimized PCR conditions in order to minimize recombination, this phenomenon cannot be excluded. Download Session 6 PDF: Abstracts 135 to 166
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| 156 | EARLY VIROLOGICAL FAILURE AND OCCURENCE OF RESISTANCE IN NAÏVE PATIENTS RECEIVING TENOFOVIR, DIDANOSINE AND EFAVIRENZ Antiviral Therapy 2004;9:S172 D Podzamczer1, E Ferrer1, JM Gatell2, J Niubo1, D Dalmau3, A Leon2, H Knobel4, D Iniguez1 and I Ruiz1 A high early virological failure rate was found in a group of naïve patients with advanced disease and high VL, treated with tenofovir/didanosine/ efavirenz. A peculiar resistance pattern was detected including G190E/S and L74V/I in most patients. It should be elucidated if an interference between tenofovir and didanosine or other mechanisms, are involved. Download Session 6 PDF: Abstracts 135 to 166
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| 157 | BASELINE GENOTYPIC ANALYSIS OF TREATMENT-NAÏVE PATIENTS TAKING TENOFOVIR DF (TDF) OR STAVUDINE (D4T) IN COMBINATION WITH LAMIVUDINE (3TC) AND EFAVIRENZ (EFV) Antiviral Therapy 2004;9:S173 MD Miller1, NA Margot1, JM Waters2, J Harris2, B Lu1 and AK Cheng1 Non-B subtypes and baseline NRTI-associated mutations did not significantly impact treatment response in this study. Primary NNRTI-associated mutations were very rarely observed. A natural polymorphism of V179D was associated with development of V106M and high-level NNRTI resistance. These results suggest that in the absence of primary NNRTI-resistance, baseline NRTI-associated mutations among treatment-naïve patients have a negligible clinical impact through 144 weeks of therapy in these regimens. Download Session 6 PDF: Abstracts 135 to 166
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| 158 | PRE-EXISTING L74V IS A RISK FACTOR FOR VIROLOGICAL NON-RESPONSE AND DEVELOPMENT OF K65R IN PATIENTS TAKING TENOFOVIR DF (TDF) Antiviral Therapy 2004;9:S174 AS Bae1, JM Waters1, NA Margot2, K Borroto-Esoda1 and MD Miller1 As previously observed in clonal analyses of didanosine-failure, the K65R and L74V mutations occur on distinct genomes and appear to represent an unfavoured combination for the virus in vivo. Prior therapy with NRTIs that can select for either L74V or K65R (abacavir, didanosine, and possibly stavudine) can result in a bulk population genotype that shows L74V but does not detect low-level K65R. Subsequent therapy with TDF, an NRTI that selects only for K65R, may result in expansion of a pre-existing K65R mutant and poor virological response. These data may have implications for how NRTIs are sequenced as part of HAART regimens. Download Session 6 PDF: Abstracts 135 to 166
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| 159 | IMPACT OF HIV RESISTANCE MUTATIONS, DRUG RESISTANCE AND VIRAL FITNESS ON ANTIVIRAL ACTIVITY OF TENOFOVIR/ABACAVIR/LAMIVUDINE IN THE ESS30009 STUDY Antiviral Therapy 2004;9:S175 LL Ross1, P Gerondelis1, EG Rouse1, ML Lim1, Q Liao1, BC Wine1, SK Griffith1, MH St Clair1, MS Shaefer1, AE Rodriguez2, JE Gallant3 and ER Lanier1 By week 12, 98% of tenofovir/abacavir/ lamivudine VNR subjects selected for virus with M184I/V/mixtures, 54% had K65R or mixtures, with only modest changes from baseline observed in replicative capacity despite substantial rebounds in viral load. Phenotypic resistance was not as reflective of viral response as genotype. Detection of genotypic resistance at rebound or shortly afterward suggests that the low efficacy may result in part from a low genetic barrier. Clonal analysis indicates resistance arose from distinct viruses with K65R or M184V followed by selection for viruses containing both mutations. Download Session 6 PDF: Abstracts 135 to 166
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| 160 | PERSISTANCE OF NEVIRAPINE-RESISTANT VIRUS AND PHARMACOKINETIC ANALYSIS IN WOMEN WHO RECEIVED INTRAPARTUM NVP ASSOCIATED TO A SHORT COURSE OF ZIDOVUDINE (ZDV) TO PREVENT PERINATAL HIV-1 TRANSMISSION: THE DITRAME PLUS ANRS 1201/02 STUDY, ABIDJAN, CÔTE D'IVOIRE Antiviral Therapy 2004;9:S176 ML Chaix1, DK Ekouevi2, G Peytavin3, F Rouet4, L Bequet2, C Montcho4, I Viho2, P Fassinou5, V Leroy6, F Dabis6, C Rouzioux1 and The Ditrame Plus Study Group NVP concentration analysis showed wide inter-individual variability. Therefore, emergence of NVP-R mutations strongly correlated with a high level of NVP concentration, owing to a prolonged period of viral replication under NVP selective pressure. The clinical follow-up of the cohort confirms the archival of viral resistance. Its impact on the response to treatment for mothers and children should be evaluated. Download Session 6 PDF: Abstracts 135 to 166
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| 161 | THE V106M MUTATION IN TREATMENT FAILURES FROM A RANDOMIZED CONTROLLED TRIAL OF LAMIVUDINE AND STAVUDINE, WITH NEVIRAPINE AND/OR EFAVIRENZ Antiviral Therapy 2004;9:S177 DB Hall1, F van Leth2, P Robinson1, P McKenna3, FWMN Wit2 and JMA Lange2 The V106M mutation is observed in subtype C, almost exclusively in EFV or NVP/EFV treated patients. The mutation which emerged after virological response was associated with return of the viral load to near baseline. The V106M mutation was not associated with CD4 count decline and was not well-sustained. Download Session 6 PDF: Abstracts 135 to 166
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| 162 | SUBSTITUTIONS WITHIN HIV GP41 AMINO ACIDS 36-45 ARE IDENTIFIED AS THE PRIMARY DETERMINANTS FOR LOSS OF IN VITRO SUSCEPTIBILITY TO ENFUVIRTIDE: RESULTS OF DATA MINING ANALYSES OF GENOTYPIC CHANGES IN GP41 IN TORO 1 AND TORO 2 THAT ASSOCIATE WITH CHANGES IN PHENOTYPIC SUSCEPTIBILITY TO ENFUVIRTIDE Antiviral Therapy 2004;9:S178 C Su1, G Heilek-Snyder1, P Ravindran1, T Melby2, S Chiu1 and N Cammack1 Our data mining confirmed aa 36–45 as the only primary resistance predictors for losses of susceptibility to enfuvitide. Other positions were identified as loci for accessory mutations that may increase the level of phenotypic resistance in the presence of the primary mutations. Download Session 6 PDF: Abstracts 135 to 166
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| 163 | LOW LEVELS OF ADHERENCE CONFERS GREATER RISK FOR NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) RESISTANCE THAN PROTEASE INHIBITOR (PI) RESISTANCE Antiviral Therapy 2004;9:S179 DR Bangsberg1, R Gupta2, R Harrigan3, D Guzman1, ED Riley1, R Clark and SG Deeks1 Among participants with low medication adherence, resistance was more common in NNRTI than PI treated individuals. Whereas low-pill burden NNRTI regimens are often advocated for patients at risk for nonadherence, these data suggest that such individuals may be at higher risk for resistance on NNRTI based therapy than PI based therapy. Download Session 6 PDF: Abstracts 135 to 166
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| 164 | A META-ANALYSIS OF THE VIROLOGICAL EFFICACY OF REGIMENS CONTAINING FOUR VERSUS THREE ACTIVE ANTIRETROVIRAL AGENTS AS INITIAL THERAPY FOR HIV-1 INFECTION Antiviral Therapy 2004;9:S180 A Hill This meta-analysis of randomized controlled studies indicates that four drugs do not improve ITT virological efficacy outcomes relative to standard three drug regimens. Four drug regimens cannot be recommended as initial therapy for HIV-1 infection. There may be an upper limit to the antiviral efficacy of HAART using the available three classes of antiretrovirals. Download Session 6 PDF: Abstracts 135 to 166
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| 165 | ANALYSES OF VIROLOGICAL RESPONSE AND ENFUVIRTIDE RESISTANCE THROUGH 48 WEEKS IN THE TORO 1 AND 2 STUDIES Antiviral Therapy 2004;9:S181 T Melby1, R DeMasi1, D Kuritzkes2, G Heilek-Snyder3, M Salgo4, N Cammack3, TJ Matthews1 and ML Greenberg1 Consistent with earlier reports, no correlation was seen between virological response to enfuvirtide and baseline tropism or clade but response trended with lower baseline IC50. Change in susceptibility on treatment correlated significantly with viral load and substitutions in gp41 aa 36–45 and was higher for VF than non-VF patients. The relationship observed between time after discontinuation and enfuvirtide susceptibility agrees with previous findings suggesting that enfuvirtide resistance mutations impair viral fitness in vivo. Download Session 6 PDF: Abstracts 135 to 166
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| 166 | RATE OF VIROLOGICAL FAILURE AND RESISTANCE PROFILES IN PATIENTS TREATED WITH TRIPLE NUCLEOSIDE REGIMENS Antiviral Therapy 2004;9:S182 P Gil, A Barrios, T García-Benayas, L Valer, L Martín-Carbonero, I Maida and V Soriano Virological failure rate is frequent in patients receiving triple nucleoside combinations, particularly in drug-naïve patients and rescue interventions. It is less frequent when prescribed for simplification purposes. The inclusion of AZT seems to reduce the risk of virological failure as well as the chances for selecting K65R Download Session 6 PDF: Abstracts 135 to 166
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