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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
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Session 1: New antiretrovirals Abstracts 1 thru 17, Pages 3 to 14 |
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| 1 | EVALUATING HIV-1 CO-RECEPTOR USAGE AND INHIBITORS OF VIRUS ENTRY 1 USING RECOMBINANT VIRUS ASSAYS Antivir Ther. 2001;6 Suppl 1:3 T Wrin, W Huang, J Yap, S Fransen, EE Paxinos, NT Parkin, JW Whitcomb and CJ Petropoulos In summary, these studies indicate that defining X4, R5 co-receptor tropism and measuring virus entry/fusion inhibitor susceptibility are amenable to testing with recombinant virus assays.  Download Abstracts
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| 2 | THE FUSION INHIBITORS T-20 AND T-1249 DEMONSTRATE POTENT IN VITRO 2 ANTIVIRAL ACTIVITY AGAINST CLADE B HIV-1 ISOLATES RESISTANT TO REVERSE TRANSCRIPTASE AND PROTEASE INHIBITORS AND NON-B CLADES Antivir Ther. 2001;6 Suppl 1:3 P Sista1, T Melby1, U Dhingra2, N Cammack3, P McKenna4, P Dehertogh4 and T Matthews1 These results demonstrate that the in vitro antiviral activities of T-20 and T-1249 are independent of resistance to any of the classes of currently approved ARVs. T-20 and T-1249 also demonstrated antiviral activity against non-clade B virus isolates comparable to activity against clade B viruses. Download Abstracts
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| 3 | BASELINE GENOTYPE AND PRIOR ANTIRETROVIRAL HISTORY DO NOT AFFECT VIROLOGICAL RESPONSE TO T-1249 Antivir Ther. 2001;6 Suppl 1:4 GD Miralles1, R DeMasi1, P Sista1, T Melby1, F Duff2 and T Matthews1 for the T-1249-101 Study Group These results indicate that T-1249 provides dose-related suppression of plasma HIV RNA. The antiviral activity of T-1249 in vivo is unaffected by prior exposure to available ARVs or by multiple resistance mutations to NRTIs, NNRTIs or PIs. Download Abstracts
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| 4 | VAGINAL TRANSMISSION OF HIV-1 IN huSCID MICE: A MODEL FOR THE EVALUATION OF VAGINAL MICROBICIDES Antivir Ther. 2001;6 Suppl 1:4 S Vella, S Di Fabio, G Giannini, C Lapenta, M Spada, A Binelli, E Germinario, P Sestili, F Belardelli and E Proietti Because of its simplicity and practical features compared to other animal models, the vaginal HIV-infected hu-SCID mouse model may prove useful to test the activity of compounds against cellassociated HIV and, possibly, other sexually transmitted diseases. Download Abstracts
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| 5 | EMTRICITABINE: ANTIVIRAL EFFICACY AND LACK OF DEVELOPMENT OF RESISTANCE IN PATIENTS TREATED 1 YEAR FOR CHRONIC HEPATITIS B VIRUS INFECTION PARALLEL RESULTS IN HIV INFECTION Antivir Ther. 2001;6 Suppl 1:5 F Rousseau, L Fang, A Sykes, A Rigney and E Mondou Emtricitabine produced potent and durable viral suppression of HBV, a high rate of loss of e antigen with a low incidence of mutations at the high dose. These results are very encouraging in view of the 14–30% incidence of YMMD mutation observed with lamivudine at 1 year in HBV and close to 90% at 4 years in HIV-infected patients with dual infection. Emtricitabine has a significant potential for the treatment of patients with HIV–HBV co-infection. Download Abstracts
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| 6 | RESISTANCE PROFILES OF SECOND GENERATION HIV PROTEASE INHIBITORS DPC 681 AND DPC 684 Antivir Ther. 2001;6 Suppl 1:5 LT Bacheler1, S Jeffrey1, K Logue1, S Garber1, S Diamond1, R Kaltenbach1, G Trainor1, D Getman2 and S Erickson-Viitanen1 HIV protease inhibitors (PIs) are important components of many HAART regimens. There is now a growing and unmet need for second generation PIs able to inhibit viruses that have developed resistance to some or all of the currently marketed PIs. Two such potential inhibitors, DPC 681 and DPC 684 have been identified and evaluated. Download Abstracts
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| 7 | IN VITRO SELECTION EXPERIMENTS DEMONSTRATE REDUCED DEVELOPMENT OF RESISTANCE WITH TMC120 AND TMC125 COMPARED WITH FIRST GENERATION NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Antivir Ther. 2001;6 Suppl 1:6 M-P de Béthune1, H Azijn1, K Andries2, P Janssen2 and R Pauwels1 In this experimental setting, characterized by high genetic diversity of the virus population, HIV-1 resistant to first generation NNRTIs (nevirapine and efavirenz) was selected very rapidly. Emerging resistant viruses harboured only one mutation. In contrast, emergence of HIV-1 resistant to TMC120 or TMC125 was delayed or did not occur, and usually required the presence of two mutations. Similar experiments with NNRTI-resistant strains are ongoing. Download Abstracts
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| 8 | CHARACTERISTICS OF TENOFOVIR PHENOTYPIC SUSCEPTIBILITY Antivir Ther. 2001;6 Suppl 1:7 MD Miller1, P McKenna2, BA Larder2 and PR Harrigan2 The normal range for biological variability in tenofovir susceptibility among treatment-naïve patients is threefold in the Antivirogram assay. In a clinical panel of nearly 5000 HIV samples representing predominantly treatment-experienced patients, reduced susceptibility to tenofovir beyond the normal range was infrequent and <10-fold in 99% of cases. Reduced tenofovir susceptibility was not closely associated with resistance to any licensed NRTI or NNRTI. These results suggest that the majority of treatment-naïve and treatment-experienced patients have HIV that could be susceptible to tenofovir DF therapy. Download Abstracts
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| 9 | RESISTANCE TO INTEGRATION INHIBITORS: EVOLUTION OF ACTIVE SITE MUTATIONS, RELATIONSHIP TO FITNESS AND ENZYME CO-FACTOR UTILIZATION Antivir Ther. 2001;6 Suppl 1:7 D Hazuda, W Schleif, L Gabryelski, J Grobler, P Felock, K Stillmock, A Espeseth, R Danzeisen, R Danovich, M Miller and M Witmer These studies provide the first evidence that Mg is the relevant divalent cation for integration in vivo, provide additional evidence validating integrase as an important and viable therapeutic target for HIV-1 and suggest fitness is an important factor influencing the acquisition of resistance to these novel antiretroviral agents. Download Abstracts
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| 10 | ANTIVIRAL ACTIVITY OF THE HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) CAPRAVIRINE AGAINST HIV-1 VARIANTS FROM NNRTI-EXPERIENCED PATIENTS Antivir Ther. 2001;6 Suppl 1:8 TN Alexander1, MC Leavitt1, JJ Rudy1, JS Isaacson1, K Hertogs2, BA Larder3 and AK Patick1 Despite the success of combination antiretroviral regimens, many patients experience a loss of viral suppression with subsequent emergence of resistant HIV. Such cases present the need for new antiretroviral agents for use in the treatment of patients resistant to currently available antiretroviral drugs. Download Abstracts
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| 11 | BCH-10618, A NEW HETEROSUBSTITUTED NUCLEOSIDE ANALOGUE AGAINST HIV-1 INFECTION Antivir Ther. 2001;6 Suppl 1:8 Z Gu1, N Nguyen-Ba1, C Ren1, JM De Muys1, B Allard1, MA Wainberg2, P McKenna3, DL Taylor4 and RC Bethell1 BCH-10618 is an effective inhibitor of the replication of wild-type and drug-resistant HIV- 1, and low-level resistance to BCH-10618 emerges slowly in vitro. The promising antiviral and safety profile of this compound in vitro support its further development as an anti-HIV-1 agent. Download Abstracts
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| 12 | THE EFFECT OF MYCOPHENOLIC ACID AND RIBAVIRIN ON THE ANTIVIRAL ACTIVITY OF AMDOXOVIR Antivir Ther. 2001;6 Suppl 1:9 K Borroto-Esoda, D Wakefield, J Jeffrey, F Myrick, G Painter and P Furman The combination of 0.25 µM MPA or 20 µM ribavirin was not cytotoxic to the cells in these assays. In addition, when tested at physiologically relevant concentrations, neither compound demonstrated mitochondrial toxicity, alone or in combination with DAPD or DXG. These data suggest a potential role for the use of IMPDH inhibitors in combination therapy with amdoxovir in the treatment of HIV. Download Abstracts
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| 13 | ANTIVIRAL RESISTANCE AND MECHANISM OF ACTION OF SJ-3366, A NOVEL NON-NUCLEOSIDE INHIBITOR OF HIV-1 AND HIV-2 WITH TWO DISTINCT MECHANISMS OF ACTION Antivir Ther. 2001;6 Suppl 1:10 RW Buckheit Jr1, JA Turpin1, LA Pallansch1, KM Watson1, TL Loftus1, S-G Chung2 and E-H Cho2 The compound SJ-3366 inhibits HIV-1 and HIV-2 through specific inhibition of the reverse transcriptase (RT) of HIV-1 and inhibition of envelope mediated infection events (HIV-1 and HIV-2). Download Abstracts
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| 14 | AMDOXOVIR, A NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR, IS ACTIVE AGAINST HIV MUTANTS RESISTANT TO STANDARD NUCLEOSIDE THERAPY Antivir Ther. 2001;6 Suppl 1:10 J Jeffrey, K Borroto-Esoda, J Feng, S Fleming, P Furman, J Mewshaw, F Myrick, R Qi, L Rimsky and D Wakefield The frequency of HIV-1 mutations in response to antiviral therapy and the resulting drug resistance is of major concern. Amdoxovir, the prodrug of dioxolane guanosine (DXG), is currently in Phase I/II clinical development for the treatment of HIV-1. Download Abstracts
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| 15 | EMERGENCE OF AN UNUSUAL RESISTANCE PROFILE FOR CONOCURVONE, AN EARLY-STAGE INHIBITOR OF HIV-1 REPLICATION Antivir Ther. 2001;6 Suppl 1:11 M Kearney1,2, L Pallansch1, S Cox3, J Coates3 and RW Buckheit Jr1 This study suggests that HIV-1 may escape the activity of fusion inhibitors by introducing specific mutations that alter envelope conformation and receptor usage. Download Abstracts
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| 16 | THE ADDITION OF MYCOPHENOLATE MOFETIL CAN INDUCE DECREASES IN HIV-1 RNA AND INTRACELLULAR DEOXYGUANOSINE TRIPHOSPHATE Antivir Ther. 2001;6 Suppl 1:11 D Margolis1, M Hossain1, L Shaw2 and D Back3 HIV-1 RNA declined a mean of 1.05 log10 copies/ml 3–6 weeks following only the addition or dose escalation of MMF. Plasma MPA levels appear linearly correlated with dose. Measurable changes in the CBV-TP/dGTP ratio appear to be achievable with doses of MMF 50% lower than those used in organ transplantation. Download Abstracts
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| 17 | SENSITIVITY OF HIV-1 TO FUSION INHIBITORS TARGETTED TO THE GP41 FIRST HEPTAD REPEAT INVOLVES DISTINCT REGIONS OF GP41 AND IS CONSISTENTLY MODULATED BY GP120 INTERACTIONS WITH CO-RECEPTOR Antivir Ther. 2001;6 Suppl 1:12 CA Derderyn1, JM Decker1, JN Sfakianos1, Z Zhang1, WA O’Brien2, L Ratner3, GM Shaw1 and E Hunter1 Virus affinity for co-receptor may influence accessibility of fusion inhibitors to their target sequence. These results implicate gp120-coreceptor interactions in driving the complex conformational changes that occur in gp41 to promote fusion and entry. Download Abstracts
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Session 2: Host immunology, HIV pathogenesis and dynamics Abstract 18 thru 40, Pages 15 to 30 |
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| 18 | HIV-1 POPULATION DYNAMICS DURING PASSAGE THROUGH A DRUG-INDUCED BOTTLENECK Antivir Ther. 2001;6 Suppl 1:17 W Resch, KM McGrath, JAE Nelson and R Swanstrom Treatment with a potent antiviral introduces a strong genetic bottleneck. During therapy failure with resistance development, the virus passes through this bottleneck and typically regains its original virus load. We have used the heteroduplex tracking assay to follow the effects of a ritonavir-induced bottleneck in a cohort of subjects with low CD4 cell counts who had ritonavir added to their pre-existing therapy (Abbott Trial M94-247). Download Abstracts
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| 19 | HIV EVOLUTION DURING REPEATED SUPERVISED TREATMENT INTERRUPTIONS FOLLOWING EARLY ANTIRETROVIRAL TREATMENT OF ACUTE INFECTION Antivir Ther. 2001;6 Suppl 1:17 C Tremblay, J Hicks, L Sutton, MP DePasquale, N Kartsonis, F Giguel, E Rosenberg, BD Walker, MS Hirsch and RT D’Aquila In this cohort of HIV-1-infected subjects treated early during acute infection and then undergoing STIs that boosted HIV-specific immunity, an STI did not replenish the amount of HIV in the blood reservoir. Genetic data suggest virus evolution off-drug in some, but not all, subjects. The emergence of RT 184V in one of 14 subjects may have occurred at the start of an STI, suggesting that intracellular lamivudine triphosphate may sometimes persist longer than other drugs. Download Abstracts
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| 20 | REDUCED FITNESS OF HIV-1 THAT ARE RESISTANT TO CXCR4 ANTAGONISTS DUE TO ALTERATIONS IN GP120 FUNCTION Antivir Ther. 2001;6 Suppl 1:18 JA Esté1, ME Quińones-Mateu2, J Barretina1, M Armand-Ugon1, D Schols3, J Blanco1, A Gutierrez1, B Clotet1 and E De Clercq3 Virus-infected cells expressing viral gp120 were prone to cell death with lower viral replication, if infected with AMD3100-resistant, as compared to wild-type, virus strains. AMD3100-resistant virus has reduced fitness, an observation that may have significant implications in the treatment of HIV-infected individuals with this class of anti-HIV agents. Download Abstracts
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| 21 | FITNESS ANALYSIS OF VIRUSES WITH UNIQUE T215D/C/S MUTATIONS FROM TREATMENT-NAĎVE PERSONS: IMPLICATIONS ON PERSISTENCE IN VIVO AND MECHANISMS OF REVERSION OF T215Y Antivir Ther. 2001;6 Suppl 1:18/font> JG García-Lerma1, S Nidtha1, K Blumoff1, H Weinstock2 and W Heneine1 Our findings suggest that reversion of 215Y may be a stepwise process in which several intermediates may be involved, and in which the RT background may favour specific intermediates. The observed efficient replication of all three intermediates suggests that they are stable mutations that may persist in drug-naïve persons. Download Abstracts
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| 22 | INCREASED ABILITY FOR SELECTION OF ZIDOVUDINE RESISTANCE IN A DISTINCT CLASS OF WILD-TYPE HIV-1 FROM DRUG-NAĎVE PERSONS Antivir Ther. 2001;6 Suppl 1:19 JG García-Lerma1, S Nidtha1, K Blumoff1, H Weinstock2 and W Heneine1 Our data demonstrate that the prevalence of HIV-1 with unusual amino acids at codon 215 is substantial in treatment-naďve persons. These viruses are fit and represent a distinct class of HIV-1 that have WT phenotypes but show increased ability for selecting the 215Y mutation. These findings may have clinical implications on the long-term efficacy of regimens containing zidovudine in patients infected with these viruses. Download Abstracts
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| 23 | IMPAIRED FITNESS OF HIV-1 SITE-DIRECTED MUTANTS RESISTANT TO T-20 Antivir Ther. 2001;6 Suppl 1:19 J Lu and DR Kuritzkes This study demonstrated a fitness loss of approximately 10% for NL4-3 carrying T-20 resistance mutations I37T, V38M or D36S/V38M in the HR-1 domain of gp41, which is comparable to the effect on fitness of the M184V mutation for lamivudine resistance. Reduced fitness could contribute to persistent antiviral activity of T-20 in the absence of complete viral suppression. Comparison of baseline and follow-up samples from patients receiving T-20 in ongoing clinical trials may provide confirmation of these in vitro results. Download Abstracts
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| 24 | NATURAL VARIATION OF REPLICATION CAPACITY MEASUREMENTS IN DRUG-NAĎVE/SUSCEPTIBLE HIV-1 Antivir Ther. 2001;6 Suppl 1:20 T Wrin, A Gamarnik, N Whitehurst, J Beauchaine, JM Whitcomb, NS Hellmann and CJ Petropoulos Replication capacity of ‘wild-type’ HIV-1, as measured in a single cycle assay, spanned a broad range , with a mean of 70% of the NL4-3 reference. This distribution is distinct from that observed in drug-resistant viruses. Reduced drug susceptibility, as well as protease inhibitor hypersusceptibility, is associated with reduced replication capacity. Major changes in replication capacity are correlated with significantly impaired RT and protease function. Download Abstracts
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| 25 | ANTIRETROVIRAL RESISTANCE AND RESPONSE TO INITIAL THERAPY AMONG RECENTLY HIV-INFECTED SUBJECTS IN NORTH AMERICA Antivir Ther. 2001;6 Suppl 1:21 SJ Little1, S Holte2, JP Routy3, ES Daar4, M Markowitz5, AC Collier6, RA Koup7, B Conway8, E Connick9, MS Saag10, A Mwatha2, L Corey6, PH Keiser7, M Kilby10, K Dawson11, JM Whitcomb11, NS Hellmann11 and DD Richman1,12 The prevalence of transmitted drug resistant virus has increased significantly for all three classes of drugs as assessed by both phenotype and genotype compared to earlier reports. These results support the use of resistance testing in the initial selection and management of ARV therapy in all newly infected patients. Download Abstracts
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| 26 | PARTIAL VIRAL SUPPRESSION WITH COMBINATION THERAPY IS ASSOCIATED WITH ENHANCED HIV-SPECIFIC CD4 AND CD8 T CELL RESPONSES Antivir Ther. 2001;6 Suppl 1:21 SG Deeks1, E Sinclair2, J Harris2, E Hagos1, L Epling2, R Ronquillo2, B Bredt2, JN Martin1 and JM McCune2 Partial suppression of viral replication with HAART was associated with the presence of both a CD4 and CD8 HIV-specific T cell response. In contrast, untreated HIV infection was associated with a detectable CD8 cell response but a significantly reduced CD4 cell response. The presence of a robust CD4 and CD8 response in patients with partial viral suppression suggests that these cells may contribute to a lower viral set-point in treated patients with drug-resistant viraemia. Download Abstracts
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| 27 | SIGNIFICANCE OF INTERMITTENT LOW-LEVEL PLASMA HIV-1 RNA (BLIPS) DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2001;6 Suppl 1:22 NH Tobin1, Y Wang1, AJ Melvin1, S DeVange1, J McKernan1, GM Ellis1, KM Mohan1, G Pepper1, L Heath1, WE Naugler1, I Beck1, P Lewis2, GH Learn1, JI Mullins1 and LM Frenkel1 Infrequent low-level blips do not result in measurable new mutations and this RNA appears to reflect transcription of latent virus, with insignificant infection of new cells and with minimal evidence of selective pressure. Drug-resistant virus was selected in association with more frequent blips. The clinical significance of plasma blips appears to depend not only their magnitude and frequency but on the selective pressure of the HAART regimen, with potent therapy limiting outgrowth of fit virus. Download Abstracts
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| 28 | CHARACTERIZATION OF HIV-1 EVOLUTION AND DYNAMICS IN PERIPHERAL BLOOD MONONUCLEAR CELLS DURING EFFECTIVE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2001;6 Suppl 1:23 LM Frenkel1, Y Wang1, AJ Melvin1, SM DeVange1, JL McKernan1, GM Ellis1, KM Mohan1, GL Sylva1, L Heath1, M Mahalanabis1, WE Naugler1, I Beck1, P Lewis2, GH Learn1 and JI Mullins1 The majority of long-lived infected PBMC have virus that appear to be from near the time of primary infection. The low-levels of HIV-1 replication detected by various research assays during HAART may not have clinical consequences, or may lead to selection of drug-resistant virus. The potency of the HAART regimen may determine whether viral replication is suppressed sufficiently to prevent the selection of fit drug-resistant virus. Individuals without viral evolution could be identified by marked decreases in HIV-1 DNA copy number and a narrowing of the genetic distance of env and pol to the most recent common ancestor after initiating HAART. Download Abstracts
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| 29 | IMPACT OF AMINO ACID INSERTIONS IN P6 IDENTIFIED IN PATIENTS WITH FAILURE OF COMBINATION ANTIRETROVIRAL THERAPY: ALTERATIONS IN VPR INCORPORATION AND VIRUS MATURATION Antivir Ther. 2001;6 Suppl 1:23 K Suzuki1, G Kaufmann2, D Jones1, S Piller1, L Leas1, C Harris1, P Cunningham1, P Mallon3, M Mukaide2, A Kelleher1,3 and DA Cooper1,3 We describe novel amino acid insertions in the p6-gag. When these insertions are incorporated into recombinant HIV, the resulting virus is characterized by: (i) extremely low RT activity; and (ii) lack of Vpr incorporation. Moreover, sequence analysis of the vpr gene showed amino acid changes in patients but not in the recombinant virus. These data suggest that the p6 insertions may confer an assembly problem in the recombinant virus, perhaps requiring compensatory amino acid changes within Vpr. Download Abstracts
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| 30 | THE THYMUS IS INVOLVED IN EARLY T-CELL REPOPULATION IN ADULT HIV-INFECTED PATIENTS UNDER HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2001;6 Suppl 1:24 JM Franco1, M Leal1, A Rubio1, M Martínez-Moya2, E Ruíz-Mateos1, J Delgado1, A Sánchez-Quijano1 and E Lissen1 These results show evidences of an early thymic rebound involved in T-cell reconstitution after HAART, even in the patients who had a more advanced disease. Download Abstracts
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| 31 | IMMUNOSUPPRESSIVE THERAPY WITH HYDROXYUREA CAN IMPROVE THE EFFICACY OF STRUCTURED TREATMENT INTERRUPTION IN CHRONIC HIV-1 INFECTION: A PILOT RANDOMIZED STUDY Antivir Ther. 2001;6 Suppl 1:25 F García1, M Plana1, GM Ortiz2, C Vidal1, A Cruceta1, M Arnedo1, C Gil1, JI Arostegui1, T Pumarola1, T Gallart1, DF Nixon2, JM Miró1 and JM Gatell1 Immunosuppressive therapy can increase the percentage of patients able to achieve a reasonable control of viral replication (PVL<5000 copies/ml) after cycles of STI and a long period off therapy. Download Abstracts
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| 32 | PERSISTENCE OF HIV-1 RESISTANCE IN LYMPH NODE MONONUCLEAR CELLS DESPITE EFFECTIVE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2001;6 Suppl 1:26 A Lafeuillade1, S Chadapaud1, G Hittinger1, H Khiri2 and P Halfon2 LNMC can produce resistant HIV-1, which was previously selected by sub-optimal combinations, during up to 180 weeks despite an effective HAART regimen. These data are concordant with recent studies showing continuous release of viral RNA by previously infected cells despite effective therapy. Download Abstracts
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| 33 | SEQUENTIAL GENOTYPING OF TREATED PATIENTS IN PLASMA, BLOOD PROVIRUS, SEMINAL PLASMA AND SEMINAL PROVIRUS COMPARTMENTS Antivir Ther. 2001;6 Suppl 1:26 RM Lloyd Jr1, M Tanner2, H Stang1, J Huong1, C Rold1, R Mathis1, D Burns1, L Hough1 and D Dolinger1 Plasma-free virus, blood provirus and seminal plasma-free virus had similar resistance-associated mutations, which reflected past or currently failing drug regimens. Comparison of polymorphic variations not associated with drug resistance in these compartments (polymorphic fingerprint) was highly correlative. These results were consistent in all five patients tested. However, the seminal cell provirus, did not match genotypes obtained from the other genotyped compartments. One patient, who had been sequentially genotyped since 1994 in plasma and blood provirus compartments, had a seminal cell provirus in 2000, which matched the plasma genotype sequence from 1997. Because the cellular component of seminal fluid is genetically different in proviral content from other compartments tested, compartmentalized genotyping in seminal reservoirs relating to mutant transmission and salvage therapy should be examined. Download Abstracts
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| 34 | THE LATENT RESERVOIR OF HIV-1 INFECTION IS MAINTAINED BY HOST TRANSCRIPTION FACTORS Antivir Ther. 2001;6 Suppl 1:27 DM Margolis1,3, G He1, JJ Coull1, C Melander2, VC Rucker2 and PB Dervan2 The latent reservoir of HIV-1 within resting CD4+ T cells is a crucial barrier to eradication of HIV infection. Without activation, the HIV-1 long terminal repeat (LTR) remains repressed within these cells. Host factors LSF and YY1 bind the LTR, recruit histone deacetylase, and inhibit LTR expression. Download Abstracts
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| 35 | LYMPHOID TISSUE VIRAL BURDEN DURATION OF VIRAL SUPPRESSION IN PLASMA Antivir Ther. 2001;6 Suppl 1:27 E Martinez, M Arnedo, V Giner, C Gil, M Caballero, L Alos, F Garcia, C Holtzer, J Mallolas, JM Miro, T Pumarola and JM Gatell In patients with sustained viral suppression in plasma, triple therapy including a HIV-1 protease inhibitor was more potent than triple therapy containing nevirapine or dual therapy with nucleoside analogues to reduce viral burden in lymphoid tissue. Worse response in lymphoid tissue could not be explained by local selection of resistance and was associated with a less durable virological response in plasma. Download Abstracts
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| 36 | SELECTION OF THE M184V MUTATION DURING REPETITIVE CYCLES OF STRUCTURED ANTIRETROVIRAL TREATMENT INTERRUPTIONS Antivir Ther. 2001;6 Suppl 1:28 J Martinez-Picado1, K Morales-Lopetegi1, T Wrin2, J Garcia-Prado1, S Frost3, CJ Petropoulos2, B Clotet1 and L Ruiz1 Consecutive STIs may promote the selection of drug-resistant virus variants present as minor populations prior to STIs. Expansion of the resistant virus population relative to WT takes place during the treatment phase, with absolute increases in resistant viruses occurring during the relatively short time periods without antiretroviral therapy. Download Abstracts
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| 37 | GENETIC AND BIOLOGICAL PROPERTIES OF NON-B SUBTYPES AND RECOMBINANTS HIV-1 VIRUSES CIRCULATING IN SPAIN: EVIDENCE FOR DIFFERENCES IN G/B RECOMBINANTS IN GALICIA Antivir Ther. 2001;6 Suppl 1:28 L Pérez-Alvarez, ML Villahermosa, E Delgado, MT Cuevas, E Vázquez de Parga, MM Thomson, L Medrano and R Nájera In the 69% of these non-B and recombinant HIV-1 strains, the viral phenotype was in agreement with that previously described in B subtype. The most frequent viral phenotype was NSI/CCR5. Inter-subtype recombinants including F subtype in V3 were associated with SI/CXCR4 phenotype. All G/B recombinants resulted SI/CXCR4/MULTITROPIC and unrelated to HIV clinical stage, suggesting that a follow-up is needed to establish whether these findings are associated with a faster progression of the disease in these patients. Download Abstracts
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| 38 | LOW INTRA-HOST DIVERSITY AND SELECTIVE PRESSURE IN HIV-1 PROTEASE GENE SUGGEST A CRUCIAL ROLE FOR PURIFYING SELECTION AT THE TIME OF PRIMARY INFECTION Antivir Ther. 2001;6 Suppl 1:29 A Cenci1, A Bertoli1, S Menzo2, F Erba3, F Marcuccilli3, T Guenci3, G Tambussi4, A Lazzarin4, M Clementi5, R Caliň3 and CF Perno1,3 Intrapatient variation of HIV-protease clones taken from plasma and CSF (therefore representing actively replicating virus) is very limited at the time of primary infection. Differences among different patients were also very limited. Overall data suggest that a purifying selection for the HIV-1 protease sequence predominates upon positive selection or genetic drift in primary infection. Download Abstracts
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| 39 | DECREASED VIRAL FITNESS CONFERRED BY A MULTIDRUG-RESISTANT HIV-1 REVERSE TRANSCRIPTASE HARBOURING A DIPEPTIDE INSERTION BETWEEN CODONS 69 AND 70 Antivir Ther. 2001;6 Suppl 1:30 ME Quińones-Mateu1, M Tadele1, M Parera2, A Mas3, B Clotet2, E Domingo3, L Menéndez-Arias3 and MA Martinez2 These results suggest that selection of compensatory mutations is necessary to improve the replicative fitness of viruses harbouring RT insertions. Comparing these mutation patterns with viral fitness will help to elucidate the role of uncharacterized drug resistance mutations, and their interactions in vivo provoking antiretroviral failure. Download Abstracts
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| 40 | DISTINCT HIV REPLICATION OUTCOME AFTER FOUR STRUCTURED TREATMENT INTERRUPTIONS IN CHRONIC HIV-INFECTED PATIENTS Antivir Ther. 2001;6 Suppl 1:30 L Ruiz, J Martinez-Picado, S Marfil, K Morales-Lopetegi, E Ferrer, J Romeu and B Clotet Controlled exposure to HIV-1 antigen produced an increase in HIV-specific CD8+ T-cell responses in 30% of patients. Moreover, STI strategies may control virus replication in a limited number of patients with chronic HIV infection for at least 3 months. Short STIs were not associated with a significant CD4 decrease or clinical complications. However, a substantial decline in CD4 count may occur after 3 months off therapy. Download Abstracts
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Session 3: Mechanisms of HIV drug resistance Abstracts 41 thru 76, Pages 33 to 57 |
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| 41 | STRUCTURAL BASIS OF HIV RESISTANCE TO ZIDOVUDINE: CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE WITH TEMPLATE:ZIDOVUDINE MONOPHOSPHATE-BLOCKED PRIMER BOUND AT THE DNTP-BINDING SITE Antivir Ther. 2001;6 Suppl 1:35 SG Sarafianos1, AD Clark Jr1, K Das1, P Ilankwnaran2, JM Sayer2, DM Jerina2, PL Boyer3, SH Hughes3 and E Arnold1 To understand the molecular details of the nucleotide-dependent excision mechanism that underlies the resistance of HIV-1 to zidovudine. Download Abstracts
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| 42 | CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE WITH TEMPLATE–PRIMER TERMINATED WITH THE ACYCLIC NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR TENOFOVIR Antivir Ther. 2001;6 Suppl 1:35 S Tuske1, S Sarafianos1, AD Clark Jr1, J Ding1, LK Naeger2, MD Miller2, C Gibbs2, DM Jerina3, S Hughes4 and E Arnold1 The acyclic nature of tenofovir may help to explain its favourable resistance profile. M184V discriminates against the modified ribose ring of lamivudine at the level of incorporation by steric hindrance. A valine at 184 would not interact with the relatively small acyclic phosphonate moiety. Zidovudine resistance involves an excision mechanism. The non-canonical base pairing of tenofovir, together with the acyclic linker, may not provide a substrate favourable for excision. Download Abstracts
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| 43 | STRUCTURAL FEATURES OF NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS IMPORTANT FOR SELECTION OF RESISTANCE MUTATIONS IN HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 2001;6 Suppl 1:36 JL Hammond1, CK Chu2, RF Schinazi3, U Parikh1, E Arnold4, S Serafianos4 and JW Mellors1 These results confirm that NRTI stereochemistry is an important determinant of RT mutant selection and demonstrate for the first time that the base component of NRTIs can impact the RT mutations that are selected. These results provide insight into the structural determinants of NRTI resistance, which should aid in the design of RT inhibitors with improved activity and cross-resistance profiles. Download Abstracts
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| 44 | A MUTATION IN HIV-1 REVERSE TRANSCRIPTASE AT CODON 318 (Y–F) CONFERS HIGH-LEVEL NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR RESISTANCE IN CLINICAL SAMPLES Antivir Ther. 2001;6 Suppl 1:36 SD Kemp1, M Salim1, DK Stammers2, B Wynhoven3, BA Larder1 and PR Harrigan1 The Y318F mutation in the 3´ region of RT can increase NNRTI resistance alone and in combination with other common NNRTI drug resistance mutations. This underlines the importance of including this region in HIV-1 drug resistance assays. Download Abstracts
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| 45 | QUANTIFICATION OF THE EFFECT OF RESISTANCE MUTATIONS ON REVERSE TRANSCRIPTASE ACTIVITY DURING ENDOGENOUS RETROTRANSCRIPTION Antivir Ther. 2001;6 Suppl 1:37 AJ Hance, F Bouchonnet, F Mammano and F Clavel Resistance mutations can markedly affect HIV replicative capacity. Although extensive data are available on the replicative impact of protease mutations, less information is available concerning the defects induced by reverse transcriptase (RT) mutations. Download Abstracts
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| 46 | BLOCKAGE OF TRNA-PRIMED INITIATION OF REVERSE TRANSCRIPTION PROVIDES A MECHANISM FOR THE DIMINISHED FITNESS OF VIRUSES CONTAINING L74V AND M184V MUTATIONS Antivir Ther. 2001;6 Suppl 1:38 M Götte, X Wei, K Diallo, B Marchand, A Schaffer and MA Wainberg Our data suggest that the efficiency of initiation is a crucial determinant for viral replication fitness. It appears that enzymes containing the 74V and/or 184V mutations do not efficiently recognize RNA primers, which may significantly upset reverse transcription. This helps to explain the sustained antiviral effects of abacavir and zidovudine, if one considers additional reductions in the overall rate of reverse transcription through the slow primer unblocking events. Download Abstracts
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| 47 | ANALYSIS OF CLINICAL ISOLATES AND SITE-DIRECTED MUTANTS REVEALS THE GENETIC DETERMINANTS OF DIDANOSINE RESISTANCE Antivir Ther. 2001;6 Suppl 1:38 BA Larder and S Bloor Phenotypic didanosine resistance was less frequent than zidovudine, lamivudine or abacavir. Modest didanosine resistance can be explained by a combination of zidovudine mutations, plus other NAMS (particularly 118I and 69D), or the 74V mutation, but not 184V. High-level resistance is due to the 151M complex. Download Abstracts
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| 48 | COMPARISON OF NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR REMOVAL BY THE ADENOSINE TRIPHOSPHATE-DEPENDENT CHAIN-TERMINATOR REMOVAL MECHANISM Antivir Ther. 2001;6 Suppl 1:39 LK Naeger1, NA Margot1, S Tuske2, SG Sarafianos2, E Arnold2 and MD Miller1 Our results confirm that chainterminator removal is a potential mechanism of NRTI resistance, most notably for zidovudine and stavudine, and that this effect for stavudine and zalcitabine can be moderated by the presence of dNTPs. Tenofovir, didanosine and lamivudine are minimally removed under these conditions, consistent with the minor changes in HIV susceptibility for these drugs associated with zidovudine/thymidine analogue resistance mutations. Crystallographic analysis of HIV-1 RT bound with a tenofovir-terminated primer-template in the post-translocation position suggests that achieving a conformation of tenofovir suitable for nucleotidemediated removal may be disfavoured by the relative flexibility of its acyclic linker and the non-canonical base pairing observed between tenofovir and the template. The inefficient removal of tenofovir by this mechanism of resistance may contribute to the durable anti-HIV activity observed in nucleoside-experienced patients treated with its oral prodrug, tenofovir disoproxil fumarate. Download Abstracts
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| 49 | QUANTITATION OF LOPINAVIR RESISTANCE AND CROSS-RESISTANCE AND PHENOTYPIC CONTRIBUTION OF MUTATIONS SHARED WITH OTHER PROTEASE INHIBITORS Antivir Ther. 2001;6 Suppl 1:40 PR Harrigan1, C Van Den Eynde2 and BA Larder1 Samples with high level phenotypic resistance to other PIs (particularly indinavir and ritonavir) may be expected to have decreased lopinavir susceptibility. A large number of mutations in the HIV protease can be associated with resistance to lopinavir in clinical isolates. Download Abstracts
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| 50 | POLYMORPHISMS IN P6/P6* OF HIV-1 GAG ARE ASSOCIATED WITH HYPERSUSCEPTIBILITY TO PROTEASE INHIBITORS Antivir Ther. 2001;6 Suppl 1:40 N Whitehurst, C Chappey, CJ Petropoulos and A Gamarnik These results demonstrate a strong correlation between PI HS and decreased viral replication capacity. However, the relationship between the two is not well understood. Based on the putative role of p6* in virion maturation, we hypothesize that unusual p6/p6* polymorphisms in the viruses described here alter PR activation, resulting in PI HS and reduced replication capacity. Download Abstracts
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| 51 | HIV-1 NUCLEOTIDE SUBSTITUTION PATTERNS FOR TWO-HIT RESISTANCE MUTATIONS: DETECTION AND FREQUENCY OF INTERMEDIATE AND INFREQUENT AMINO ACIDS SUGGEST GENETIC PATHWAYS TO DRUG RESISTANCE Antivir Ther. 2001;6 Suppl 1:41 F Hassid and A Bakker Several drug-sensitive amino acid substitutions not commonly identified by rules-based algorithms are immediate precursors or revertants in pathways leading to drug resistance. We suggest that detection of revertant amino acids at positions with double substitutions be considered for ruling out drugs in treatment regimens. Download Abstracts
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| 52 | P-GLYCOPROTEIN EXPRESSION ON PRIMARY CELLS AND HIV-1 INFECTIVITY IN VITRO Antivir Ther. 2001;6 Suppl 1:41 MP De Pasquale, DP Olson, JL Hicks, DT Scadden and RT D’Aquila Levels of Pgp in some cell lines are much higher than in PBMCs from uninfected subjects. HIV-1 infectivity may be reduced in some cell lines with supra-physiologic levels of Pgp, but not in cells with more physiological levels. Different viruses vary in ability to infect cells expressing high levels of Pgp. There is a higher level of functional Pgp in CD45RA+ PBMCs, than in the CD45RA– subset. The role of Pgp in HIV pathogenesis requires further study, including better definition of expression in vivo and virus variation in infection of Pgp overexpressing cells. Download Abstracts
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| 53 | MOST MULTIDRUG-RESISTANT HIV-1 REVERSE TRANSCRIPTASE CLONES IN PLASMA ENCODE FUNCTIONAL REVERSE TRANSCRIPTASE ENZYMES Antivir Ther. 2001;6 Suppl 1:42 KM Dupnik, MJ Gonzales and RW Shafer Eighty percent (95% CI: 69–91%) of multidrug-resistant HIV-1 RT clones placed in pNL4-3 resulted in infectious recombinant virus. If one assigns a uniform rate of inactivating mutations throughout the virus genome, the proportion of replication- competent viruses is about 9% (871 bp is 1/11 of the HIV-1 genome; 0.811=0.09). The rate of inactivating mutations, however, may not be uniform and may be different in wild-type virus populations. This study is further evidence that a small proportion of circulating HIV-1 virions are replication-competent, but presents a larger than expected level of viability for the RT. Download Abstracts
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| 54 | MOLECULAR MECHANISM OF I50V HIV-1 PROTEASE RESISTANCE AND CROSS-RESISTANCE TO PROTEASE INHIBITORS Antivir Ther. 2001;6 Suppl 1:43 R Xu, W Andrews, A Spaltenstein, D Danger, W Dallas, L Carter, M Hanlon, L Wright and E Furfine Amprenavir has the most condensed conformation of P81, thus cannot collapse in the I50V protease structure. Indinavir– and nelfinavir–WT complexes have less dense protein ‘footprints’; therefore, greater compensation (condensation) by the I50V protease, resulting in a smaller loss of affinity and less resistance. Inhibitors designed to bind protease with a condensed ‘footprint’ may have unique resistance profiles. Download Abstracts
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| 55 | PRESSURE OF ZIDOVUDINE ACCELERATES THE DISAPPEARANCE OF THE M184V MUTATION IN HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 2001;6 Suppl 1:43 M Götte, K Diallo, B Brenner, M Oliviera, D Moisi and MA Wainberg The reversion of the M184V substitution, in the absence of drug pressure, is most likely attributable to the diminished fitness of the mutant virus. The finding that zidovudine accelerates this reversion points to an additional, significant contribution of the drug. The diminished rate of rescue of zidovudine-terminated DNA synthesis, seen with the mutant enzyme, is likely one of the reasons that accounts for this effect. Our data suggest that hypersensitivity to a particular antiviral drug may cause an accelerated disappearance of the mutation that increased susceptibility to the drug. Download Abstracts
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| 56 | HIV-1 WITH AN INSERTION IN PROTEASE IS DRUG-SUSCEPTIBLE, REPLICATION-COMPETENT AND TRANSMISSIBLE Antivir Ther. 2001;6 Suppl 1:44 RM Grant1,2, JO Kahn2, T Wrin3, B Drews1, J Javier1, M Webb2, CJ Petropolous3 and FM Hecht2 Insertion mutations in HIV-1 protease have been identified in less than 0.1% of drug-experienced subjects. The drug susceptibility, virological response to drug therapy and transmissibility of protease insertion variants are not known. Download Abstracts
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| 57 | RESPONSE TO ANTIRETROVIRAL THERAPY IN HIV-2-INFECTED PERSONS: INCREASED SELECTION OF Q151M MUTATIONS Antivir Ther. 2001;6 Suppl 1:44 C Adje1, R Cheingsong2, JG Garcia-Lerma2, T Roels1, T Chorba1, DR Adams2, RA Otten2, R Respess2, J Nkengasong1 and W Heneine2 The development of multi-nucleoside resistance severely limits the choices of drugs for these HIV-2-infected patients. A better understanding of the basis for the increased selection of Q151M in HIV-2 is needed. Enzymatic analysis of plasma RT activity provides a rapid phenotypic assay for drug susceptibility testing of HIV-2 to RT inhibitors. Download Abstracts
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| 58 | MUTATIONS AT CONSERVED CYSTEINES IN HIGHLY RESISTANT HIV-1 PROTEASE PROMOTE DIMER STABILITY Antivir Ther. 2001;6 Suppl 1:45 RM Kagan1, M Shenderovich2, J Kottalam2, K Ramnarayan2 and PNR Heseltine1 Resistance-associated mutations reduce the stability of the protease dimer and may reduce the affinity of PIs designed against the dimeric enzyme. In highly mutated proteases, an aromatic substitution at residue 95 may increase the stability of the dimer by introducing aromatic ring interactions at the dimer interface. These stabilizing interactions may compensate for the destabilizing affects of multiple resistance mutations. These findings have implications for the design of future PIs that target the protease dimer interface. Download Abstracts
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| 59 | ASSOCIATION OF THE NUCLEOCAPSID-P1 (NC-P1) GAG CLEAVAGE SITE ALANINE TO VALINE MUTATION WITH MUTATIONAL PATTERNS IN HIV PROTEASE PRODUCING PROTEASE INHIBITOR RESISTANCE Antivir Ther. 2001;6 Suppl 1:46 D Kempf, M King, S Brun, J Sylte, T Marsh, K Stewart and E Sun In 116 isolates from PI-experienced patients, the A431V Gag cleavage site mutation was associated with the presence of mutations in HIV protease. However, in this study, the presence of the cleavage site mutation did not appear to impact response to subsequent PI therapy. Download Abstracts
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| 60 | MECHANISMS AND FREQUENCIES OF INSERTION MUTATIONS IN THE PROTEASE AND REVERSE TRANSCRIPTASE GENE OF HIV-1 ISOLATES Antivir Ther. 2001;6 Suppl 1:46 E-Y Kim1, MA Winters1, RL Lobato1, GP Harrison2, R Kagan3 and TC Merigan1 These studies demonstrate that insertion mutations can develop in the HIV-1 pol gene. The start of a bulge in the secondary structure of protease and RT RNA could cause the HIV RT to pause and the weaker base pairing between AUs at the point of pausing would encourage dissociation of the nascent strand from the RNA template. So the nascent cDNA reanneals back 3´ to the point where it dissociated and then inserts the same bases to produce a duplication. This result would explain the mechanism of insertions in the pol gene and contribute to understanding RT processivity, which is important in the development and improvement of antiviral agents. Download Abstracts
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| 61 | ANALYSIS OF MUTATIONAL PATTERNS ASSOCIATED WITH RESPONSE TO LOPINAVIR/RITONAVIR IN MULTIPLE PROTEASE INHIBITOR-EXPERIENCED PATIENTS Antivir Ther. 2001;6 Suppl 1:47 D Kempf, M King, J Isaacson, R Rode, S Brun and E Sun A pattern containing PI mutations at positions 82, 54, 10 plus multiple other mutations at baseline is associated with increased risk of failure of lopinavir/ritonavir therapy in multiple PI-experienced subjects. However, with complicated baseline genotypes of =6 mutations, viral phenotype may provide additional predictive power over genotype. In contrast to the above pattern containing a mutation at position 82, mutations at positions 84 and/or 90 in the context of other mutations are not predictive of failure. Download Abstracts
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| 62 | DIFFERENT DRUG RESISTANCE MUTATIONS MAY LEAD TO THE LOSS OF THE SAME HIV PROTEASE–INHIBITOR CONTACTS Antivir Ther. 2001;6 Suppl 1:48 LC Kovari1, JF Vickrey1, T Lu1, K Heller1, A Smith1, S Draghici1 and TC Merigan2 A systematic study of individual resistance mutations of HIV protease complexes with indinavir, ritonavir and saquinavir supports the hypothesis that drug resistance is associated with the loss of key interactions between the HIV protease and the inhibitor. A surprising observation is that different drug resistance mutations may lead to the loss of the same HIV protease–inhibitor contacts. Mapping of the lost HIV protease–drug interactions is anticipated to assist in the design of the next generation of inhibitors. Download Abstracts
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| 63 | INTERACTION OF HIV-1 PROTEASE AND GAG GENE MUTATIONS IN RESPONSE TO AMPRENAVIR-SELECTIVE PRESSURE EXERTED IN AMPRENAVIR-TREATED SUBJECTS – CONTRIBUTION OF GAG P6 CHANGES L449F AND P453L Antivir Ther. 2001;6 Suppl 1:48 MF Maguire1, S MacManus1, P Griffin1, C Guinea1, W Harris1, N Richards2, J Wolfram2, M Tisdale1, W Snowden1 and J-P Kleim1 Multiple mutations contribute to the appearance and stabilization of I50V-containing amprenavir escape variants. These data suggest an influence of mutations in both protease and Gag on viral replicative capacity and phenotypic resistance to amprenavir. Download Abstracts
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| 64 | PATTERNS OF RESISTANCE TO LOPINAVIR IN PROTEASE INHIBITOR-EXPERIENCED PATIENTS FOLLOWING VIRAL REBOUND DURING LOPINAVIR/RITONAVIR THERAPY Antivir Ther. 2001;6 Suppl 1:49 A Molla, S Brun, K Garren, H Mo, B Richards, T Marsh, J Sylte, M King, L Han, E Sun and D Kempf Viruses from single or multiple PI-experienced patients with viral rebound during continued lopinavir/ritonavir therapy evolve additional mutations, leading to further decreased susceptibility to lopinavir. Mutations at positions 10, 46, 54 and 82 appeared most commonly in the rebound isolates. The additional presence of mutations at positions 20, 24, 33, 50 or 53 appears to contribute to higher levels of phenotypic resistance. Download Abstracts
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| 65 | GENOTYPIC AND PHENOTYPIC ANALYSIS OF A LARGE DATABASE OF PATIENT SAMPLES REVEALS DISTINCT PATTERNS OF PROTEASE INHIBITOR CROSS-RESISTANCE Antivir Ther. 2001;6 Suppl 1:49 NT Parkin, C Chappey, M Maranta, N Whitehurst, CJ Petropoulos and the ViroLogic Clinical Reference Laboratory Complex interactions among resistance-associated mutations can dramatically influence PI cross-resistance. Proper interpretation of PI genotypic patterns requires further assessment of genotypic/phenotypic correlations. Download Abstracts
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| 66 | LIMITED DEVELOPMENT AND PROGRESSION OF RESISTANCE TO HIV-1 REVERSE TRANSCRIPTASE INHIBITORS IN HUMAN PRIMARY MACROPHAGES Antivir Ther. 2001;6 Suppl 1:50 CF Perno1,2, A Cenci1, F Ceccherini-Silberstein2, S Menzo3, M Clementi4, L Marcon5, F Marcuccilli2, S Giannella2, P Bonino2, R CaliÚ2, A Antinori1 and S Aquaro2 Under the selective pressure of RT inhibitors, resting primary M/M show a limited ability to develop HIV-resistant variants; they support viral replication of lamivudine-resistant virus, though with efficiency lower than that of WT virus. This suggests that in vivo M/M may harbour HIV strains different than those actively replicating in lymphocytes, and may help in explaining the different pattern of resistance often found in cerebrospinal fluids and plasma of heavily treated patients. Download Abstracts
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| 67 | LOPINAVIR RESISTANCE OF AMPRENAVIR-SELECTED, REPLICATION-IMPAIRED MUTANTS OF HIV-1 Antivir Ther. 2001;6 Suppl 1:51 JG Prado1, T Wrin2, J Beauchaine2, L Ruiz1, CJ Petropoulos2, B Clotet1, R D´Aquila3 and J Martínez-Picado1 Some amprenavir-selected mutants with fewer than five mutations may have a >10-fold increase in lopinavir IC50, in contrast to earlier reports. This raises questions about reliance on a given number of mutations as a criterion for lopinavir resistance and suggests that lopinavir/ritonavir use, after an amprenavir- containing regimen fails, should be guided by phenotypic resistance testing. The single-cycle growth assay for replicative capacity yielded similar results as competitive cultures, although small relative differences were more apparent with competitive cultures. These data suggest further study of cross-resistance to lopinavir in specimens from patients failing amprenavir and provide initial data on concordance between a rapid single-cycle growth assay and a slower, more laborious measure of replicative capacity. Download Abstracts
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| 68 | AMPRENAVIR AND LOPINAVIR CROSS-RESISTANCE IN HIV-1 FROM SUBJECTS FAILING PROTEASE INHIBITOR THERAPIES; MUTATIONS IN HIV-1 WITH RESISTANCE TO ONE OR BOTH DRUGS Antivir Ther. 2001;6 Suppl 1:51 D Paulsen, M Shaefer, G Fusco and L Ross Samples from subjects previously treated with 1–4 non-boosted PI(s) had lower -fold resistance to amprenavir than to lopinavir. For amprenavir- susceptible samples with >10-fold lopinavir-resistance, the I84V mutation was not observed, but I84V was present in 45% of the amprenavir- resistant, lopinavir-susceptible samples. Samples with cross-resistance to both amprenavir and lopinavir had >5 PI mutations. Subjects failing their first nonboosted PI with multiple PI mutations but lacking I50V or I84V could benefit by switching to an amprenavir- or ritonavir-boosted/amprenavir-containing regimen, thus preserving lopinavir as a salvage therapy option. Download Abstracts
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| 69 | THE UNCOMMON HIV-1 PROTEASE MUTATION I54T IS HIGHLY ASSOCIATED WITH G48V AND MAY AFFECT CLEAVAGE DYNAMICS BY STABILIZING THE STRUCTURE OF THE FLAPS Antivir Ther. 2001;6 Suppl 1:52 CA Schiffer1, WRP Scott2, K Stewart3, M King3 and D Kempf3 The I54T mutation in protease is highly correlated with the G48V mutation in patients failing PI therapy. We hypothesize that the mechanistic basis for this association is the stabilization of the conformations of the G48V-containing flaps as they open to allow substrate to enter the active site. Download Abstracts
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| 70 | PREDICTION OF ABACAVIR RESISTANCE FROM GENOTYPIC DATA: IMPACT OF ZIDOVUDINE AND LAMIVUDINE RESISTANCE IN VITRO AND IN VIVO Antivir Ther. 2001;6 Suppl 1:53 B Schmidt, K Korn, M Werwein, E Schwingel and H Walter M184V alone does not confer resistance to abacavir. However, resistance rises to a level which may be clinically relevant if zidovudine mutations are additionally present. Thus, abacavir resistance combines the resistance profiles of thymidine and cytosine analogues. This may indicate that cross-resistance is also frequently observed within the class of NRTI. Download Abstracts
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| 71 | DIFFERENTIAL IMPACT OF SPECIFIC KEY MUTATIONS IN HIV PROTEASE ON PHENOTYPIC SUSCEPTIBILITY TO AMPRENAVIR AND LOPINAVIR Antivir Ther. 2001;6 Suppl 1:53 R Elston, J Wolfram, N Richards, M Tisdale, JP Kleim and W Snowden Response to lopinavir/ritonavir would be more compromised by V82A/T than I84V. Since development of amprenavir resistance does not involve V82A/T or I54V, although occasionally involves I84V, early use of amprenavir is likely to preserve lopinavir for subsequent regimens. Download Abstracts
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| 72 | CRYSTAL STRUCTURES OF HIV-1 REVERSE TRANSCRIPTASE RESISTANT TO ZIDOVUDINE OR LAMIVUDINE CONTAINING MUTATIONS AT 41, 184 AND 215 Antivir Ther. 2001;6 Suppl 1:54 DK Stammers1, J Ren1, C Nichols1, P Chamberlain1, L Douglas1, J Lennerstrand2, B Larder2 and DI Stuart1 The RTs studied here show that conformational changes do not appear to contribute to the mechanisms of resistance for M41L and T215Y. The T215Y mutation does however appear to be able to interact with dNTP directly. Download Abstracts
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| 73 | CONTRIBUTION OF ACCUMULATED GAG AND PROTEASE MUTATIONS TOWARDS RECOVERY OF THE FITNESS AND THE VIRUS PARTICLE FORMATION IN THE PROTEASE INHIBITOR-RESISTANT HIV-1 WITH D30N AND L90M Antivir Ther. 2001;6 Suppl 1:55 L Myint1, Z Matsuda1, Y Yokomaku1, K Matsuo2, T Iwasaki2, K Yamada3 and W Sugiura1 Accumulation of protease mutations can partially recover the impaired viral fitness of D30N + L90M. However, coincidence of gag mutations including cleavage sites is necessary for full recovery of viral infectivity and virus particle production. Download Abstracts
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| 74 | LAMIVUDINE CAN EXERT A MODEST ANTIVIRAL EFFECT IN THE PRESENCE OF THE M184V MUTATION Antivir Ther. 2001;6 Suppl 1:55 MA Wainberg, M Oliveira, M Detorio and M Götte These findings provide further support for the notion that the 184V substitution in RT may have clinical significance by potentiating the antiviral activity of nucleoside RT antagonists and that this concept includes lamivudine itself. In contrast, antiviral activity on the part of lamivudine cannot be easily discerned when this drug is studied in monotherapy against 184V-containing viruses, because of the high level of resistance involved. Download Abstracts
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| 75 | VARIANTS OTHER THAN ASPARTIC ACID AT CODON 69 OF THE HIV-1 REVERSE TRANSCRIPTASE GENE AFFECT SUSCEPTIBILITY TO NUCLEOSIDE ANALOGUES Antivir Ther. 2001;6 Suppl 1:56 MA Winters and TC Merigan These results suggest that the T69D mutation is not the only codon-69 variant associated with drug resistance and that zalcitabine is not the only drug affected by codon-69 variants. Download Abstracts
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| 76 | SECONDARY STRUCTURE PREDICTIONS OF HIV-1 REVERSE TRANSCRIPTASE PROVIDE NEW INSIGHTS INTO THE DEVELOPMENT OF DRUG-RESISTANCE GENOTYPES: A REASSESSMENT OF L210W AND D67E MUTATIONS Antivir Ther. 2001;6 Suppl 1:57 J Fantini1, N Yahi2 and C Tamalet2 These data provide a new concept for anticipating the effect of some drug-resistance mutations on the structure of RT. Secondary structure predictions may help to explain why the enzyme can accomodate certain mutations and not others in a definite genetic background. Download Abstracts
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Session 4: Drug resistance, drug exposure and treatment response Abstracts 77 thru 132, Pages 59 to 97 |
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| 77 | DETERMINATION OF CLINICALLY RELEVANT PHENOTYPIC RESISTANCE BREAKPOINTS FOR INDINAVIR/RITONAVIR-CONTAINING ANTIRETROVIRAL REGIMENS Antivir Ther. 2001;6 Suppl 1:61 H Rice1, A Zolopa1, N Shulman1 and J Condra2 In this heavily treatment experienced clinical cohort, indinavir/ritonavir therapy demonstrates virological activity in a majority of patients with indinavir phenotypes of up to 25-fold change. Download Abstracts
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| 78 | THE EXTENT OF ASSOCIATION BETWEEN RESISTANCE PHENOTYPE AND TREATMENT RESPONSE IS HIGHLY DEPENDENT UPON THE DRUG Antivir Ther. 2001;6 Suppl 1:61 V Obry1, D Costagliola2, E Race1, E Dam1, L Morand-Joubert3, M Vray2, PM Girard3 and F Clavel4 In this group of patients, the extent and pattern of the association between baseline drug resistance and response varied widely according to the drug. These results should improve the interpretation of individual drug phenotype results in orienting therapeutic changes. Download Abstracts
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| 79 | EVOLUTION OF PHENOTYPIC DRUG SUSCEPTIBILITY AND VIRAL REPLICATION CAPACITY DURING STABLE PROTEASE INHIBITOR-BASED THERAPY DESPITE INCOMPLETE VIRAL SUPPRESSION Antivir Ther. 2001;6 Suppl 1:62 SG Deeks1, T Wrin2, J Barbour3, JN Martin1, N Hellmann2, RM Grant3 and C Petropoulos2 Long-term virological failure of a PI-based regimen is associated with the emergence of primary active site mutations and correspondingly large increases in phenotypic resistance. These evolutionary changes result in a virus with reduced replicative capacity. Subsequent viral evolution is marked by more gradual increases in both resistance and replicative capacity Download Abstracts
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| 80 | CCTG 575: A RANDOMIZED, PROSPECTIVE STUDY OF PHENOTYPE TESTING VERSUS STANDARD OF CARE FOR PATIENTS FAILING ANTIRETROVIRAL THERAPY Antivir Ther. 2001;6 Suppl 1:63 R Haubrich1, P Keiser2, C Kemper3, M Witt4, J Leedom5, D Forthal6, M Leibowitz7, J Hwang1, E Seefried1, JA McCutchan1, N Hellmann8, D Richman1 and the CCTG Study Team The similar HIV suppression in both arms may reflect the need for more precise sensitivity cut-off values for stavudine and didanosine in the PHENO arm and the improved ability to salvage these single PI (NNRTI-naďve) treatment failures, leading to a good response (48% undetectable) in the SOC arm. However, baseline phenotype remained a strong independent predictor of outcome. This study will help to improve the utility of phenotypic assays by clarifying the clinically relevant sensitivity cut-off points. Download Abstracts
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| 81 | SWATCH STUDY: A MULTI-CENTRE TRIAL OF PROACTIVE TREATMENT SWITCHING. RESULTS AT 48 WEEKS OF FOLLOW-UP Antivir Ther. 2001;6 Suppl 1:63 J Martinez-Picado1, E Negredo2, L Ruiz1, C Zala3, K Hertogs4, C Boucher5, R D’Aquila6, B Clotet1,2 and the SWATCH Study Team Preliminary analysis after 48 weeks of follow-up shows that proactive switching of HAART has a better virological outcome than the current standard strategy of switching when viral load rebounds. Immunological outcome, adherence and adverse events were similar in all study groups. Download Abstracts
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| 82 | IDENTIFICATION OF INDIVIDUAL MUTATIONS IN HIV PROTEASE ASSOCIATED WITH VIROLOGICAL RESPONSE TO LOPINAVIR/RITONAVIR THERAPY Antivir Ther. 2001;6 Suppl 1:64 V Calvez1, I Cohen-Codar2, AG Marcelin1, D Descamps1, C Talamet1, J Ritter1, M Segondy1, H Peigue-Lafeuille1, F Brun-Vezinet1, E Guillevic2, J Isaacson3, R Rode3, B Bernstein3, E Sun3, D Kempf3 and JP Chauvin2 Specific mutations at positions 54, 20, 46 and 10 in HIV protease appear to be more highly associated with virologic failure on lopinavir/r therapy than other common mutations associated with PI resistance. Download Abstracts
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| 83 | BINDING ENERGETICS OF HIV PROTEASE INHIBITORS TO A1-ACID GLYCOPROTEIN: IS THIS A USEFUL PARAMETER TO PREDICT DRUG EFFICACY IN AIDS PATIENTS? Antivir Ther. 2001;6 Suppl 1:65 W Cao1, H Azijn2, M-P de Béthune2, S Gulnik1, 1 Tibotec, Rockville, Md., USA; and 2 Tibotec, Mechelen, Belgium This analysis brings us closer towards being able to formulate an algorithm that can quantitatively predict the in vivo efficacy of PIs from their pharmacokinetic and pharmacodynamic profiles. Download Abstracts
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| 84 | HIV-1 DRUG RESISTANCE AND MEDICATION ADHERENCE IN PATIENTS RECEIVING NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Antivir Ther. 2001;6 Suppl 1:65/font> DR Kuritzkes1, J Ickovics2, R Bassett3, N Hellmann4 and VA Johnson5 for the ACTG 370 Protocol Team Better adherence, not delavirdine hypersusceptibility, was a more likely explanation of the association between presence of TAMs and improved virological outcome in ACTG 370. Download Abstracts
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| 85 | RACIAL DIFFERENCES IN CLINICAL EFFICACY OF EFAVIRENZ-BASED ANTIRETROVIRAL THERAPY Antivir Ther. 2001;6 Suppl 1:66 S Wegner1, M Vahey1, M Dolan1, M Wallace1, N Aronson1, A Barile1, W Emmons1, S Frazier1, K Stephan1, M Nau2, S Piscitelli3, R Harrigan4 and B Larder4 In our cohort of HIV-1-infected military health care beneficiaries with uniform access to health care, we have observed significant racial differences in time to virological failure that appear to be specific for efavirenz-based therapy. Recent reports have shown marked variability in efavirenz trough levels for subjects with different CYP 2D6 genotypes. Racial heterogeneity for CYP 2D6 alleles has been reported, and may be responsible for observed response differences in this study. Download Abstracts
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| 86 | RESPONSE TO GENOTYPE-GUIDED THERAPY AFTER TREATMENT INTERRUPTION IN HIV-1-INFECTED PATIENTS Antivir Ther. 2001;6 Suppl 1:67 A Antinori, MP Trotta, A Bertoli, G Liuzzi, R D’Arrigo, P De Longis, F Forbici, G D’Offizi, E Girardi, G Ippolito and CF Perno TI followed by GRT-therapy may be an acceptable strategy in multiple-failed patients with limited options. Download Abstracts
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| 87 | BOTH DRUG RESISTANCE AND ANTIRETROVIRAL DRUG LEVELS ARE ASSOCIATED WITH SHORT-TERM VIROLOGICAL RESPONSES TO SUBSEQUENT DRUG REGIMENS IN CPCRA 046 (GART STUDY) Antivir Ther. 2001;6 Suppl 1:67 D Mayers1, T Merigan2, D Wentworth3, J Neaton3, M Hoover4, R Hoetelmans5, S Piscitelli5, W Verbiest5, J Baxter6 and the CPCRA 046 Study Team In salvage therapy, both the number of active drugs and the drug levels for each drug in the new regimen determine the antiviral response. IQ ratios were also predictive of virological response. Download Abstracts
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| 88 | LOWER INCIDENCE OF THE M184V MUTATION IN PATIENTS RECEIVING COMBINATION THERAPY WITH EMTRICITABINE COMPARED TO LAMIVUDINE Antivir Ther. 2001;6 Suppl 1:68 K Borroto-Esoda, J Harris, A Shaw, C Wakeford, J Quinn, G Painter and F Rousseau These results indicate that patients receiving combination therapy with emtricitabine are less likely to develop the M184V mutation than patients treated with a lamivudine-containing regimen. The lower incidence of M184V may allow for a greater number of subsequent treatment options following therapy with emtricitabine. Download Abstracts
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| 89 | THE INHIBITORY QUOTIENT AS A PREDICTOR OF VIRAL EVOLUTION FOLLOWING VIRAL LOAD REBOUND DURING LOPINAVIR/R THERAPY Antivir Ther. 2001;6 Suppl 1:69 S Brun, D Kempf, K Garren, A Molla, M King, B Richards, T Marsh, R Bertz, A Hsu and E Sun for the M97-765/M98-957 Study Groups Evolution during viral rebound on lopinavir/r therapy is related to the lopinavir IQ. At low IQ, selective pressure appears to be insufficient to drive evolution. At intermediate IQ, selective pressure is high and the genetic barrier is low. At high IQ, the high pharmacologic barrier prohibits the selection of mutants, suggesting that virologic rebound may be a consequence of temporary non-adherence in these patients. Download Abstracts
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| 90 | ANALYSIS OF THE CORRELATION BETWEEN BASELINE GENOTYPIC PROFILE AND VIROLOGICAL RESPONSE TO LOPINAVIR/RITONAVIR IN 104 MULTIPLE PROTEASE INHIBITOR-EXPERIENCED PATIENTS TREATED UNDER THE LOPINAVIR/RITONAVIR AUTORISATION TEMPORAIRE D’UTILISATION PROGRAM Antivir Ther. 2001;6 Suppl 1:69 V Calvez1, I Cohen Codar2, AG Marcelin1, E Guillevic2, J Isaacson3, R Rode3, B Bernstein3, E Sun3, D Kempf3 and JP Chauvin2 Virological response with lopinavir/r has been observed in these heavily pretreated patients, The clinically relevant genotypic breakpoints for lopinavir/r observed in this cohort study (lopinavir mutation score 0–5 versus ≥6) confirm those found previously in smaller Phase I/II clinical trials. Download Abstracts
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| 91 | PREDICTION OF VIROLOGICAL AND IMMUNOLOGICAL OUTCOMES BY DIFFERENT INTERPRETATION SYSTEMS FOR GENOTYPIC RESISTANCE IN A COHORT OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY-FAILED PATIENTS Antivir Ther. 2001;6 Suppl 1:70 A De Luca1, A Cingolani1, MP Trotta2, S Di Giambenedetto1, A Bertoli2, MG Rizzo1, G Liuzzi2, R Murri1, F Baldini1, G Ippolito2, CF Perno2 and A Antinori2 Prediction of subsequent outcomes differs significantly among IS with a stronger difference on the immunological rather on the virological outcome. Those IS based on algorithms show the best prediction of subsequent outcomes. There is an urgent need for standardization of the criteria and rules on which IS are based. Download Abstracts
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| 92 | GENOTYPIC-GUIDED ANTIRETROVIRAL TREATMENT EFFICACY IS DEPENDENT OF THE CENTRE PROVIDING ANTI-HIV THERAPY Antivir Ther. 2001;6 Suppl 1: P Clevenbergh1, MC Bozonnat2, M Kirstetter3, J Durant1, E Cua1, P del Giudice4, N Montagne5, P Simonet5, P Dellamonica1 and the InfectioSud group With similar baseline characteristics, patient’s outcome is different according to participating centre. Centre type is an independent predictive factor of virological success. Factors responsible for these centre-to-centre differences in treatment efficacy should be further analysed. Download Abstracts
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| 93 | IS THERE A RELATIONSHIP BETWEEN NUCLEOSIDE ANALOGUE MUTATIONS AND CLINICAL RESPONSE ON STAVUDINE MONOTHERAPY? A RETROSPECTIVE ANALYSIS OF SAMPLES FROM CLINICAL STUDY AI455-019 Antivir Ther. 2001;6 Suppl 1:71 RJ Colonno, V Rutkiewicz and R Rose This retrospective study supports earlier studies indicating that stavudine therapy can induce/maintain the presence of some NAMs. However, the presence of NAMs was not predictive of clinical response on stavudine monotherapy as measured by CD4 counts. Download Abstracts
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| 94 | FOCUS TRIAL: GENOTYPE ANALYSIS OF HIV-INFECTED ANTIRETROVIRAL-NAĎVE PATIENTS TREATED ON A ONCE DAILY REGIMEN OF SAQUINAVIR SOFT GEL CAPSULES Antivir Ther. 2001;6 Suppl 1:72 C Craig1, B Hathaway2, JSG Montaner3 and C Barylski4 Protease inhibitor resistance associated mutations were not detectable to date in this cohort on once daily saquinavir. The reasons for some patients failing this treatment regimen without development of significant protease inhibitor resistance are being assessed. Download Abstracts
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| 95 | GENOTYPIC RESISTANCE AND RESPONSE TO SALVAGE THERAPY WITH AMPRENAVIR PLUS LOPINAVIR/R PLUS NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS IN HEAVILY THREE CLASS-EXPERIENCED PATIENTS: A PROSPECTIVE STUDY Antivir Ther. 2001;6 Suppl 1:73 A Cingolani, F Baldini, MG Rizzo, R Murri, M Fantoni and A De Luca In preliminary short-term data, heavily pretreated patients failing all three drug classes and with significant HIV-1 drug resistance salvaged with amprenavir plus lopinavir/r plus NRTIs showed significant virological inhibition and CD4 recovery. I84V was negatively associated with virological response. Extended 16-week data will be presented. Download Abstracts
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| 96 | CLINICAL OUTCOME IN HIV-INFECTED PATIENTS HARBOURING MULTINUCLEOSIDE-RESISTANT GENOTYPES (Q151M, 67/69 INSERTS) Antivir Ther. 2001;6 Suppl 1: O Gallego, L Valer, A Corral, C de Mendoza and V Soriano The prevalence of MNR genotypes (Q151M and 67/69 inserts) is low (2.8%) among pretreated HIV-infected patients failing therapy in Spain. In all subjects experiencing a favourable virological and clinical outcome, the rescue regimen was based on potent PI combinations. Therefore, the expected poor prognosis of subjects harbouring MNR viruses may be overcome using rescue interventions based on potent PIs. Download Abstracts
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| 97 | BASELINE RESISTANCE IS SIGNIFICANTLY ASSOCIATED WITH LONG-TERM THERAPY RESPONSE, ESPECIALLY IN NON-ADHERENT PATIENTS Antivir Ther. 2001;6 Suppl 1:74 I Derdelinckx1, K Van Vaerenbergh1, S De Geest1,3, A Deschamps1, V De Graeve1, V De Saar1, B Maes1, H Ceunen1, K De Smet2, W Peetermans1, H Bobbaers1, M Van Ranst1, J Desmyter1, E De Clercq1, E Van Wijngaerden1 and AM Vandamme1 In our population, we found therapy response to be associated with the number of ‘sensitive’ drugs at baseline. This association was significant in the overall analysis as well as in the NA group, but could not be demonstrated in the A group. Download Abstracts
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| 98 | GENOTYPIC RESISTANCE ANALYSES AT TIME TO FAILURE IN NOVAVIR (ANRS 073) TRIAL Antivir Ther. 2001;6 Suppl 1:75 D Descamps1, P Flandre2, V Joly1, J Izopet3, G Peytavin1, C Tamalet4, A Ruffault5, F Zeng1, V Meiffredy2, JP Aboulker2, P Yeni1 and F Brun-Vezinet1 In patients previously treated with nucleosides, failure to PI-containing treatment is associated with emergence of PI mutations in half of the cases. Patients failing without PI mutations had undetectable PI plasma levels. These results suggest that, although PIs have a high genetic barrier, sub-optimal activity of associated drugs may favour the selection of PI resistance mutations. Download Abstracts
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| 99 | ACCURACY OF SEQUENCING USING A KIT-BASED HIV-1 GENOTYPING ASSAY COMPARED TO THE AGENCE NATIONALE DE RECHERCHE SUR LE SIDA CONSENSUS GENOTYPING TECHNIQUE Antivir Ther. 2001;6 Suppl 1:75 D Descamps1, F Telles1, G Collin1, S Delarue1, Y Louis2, SP Day2 and F Brun-Vezinet1 This commercial genotyping kit demonstrated high concordance with the ANRS method in detecting resistance mutations on B and non-B subtypes and provides a suitable alternative for routine clinical testing. Download Abstracts
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| 100 | GENOTYPIC AND PHENOTYPIC RESISTANCE AND VIROLOGICAL FAILURE IN HIV-1-INFECTED ANTIRETROVIRAL THERAPY-NAĎVE ADULTS: AN OPEN-LABEL COMPARATIVE STUDY (CNAF3007) Antivir Ther. 2001;6 Suppl 1:76 D Descamps1, F Brun-Vezinet1, J Izopet2, A Vabret3, F Boue4, C Thiaux5, A Goetschel5 and S Matheron1 on behalf of the CNAF3007 study group No key mutation to zidovudine (except one patient) or nelfinavir developed at virological failure or non-response. Most patients experiencing virological failure or non-response did not present genotypic or phenotypic resistance. Download Abstracts
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| 101 | VIRAL RESISTANCE IN PATIENTS RECEIVING INTERMITTENT HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2001;6 Suppl 1:77 C Apetrei1, D Descamps2, G Collin2, I Pandrea1, F Damond2, P Groza1, V Luca1 and F Brun-Vezinet2 The results show a very high frequency of selection of NNRTI mutations in patients receiving a discontinued treatment containing this class of drug. NNRTIs should be avoided in those countries where, for economic reasons, there are risks of discontinuation of treatment. Download Abstracts
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| 102 | WILD-TYPE REBOUND IN WOMEN ON COMBINATION ANTIRETROVIRAL THERAPY IS COMMON AND ASSOCIATED WITH LOSS OF PARTIAL VIROLOGICAL AND IMMUNOLOGICAL RESPONSES Antivir Ther. 2001;6 Suppl 1:77 RM Grant1,2, T Liegler1, SJ Gange3, M Schneider3, P Bacchetti2, T Wilson4, K Anastos4, M Young4, M Cohen4, A Levine4, C Williams4 and RM Greenbatt1,4 The incidence of virological failure of PI-containing regimens without protease gene mutations is high in this cohort. This may represent drug exposure that is insufficient to select PI resistant HIV-1. Higher CD4+ cell density may favour WT viral rebound by increasing replication opportunities, which would be more rapidly exploited by wild-type viruses having greater replication capacity and fitness. Viral rebound with MUT protease was associated with partial virological and immune responses, likely reflecting greater drug exposure and less fit virus in these subjects. Download Abstracts
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| 103 | CLINICAL TRIAL END-POINT CHOICE Antivir Ther. 2001;6 Suppl 1:78 SM Hammer, KS Bennett, F Vaida, V DeGruttola and JW Mellors, for the ACTG 398 Study Team Response rates in trials are sensitive to end-point choice and handling of missing data. Virological and composite end-points are complementary and, together, provide a more complete picture. Download Abstracts
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| 104 | GENOTYPIC ANALYSIS OF HIV-1-INFECTED ANTIRETROVIRAL THERAPY-NAĎVE PATIENTS RECEIVING EMTRICITABINE OR LAMIVUDINE IN A DOUBLE-BLIND EQUIVALENCE TRIAL Antivir Ther. 2001;6 Suppl 1:78 J Harris, A Shaw, K Borroto-Esoda, A Bae, J Hinkle, J Quinn, T Gurley, C Moxham and F Rousseau The incidence of wild type virus also differed between the two arms, occurring in 2/16 (12.5%) of lamivudine failures and in 13/29 (44.8%) of emtricitabine failures. The results of this study indicate that antiretroviral therapy-naďve patients receiving emtricitabine as part of a triple drug regimen have a lower incidence of the M184V mutation compared to patients who received lamivudine. Download Abstracts
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| 105 | NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR PHENOTYPIC AND GENOTYPIC RESISTANCE IN PATIENTS WITH VIROLOGICAL FAILURE DURING SALVAGE THERAPY: 12-WEEK OUTCOME DATA FROM THE GART STUDY (CPCRA 046) Antivir Ther. 2001;6 Suppl 1:79 M Hoover1, D Mayers2, D Wentworth3, J Neaton3, K Hertogs4, W Verbiest4, T Merigan5, J Baxter6 and the CPCRA 046 study team Among patients failing on a PIcontaining regimen, who were placed on a NNRTI-containing salvage regimen, there was a high incidence of NNRTI resistance after 12 weeks that was associated with the number of additional AD prescribed in the salvage regimen. These findings suggest that the use of a NNRTI in a salvage regimen should only be considered when at least two or more additional AD are being prescribed. Download Abstracts
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| 106 | EVOLUTION OF IAS-USA PRIMARY PROTEASE RESISTANCE MUTATIONS DURING PROTEASE INHIBITOR SALVAGE THERAPY Antivir Ther. 2001;6 Suppl 1:80 R Kantor1, AR Zolopa1, D Israelski1, N Shulman1, J Montoya1, M Harbour1, J Fessel2 and RW Shafer1 Despite changes in PI therapy, primary PI mutations were maintained in 50/62 (81%) patients. D30N was the mutation most likely to recede. The most common new primary PI mutations during salvage were L90M, I84V, V82A, G48V. The persistence of primary PI mutations during salvage therapy suggests that most primary PI mutations confer resistance to multiple PIs. Download Abstracts
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| 107 | GENOTYPIC PREDICTORS OF NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR HYPERSUSCEPTIBILITY AND CLINICAL RESPONSE TO EFAVIRENZ IN PATIENTS WITH HYPERSUSCEPTIBILITY Antivir Ther. 2001;6 Suppl 1:80 P Keiser, L Evans, D Skiest, R Haubrich and WA O’Brien HS is was associated with the number of mutations at M41L, T69D and T215F/Y. HS subjects were treated with fewer sensitive agents and had a rapid time to treatment failure. Potential benefits of HS may be outweighed by accumulation of resistance to other agents in highly experienced patients. Download Abstracts
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| 108 | A 15-BASE GENETIC TRANSLOCATION OCCURRING BETWEEN REVERSE TRANSCRIPTASE CODONS 69 AND 70 OF HIV-1 Antivir Ther. 2001;6 Suppl 1:81 RL Lobato1, E-Y Kim1, R Kagan2 and TC Merigan1 The observations demonstrate that the 15-base insertion confers multiple nucleoside resistance, as expected of an insertion in this region. Data from competition and replication assays indicate that the insertion also leads to increased fitness under drug pressure. Sequencing results suggest that the mutation found between RT codons 69 and 70 is in fact a genetic translocation that originated in the envelope gene. Although exceedingly rare, a translocation could result from an RT pausing or strand transfer event. Download Abstracts
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| 109 | EVOLUTION OF DRUG RESISTANCE IN ANTIRETROVIRAL THERAPY-NAĎVE CHILDREN IN THE PENTA 5 TRIAL Antivir Ther. 2001;6 Suppl 1:82 C Loveday1, S Walker2, DM Gibb2 on behalf of the PENTA Virology Group In this study, the most sustained VL response was seen in lamivudine plus abacavir arm. The M184V mutation was detected most often with higher incidence in Part A. Time to develop M184V was shortest in lamivudine plus zidovudine arm. However, mutations were more likely to evolve if rebound/non-response occurred with lamivudine plus abacavir than with zidovudine plus abacavir (less mutations, no M184V). There was some evidence that if mutations were not present at rebound (30% cases), they only developed slowly thereafter. Download Abstracts
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| 110 | A COMPARISON OF IMMUNOLOGICAL RESPONSES TO HIGHLY ACTIVE ANTIRETROVIRAL THERAPY AND RESISTANCE PROFILES IN PATIENTS WITH HIV-1 SUBTYPE NON-B AND B INFECTIONS: A CASE-CONTROLLED STUDY Antivir Ther. 2001;6 Suppl 1: C Loveday, F van Hooff, A Vrettou, J Page and M Johnson In an open, retrospective/prospective case-controlled study of clinical patients infected with field strains of HIV-1 NB or B viruses there were equivalent CD4 responses over 48 weeks of follow-up. Download Abstracts
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| 111 | EPIDEMIOLOGICAL SURVEY OF MAJOR PROTEASE INHIBITOR RESISTANCE MUTATIONS IN 2000 Antivir Ther. 2001;6 Suppl 1:83 AG Marcelin, C Delaugerre, P Viegas, M Wirden, M Mouroux, R Tubiana, A Simon, MA Valantin, M Bonmarchand, F Bricaire, H Agut, JM Huraux, C Katlama and V Calvez The genotypic resistance assays performed in context of virological failure showed that 80% of viruses harboured less than three major protease inhibitor resistance mutations. In contrast, only 3% of viruses harbored four to five major protease inhibitor resistance mutations. These results suggest that, for an important percentage of patients, a salvage therapy is possible and should be guided by resistance tests. The fact that 40% of the sequenced protease were wild-type confirms that compliance is an important factor for treatment failures. |