5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona


Session 1: New antiretrovirals
Abstracts 1 thru 17, Pages 3 to 14
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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Session 2: Host immunology, HIV pathogenesis and dynamics
Abstract 18 thru 40, Pages 15 to 30
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).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Session 3: Mechanisms of HIV drug resistance
Abstracts 41 thru 76, Pages 33 to 57
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Session 4: Drug resistance, drug exposure and treatment response
Abstracts 77 thru 132, Pages 59 to 97
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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.