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1st International Workshop on HIV Drug Resistance & Treatment Strategies25-28 June 1997, St. Petersburg, Florida, USA |
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Session 1: New antiretrovirals Abstracts 1 thru 9, Pages 1 to 6 |
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| 1 | THE DISCOVERY AND DEVELOPMENT OF ANTIRETROVIRAL DRUGS Antiviral Therapy 1997;2 (Suppl 5):1 Joel R Huff Recently, a number of promising therapeutic agents for the treatment of HIV have emerged. While long-term efficacy remains to be established, initial results with several new treatment regimens appear to be quite encouraging. Discovery and development of these new agents have required almost a decade of intense effort, despite quite early identification of key targets for drug discovery. |
| 2 | NEW CYCLIC UREA-BASED PROTEASE INHIBITORS WITH IMPROVED POTENCY, ORAL BIOAVAILABILITY AND RESISTANCE PROFILES Antiviral Therapy 1997;2 (Suppl 5):1 Lee T Bacheler, James D Rodgers, Patrick YS Lam, Matt Wright, Sean Garber, Carol Reid and Sue Erickson-Viitanen Pharmacokinetic studies of plasma levels in dogs after a single 10 mg/kg oral dose reveal 8 h trough levels of inhibitor which meet or exceed the protein binding-adjusted IC90 of wild-type and single amino acid mutants of HIV. The combination of these properties into a PPPP suggests that DMP 850 and DMP 851 each represent an attractive candidate for further development. Safety assessment studies are currently in progress. |
| 3 | THE BICYCLAM AMD3100, A POTENT INHIBITOR OF T-TROPIC HIV STRAINS, IS TARGETED AT THE HIV CO-RECEPTOR CXCR4 Antiviral Therapy 1997;2 (Suppl 5):2 Dominique Schols1, José A Esté1, Geoffrey Henson2 and Erik De Clercq1 [T]he bicyclams are the first low molecular weight anti-HIV agents found to interact specifically with CXCR4, the co-receptor for HIV. AMD3100 holds great promise as a candidate anti-HIV drug and clinical trials with the compound are planned. |
| 4 | A PHASE I/II STUDY OF BB-10010, AN ANALOGUE OF HUMAN MIP1-α, IN ASYMPTOMATIC HIV-INFECTED PATIENTS WITH CD4+ CELL COUNTS LESS THAN 500 cells/ml Antiviral Therapy 1997;2 (Suppl 5):2 IG Williams1, JA McKeating2, J Lewis3, KM Dawson3, LG Czaplewski3, R Puttick3, P Balfe1 and IVD Weller1 There was no change in CD4+ count and plasma HIV RNA levels during treatment with BB-10010. Plasma levels of BB-10010 were low and may account for this lack of antiviral effect. There may also be variation in viral sensitivity to neutralization by BB-10010. In vitro sensitivities of the patients virus isolates to BB-10010 will be presented |
| 5 | IDENTIFICATION AND CHARACTERIZATION OF NOVEL INHIBITORS OF HIV-1 INTEGRASE Antiviral Therapy 1997;2 (Suppl 5):3 DJ Hazuda, AL Wolfe, PJ Felock, JC Hastings, C Uncapher Blau, WA Schleif and MD Miller These compounds are structurally and mechanistically distinct from the phenolic inhibitors of integrase and are the first compounds identified which inhibit the catalytic activity of integrase subsequent to assembly. Unlike previously described integrase inhibitors, many of these compounds have comparable activity against recombinant integrase and HIV-1 pre-integration complexes in vitro. |
| 6 | THERAPEUTIC POTENTIAL OF OXATHIIN CARBOXANILIDE ANALOGUES: IN VITRO AND IN VIVO EFFICACY, PHARMACOKINETICS AND RESISTANCE Antiviral Therapy 1997;2 (Suppl 5):3 RW Buckheit Jr1, TL Stup1, TL Kinjerski1, Hollingshead2 and S Stinson2 Our preclinical anti-HIV evaluations suggest that several of the UC analogues merit further consideration for use in patients. We propose that the UC compounds may be effectively used in combination with nucleoside analogues as a first line of antiviral therapy in infected patients, as well as in cases of needle stick injuries and in combination with microbicides to prevent the sexual transmission of HIV. |
| 7 | INTERFERENCE OF HIV ENTRY BY INHIBITING INTERACTIONS WITH CXCR4 Antiviral Therapy 1997;2 (Suppl 5):4 WA O'Brien1, K Grovit-Ferbas2,4, ES Daar2,3, BJ Doranz5 and RW Doms5 Sequence analysis of the V3 region of these primary isolates revealed a high net positive charge on the SI strains, similar to that seen with T cell line-adapted strains. These findings support other studies which showed that primary SI strains may utilize CCR5 preferentially, or in addition to CXCR4. Alternatively, the HIV SI isolates may contain quasispecies which exhibit different sensitivities to ALX40-C. Compounds which inhibit CCR5 interactions may suppress replication in a larger subset of primary HIV-1 strains, and prove to be effective therapeutic agents. |
| 8 | UNIQUE ANTI-HIV PROPERTIES OF THE CALANOLIDE A ANALOGUES COSTATOLIDE AND DIHYDROCOSTATOLIDE Antiviral Therapy 1997;2 (Suppl 5):5 TL Stup, EL White, V Fliakas-Boltz, A Weigand, MC Osterling and RW Buckheit Jr Our preclinical evaluations suggest the possible therapeutic benefit of using the calanolide A analogues in combination with other anti-HIV agents. They may be most useful in patients which have been previously exposed to NNRTIs, based on the ability of the analogues to inhibit viruses with many of the commonly occurring NNRTI-resistant amino acid changes. |
| 9 | TWO NOVEL COMPOUNDS, A NON-NUCLEOSIDE RT INHIBITOR, UC-781, AND A BINDING/FUSION INHIBITOR, NSC 651016, ARE ACTIVE IN VIVO IN THE HuPBMC SCID MOUSE MODEL Antiviral Therapy 1997;2 (Suppl 5):7 Michael A Ussery1, Owen L Wood1, Steven C Kunder1, Matthew A Bacho1, Dennis D Broud1, Susan F Papermaster1, Bradford E Hall1, Gary P Goldberg2, Melinda G Hollingshead3, John P Bader3 and Paul L Black1 These compounds are interesting candidates for further drug development. NSC-651016 ranks as one of the most active compounds we have tested in the SCID model. |
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Session 2: Mechanisms of antiretroviral resistance Abstract 10 thru 41, Pages 7 to 27 |
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| 10 | A UNIQUE MECHANISM FOR ZIDOVUDINE-RESISTANCE AND EVIDENCE FOR A ZIDOVUDINE-MEDIATED CROSS-RESISTANCE TO OTHER NUCLEOSIDE ANALOGUES BY ZIDOVUDINE-RESISTANT VIRUSES Antiviral Therapy 1997;2 (Suppl 5):7 Miguel E Quiñones-Mateu1, Jamie L Albright1, James-Paul Marois2, Mita Ghosh1, Stuart FJ Le Grice1, Charles Hough2, Mark A Wainberg2 and Eric J Arts1 These results suggest that the mechanism of zidovudine resistance is not simply a preference of TTP over zidovudine-TP but rather a stimulation of the T215Y RT overriding the antiviral effects of zidovudine or other nucleoside analogues. We now have biochemical evidence supporting the zidovudine-mediated stimulation and cross-resistance effects. It appears that zidovudine-5´-monophosphate, the major zidovudine metabolite in cells, may act as a co-factor for the polymerase activity of recombinant HIV-1 RTs containing the M41L, T215Y and/or K219E mutations. |
| 11 | TWO DISTINCT MUTATIONAL PATHWAYS IN HIV-1 RT CONFER ZIDOVUDINE/LAMIVUDINE DUAL RESISTANCE Antiviral Therapy 1997;2 (Suppl 5):7 SD Kemp and S Bloor for the FASP Resistance Study Group Polymorphisms other than those responsible for zidovudine or lamivudine resistance are required for dual resistance. This study clearly identifies two possible routes to zidovudine/lamivudine dual resistance via a complex series of multiple mutations in the 5′ and 3′ regions of RT. |
| 12 | STRUCTURAL EVIDENCE FOR NUCLEIC ACID REPOSITIONING BY THE Met184ile MUTANT OF HIV-1 REVERSE TRANSCRIPTASE AND IMPLICATIONS FOR DRUG RESISTANCE Antiviral Therapy 1997;2 (Suppl 5):8 Stefan G Sarafianos1, Kalyan Das1, Jianping Ding1, Arthur D Clark Jr1, Patrick Clark2, Paul L Boyer2, Stephan H Hughes2 and Edward Arnold1 Analysis of our structural results is providing important information about how Met184Ile of HIV-1 RT can discriminate dNTP from some dNTP analogue inhibitors. Based on these results we are proposing a model for the structural basis of resistance to oxathiolane inhibitors. |
| 13 | NOVEL MECHANISM OF DRUG RESISTANCE DUE TO Lys103Asn MUTATION SUGGESTED BY CRYSTAL STRUCTURES OF UNLIGANDED AND INHIBITOR-BOUND Lys103Asn HIV-1 RT Antiviral Therapy 1997;2 (Suppl 5):9 Yu Hsiou1, Jianping Ding1, Kalyan Das1, Art Clark Jr1, Paul AJ Janssen2, Jörg-Peter Kleim3, Manfred Rösner3, Stephen H Hughes4 and Edward Arnold1 This suggests that the interactions of the inhibitors with both wild-type and Lys103Asn mutant HIV-1 RT are quite similar. In particular, the loop region containing the Lys103Asn mutation in the p66 subunit adopts a similar conformation to that observed in the wild-type HIV-1 RT/inhibitor complexes; only subtle changes in the mutant RT/inhibitor complexes are seen, mainly in the NNIBP region. The results suggests that the differences in the structures of unbound Lys103Asn and wild-type HIV-1 RT may explain the resistance of this mutant to NNRTIs. |
| 14 | KINETIC AND STRUCTURAL BASIS OF SAQUINAVIR RESISTANCE OF HIV-1 PROTEASE MUTANTS Antiviral Therapy 1997;2 (Suppl 5):9 J Ermolieff, L Hong, X Lin, S Foundling, JA Hartsuck and J Tang The crystal structure of PR mutant G48H bound to inhibitor U89360E was determined and a model for G48V bound to saquinavir was built. These structures show that these mutations at G48 result in a new interaction of Phe-53 with Val-48 or His-48 and result in increased rigidity of the flap region of PR. For the mutant enzymes there was contact of residue 48 with P2, P3 or P2´, P3´ inhibitor subsites. For both complexes, van der Waals and electrostatic interactions combine to destabilize the mutant complex as compared to that of the wild-type and predict the observed increase of Ki for these mutants. |
| 15 | BIOLOGICAL CROSS-RESISTANCE TO HIV-1 PROTEASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):10 Terri Smith and Ronald Swanstrom These virus pools represent viruses with varying degrees of resistance to the inhibitors and as such are useful reagents for exploring the issue of cross-resistance. The overlap in sequence changes that are selected and the demonstrated cross-resistance both suggest that sequential use of these inhibitors after an initial therapy failure with a protease inhibitor will be under conditions where the efficacy of the second inhibitor has been compromised. |
| 16 | SELECTION OF SAQUINAVIR-RESISTANT MUTANTS BY INDINAVIR FOLLOWING A SWITCH FROM SAQUINAVIR Antiviral Therapy 1997;2 (Suppl 5):11 A Dulioust1, S Paulous2, L Guillemot2, F Bouè1, P Galanaud1 and F Clavel2 Phenotypic evaluation of HIV resistance to protease inhibitors by a single-cycle recombinant virus assay showed that the mutant viruses selected under saquinavir, which displayed an average 10-fold increase in IC90 to saquinavir compared to pre-saquinavir virus, had a limited (threefold) cross-resistance to indinavir. Similarly, the mutant viruses that emerged under indinavir treatment, with the exception of the two viruses mutated at codon 82, displayed strong resistance to saquinavir and limited cross-resistance to indinavir. These findings reveal that in spite of a relatively modest cross-resistance, indinavir can actively select saquinavir-resistant HIV variants, a process that might preclude full response to indinavir when administered after saquinavir treatment. |
| 17 | GENOTYPIC AND PHENOTYPIC ANALYSIS OF THE PROTEASE GENE IN HIV-1-INFECTED PATIENTS THAT FAILED LONG-TERM SAQUINAVIR THERAPY AND SWITCHED TO OTHER PROTEASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):11 Mark A Winters, Jonathan M Schapiro, Jody Lawrence and Thomas C Merigan These results suggest that mutations induced by initial long-term saquinavir therapy may provide a genotypic foundation for the development of resistance to other protease inhibitors. However, further studies need to examine the development of these mutational pathways in patients that have more effective suppression of viral replication with combinations of saquinavir plus RT inhibitors. |
| 18 | GENOTYPIC AND PHENOTYPIC ANALYSES OF HIV-1 VARIANTS ISOLATED FROM PATIENTS TREATED WITH NELFINAVIR AND OTHER HIV-1 PROTEASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):12 AK Patick1, D Kuritzkes2, VA Johnson3, D Shugarts2, M Bakhtiari2, KE Potts1, A Farnsworth1, R Anderson1, JL Koel3, JD Hazelwood3, CD Nail3, M Duran4, M Markowitz4, D Ho4 and D Richman5 To study the susceptibility to nelfinavir of HIV variants which exhibit resistance to other protease inhibitors, 29 HIV isolates were obtained from patients who had failed on treatment regimens involving indinavir, saquinavir and/or ritonavir. Results indicate that 17 of the 29 (59%) isolates examined retained sensitivity to nelfinavir. Genotypic analysis of protease genes from these variants is currently underway. |
| 19 | DRUG RESISTANCE DURING INDINAVIR THERAPY IS CAUSED BY MUTATIONS IN THE PROTEASE GENE AND IN ITS GAG SUBSTRATE CLEAVAGE SITES Antiviral Therapy 1997;2 (Suppl 5):13 Y-M Zhang1, H Imamichi1, T Imamichi1, HC Lane2, J Falloon2, MB Vasudevachari1 and NP Salzman1 Optimum rates of virus replication require protease cleavage of precursor polyproteins. A mutation in a cleavage site that enhanced cleavage by the mutant protease would confer on that virus a significant growth advantage, and may explain the uniform emergence of viruses with alterations at the p7/p1 cleavage site. |
| 20 | LIMITING DNTP CONCENTRATIONS EMPHASIZE THE PROCESSIVITY DEFECT OF LAMIVUDINE-RESISTANT VARIANTS OF HIV-1 REVERSE TRANSCRIPTASE Antiviral Therapy 1997;2 (Suppl 5):13 Nicole KT Back and Ben Berkhout The nucleoside drug lamivudine triggers the selection of resistant forms of HIV-1 reverse transcriptase (RT) with a substitution of amino acid 184Met. The lamivudine-resistant RT enzymes 184Val and 184Ile exhibit a processivity defect in in vitro assays that correlates with reduced replication of the corresponding virus variants in primary cells. However, no replication defect is apparent for these two mutants in the transformed T cell line SupT1. |
| 21 | SIGNIFICANCE OF THE 225 PRO→HIS MUTATION IN HIV-1 REVERSE TRANSCRIPTASE Antiviral Therapy 1997;2 (Suppl 5):14 J Balzarini1, H Pelemans1, R Esnouf1, A Dunkler2, MA Parniak3, A-M Vandamme1, A Karlsson4, E De Clercq1 and J-P Kleim2 These data are consistent with the structure of the RT-BHAP U90152 complex, in which the inhibitor forces the main chain of Pro 225 to swing around by approximately 180°, leaving Pro 225 exposed on the surface of the enzyme at the edge of the polymerase active site binding cleft. A change from Pro to the more hydrophilic (His) residue is likely to stabilize the RT-BHAP complex, which would then explain the increased activity of BHAP U90152. The enzyme kinetics of BHAP U90152, quinoxaline HBY 097 and MKC-442 against 225 Pro→His mutant RT and wild-type enzyme were similar with respect to the natural substrate (dGTP) and the template/primer [poly(C)·oligo(dG)]. |
| 22 | PRELIMINARY GENOTYPIC ANALYSIS OF HIV-1 IN PLASMA FROM VOLUNTEERS RECEIVING REPEATED MULTIPLE DOSES OF MKC-442 Antiviral Therapy 1997;2 (Suppl 5):14 K Borroto-Esoda, DS Noel, CP Moxham and PA Furman A mutation at position 181 (Y181C) was also observed in HIV-1 virus isolated from a patient 1 month after therapy was completed. Peripheral blood mononuclear cells (PBMCs) obtained from this patient at day 0, day 29 and day 57 of treatment, and 1 month post-treatment, were co-cultured with uninfected donor PBMCs. Genotypic and phenotypic variations in the co-cultured virus samples will be presented. |
| 23 | HIV-1 VARIANTS CARRYING RESISTANCE MUTATIONS TO SAQUINAVIR ARE NOT PRE-DISPOSED TO RESISTANCE TO OTHER PROTEASE INHIBITORS IN VITRO Antiviral Therapy 1997;2 (Suppl 5):15 SM Gilbert, E Race, AR Moffatt, JG Sheldon and N Cammack Ritonavir-associated mutations were selected on a background of saquinavir-selected mutations. The mutations occurred at the same positions in the protease gene for both GB8 and GB8(SR), but the order of appearance and the amino acid changes were different. The resulting reduction in sensitivity to ritonavir was less in GB8(SR) than in GB8. Saquinavir-associated resistance mutations do not predispose the virus to an increased rate of appearance of ritonavir-associated mutations or to a greater decrease in sensitivity to ritonavir. |
| 24 | GENOTYPIC CHARACTERIZATION OF HIV-1 VARIANTS ISOLATED FROM AIDS PATIENTS TREATED WITH ADEFOVIR DIPIVOXIL (BIS-POM PMEA) Antiviral Therapy 1997;2 (Suppl 5):15 AS Mulato, PL Lamy, W Li, MD Miller and JM Cherrington These preliminary data from clinical samples suggest that HIV mutations associated with adefovir resistance do not arise readily during prolonged therapy. Recombinant viruses generated from the baseline and month 6 RT genes of the other three patients with genotypic changes in RT have been generated and are currently being analysed. Further work investigating the relationship between novel genotypes/phenotypes arising on adefovir dipivoxil therapy and virological response during treatment is ongoing. |
| 25 | KINETIC CHARACTERIZATION OF HIV-1 REVERSE TRANSCRIPTASES EXPRESSING MUTATIONS SHOWN TO CONFER REDUCED SUSCEPTIBILITY TO PMEA (ADEFOVIR) IN VITRO Antiviral Therapy 1997;2 (Suppl 5):16 AS Mulato, PD Lamy, MD Fuller, T Cihlar, MD Miller and JM Cherrington In general, the enzyme kinetic data correlated with the in vitro antiviral susceptibility data. Processivity and fidelity assays have been established for the recombinant enzymes and further experiments are underway. |
| 26 | IN VITRO SELECTION AND CHARACTERIZATION OF HIV-1 VARIANTS WITH REDUCED SUSCEPTIBILITY TO PMPA Antiviral Therapy 1997;2 (Suppl 5):17 JM Cherrington1, R Chandok2, AS Mulato1, PD Lamy1, H Mitsuya3, and M Wainberg2 Previous animal studies showed that the K65R mutation developed in RT genes from SIV-infected macaques treated with PMPA, and conferred a fourfold increase in IC50 value for PMPA in vitro. Despite this mutation, the animals maintained suppression of viral replication and remain healthy at approximately 2 years post-infection. The potent antiretrovirus activity and favourable resistance profile of PMPA are being further investigated in ongoing clinical trials. |
| 27 | A STUDY OF REDUCED SENSITIVITY TO INHIBITORS OF HIV PROTEASE IN VIRUS ISOLATES FROM SELECTED PATIENTS AFTER THERAPY WITH SAQUINAVIR Antiviral Therapy 1997;2 (Suppl 5):17 C Craig, E Race, J Sheldon, L Whittaker, J Rose, S Gilbert, IB Duncan and N Cammack These findings suggest that selection of cross-resistance during therapy with saquinavir is not inevitable, and is relatively infrequent. Our results combined with ‘incidence of reduced sensitivity’ data from NV14256 suggest >85% of patients retain sensitivity to all PIs, and approximately 95% retain activity to at least one PI after 1 year of saquinavir/zalcitabine therapy. The use of current standards of treatment with two nucleoside analogues and saquinavir might be expected to reduce this further. |
| 28 | IMPACT OF THE P236L DELAVIRDINE RESISTANCE MUTATION ON HIV-1 REPLICATION AND REVERSE TRANSCRIPTASE FUNCTION Antiviral Therapy 1997;2 (Suppl 5):18 LM Demeter1, P Gerondelis1,2, RH Archer1, C Palaniappan3, RC Reichman1,2 and R Bambara2,3 These results suggest that the P236L mutation significantly impairs HIV-1 replication, and may offer an explanation for the infrequent occurrence of this mutation in clinical isolates during delavirdine therapy. Preliminary studies suggest that wild-type and P236L recombinant RT have similar specific activities for polymerization. Studies to determine the effect of this mutation on the ratio of RNase H/polymerase activity, RT fidelity and processivity are in progress. |
| 29 | COMPARISON OF GAG-POL PRECURSOR CLEAVAGE IN NATURALLY ARISING HIV-1 VARIANTS Antiviral Therapy 1997;2 (Suppl 5):19 Gregory Bloom1, Elena Perez2, Shefal Parikh1, Maureen M Goodenow2 and Ben M Dunn1 The results show that different rates of cleavage occur at sites A and C for different protease variants. By constructing chimeric Gag-Pol vectors, in which an efficient protease variant is paired with different Gag regions, it has been demonstrated that determinants outside of protease are critical to the efficiency of processing. This implies that the mechanism of drug resistance may include alterations in the polyprotein in general, as well as in the protease region. |
| 30 | ACQUISITION OF GENOTYPIC MUTATIONS ASSOCIATED WITH REDUCED SUSCEPTIBILITY TO PROTEASE INHIBITORS DURING SAQUINAVIR MONOTHERAPY Antiviral Therapy 1997;2 (Suppl 5):19 P Scott Eastman1, Ian B Duncan2, Chris Gee1 and Esther Race2 Loss of in vivo suppression of viral replication during saquinavir monotherapy is associated primarily with the development of an L90M mutation. A V82A mutation was observed only in the presence of a G48V mutation. The L90M mutation was lost in the presence of both the G48V and the V82A mutation. These results indicate the potential for switching from saquinavir to other protease inhibitors following viral load rebounds in the presence of an L90M mutation and the absence of a G48V mutation. The phenotypic and therapeutic consequences of V82A in the context of G48V remain to be established. Additionally, these results suggest a potential added benefit to saquinavir/ritonavir combination therapy beyond inhibition of cytochrome P450 metabolism of protease inhibitors. |
| 31 | COMPARATIVE STRUCTURAL ANALYSIS OF INHIBITOR COMPLEXES OF WILD-TYPE AND DRUG-RESISTANT HIV-1 PROTEASE MUTANTS: IS A PATTERN EMERGING? Antiviral Therapy 1997;2 (Suppl 5):20 John W Erickson, TN Bhat, R Randad, S Gulnik and B Yu Resistance to HIV-1 protease inhibitors is generally associated with the acquisition of one or more mutations in the active site of the enzyme upon prolonged exposure to drug. Initial studies on the structural effects of drug resistance-conferring mutations on inhibitor-enzyme interactions revealed a complex and idiosyncratic assortment of structural, electronic and solvation changes that can contribute to changes in the Ki, or free energy of binding, of an inhibitor with a particular mutant enzyme. |
| 32 | GENOTYPIC AND PHENOTYPIC CHARACTERIZATION OF HIV-1 STRAINS ISOLATED FROM IN VITRO SELECTION STUDIES WITH NEGATIVELY CHARGED ALBUMINS Antiviral Therapy 1997;2 (Suppl 5):20 José A Esté1,2, Cecilia Cabrera2, Dirk KF Meijer3, Bonaventura Clotet2, Jan Desmyter1, Dominique Schols1 and Erik De Clercq1 This phenomenon and the greater potency of Aco-HSA as an anti-HIV agent could explain the slower emergence of resistance to this compound than to Suc-HSA. We have previously selected strains that are resistant to virus-cell binding and fusion inhibitors such as dextran sulphate, AR177 and the bicyclam AMD3100, which share similarities in the mode of action with the NCAs but differ in the mutation patterns of the resistant strains. These results suggest that resistance to polyanions or to compounds that inhibit binding or fusion of HIV with CD4+ cells may not depend solely on the substitution of one or several specific amino acids but rather dependent on the overall change in the conformation of the gp120 molecule. |
| 33 | ANTIVIRAL AND RESISTANCE STUDIES OF RPR103611, AN INHIBITOR OF HIV REPLICATION Antiviral Therapy 1997;2 (Suppl 5):21 B Labrosse1, O Pleskoff1, N Sol1, C Jones1, Y Henin2 and M Alizon1 RPR103611 is to our knowledge the only chemical reagent blocking HIV-1 entry by affecting gp41, except for peptides such as DP-107 and DP-178, derived from the alpha-helix domain. Drugs acting on a gp41 target could be interesting candidates for the chemotherapy of HIV infection since gp41 is far more conserved than gp120 across HIV-1 strains. A critical parameter in determining the clinical efficacies of antiviral drugs is the rate of resistance development. We have isolated resistant variants of the HIV-1LAI after long-term passaging in the presence of RPR103611. The drug resistance was due to a non-conservative mutation at a highly conserved residue of gp41, suggesting that the genetic constraints on gp41 are much lower than expected. |
| 34 | THE INFLUENCE OF INCREASED REVERSE TRANSCRIPTASE FIDELITY OF CODON 184 VARIANTS USING COMPETITION EXPERIMENTS UNDER ANTIVIRAL PRESSURE Antiviral Therapy 1997;2 (Suppl 5):22 Wilco Keulen1, Monique Nijhuis1, Albert van Wijk1, Rob Schuurman1, Ben Berkhout2 and Charles Boucher1 In conclusion, with this novel approach we observe differences in the capacity to generate drug-resistant mutations between the 184 variants. However the outgrowth of the codon 184 variants was also observed in control competition experiments in the absence of drug. This indicates that the overall fitness of the codon 184 mutant variants is higher in supT1 cells than wild-type virus and that other factors than the capacity to generate secondary resistant mutations are responsible of the outgrowth of the lamivudine resistant variants. |
| 35 | DEVELOPMENT OF GENOTYPIC ZIDOVUDINE RESISTANCE DURING ZIDOVUDINE MONOTHERAPY AND ALTERNATING ZIDOVUDINE-DIDANOSINE THERAPY Antiviral Therapy 1997;2 (Suppl 5):22 Louise Bruun1, Terese Katzenstein2, Jan Gerstoft2, Court Pedersen2,3, Lars R Mathiesen3 and C Nielsen1 (1) As previously shown, the 70 mutation appeared as the first zidovudine-associated mutation during zidovudine therapy. During therapy the 70 mutation was replaced by mutations in codon 41 and 215. After 24 months of therapy the 70 mutation reappeared together with a mutation in codon 67. (2) Compared to zidovudine therapy, the 70 mutation was only present in a low proportion of the patients during alternating zidovudine-didanosine therapy. (3) Based on the phenotypic susceptibility of the isolated virus from PBMC, the appearance of the different combinations of mutations could be explained by outgrowth of virus with an increased level of phenotypic resistance. (4) The fact that no difference in phenotypic resistance and in viral load could be shown between zidovudine monotherapy and alternating therapy indicates that the presence of the 70 mutation in proviral DNA has a minor role after 6 months of zidovudine therapy. |
| 36 | DRUG SUSCEPTIBILITY AND SEQUENCE ANALYSIS OF NON-SUBTYPE B HIV-1 ISOLATES Antiviral Therapy 1997;2 (Suppl 5):23 S Palmer1,2, R Shafer2, A Alaeus3, S Cox1, TC Merigan2, D Katzenstein2 and J Albert1 Non-B subtype isolates of HIV-1 were similar in their drug susceptibility to RT inhibitors compared to subtype B isolates. Moreover, no drug-resistance mutations were observed in the RT genes of subtype A, C and D isolates from untreated patients. The reduced susceptibility to zidovudine of non-B subtype isolates from patients already receiving zidovudine may indicate development of zidovudine resistance mutations in these isolates. This study suggests that similar clinical benefits of anti-retroviral therapy might be anticipated in persons infected with subtypes of HIV-1 other than subtype B. |
| 37 | PHENOTYPIC AND GENOTYPIC RESISTANCE TO INDINAVIR IN INDIVIDUALS WITH ADVANCED HIV-1 DISEASE Antiviral Therapy 1997;2 (Suppl 5):24 L Ruiz1, M Nijhuis3, CAB Boucher3, T Puig1, S Marfil1, A Bonjoch2, D de Jong3, A Arnô1 and B Clotet1,2 In conclusion, we observed an initial response to indinavir in 76% of patients despite their advanced stage of the disease. This immunological and virological response was sustained in 54% of the patients at 24 weeks. A rebound in HIV-1 RNA levels was associated with a small increase in IC50 and 2-3 mutations in the protease gene. Explanations for failure in the absence of phenotypic or genotypic resistance may be low drug levels due to incomplete compliance or pharmacokinetic interactions. |
| 38 | MULTIPLE DIDEOXYNUCLEOSIDE ANALOGUE-RESISTANT HIV-1 IN EUROPE Antiviral Therapy 1997;2 (Suppl 5):25 JC Schmit1,2, B Clotet3, L Ruiz3, P Hermans4, S Sprecher4, V Arendt2, M Leal5, E Lissen5, T Harrer6, E De Clercq1, M Witvrouw1 and A-M Vandamme1 Multi-dideoxynucleoside analogue resistance under combination therapy is an emerging problem in European patients. Although treatment options are currently limited for patients harbouring multi-dideoxynucleoside analogue-resistant strains, a combination of two protease inhibitors may be a promising alternative. |
| 39 | MULTIPLE CONCURRENT RT AND PROTEASE MUTATIONS AND MULTIDRUG RESISTANCE IN HEAVILY TREATED HIV-1-INFECTED PATIENTS Antiviral Therapy 1997;2 (Suppl 5):25 RW Shafer, MA Winters and TC Merigan Simultaneous resistance to nearly all available anti-HIV drugs (including four protease inhibitors) may occur. The frequency of this phenomenon is not known, though it may be particularly common in patients who began therapy prior to the availability of potent three-drug combinations. The striking concordance of mutations in these multi-drug-resistant HIV-1 isolates suggests that these sets of RT and protease mutations provide a selective advantage in a variety of genetic contexts and in the presence of multiple different drug combinations. New drugs and drug regimens that are active against isolates with these mutations should be developed. |
| 40 | REDUCED SENSITIVITY OF CLINICAL ISOLATES OF HIV TO SAQUINAVIR IS ASSOCIATED ONLY WITH 48V OR 90M Antiviral Therapy 1997;2 (Suppl 5):26 J Sheldon, C Craig, E Race, L Whittaker, J Rose, A Moffatt, L Rawlings, IB Duncan and N Cammack Correlation between the saquinavir- resistance mutations (48V and 90M) and the accompanying compensatory changes was examined. During monotherapy with the current hard-gelatin formulation of saquinavir (1800mg/day), significant correlation (P<0.05, Chi-squared) was observed between 90M and specific residues at the polymorphic sites 10(I), 71(T/V) and, to a lesser extent, 63(P/Q/T). However, no significant correlation was found with these residues at higher doses of saquinavir or following combination therapy. Furthermore, isolates containing 90M plus 10I and/or 71T,V were no less sensitive to saquinavir than isolates containing 90M with consensus residues 10L and 71A, demonstrating their compensatory role. The presence of variation at these positions in pretreatment sequences does not predict the selection of 90M post-treatment. Correlative analysis will also be presented for the 48V mutation. |
| 41 | PHENOTYPIC CHANGES IN VIRAL ISOLATES TREATED WITH DELAVIRDINE TABLETS PLUS ZIDOVUDINE OR ZIDOVUDINE ALONE Antiviral Therapy 1997;2 (Suppl 5):26 LK Wathen, WW Freimuth, SR Cox, CA Greenwald, CL Daenzer, Y Wang, JM Mahrer and the Delavirdine Team These data establish that the 400 mg three times daily regimen of delavirdine tablets with zidovudine were effective in maintaining a relatively low rate of both delavirdine and zidovudine resistance. They also demonstrated that 400 mg three times daily was more effective in maintaining phenotypic susceptibility to delavirdine and zidovudine than the 300 mg dosage. |
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Session 3: New technologies for measuring resistance Abstracts 42 thru 55, Pages 28 to 36 |
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| 42 | THE PROTEASE-RT ANTIVIROGRAM™: SIMULTANEOUS DETECTION OF PHENOTYPIC (MULTI-) DRUG RESISTANCE OF PLASMA HIV-1 FROM PATIENTS TREATED WITH VARIOUS REVERSE TRANSCRIPTASE AND/OR PROTEASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):28 K Hertogs2, M-P de Béthune1, V Miller3, S Staszewski3, T Ivens1, H Azijn1, P Schel2, A Van Cauwenberge2, C Van den Eynde2, V van Gerwen2, M Van Houtte2, F Peeters2 and R Pauwels1,2 Phenotypic resistance testing can play an important role in the virological evaluation of new drugs (RT and PR inhibitors) and combinations of these drugs, in clinical trials. More extensive studies using the PR-RT Antivirogram™ as a tool for individualized patient management will be performed. The designed in vitro system will facilitate the rapid simultaneous phenotypic resistance determination for all RT and PR inhibitors on a large-scale basis |
| 43 | PERFORMANCE CHARACTERISTICS OF PHENOTYPIC DRUG RESISTANCE TESTING (ANTIVIROGRAM™) IN MONITORING OF ANTI-HIV THERAPY Antiviral Therapy 1997;2 (Suppl 5):28 K Hertogs1, M-P de Béthune2, V Miller3, B Larder4, S Kemp4 , S Bloor4, S Staszewski3, M Van Houtte1, F Peeters1 and R Pauwels1,2 We have designed an in vitro system facilitating rapid and simultaneous phenotyping for all RT and PR inhibitors on a large-scale basis. |
| 44 | RECOMBINANT RETROVIRAL SYSTEMS FOR RAPID IN VIVO ANALYSIS OF HIV-1 SUSCEPTIBILITY TO
REVERSE TRANSCRIPTASE AND PROTEASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):29 Chaofu Shi1, Rong Dong1 and John W Mellors1,2 Experiments have shown that (1) the recombinant viruses constructed proportionally represent starting virus mixtures; (2) the emergence of HIV variants resistant to RT or protease inhibitors can be detected in plasma samples; (3) drug-resistant viral quasispecies can be cloned and analysed phenotypically and genotypically at the clonal level; and (4) novel genetic mechanisms of drug resistance can be identified (for example lamivudine/zidovudine co-resistance). These systems can be used to characterize predominant as well as minor drug-resistant species in plasma, and correlate drug susceptibility phenotype with genotype at the clonal level. |
| 45 | NOVEL CLONAL ANALYSES OF RESISTANCE TO HIV-1 RT AND PROTEASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):30 J Martinez-Picado1,2, L Sutton2, A Hoes Helfant2, A Savara2, J Kaplan2 and RT D'Aquila2 Multiply-resistant mutants were not commonly found in bulk sequences from patients failing lamivudine/zidovudine/indinavir, but were found in 1/3 patients in clonal analyses. The novel deletion vectors facilitate clonal resistance analyses. Data analysis is faster with SSS than cycle sequencing and SSS offers advantages over hybridization-based genotyping. The potential for PCR misincorporation can be limited and monitored, but must be factored into interpretations of clonal analyses. |
| 46 | A 1 WEEK, SINGLE-CYCLE PROTEASE INHIBITOR RESISTANCE ASSAY Antiviral Therapy 1997;2 (Suppl 5):30 S Paulous, V Zennou and F Clavel We conclude that the SC-RVA described here is a fast, reliable method for phenotypic assessment of HIV resistance to PR inhibitors. It is currently being extended to RT inhibitor resistance testing and could prove useful for routine monitoring of antiretroviral treatments. |
| 47 | GENOTYPIC OR PHENOTYPIC SUSCEPTIBILITY TESTING MAY NOT PREDICT CLINICAL RESPONSES TO INDINAVIR Antiviral Therapy 1997;2 (Suppl 5):31 JH Condra, DJ Holder, DJ Graham, M Shivaprakash, DT Laird, WA Schleif, JA Chodakewitz and EA Emini These methods are generally unable to detect mutants comprising less than 10 to 25% of mixed populations. This pre-existing resistance was also undetectable phenotypically. Thus, standard viral genotypic and phenotypic assays may not adequately predict clinical responses to indinavir. The complexity of HIV viral populations and the insensitivities of available assays may thus limit the ability of in vitro techniques to predict clinical responses to antiviral therapy. |
| 48 | GENOTYPING AND PATTERN RECOGNITION OF HIV-1 AND MYCOBACTERIUM USING HIGH DENSITY OLIGONUCLEOTIDE ARRAYS Antiviral Therapy 1997;2 (Suppl 5):32 TR Gingeras1, P Small2, M Holodniy3 and J Drenkow1 The analysis of rpoB gene and the protease/reverse transcriptase genes using genotypic and pattern recognition capabilities of high density oligonucleotide arrays permits the simultaneous detection of drug resistance conferring mutations and speciation/clade identification in Mycobacterium and HIV-1. |
| 49 | STABILITY OF HIV RNA IN BLOOD SPECIMENS Antiviral Therapy 1997;2 (Suppl 5):33 Sally Land, Kim Sebire, Kate McGavin, Tracey Middleton and Chris Birch The ability to isolate HIV from PBMC was directly proportional to the RNA copy number. These results enable us to guide clinicians and laboratory staff as to the appropriate handling of specimens. |
| 50 | A COMPARISON OF COMMERCIAL HIV-1 RNA LOAD ASSAYS FOR BASELINE VALUES, PRIOR TO COMMENCING THERAPY IN A CLINIC POPULATION WITH EPIDEMIOLOGICAL EVIDENCE OF NON-CLADE B VIRUS Antiviral Therapy 1997;2 (Suppl 5):37 C Loveday1, H Devereux1, A Burke1, L Dann1 and M Johnson2 In these patients we concluded the RT-PCRnb gave the highest signal and detection rates, however this cross-sectional analysis does not allow comment on evolution of these subtypes with time and thus the reliability of longitudinal measures. Further work is underway to sequence and subtype these patient samples and to follow them over time to identify the best approach for virological follow-up of their antiretroviral therapy. |
| 51 | DETECTION OF HIV-1 RNA IN THE PLASMA OF PATIENTS IN WHOM HIV-1 RNA IS UNDETECTABLE USING COMMERCIAL ASSAYS Antiviral Therapy 1997;2 (Suppl 5):34 V Natarajan1, HC Lane2, DP O'Neill1, RL Dewar1, JA Metcalf2, S Vogel2, C Bechtel2, J Mican2, D Ward, J Rosenthal3 and JA Kovacs4 Plasma HIV-1 RNA can be detected in the majority of patients in whom levels are undetectable using commercial assays. Persistent low-level HIV-1 replication can occur in many patients despite the use of highly active antiretroviral therapy combinations. Changes in titres of HIV-1-specific antibodies may prove to be a sensitive technique for determining the persistence of HIV-1. |
| 52 | DETECTION AND QUANTIFICATION OF NUCLEOSIDE ANALOGUE RESISTANCE MUTATIONS USING THE HIV-1 REVERSE TRANSCRIPTASE LINE PROBE ASSAY ON LONGITUDINAL PATIENT SAMPLES Antiviral Therapy 1997;2 (Suppl 5):34 Rob Schuurman, Loek de Graaf, Jolanda Tijnagel and Charles Boucher The HIV-1 RT LiPA can be used to study the emergence of drug resistance mutations in longitudinal samples of patients receiving antiretroviral therapy with nucleoside inhibitors. Automated quantitative interpretation of the results may further improve application of the assay. |
| 53 | VALIDATION OF A HIV-1 DRUG RESISTANCE GENOTYPING PROCEDURE Antiviral Therapy 1997;2 (Suppl 5):35 G Sitbon, A Lindén, C Moberg, H Persson and J Lönngren In summary, this procedure is a valuable asset for patient care and in clinical studies as required by the latest development in treatment regimens |
| 54 | GENETIC VARIABILITY OF THE HIV-1 RT REGION, SUBTYPE B VERSUS NON-B, AT DRUG-RESISTANT CODON POSITIONS Antiviral Therapy 1997;2 (Suppl 5):36 Lieven Stuyver1, Annelies Rombout1, Ann Wyseur1, Rita Verhelst1, Anne Schoolmeester1, Annemie Vandamme2, Martine Peeters3, Raymond Schinazi4, Chris Verhofstede5 and Rudi Rossau1 One polymorphism (third position) was found in genotype E samples at T215; however, this motif was also occasionally found in subtype B and C. In adjacent codons, some motifs tended to be genotype-specific. These polymorphisms are as yet not included in the LiPA HIV-1 RT, and are responsible for the absence of reactivity at probes targeting the corresponding drug-resistant codon positions. |
| 55 | COMPARISON OF THE LINE PROBE HIV-1 REVERSE TRANSCRIPTASE ASSAY, SELECTIVE PCR AND DIRECT SOLID PHASE SEQUENCING FOR THE DETECTION OF HIV-1 DRUG RESISTANCE MUTATIONS Antiviral Therapy 1997;2 (Suppl 5):36 JC Schmit1, L Ruiz2, L Stuyver3, K Van Laethem1, I Vanderlinden1, J Martinez-Picado2, R Rossau3, J Desmyter1, E De Clercq1, B Clotet2 and AM Vandamme1 LiPA detected more mixtures of wild-type and mutant, a finding which could not be confirmed by direct sequencing. In our study, the LiPA HIV-1 RT test proved to be an interesting and reliable alternative to DNA sequencing or selective PCR for the detection of drug resistance mutations in HIV samples from patients. |
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Session 4: Combination therapy and its failure Abstracts 56 thru 90, Pages 37 to 60 |
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| 56 | ZIDOVUDINE PLUS DIDANOSINE IN PATIENTS WITH PRIMARY HIV INFECTION: EMERGENCE OF GENOTYPIC REVERSE TRANSCRIPTION RESISTANCE Antiviral Therapy 1997;2 (Suppl 5):37 S Yerly1, G Schockmel1, G Tambussi3, P Hermans2, A Lazzarin3, N Clumeck2, B Hirschel1 and L Perrin1 This study confirms that complete suppression of viraemia is required to prevent emergence of resistance mutations. Patients with resistance mutations already had higher HIV RNA and lower CD4/CD8 ratio at baseline. Emergence of didanosine-associated mutations was observed in one patient only. |
| 57 | ZIDOVUDINE PLUS DIDANOSINE PLUS NEVIRAPINE VERSUS ZIDOVUDINE PLUS DIDANOSINE IN ANTIRETROVIRAL-NAIVE PATIENTS WITH VERY ADVANCED DISEASE (TRIAL ISS 047) Antiviral Therapy 1997;2 (Suppl 5):37 S Vella, M Floridia, C Tomino, V Fragola, R Bucciardini, D Ricciardulli, LE Weimer, MC Galluzzo, G Giannini, MF Pirillo, M Andreotti and M Giuliano for the ISS 047 Study Group The present trial, conducted on treatment-naïve patients with advanced HIV disease, show that even in this particular population of patients with high baseline viral load, a triple combination based on reverse transcriptase inhibitors can produce pronounced and sustained effect on virological and immunological markers. |
| 58 | HIV-1 DRUG RESISTANCE AND VIROLOGICAL FAILURE DURING COMBINATION THERAPY WITH NEVIRAPINE, ZIDOVUDINE AND DIDANOSINE Antiviral Therapy 1997;2 (Suppl 5):38 VA Johnson1, DR Kuritzkes2, DD Richman3, MS Hirsch4, MA Fischl5, V DeGruttola6 and RT D‘Aquila4 for the ACTG 241 Virology Team Patients starting triple therapy with minimum zidovudine resistance evolved fewer nevirapine-selected mutations over 48 weeks. Didanosine resistance mutations did not explain loss of plasma HIV-1 RNA response in either treatment arm. Nevirapine resistance mutations continued to evolve through week 48. Resistance to each component agent in the triple therapy was not required for virological failure. |
| 59 | HIV-1 RNA QUANTIFICATION IN 1280 PATIENTS IN THE DELTA TRIAL AND RELATIONSHIP TO CLINICAL OUTCOME Antiviral Therapy 1997;2 (Suppl 5):39 Jean-Pierre Aboulker for the Delta Coordinating Committee and Virology Group The virological response in the first 16 weeks was highly predictive of clinical outcome. CD4 cell counts were also highly predictive. |
| 60 | PREDICTION OF LONG-TERM HIV RNA SUPPRESSION DURING ZIDOVUDINE/ LAMIVUDINE TREATMENT Antiviral Therapy 1997;2 (Suppl 5):40 M Opravil1, R DeMasi2 and A Hill2 Treatment with zidovudine/lamivudine induced sustained reductions in HIV RNA <400 copies/ml mainly in patients with baseline HIV RNA under 5,000 copies/ml. These results emphasize the need for combining zidovudine/lamivudine with protease inhibitors to achieve sustained HIV RNA undetectability, particularly in pretreated patients and in those with high baseline HIV RNA. |
| 61 | VALIDATION OF HIV-1 RNA AND CD4 COUNT AS SURROGATE MARKERS IN THE CAESAR TRIAL: PRELIMINARY RESULTS Antiviral Therapy 1997;2 (Suppl 5):40 Julio Montaner1, Ralph DeMasi2, Debra Dawson2 and Andrew Hill2 on behalf of the CAESAR Coordinating Committee The combination of rises in CD4+ cell count and reductions in HIV-1 RNA predicted nearly all of the effect of lamivudine on reducing progression to AIDS/death. The power of HIV-1 RNA and CD4+ cell levels to predict clinical benefit is very strong, compared to markers in other disease areas. |
| 62 | THE DURABILITY OF RESPONSE TO PROTEASE INHIBITOR THERAPY IS PREDICTED BY VIRAL LOAD Antiviral Therapy 1997;2 (Suppl 5):41 D Kempf1, R Rode1, Y Xu1, E Sun1, A Japour1, S Danner2, C Boucher3, J Leonard1 and A Molla1 The results of this study indicate that the degree of suppression of viral replication, as measured by plasma viral RNA, is predictive of the durability of maximal response to treatment. Viral load determinations at intermediate time points may therefore serve as a prognosticator for the time to eventual viral rebound on protease inhibitor therapy. These results may provide the basis for therapeutic strategies wherein initial treatment regimens with protease inhibitors may be intensified in the subset of patients with incomplete viral suppression by additional antiretroviral therapy before the emergence of high level resistance. |
| 63 | CONTINUED EVOLUTION OF HIV-1 DURING COMBINATION THERAPY DESPITE LEVELS OF HIV-1 RNA <500 COPIES/ML Antiviral Therapy 1997;2 (Suppl 5):41 H Imamichi1, Y-M Zhang1, HC Lane2, J Falloon2 and NP Salzman1 The drastic reduction in the total number of rounds of virus replication that occur during drug therapy and the requirement for the accumulation of at least three mutations to confer protease drug resistance is consistent with the extended time required for drug resistant virus to emerge. The evolution of HIV in the presence of active combination therapy indicates continued virus replication despite HIV-1 RNA levels <500 copies/ml. |
| 64 | CLINICAL RESPONSE AND GENOTYPIC RESISTANCE PATTERNS OF SEQUENTIAL THERAPY WITH NELFINAVIR FOLLOWED BY INDINAVIR PLUS NEVIRAPINE IN SAQUINAVIR/REVERSE TRANSCRIPTASE INHIBITOR-EXPERIENCED PATIENTS Antiviral Therapy 1997;2 (Suppl 5):42 Jody Lawrence1, Jonathan Schapiro1, Rick Pesano1, Mark Winters1, Pat Cain1, Dean Winslow2 and Thomas C Merigan1 The transient response to nelfinavir may be due to limitations in adding new RTIs and to cross-resistance between protease inhibitors. While mutations at codon 30, and 90 plus others, appeared to be associated with nelfinavir failure in some patients, no clear genotypic pattern was identified which predicted clinical response in others. Preliminary data suggest patients failing saquinavir and nelfinavir respond to indinavir plus nevirapine, but durability is still being assessed. |
| 65 | GENOTYPIC ANALYSIS OF HIV-1 PROTEASE FROM PATIENTS FAILING HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY: PRELIMINARY ANALYSIS Antiviral Therapy 1997;2 (Suppl 5):43 Benjamin Young, Steven Johnson, Minoo Bakhtiari, David Shugarts, Russell Young, Michael Allen and Daniel Kuritzkes Mutations in PR and RT were common in patients with clinical failure of combination therapy. However, the number of observed mutations in PR was lower than expected. These data suggest that relatively few PR mutations are required for treatment failure. Mutations at codon 90 were common, despite the relatively infrequent use of saquinavir. Clinical failure in the absence of resistance mutations implies inadequate drug exposure due to pharmacologic factors or poor compliance. |
| 66 | EMERGENCE OF DRUG RESISTANCE IN DIFFERENT TISSUE COMPARTMENTS IN 10 PATIENTS USING POPULATION-BASED SEQUENCING AFTER 1 YEAR OF POTENT ANTIRETROVIRAL THERAPY Antiviral Therapy 1997;2 (Suppl 5):43 H Günthard1, J Wong1, C Ignacio1, D Havlir1,3 and D Richman1,2 Complete suppression of viral replication during 1 year of triple therapy in three patients with plasma RNA levels below the limit of detection was reflected by the lack of emergence of the otherwise rapidly emerging M184V lamivudine mutation in LN DNA and RNA. Concordance at resistance positions in HIV-1 pol generated by population-based sequencing from different compartments (RNA/DNA) was high. The lower match in the RT region is due to a higher viral replication and therefore higher selection pressure in patients on zidovudine/lamivudine alone, which enhances the development of mixed viral populations. Sequences directly generated from clinical samples were more likely to reveal resistance than sequences from viral stocks because isolation conditions favour the growth of wild-type virus from mixtures. The viral diversity in partially suppressed patients was higher than in poorly suppressed ones, consistent with studies of natural history. |
| 67 | CLINICAL, IMMUNOLOGICAL AND VIROLOGICAL OUTCOMES IN ACTG 320, A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF INDINAVIR IN COMBINATION WITH TWO NUCLEOSIDES IN HIV-1-INFECTED PERSONS WITH CD4+ CELL COUNTS ≤200/MM3 Antiviral Therapy 1997;2 (Suppl 5):44 SM Hammer, LM Demeter, MA Fischl, KE Squires, RJ Bosch and MD Hughes for the ACTG 320 Study and Virology Substudy Teams Firstly, the indinavir plus zidovudine plus lamivudine combination (with the option to substitute stavudine for zidovudine) is superior to zidovudine (or stavudine) plus lamivudine in delaying clinical HIV-1 disease progression. Secondly, HIV-1 disease marker responses parallel the clinical results. Thirdly, ACTG 320 provides the clinical confirmation of previous marker studies (Merck 035 and 039) and will permit a detailed correlation of plasma HIV-1 RNA levels, CD4+ cell counts and antiretroviral resistance with clinical outcome for an indinavir-containing three-drug combination. |
| 68 | FIRST-LINE TREATMENT WITH ZIDOVUDINE/LAMIVUDINE OR STAVUDINE/LAMIVUDINE RAPIDLY LEADS TO LAMIVUDINE RESISTANCE EVEN IN PATIENTS WITH A SERUM HIV RNA LOAD BELOW 50,000 COPIES/ML Antiviral Therapy 1997;2 (Suppl 5):45 J Jacques de Jong1, N Foudraine2,3, R Huismans1, E Baan1, A van der Schoot1, JMA Lange2 and F de Wolf1 The results of this study suggest otherwise. Even in a patient with an initial serum HIV RNA load below 4,000 copies/ml, the lamivudine resistance mutation appeared rapidly. A serum HIV load at the start of therapy below 50,000 copies/ml does not preclude the rapid emergence of lamivudine resistance during first line therapy with zidovudine/ lamivudine or stavudine/lamivudine. It thus seems unwarranted to initiate antiretroviral therapy with lamivudine-containing double nucleoside combinations. |
| 69 | ADDITION OF SAQUINAVIR SOFT GEL CAPSULE TO EXISTING ANTIRETROVIRAL THERAPY: VIROLOGICAL PREDICTORS OF RESPONSE Antiviral Therapy 1997;2 (Suppl 5):45 S Deeks1, S Eastman2, C Horton1, C Gee2, L Fischer3, M Salgo3 and R Grant4 These results provide evidence of the potency of saquinavir SGC in patients with prior ARV experience. When adding saquinavir SGC alone to a stable or failing ARV regimen, high baseline viral RNA is the best predictor of a transient response to saquinavir SGC, supporting the recommendation that nucleoside analogues should be changed when initiating protease inhibitor (PI) therapy. Observed viral genotypes at week 24 suggest that these patients may respond to other PI agents. |
| 70 | HIV-1 DELAVIRDINE SUSCEPTIBILITIES DURING THERAPY WITH DELAVIRDINE PLUS ZIDOVUDINE, DELAVIRDINE PLUS DIDANOSINE, OR DELAVIRDINE PLUS ZIDOVUDINE PLUS DIDANOSINE (ACTG 261) Antiviral Therapy 1997;2 (Suppl 5):46 LM Demeter1, W Scott2, M Nokta3, RJ Bosch4, E Fisher2, G Friedland5, MA Fischl2, RB Pollard3, WW Freimuth6 and B Griffith5 There appeared to be a delay in the development of HIV isolates with increased delavirdine IC50 values in the delavirdine + zidovudine + didanosine arm (three group comparison of median delavirdine IC50 by non-parametric Kruskal-Wallis test: P=0.007 at 4 weeks, P=0.035 at 48 weeks). Phenotypic susceptibility studies of isolates from additional patients, and sequence analysis of the reverse transcriptase genotype are in progress. |
| 71 | GENOTYPIC RESISTANCE IN ALTIS 2 (STAVUDINE/LAMIVUDINE) TRIAL Antiviral Therapy 1997;2 (Suppl 5):47 D Descamps1, V Calvez2, R Lancar3, A Cécille2, MA Valantin2, F Damond1, A Coutellier2, C Longuet1, M De Sa2, M Bonmarchand2, S Matheron1, D Costagliola3, F Brun-Vézinet1 and C Katlama2 At week 24, mutation at codon 184 (M184V/I) appeared in all but two patients; no mutations associated with stavudine resistance were observed (I50T, V75T) and no MDR mutations was present except in one patient (V75I). Statistical analyses are in progress to evaluate the role of zidovudine, didanosine or zalcitabine resistance associated mutations at baseline on CD4 and viral load responses to stavudine and lamivudine combination. |
| 72 | GENOTYPIC ANALYSIS OF HIV PROTEASE IN PATIENTS UNDERGOING COMBINATION THERAPY WITH
SAQUINAVIR AND NELFINAVIR Antiviral Therapy 1997;2 (Suppl 5):47 IB Duncan1, AK Patick2, S Gilbert1, G Sitbon3, N Cammack1, S Kravcik4 and W Cameron4 Compliance was a particular issue in this patient, along with some others in the study, which together with the added dimension of RT inhibitor use complicates the assessment of this protease inhibitor combination. However, the absence of the D30N substitution or a new genotypic pattern are noteworthy. |
| 73 | EFFICACY OF DRUG COMBINATION AND DOSING REGIMEN IN ANTIVIRAL THERAPY Antiviral Therapy 1997;2 (Suppl 5):48 Paulina Essunger1, Martin Markowitz2, David D Ho2 and Alan S Perelson1 We define a new parameter in HIV therapy-related dynamics, the relative efficacy (RE) of a drug combination or dosing regimen, and describe how to determine RE with two serial HIV RNA measurements. We propose RE measurement as a rapid and precise method of assessing a new antiretroviral agent and determining the most effective dosing. |
| 74 | INFLUENCE OF BASELINE VIRAL LOAD IN THE PEAK REDUCTION OF PLASMA RNA VIRAEMIA WITH ANTIRETROVIRAL THERAPY (NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR) Antiviral Therapy 1997;2 (Suppl 5):48 F García1, JM Gatell1, C Vidal2, M Leal3, B Clotet4, T Pumarola2, JM Miró1, J Mallolas1 and C Tortajada1 These data suggest that the reduction of viral load with a two drug regimen is higher in patients with a high level BVL than in patients with a low level BVL |
| 75 | EMERGENCE OF RESISTANT PROTEASE ALLELES AND VARIANT GAG SEQUENCES IN HIV-1-INFECTED CHILDREN ENROLLED IN PROTEASE INHIBITOR PHASE I/II CLINICAL TRIALS Antiviral Therapy 1997;2 (Suppl 5):49 E Perez1, S Lamers1, M Heath-Chiozzi2, B Mueller3, P Pizzo3, B Dunn1, J Sleasman1 and M Goodenow1 We found no evidence of multiple resistant changes occurring together before drug therapy. Because resistance to PI may map to regions outside of protease, we studied the variability of Gag, p6, p7 and cleavage sites B-F. We found length variation in p7, and overall more variation in gag regions than in protease. Cleavage site C is the most variable, while other sites are, in general, conserved over time. Because HIV-infected children have higher viral loads compared with adults, PI therapy is unlikely to suppress viral replication completely. An understanding of the emergence of resistant viruses is an important component of paediatric antiretroviral therapy. |
| 76 | FAILURE OF THE ASSOCIATION OF RITONAVIR AND SAQUINAVIR IN MULTI-EXPERIENCED HIV-1-INFECTED PATIENTS Antiviral Therapy 1997;2 (Suppl 5):50 V Calvez1, A Coutellier2, P Bossi1, M Bonmarchand2, S Herson2 and JM Huraux1 In conclusion, the association of ritonavir and saquinavir was well tolerated, but the effect of this treatment was transitory and is not recommended as bitherapy. This combination must be evaluated in association with two nucleoside analogues. |
| 77 | MULTIDRUG-RESISTANT HIV-1 ISOLATES FROM PATIENTS WITH RISING PLASMA VIRAL BURDEN DURING DOUBLE OR TRIPLE COMBINATION THERAPY IN CLINICAL PRACTICE Antiviral Therapy 1997;2 (Suppl 5):50 VA Johnson1, CD Nail1, JD Hazelwood1, M Marangos2, R Smith2, M Thompson2 and JL Koel1 Virological failure was associated with detection of multiple RT/PI mutations during combination therapy. Virological failure was not uniformly linked to detectable genotypic resistance to each component agent in the current two- or three-drug regimen. Lamivudine-experienced patients who stopped lamivudine therapy (i.e. ≥3-4 months prior to specimen collection) lacked a predominant lamivudine-selected M184V RT codon mutation in their PBMC-derived viruses, suggesting that reversion of this genotypic mutation occurs rapidly within this RT region. The implication for ‘recycling’ selected therapies is unknown and deserves study. The role of genotypic analysis of viruses from HIV-1-infected patients in the clinical arena requires further investigation. |
| 78 | STOCHASTIC EFFECTS IN THE EVOLUTION OF HIV-1 PROTEASE SEQUENCES UNDER INDINAVIR THERAPY Antiviral Therapy 1997;2 (Suppl 5):51 Andrew J Leigh Brown1 and Jon H Condra2 The Neighbor-Joining algorithm revealed clusters in baseline sequences but these generally did not persist in later samples, suggesting a strong stochastic influence in the acquisition of resistance. Unexpectedly, despite the number of sites involved in resistance, some new associations were formed in the latest samples. The reduced amino acid distances (3%; down from 5% in week 24) between these sequences indicate a substantial degree of parallel evolution. More detailed analysis of patient-derived sequences will be required to reveal the pathways by which this has occurred. |
| 79 | HIV-1 ZIDOVUDINE PHENOTYPIC RESENSITIZATION IN THE DELTA LAMIVUDINE ROLL-OVER STUDY Antiviral Therapy 1997;2 (Suppl 5):51 B Masquelier for the French ANRS Antiretroviral Resistance Study Group and the Delta Coordinating Committee and Virology Group In this studied population, zidovudine resensitization might be considered as a frequent event but submitted to qualitative and temporal variation. |
| 80 | DRUG RESISTANCE GENOTYPES FROM PLASMA VIRUS OF HIV-INFECTED PATIENTS FAILING COMBINATION DRUG THERAPY Antiviral Therapy 1997;2 (Suppl 5):52 DL Mayers1, DL Gallahan2, GJ Martin3, WW Emmons4, RCY Chung5, KM Spooner3, JA Newton4, NE Aronson5 and OS Weislow2 These results show that more than 50% of patients failing combination drug regimens containing an HIV-1 protease inhibitor have no genotypic evidence of protease resistance. Potential reasons for this include: poor drug potency, poor drug absorption, enhanced drug metabolism via P450 enzyme induction, non-compliance with the drug regimen and enhanced viral virulence in late-stage HIV-infected patients. A pharmacokinetic study of patients failing indinavir-containing drug regimens is being initiated to address the issue of drug absorption/metabolism versus non-compliance as a cause of failure in patients on combination drug regimens. |
| 81 | INCIDENCE OF HIV-1 RESISTANCE AND CROSS-RESISTANCE TO PROTEASE INHIBITORS AFTER INDINAVIR FAILURE: IMPACT ON SUBSEQUENT RITONAVIR/SAQUINAVIR COMBINATION THERAPY Antiviral Therapy 1997;2 (Suppl 5):53 V Miller1, K Hertogs2, M-P de Bèthune3, R Pauwels2,3, T Ivens3, H Azijn3, C Schlecht1, B Nolde1, M Stürmer1, B Morgenstern1, M Kortenbusch1 and S Staszewski1 Virological failure to indinavir therapy was associated with detectable levels of phenotypic resistance to indinavir in approximately half of the patients. Cross-resistance to other PI's was extensive but not predominantly correlated with genotypic changes associated with resistance to specific compounds. No virological response was observed in patients with high saquinavir resistance. A proportion of patients sensitive to both saquinavir and ritonavir did not respond virologically at week 4. Longer follow-up data will be presented. |
| 82 | DUAL RESISTANCE TO ZIDOVUDINE AND LAMIVUDINE UNDER ZIDOVUDINE/LAMIVUDINE COMBINATION THERAPY: ASSOCIATION WITH CLINICAL PROGRESSION Antiviral Therapy 1997;2 (Suppl 5):53 V Miller and A Phillips for the FASP Resistance Study Group These results are based on a small number of patients and need to be confirmed in larger, prospective studies which include phenotypic and genotypic resistance analysis. The possibility that a more complete genotypic analysis, including recently described novel mutations at the 5′ and 3′ end of RT will affect the predictive value of genotypic patterns should be considered. |
| 83 | CHARACTERIZATION OF HIV-1 PROTEASE MUTATIONS, COMPLIANCE AND DRUG CONCENTRATIONS IN PATIENTS WHO HAVE AN HIV RNA REBOUND ON RITONAVIR-SAQUINAVIR Antiviral Therapy 1997;2 (Suppl 5):54 A Molla1, M Korneyeva1, T Chernyavskiy1, R Colgrove2, PH Chung2, A Japour1,2, J Mellors3, Y Xu1, R Rode1, A Hsu1, GR Granneman1, D Kempf1, J Leonard1, E Sun1 and the M96-462 Study Team There were no significant differences in HIV RNA response between the treatment arms. As there was no relationship between dose and the appearance of mutations, the plasma concentrations of ritonavir and saquinavir were examined for each subject and compared with concentrations for the respective dose group. Two of the five subjects had trough ritonavir and saquinavir concentrations consistently and substantially lower than the median concentrations of their respective dose groups throughout the 24-week period. Taken together, our data suggests viral rebound associated with resistance to protease inhibitors can be reversed by early intensification with additional agents. |
| 84 | PRESENCE OF MUTATION AT CODON 90 MAY PREDICT RESPONSE TO RITONAVIR/SAQUINAVIR COMBINATION IN HIV SEROPOSITIVE PATIENTS PRETREATED WITH SAQUINAVIR MONOTHERAPY Antiviral Therapy 1997;2 (Suppl 5):55 AS Pym1, DR Churchill1, S Galpin1, S Kaye2, B Wills3, P King3, S Coles4 and JN Weber1 (1) Despite prolonged pre-treatment with saquinavir monotherapy for a median 4.9 years, a proportion of patients had no L90M or G48V mutation and responded to the addition of ritonavir. (2) Acquisition of an L90M mutation following extensive pre-treatment with saquinavir monotherapy was associated with a transient response to ritonavir plus saquinavir. |
| 85 | ANALYSIS OF GENETIC CORRELATES OF VIRAL LOAD REBOUND IN PATIENTS TREATED WITH SAQUINAVIR OR SAQUINAVIR PLUS ZALCITABINE Antiviral Therapy 1997;2 (Suppl 5):56 E Race1, JSL Rose1, JG Sheldon1, AR Moffat1, SM Gilbert1, LA Rawlings1, PS Eastman2 and IB Duncan1 Most cases of breakthrough on monotherapy were accompanied by mutations associated with reduced sensitivity to saquinavir, however such mutations have not been found to guarantee rebound. In combination therapy rebound was associated more clearly with a change in RT sequence. Studies are in progress to investigate the role of other factors such as mutations in other regions of the HIV genome and immunological parameters. |
| 86 | ANTIVIRAL EFFECT OF ZIDOVUDINE PLUS LAMIVUDINE COMPARED WITH STAVUDINE PLUS LAMIVUDINE IN ZIDOVUDINE-EXPERIENCED HIV-1-INFECTED PATIENTS Antiviral Therapy 1997;2 (Suppl 5):56 S Rusconi, L Milazzo, L Testa, M Galazzi, S Kurtagic, M Moroni, M Galli and A d‘Arminio-Monforte Cell cultures were positive in all of the subjects at the baseline and T3, and the MT-2 test always showed a non-SI HIV-1 isolate, with the exception of a patient who maintained almost 50,000 copies/ml of HIV-1 RNA in plasma. A further analysis of the development or reversion of drug resistance will be conducted from plasma and cell culture supernatants that were obtained at the same time points. So far, virological markers showed a rebound in viral load after the first month of treatment within patients belonging to group 2. |
| 87 | CLINICAL AND GENOTYPIC CROSS-RESISTANCE BETWEEN THE PROTEASE INHIBITORS SAQUINAVIR AND INDINAVIR Antiviral Therapy 1997;2 (Suppl 5):57 Jonathan M Schapiro, Mark Winters, Jody Lawrence, Jane Norris and Thomas C Merigan Prolonged saquinavir use in the presence of elevated viral load resulted in the development of multiple resistance mutations, some of which could lead to early failure of other protease inhibitors. Despite this, indinavir therapy can still effectively suppress viral load in these patients with a continued response up to 24 weeks with the addition of two reverse transcriptase inhibitors. The effect of these mutations on the durability of the response remains to be determined. |
| 88 | EFFICIENCY AND TOLERANCE OF TRIPLE DRUG COMBINATIONS COMPARED TO TWO DRUG COMBINATIONS OR ZIDOVUDINE MONOTHERAPY IN HIV-1 INFECTION Antiviral Therapy 1997;2 (Suppl 5):58 JC Schmit, K Kleiber, T Staub, V Arendt, E Fontaine, JM Plesséria, C Lambert, P Kirpach, P Chen, D Ninove, F Schneider and R Hemmer In conclusion, triple drug combinations result in a more prolonged plasma virus suppression in a higher proportion of patients, compared to two drug treatments or monotherapy, although the results are less favourable than expected from controlled trials in selected populations. In ‘real life situations’, a low frequency of drug side effects, treatment compliance and absence of previous drug exposures seem to be crucial points in achieving a good treatment response. Even if virus suppression is obtained in plasma, increases in CD4+ cell counts remain generally moderate, suggesting that additional immune function restoring treatments might be necessary. |
| 89 | HIV-1 POL GENOTYPING BY DNA SEQUENCING IN PATIENTS WITH TRIPLE COMBINATION ANTIRETROVIRAL TREATMENT IN WHOM VIRAL LOAD REMAINS HIGH AFTER 6 MONTHS OF THERAPY Antiviral Therapy 1997;2 (Suppl 5):58 PA Vial1, K Liegmann3, LM Noriega1, C Vial1, G Acuña1, A Marcotti2, O Palacios1 and P Bean3 During treatment, resistance mutations were detected at RT codons 41, 67, 70, 210 and 215 and protease codons 10, 12, 63 and 82. This patient remained asymptomatic and his CD4+ counts increased steadily from 340/mm3 to 1,050/mm3. In this cohort, the development of multiple resistance mutations resulted in persistent high viral loads; all patients remained asymptomatic, with variable CD4+ changes. |
| 90 | CROSS-SECTIONAL STUDY OF PHENOTYPIC RESISTANCE TO REVERSE TRANSCRIPTASE INHIBITORS IN SUBJECTS ON LONG-TERM LOVIRIDE AND ZIDOVUDINE Antiviral Therapy 1997;2 (Suppl 5):59 M Youle1, R Pauwels2, M Van Houtte2, P Stoffels3, B Gazzard1, S Davies1 and W Sawyer1 Subjects who take antiretrovirals for extended periods develop a degree of phenotypic resistance. Our data suggests that exposure to one non-nucleoside (loviride) may result in cross resistance to other drugs of the same class (nevirapine) to which the patient had not been exposed, clinical evidence of a previously suggested theoretical phenomenon. |
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Session 5: Pathogenesis dynamics and transmission Abstracts 91 thru 118, Pages 61 to 77 |
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| 91 | ANALYSIS OF STEADY STATE LEVELS AND DECAY RATES OF LATENT VIRAL RESERVOIRS IN HIV-INFECTED INDIVIDUALS Antiviral Therapy 1997;2 (Suppl 5):61 Diana Finzi and Robert F Siliciano We have therefore examined the latent viral reservoirs in patients on effective antiretroviral therapy. By comparing cross-sectional data on treated patients with previous measurements of blood and tissue reservoirs in patients with detectable plasma RNA, we have obtained preliminary estimates of the half-life of this viral reservoir. |
| 92 | SELECTION OF HIV-1 VARIANTS WITH INCREASED FITNESS DURING RITONAVIR THERAPY Antiviral Therapy 1997;2 (Suppl 5):61 Monique Nijhuis1, Rob Schuurman1, Dorien de Jong1, Pauline Schipper1, Sven Danner2 and Charles Boucher1 We have demonstrated initial selection of drug resistant variants with a reduced replication efficiency relative to wild-type. However continuous antiviral therapy resulted in the selection of variants with an increase in the replication efficiency; the replication capacity of these variants was even higher than wild-type. Selection of these variants with an increase in the replication efficiency compared with wild-type indicates that they were not present in the viral population before start of therapy but were generated and selected during ritonavir therapy. In conclusion, continuous antiviral therapy may result, after an initial decrease in fitness, in the selection of variants with an increased fitness compared with wild-type. |
| 93 | HIV GENOTYPIC VARIATION IN PLASMA AND VAGINA LAVAGES IN RESPONSE TO ANTIRETROVIRAL THERAPY Antiviral Therapy 1997;2 (Suppl 5):62 RF Schinazi1, RM Lloyd Jr1, LM Hough1, JL Lennox2, C Hart3, L Stuyver4, TV Ellerbrock3 and the EVE Study Group To date, no mutations have been detected in vaginal lavage specimens from multiple visits in three of four women. In one women, changes at codons M184V (GTG) and T70R (AGA) occurred simultaneously in plasma and vaginal lavage. This information supports the hypothesis that HIV in vaginal secretions is produced locally. Since resistance is less likely to occur in cells with a slow rate of viral replication, we suspect that tissue macrophages or dendritic cells may be the primary reservoir of HIV in the vagina. |
| 94 | CCR5 GENOTYPE AND OTHER RISK FACTORS FOR HIV-1 TRANSMISSION AND PROGRESSION TO AIDS Antiviral Therapy 1997;2 (Suppl 5):63 H Blaak1, AM de Roda Husman1, M Koot1, R van Rij1, AB van't Wout1, IPM Keet2, M Cornelissen3, J Goudsmit3, RA Coutinho2 and H Schuitemaker1 The PBMC from five of these eight non-recipients and of one of the three R had an equal or even lower susceptibility than PBMC from healthy CCR5 Δ32 heterozygous blood donors. Three individuals (all non-recipients) also had a CCR5 Δ32 heterozygous genotype. All three recipients with reduced susceptible PBMC had partners with high cellular load and both NR with normally susceptible PBMC had partners with low cellular infectious load, indicating that a combination of susceptibility of target cells and inoculum size largely determines homosexual HIV-1 transmission. |
| 95 | CCR5/ΔCCR5 HETEROZYGOSITY: A SELECTIVE PRESSURE FOR THE SYNCYTIUM-INDUCING HIV-1 PHENOTYPE Antiviral Therapy 1997;2 (Suppl 5):63 RT D‘Aquila1, L Sutton1, A Savara1, MD Hughes2 and VA Johnson3 for the ACTG 241 Virology Team SI viral phenotype was more common in CCR5/ΔCCR5 heterozygotes than in CCR5/CCR5 homozygotes with moderately advanced HIV-1 disease. This greater selection of SI phenotype among CCR5/ΔCCR5 heterozygotes than CCR5/CCR5 homozygotes suggests that decreases in levels of unliganded, cell-surface CCR5 late in pathogenesis may be a mechanism for delayed SI predominance. Since CCR5/ΔCCR5 heterozygotes have been reported to have decreased cell surface CCR5, blockade of CCR5 as a single antiviral target may also elicit similar selection and be limited by HIV-1 resistance. |
| 96 | USE OF ULTRA-SENSITIVE PCR TECHNOLOGY TO PROVIDE INSIGHT INTO VIRAL DYNAMICS Antiviral Therapy 1997;2 (Suppl 5):64 Brian Conway1, Andrew Shillington1, Signe Fransen1, John Sninsky2, Shirley Kwok1,2 and Julio SG Montaner1 These data underscore the need to use more sensitive assays to measure the true virological benefit of novel therapeutic approaches. We have also repeated Ultra Direct measurements from 15 patients with <20 copies/ml using a 10× plasma input. In all but one case, HIV sequences were detected, suggesting that the ‘negative’ result that was obtained initially probably resulted from sampling at low circulating viral loads. The implications of these findings on the modelling of viral eradication will be discussed. |
| 97 | REBOUND OF PLASMA HIV-1 RNA AFTER DISCONTINUATION OF LONG-TERM LAMIVUDINE/ZIDOVUDINE Antiviral Therapy 1997;2 (Suppl 5):65 JJ Eron Jr1, M St Clair2, C Gilbert2, AN Phillips4, A Keller2, J Johnson2 and VA Johnson3 After a delay of 24-48 h plasma HIV-1 RNA levels rapidly rose post-discontinuation of therapy with 2-50-fold increases over 14 days. The rapidity of virus rebound in plasma following discontinuation of lamivudine/zidovudine therapy supports previous findings that HIV-1 viraemia is sustained primarily by a dynamic process of continuous rounds of de novo virus infection and rapid cell turnover. Values after 14 days were remarkably close to pre-treatment values obtained 2 years previously supporting previous observations that a steady-state 'set-point' is maintained by complex virological and host factors not completely defined. In these select subjects the antiviral effect of lamivudine/zidovudine persisted for up to 2 years despite likely lamivudine resistance |
| 98 | PLASMA VIRUS DECAY IN NON-PATHOGENIC SIV INFECTION OF SOOTY MANGABEYS Antiviral Therapy 1997;2 (Suppl 5):65 RM Grant1, N Bandrapalli1, H McClure2, A Kaur3, RP Johnson3, SI Staprans4, N Bishofberger5 and MB Feinberg6 Circulating CD4+ cell counts (naïve and memory) remained stable during treatment and post-treatment viral rebound. These data suggest that high level viraemia in non-pathogenic SIV infection may represent high viral replication, rather than low viral clearance associated with partial immune tolerance or low cell turnover expected with non-cytolytic viral replication. Indeed, viraemia level and turnover in mangabeys is similar to what has been observed in pathogenic lentiviral infections. The lack of SIV disease in sooty mangabeys may indicate that the range of tissues infected may be restricted so that cellular proliferative capacity is preserved and the balance between viral injury and host regeneration persists indefinitely. |
| 99 | INTERPATIENT VARIATION OF VIRAL DYNAMICS IN HIV-1 INFECTION Antiviral Therapy 1997;2 (Suppl 5):66 H Wu1,7, DR Kuritzkes2, MS Clair3, H Kessler4, E Connick2, A Landay4, M Heath-Chiozzi5, F Rousseau3, L Fox6, J Spritzler7, JM Leonard5, DR McClernon3 and MM Lederman8 These new findings suggest that host-specific factors may contribute to the variations in viral clearance and production rates. Identifying these factors will be important for further understanding of HIV pathogenesis and for the design of future treatment strategies. Although viral decay slopes in the fast decay phase were not correlated with baseline plasma HIV-1 RNA level, both viral clearance and production rates in the two-phase decay model were found to be correlated with baseline virus load. To reduce the production/clearance ratio (P/c), treatment should be initiated when the virus load is as low as possible (irrespective of CD4+ T cell counts). These findings provide theoretical support for the early aggressive treatment of HIV infection with potent antiretroviral agents. |
| 100 | HIV-1 PROVIRAL DNA DECAY RATE IN PATIENTS TREATED WITH POTENT ANTIRETROVIRAL REGIMENS Antiviral Therapy 1997;2 (Suppl 5):67 M Vesanen, Y Cao, A Hurley, R Schluger, DD Ho and M Markowitz Compared to proviral DNA, the decay rate of plasma viraemia and infectious virus in PBMCs was much faster (<6 h and approximately 1.1 day, respectively), rapidly decreasing to undetectable levels, even when the most sensitive assays were used. However, persistence of proviral DNA in mononuclear cells coexisting with culture-negative PBMCs suggests that the most of the proviruses are defective and cannot produce infectious viral particles. Our data suggests that proviral DNA might be detectable for years in an infected person after initiation of potent antiretroviral therapy, but its presence might not be rate limiting in attempts to eradicate infectious virus. |
| 101 | DYNAMICS OF HIV-1-INFECTED CELL TURNOVER EVALUATED USING MATHEMATICAL MODELS Antiviral Therapy 1997;2 (Suppl 5):67 John Mittler The models presented here suggest that HIV-1-infected cell populations turn over faster in patients with higher viral loads. Although immune control models cannot be ruled out, these observations are somewhat easier to understand in the context of the target cell limited models. |
| 102 | HIV-1 RNA LEVELS IN PLASMA AND CSF OF 52 HIV-INFECTED PATIENTS Antiviral Therapy 1997;2 (Suppl 5):68 P Bossi1, N Dupin1, A Coutellier2, A Cècille1, F Bricaire3, C Lubetski4, JM Huraux1, C Katlama3 and V Calvez1 The correlation between plasma and CSF viral load suggests two possibilities: CSF virus could come from either plasma or brain, where HIV replication could be synchronized with lymphoid tissue replication. The high correlation between CSF viral load and CSF white cell counts seems to indicate the second possibility is most likely. In conclusion, CSF HIV-1 RNA levels reflect plasma HIV-1 RNA levels. The absence of any significant difference between patients with or without CNS disease, including HIV encephalopathy, suggests that the CSF HIV-1 RNA level is not a good marker for HIV encephalopathy diagnosis. |
| 103 | PRIMARY LAMIVUDINE RESISTANCE IN ACUTE HIV INFECTION Antiviral Therapy 1997;2 (Suppl 5):68 Brian Conway1, Val Montessori1, Danielle Rouleau1, Julio SG Montaner1, Signe Fransen1, Andrew Shillington1 and Douglas Mayers2 Primary lamivudine resistance has been identified in isolates recently transmitted in Vancouver, British Columbia. This may have important implications, especially in the setting of initial empirical therapy of acute HIV infection. |
| 104 | BROAD SPECTRUM OF IN VIVO FITNESS OF HIV-1 SUBPOPULATIONS DIFFERING AT REVERSE TRANSCRIPTASE CODONS 41 AND 215 Antiviral Therapy 1997;2 (Suppl 5):69 Anthony de Ronde1, Jaap Goudsmit1, Esther de Rooij1, Jolanda Maas1, Denise Bouwhuis1 and Rob de Boer2 We determined the in vitro drug-resistance phenotype of the Y215, D215 and S215 viruses and found that 215Y and 215S were zidovudine-resistant and that 215D was zidovudine-sensitive. For the 215Y and 215D phenotypes, this is in agreement with the notion that in the absence of drug, drug-resistant viruses are generally less fit than naturally occurring drug-sensitive viruses. However, the phenotype of the 215S virus indicated that a high relative fitness and drug-sensitivity were not directly linked. |
| 105 | CONTROL OF HIV-1 RNA PREVENTS CLINICAL DISEASE PROGRESSION TO AIDS Antiviral Therapy 1997;2 (Suppl 5):69 Ralph DeMasi1, Schlomo Staszewski2, Debra Dawson1 and Andrew Hill3 Progression to AIDS/death is very rare for patients treated with nucleoside analogues and maintaining HIV-1 RNA below 5,000 copies/ml. The HIV-1 RNA level required to prevent progression to AIDS/death may be higher than that required to delay the emergence of drug resistance. |
| 106 | CIRCULATING HIV-1 AND HIV-2 GENETIC SUBTYPES IN SPAIN Antiviral Therapy 1997;2 (Suppl 5):70 A Holguín and V Soriano HIV-1 non-B subtypes are currently circulating in Spain, but are still mostly confined to immigrants. African immigrants living in Spain are infected by diverse HIV-1 genotypes and represents a potential source of introduction of HIV-1 non-B variants. This should be kept in mind for appropriate interpretation of serological and viral load testing, which are based exclusively on B variants. The presence of both HIV-2 variants in Spain, even in native Spanish born subjects, reflects the more heterogeneous nature of the HIV-2 epidemiology in our country. Lastly, AIDS caused by both HIV-2 A and B subtypes suggests that both variants are pathogenic. |
| 107 | Vβ-SPECIFIC T CELL EXPANSIONS DURING PRIMARY HIV-1 INFECTION DISPLAY AN ACTIVATED PHENOTYPE AND ARE DOWN-REGULATED FOR CD28 EXPRESSION Antiviral Therapy 1997;2 (Suppl 5):70 A Jaramillo1, J Zaunders1, T Kelleher1 and DA Cooper1,2 We have identified Vβ expansions in subjects undergoing primary HIV infection. These Vβ expansions were seen predominantly in CD8+ T cells and were characterized by an activated/effector phenotype relative to other T cell subsets in the same individuals. This differential expression of activation markers further supports the notion that oligoclonal Vβ expansions play a major role in the primary immune response to HIV. |
| 108 | THE RELATIVE PROGNOSTIC VALUE OF PLASMA HIV RNA LEVELS AND CD4+ LYMPHOCYTE COUNTS IN ADVANCED HIV INFECTION Antiviral Therapy 1997;2 (Suppl 5):71 Alessandro Cozzi Lepri2, Terese L Katzenstein1, Henrik Ullum1, Andrew N Phillips2, Peter Skinhøj1, Jan Gerstoft1 and Bente K Pedersen1 These data suggest that in patients with late-stage disease (CD4+ cell count <100 cells/mm3), in whom the HIV RNA level and CD4+ cell counts have not been markedly affected by antiretroviral treatment, the CD4+ cell count provides a more reliable indication of the patients prognosis that the HIV RNA level. |
| 109 | HIV RNA: RELATIONSHIP TO HIV NEUROLOGICAL DISEASE AND ZIDOVUDINE RESISTANCE Antiviral Therapy 1997;2 (Suppl 5):72 ER Lanier1, DR McClernon1, T Nance-Sproson2, MH St Clair1 and JC McArthur2 Resistance mutations to zidovudine were generally identical in plasma and CSF samples taken at the same time. However, one patient with dementia had 215Y (zidovudine resistant) in plasma and 215T (wild-type) in CSF while a second dementia patient had 67N in CSF (zidovudine resistant) but 67K (wild-type) in a sample from the basal ganglia. Comparisons of viral load and resistance mutations in a wider variety of tissues will also be presented. |
| 110 | THE PREVALENCE OF RITONAVIR RESISTANCE IN AN URBAN POPULATION OF PROTEASE-NAÏVE PATIENTS Antiviral Therapy 1997;2 (Suppl 5):72 J Larkin, J Nadler, L Stark, D Kazanis, L Busciglio and D Haight Many mutations known to confer resistance to protease inhibitors were identified. Our data suggests that functional ritonavir resistance in a protease inhibitor naïve population (as measured by phenotypic culture methods) is very uncommon. The potential for emergence of pre-existing, subclinical, genotypic resistant HIV strains, may reconcile the current results with those of Kozal et al. [1]. Prospective studies are warranted. |
| 111 | REPLICATIVE FITNESS OF HIV-1 VARIANTS RESISTANT TO PROTEASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):73 J Martinez-Picado1,2, A Savara2 and RT D’Aquila2 The two PI cross-resistant mutants selected during treatment with indinavir in vivo replicate in vitro as well as wild-type in the absence of an inhibitor. This seems not to require compensatory cleavage site mutations. Further studies are needed to confirm this and to test the hypothesis that such mutants may persist in vivo as well as wild-type after PI selection pressure is withdrawn, if eradication has not been achieved. |
| 112 | A LONGITUDINAL STUDY OF PLASMA AND SEMINAL FLUID HIV LOAD ON PATIENTS TREATED WITH INDINAVIR Antiviral Therapy 1997;2 (Suppl 5):73 TF Rowe1, GM Beards2, G Sontag3, M Youle3, JK Ball1 and D Pillay2 The plasma range was 1.3×103 to 9.8×103 and the seminal fluid range was below cut off to 8.2×105/ml. Clearly the development of resistant viruses in seminal fluid as well as blood is important and further quantification and sequence analysis is underway. |
| 113 | SURVEILLANCE FOR DRUG-RESISTANT HIV IN THE UNITED STATES AND EUROPE Antiviral Therapy 1997;2 (Suppl 5):74 Richard A Respess, RW Steketee, JW Ward, W Heneine and BR Edlin for the the CDC Antiretroviral Drug Resistance Working Group and the European Network for the Virological Evaluation of International Trials for New Anti-HIV Therapies (ENVA) HIV Drug Resistance Task Force Information obtained from surveillance for antiretroviral drug resistance can be used to (1) assess whether resistant virus is being transmitted from infected persons under treatment to uninfected persons; (2) describe the distribution of resistant viral genotypes among populations and their relationship to antiretroviral chemotherapy; (3) develop and target treatment strategies for communities or geographic areas; and (4) determine the need for new interventions to prevent the spread of resistant strains. Intercontinental collaboration can provide the opportunity to compare and evaluate methods and findings. |
| 114 | SHORT-TERM EVOLUTION OF HIV-1 SERUM VIRAEMIA AND CD4+ CELL COUNTS OF NAÏVE PATIENTS WITH PRIMARY MUTATION TO ZIDOVUDINE Antiviral Therapy 1997;2 (Suppl 5):74 A Rubio, M Leal, JA Pineda, M Olivera, A Galloso, C Rey, A Sanchez-Quijano and E Lissen Based on these results, we conclude that at least up to 24 weeks of follow-up there was no significant difference between patients with primary mutation to zidovudine and control ones harbouring wild-type strains in terms of serum viral load and CD4+ counts. |
| 115 | VIRAL AND HOST FACTORS LINKED TO LONG-TERM NON-PROGRESSION IN HAEMOPHILIACS Antiviral Therapy 1997;2 (Suppl 5):75 A Mas1, M Quiñones-Mateu2, C Altisent3, R Bravo1, E Domingo2 and V Soriano1 Viral load values discriminate with accuracy LTNP and TP. The presence of a 32 bp deletion in one of the CCR5 alleles is more frequent in LTNP than in TP and might influence the distinct progression rate to AIDS. Genetic abnormalities into the LTR region are more frequently recognized in LTNP than in TP. However, further analysis is required to establish its pathogenic role. |
| 116 | UNEXPECTED HIGH STABILITY OF HIV-1 VIRIONS IN WHOLE BLOOD Antiviral Therapy 1997;2 (Suppl 5):75 A-M Vandamme1, JC Schmit1,2, K Van Laethem1, E van Wijngaerden1, E De Clercq1 and J Desmyter1 NASBA HIV-1 viral load immediately dropped below the detection limit when the HIV-1 virion RNA from the laboratory virus stock was first extracted with Trizol and subsequently added to HIV-1 negative blood and medium at concentrations up to 7 log RNA copies/ml. Up to 0.5% Triton X-100 in whole blood had no influence on the efficiency of NASBA viral load detection. These results indicate that intact HIV-1 virions possess a very high stability, which is not recognized by laboratory and health workers. Extreme caution should be taken, even when handling old blood samples. |
| 117 | THERAPEUTIC EFFICACY OF PMPA TREATMENT FOR INFANT MACAQUES INFECTED WITH PMPA-RESISTANT SIMIAN IMMUNODEFICIENCY VIRUS Antiviral Therapy 1997;2 (Suppl 5):76 Koen Van Rompay1, Julie Cherrington2, Marta Marthas1, E Agatep1, Z Dehqanzada1, Patrick Lamy2, C Berardi1, Norbert Bischofberger2 and Niels Pedersen1 The simian immunodeficiency virus (SIVmac)-newborn rhesus macaque model is very useful to evaluate the therapeutic efficacy of antiviral drugs and the development and virulence of drug-resistant viral mutants. We have previously demonstrated that zidovudine therapy of SIV-infected newborn macaques resulted in the emergence of highly zidovudine-resistant SIVmac mutants [with Q151M mutation in the reverse transcriptase (RT)] which were fully pathogenic following inoculation in newborn macaques. |
| 118 | NEUTRALIZING ANTIBODY DIRECTED AGAINST THE V3 LOOP SELECTS FOR DIFFERENT ESCAPE VARIANTS IN M184V-CONTAINING COMPARED WITH WILD-TYPE HIV-1 Antiviral Therapy 1997;2 (Suppl 5):77 P Inouye1, S Zolla-Pazner2 and MA Wainberg1 In contrast, the N5Y substitution generated by an A?T transversion in V3 by M184V-containing HIV-1 suggests that this RT variant has an altered mutational bias. This bias may affect the composition of genetic variants generated by drug resistant HIV-1 and hence influence virus evolution during treatment with lamivudine. |
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Session 6: Immune reconstitution Abstracts 119 thru 125, Pages 78 to 83 |
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| 119 | T CELL IMMUNE RECONSTITUTION IN HIV-NEGATIVE HOSTS: INHERENT LIMITATIONS AND THERAPEUTIC PROSPECTS Antiviral Therapy 1997;2 (Suppl 5):78 Crystal Mackall, Frances Hakim, Thomas Fleisher, Margaret Brown, Dimiter Dimitrov and Ronald Gress In humans, thymic-dependent pathways are critical for the regeneration of CD4+ T cells, but declines in thymic function occur at a relatively young age. Thus, inherent age-related declines in thymic regenerative capacity may contribute substantially to the limited CD4+ immune reconstitution observed in patients with HIV infection. Further investigation into mechanisms responsible for thymic involution and the development of therapies to enhance thymic function are critical for improving immune reconstitution in patients with disease- or therapy-induced T cell depletion. |
| 120 | REVERSAL OF LYMPHOCYTE RA/RO RATIOS IN PATIENTS WITH PRIMARY HIV INFECTION TREATED WITH ZIDOVUDINE, LAMIVUDINE AND INDINAVIR Antiviral Therapy 1997;2 (Suppl 5):78 D Smith1, M Bloch2, P Grey1, P Cunningham4, J Zaunders4, A Kelleher4, DA Cooper3 and the CHRN PHI investigator group Absolute CD8+ counts decreased with treatment, this decrease almost entirely accounted for by a drop in CD8+ cells expressing the RO phenotype. Viral load reached undetectable levels in all patients on treatment by 16 weeks. Aggressive treatment of PHI results in a reversal of the abnormal CD8+ RA/RO ratio indicating decreased CD8+ cell activation and a trend towards the pattern seen in uninfected individuals. |
| 121 | MODELLING THE DYNAMICS OF TELOMERE LENGTH IN NAÏVE AND MEMORY CD4+ CELLS DURING CLINICAL LATENCY Antiviral Therapy 1997;2 (Suppl 5):79 AJ Noest1, RJ de Boer1, KC Wolthers2, SA Otto2 and F Miedema2 This more complicated analysis can rule out several dynamic scenarios, but leaves one with a set of allowed combinations of parameters. We will present in some detail the scenarios which are excluded or allowed by this analysis. Independent of the debate about CD4+ cell productivity, one may conclude that the replicative potential of naïve and memory cells is not curtailed by telomere-shortening. This may prove advantageous when attempting to reconstitute the immune system after successful antiviral therapy. |
| 122 | IMMUNOLOGICAL RECONSTITUTION AFTER TRIPLE COMBINATION THERAPY IN HIV-1 INFECTION Antiviral Therapy 1997;2 (Suppl 5):80 NG Pakker1, DW Notermans2, R de Boer3, M Koot1, MTL Roos1, F de Wolf4, A Hill5, JM Leonard6, SA Danner2, F Miedema1 and PTA Schellekens1 Triple therapy initially caused a quick response of repopulating memory T cells. The slow repopulation with presumably de novo produced naïve T cells points to a gradual immune reconstitution comparable to reconstitution after bone marrow transplantation and chemotherapy. |
| 123 | PARTIAL IMMUNOLOGIC RECOVERY AFTER 13 MONTHS OF POTENT ANTIRETROVIRAL THERAPY Antiviral Therapy 1997;2 (Suppl 5):80 R Kost, M Markowitz, A Hurley, D Tse, R Schluger, S Monard, D Winslow, R Anderson and D Ho The correlation of youth with immune recovery echoes the experience in cancer therapy: the patients who recover best from immune ablation are the youngest, and those with residual thymic function, namely children. In our adult patients, immune recovery is currently incomplete. It may be that specific immune modulating regimens will be required to achieve full immune reconstitution in adults. Nonetheless, it is encouraging that partial recovery of the number and proportion of naïve CD4+ T cells occurs during potent suppression of HIV replication. |
| 124 | CD8+ RESPONSE IN A STUDY OF DOUBLE VERSUS SINGLE PROTEASE INHIBITOR THERAPY IN COMBINATION WITH DOUBLE NUCLEOSIDE ANALOGUE THERAPY Antiviral Therapy 1997;2 (Suppl 5):81 J Gerstoft, C Nielsen, J Lundgren, L Krause, O Kirk-Sørensen, L Mathiesen and C Pedersen (The Danish Protease Inhibitor Study Group) The CD8+ increase might be a response to activated latent pathogens (CMV, EBV etc). The fact that a CD8+ increase was observed in this group of patients, most of whom had very low – if any – viral replication, suggests that this response is unrelated to the altered processing of viral proteins induced by protease inhibitors, rather, it is related to the decrease in viral replication induced by the drugs. The CD8+ response was unrelated to the type of protease inhibitor used and was not abrogated by the nucleoside analogues. The significance and durability of the CD8+ response after aggressive therapy remains to be determined. |
| 125 | A RANDOMIZED PHASE II STUDY OF CONTINUOUS INFUSION PROLEUKIN (ALDESLEUKIN) CHIRON RECOMBINANT INTERLEUKIN-2 (RIL-2) FOLLOWED BY HIGH DOSE SUBCUTANEOUS RIL-2 VERSUS HIGH-DOSE SUBCUTANEOUS IL-2 VERSUS LOW-DOSE SUBCUTANEOUS RIL-2 IN HIV-1 SEROPOSITIVE PATIENTS WITH CD4+ COUNTS 200-500 cells/mm3 Antiviral Therapy 1997;2 (Suppl 5):82 G Tambussi1, N Gianotti1, M Guffanti1, S Nozza1, A Ruggieri1, E Vicenzi2, G Poli2 and A Lazzarin1 Our preliminary findings indicate that well-tolerated low doses of s.c. rIL-2 may be effective in terms of stable increases of circulating CD4+ T cells in HIV-infected individuals who otherwise would experience declining lymphocyte counts. Thus, potent antivirals and agents, such as IL-2, targeting the immune system may substantially overturn the fate of HIV infection. |
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Session 7: Eradication and long-term suppression strategies Abstracts 126 thru 137, Pages 84 to 91 |
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| 126 | INTENSIVE VIROLOGICAL ASSESSMENT OF AGGRESSIVELY TREATED SUBJECTS WITH RECENT AND CHRONIC HIV INFECTION Antiviral Therapy 1997;2 (Suppl 5):84 M Markowitz1, Y Cao1, M Vesanen1, A Talal1, A Hurley1, R Schluger1, Klara Tenner-Racz2, Paul Racz2 and DD Ho1 In situ hybridization results reported to date have been negative for HIV RNA in the ritonavir-treated newly infected cohort. We conclude that intensive antiretroviral therapy appears to effectively suppress viral replication in blood and lymphatic tissue in nearly all treated subjects, particularly those treated within 90 days of infection. To date, continuing evaluation of blood, semen and lymphatic tissue has revealed virological data consistent with the mathematical model set forth by Perelson et al. [1], suggesting the feasibility of eradication. |
| 127 | SAQUINAVIR IN COMBINATION WITH ZIDOVUDINE/LAMIVUDINE AND RITONAVIR: A CONVENIENT TWICE DAILY REGIMEN Antiviral Therapy 1997;2 (Suppl 5):85 A Talal1, Y Cao1, A Hurley1, R Schluger1, L Fischer2, M Salgo2, L Smiley3, A Keller3, DD Ho1 and M Markowitz1 Two patients have been switched to stavudine secondary to nausea. Among the nine patients remaining in the study at week 32, the mean reduction in log10 HIV RNA was 3.25, while the mean increase in CD4+ count was 53 cells/mm3 and CD4+/CD8+ ratio was 0.74. After 1 year of therapy, aggressive tissue sampling will be performed to document viral clearance from various body compartments. Given our understanding of the dynamics of HIV-1 replication in vivo, this aggressive yet safe and acceptable regimen represents an mappropriate attempt toward ultimate control of HIV infection. |
| 128 | EVIDENCE FOR THE PREVENTION OF NEW HIV-1 INFECTION CYCLES IN PATIENTS TREATED WITH INDINAVIR PLUS ZIDOVUDINE PLUS LAMIVUDINE Antiviral Therapy 1997;2 (Suppl 5):85 EA Emini, DJ Holder, WA Schleif, RM Danovich, DJ Graham, DT Laird, M Shivaprakash, JA Chodakewitz and JH Condra The remaining patient yielded virus expressing a single M184V RT substitution indicative of lamivudine resistance, but no substitutions in the protease. These observations support the concept that the continued virus suppression observed in this patient population is associated, in most cases, with the prevention of new virus replication cycles, thereby preventing the accumulation of mutations needed to express full resistance to the combination therapy. |
| 129 | DURATION OF HIV-1 LOAD SUPPRESSION IN PATIENTS TREATED WITH INDINAVIR WHO EXPERIENCE VIRUS LOAD DECLINES TO <500 vRNACOPIES/ML Antiviral Therapy 1997;2 (Suppl 5):86 DJ Holder, M Shivaprakash, RM Danovich, DJ Graham, WA Schleif, JA Chodakewitz, JH Condra, and EA Emini Numerically, patients were found to be more likely to maintain suppression if initial indinavir therapy was given in combination with zidovudine plus lamivudine (96% for a duration of 48 weeks) than if indinavir was initially given as monotherapy (87% for a duration of 48 weeks), although the difference is not statistically significant. These results demonstrate that patients whose virus loads decline to below 500 vRNA copies/ml for at least 12 weeks, as a result of therapy containing indinavir, are likely to forestall loss of virus suppression due to the selection for resistant virus. |
| 130 | INDUCTION THERAPY: PROOF OF CONCEPT BY WITHDRAWAL OF DIDANOSINE FROM ZIDOVUDINE PLUS NEVIRAPINE PLUS DIDANOSINE Antiviral Therapy 1997;2 (Suppl 5):86 D Hall1 and B Conway2 for the INCAS trial team After induction with zidovudine plus nevirapine plus didanosine, patients are able to sustain viral suppression with a regimen that was only transiently effective as initial therapy, zidovudine plus nevirapine. Thus, the existence of a second phase in anti-HIV therapy is demonstrated, during which suppression BD does not require a treatment capable of full suppression during the first phase. |
| 131 | MATHEMATICAL CONSIDERATIONS OF ANTIRETROVIRAL THERAPY AIMED AT HIV-1 ERADICATION OR MAINTENANCE OF LOW VIRAL LOADS Antiviral Therapy 1997;2 (Suppl 5):87 Lawrence M Wein1, Rebecca M D&8216;Amato2 and Alan S Perelson3 For eradication to occur, therapy needs to be nearly as efficacious (roughly 60-90% of potential infectious virus production needs to be blocked) against mutant strains of virus as it is against the wild-type strain. The eradication condition for maintenance therapy is the same as the eradication condition for induction therapy, despite the fact that induction therapy is apt to be faced with a higher viral load. If induction therapy is unable to achieve eradication then the steady-state viral load and CD4+ T cell count resulting from maintenance therapy are independent of the timing of the switch to maintenance therapy. Drug therapy is unlikely to maintain viral loads at low levels; it is apt to either eradicate the virus or allow the viral load to return to near its pretreatment level. |
| 132 | UNDETECTABLE VIRAL LOAD FOR MORE THAN 18 MONTHS IN PATIENTS TREATED WITH COMBINATION THERAPIES CONTAINING TWO OR THREE NUCLEOSIDE ANALOGUES Antiviral Therapy 1997;2 (Suppl 5):87 A Arnó1, T Puig1, L Ruiz1, M Balaguè1, J Romeu2, C Tural2 and B Clotet1,2 Patients with low baseline viral load values can attain sustained suppression of HIV replication with combination nucleoside analogue therapy only. A concomitant partial immune restoration is also observed in this cohort. According to these results antiretroviral treatment should be recommended even for patients with very low baseline (<1000 copies/ml) plasma HIV-1 RNA values. In this setting, combination therapy with two nucleoside analogues may be a less expensive approach, with virological benefits similar to those achieved with triple therapy. |
| 133 | WHAT RISES OR REDUCTIONS IN HIV-1 RNA ARE CLINICALLY SIGNIFICANT? Antiviral Therapy 1997;2 (Suppl 5):88 John A Bartlett1, Ralph DeMasi2, Debra Dawson2 and Andrew Hill3 Under 5% of untreated patients show rises or falls in HIV-1 RNA of over 0.72 log10 copies/ml: for pretreated patients, under 5% show variation outside 0.69 log10 copies/ml. For individual patients rises or falls within these limits cannot be distinguished from random biological variation in HIV-1 RNA measurements. Reductions of greater than these levels may indicate a meaningful effect of treatment; rises greater than these levels may indicate the emergence of resistance. |
| 134 | RECENT HIV-1 INFECTION TREATED WITH A CONVENIENT TWICE DAILY COMBINATION REGIMEN OF SAQUINAVIR, RITONAVIR, ZIDOVUDINE AND LAMIVUDINE Antiviral Therapy 1997;2 (Suppl 5):89 CF Farthing1, L Fischer3, M Moran1, HE Chang1, Y Cao2, A Hurley2, R Schluger2, M Salgo3, A Keller4, L Smiley4, DD Ho2 and M Markowitz2 The four remaining subjects who have been on study for (12 weeks have all experienced at least 2.0 log10 plasma HIV RNA reduction from baseline. These preliminary findings suggest that this four drugs twice daily regimen can provide potent and significant suppression of HIV-1 replication in acutely infected individuals. The reduction of ritonavir dosage has resulted in a better-tolerated regimen. Virological results using the Roche ultra-direct HIV RNA assay (<25 copies/ml) will be presented. |
| 135 | INFLUENCE OF BASELINE VIRAL LOAD IN THE PEAK REDUCTION OF PLASMA RNA VIRAEMIA WITH ANTIRETROVIRAL THERAPY (NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR) Antiviral Therapy 1997;2 (Suppl 5):89 F García1, JM Gatell1, C Vidal2, M Leal3, B Clotet4, T Pumarola2, JM Miró1, J Mallolas1 and C Tortajada1 These data suggest that the reduction of viral load with a two drug regimen is higher in patients with a high level BVL than in patients with a low level BVL. |
| 136 | PREDICTIVE FACTORS OF PEAK VIRAL LOAD DROP BELOW DETECTION (200 COPIES/ML) IN RESPONSE TO TREATMENT WITH NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Antiviral Therapy 1997;2 (Suppl 5):90 JM Gatell1, F García1, C Vidal1, M Leal1, B Clotet2, T Pumarola1, JM Miro1, J Mallolas1, A Cruceta1 and C Tortajada1 In the multivariate model the likelihood of dropping below the detection level was significantly greater in those receiving double therapy (OR 16.1, 95% CI 2-128), in those with baseline CD4+ lymphocyte count above 350 (OR 2.28, 95% CI 1.1-4.9) and in those with baseline viral load below 10000 HIV-1 RNA copies/ml (OR 2.25, 95% CI 1.1-6.1). None of the 13 patients with SI phenotype virus at baseline (data were available in 85 patients) dropped below detection level. In conclusion, peak viral load reduction below detection (200 copies/ml) in response to NRTI can be predicted and was associated with double therapy, with a baseline CD4+ cell count >350 cells/mm3 and with a baseline viral load below 10,000 HIV-1 RNA copies/ml. |
| 137 | LACK OF RESISTANCE MUTATIONS (INCLUDING M184V) IN TREATMENT-NAÏVE HIV-1 SEROPOSITIVES FOR UP TO 7 MONTHS AFTER INITIATION OF A LAMIVUDINE-CONTAINING THREE- OR FOUR-DRUG COMBINATION THERAPY, EXCEPT FOR ONE PATIENT WITH PREVIOUS ZIDOVUDINE RESISTANCE Antiviral Therapy 1997;2 (Suppl 5):91 A-M Vandamme1, T Harrer2, K Van Laethem1, V De Vroey1, A Rascu2, M Grunke2, P Low2, JR Kalden2, J Desmyter1 and E De Clercq1 After 7 months, the virus showed genotypic resistance to zidovudine, lamivudine, saquinavir and indinavir. The viral load was then 5.2 log RNA copies/ml. In conclusion, initiation of three- or four-drug therapy in anti-HIV drug-naíve patients is able to postpone lamivudine resistance for several months, except when the transmitted virus is already resistant to zidovudine. |
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