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17th International HIV Drug Resistance Workshop:
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Cite as: Antivir Ther. 2008, 13(Suppl. 3):xx (abstract no. ??)
where "xx" is the page number and "??" is the abstract number.
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Plenary abstracts Abstracts P1 thru P2, Pages P3 to P4 |
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| P1 | DIVERSITY-GENERATING RETROELEMENTS Antivir Ther. 2008, 13(Suppl 3):P3 (abstract no. P1) JF Miller The potential utility of DGRs is illustrated by the identification of over 40 related elements in bacterial, phage and plasmid genomes. DGRs are present in human pathogens (Treponema, Legionella spp.), human commensals (Bacteroides, Bifidobacterium spp.), green sulfur bacteria (Chlorobium, Prosthecochloris spp.), cyanobacteria (Trichodesmium, Nostoc spp.), magneto-tactic bacteria (Magnetospirillum spp.), and many other diverse species. DGRs comprise a new family of retroelements with the potential to confer powerful selective advantages to their host genomes. |
| P2 | CELLULAR COFACTORS OF HIV INTEGRASE AS NOVEL ANTIVIRAL TARGETS Antivir Ther. 2008, 13(Suppl 3):P4 (abstract no. P2) Z Debyser Our results provide a striking example of the power of viral molecular evolution and biological relevance to the crystal structure of the LEDGF/p75 integrase interface. Demonstration of the exclusive role of LEDGF/p75 in HIV integration justifies our ongoing effort in developing small-molecule inhibitors targeting the interaction between integrase and LEDGF/p75. Cofactor-based anti-HIV therapy may become a new paradigm in antiviral research. |
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Session 1: Resistance to new antiretroviral agents Abstracts 1 thru 35, Pages A3 to A37 |
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| 1 | POTENT HIV-1 ENTRY INHIBITORS WITH A RESERVE OF BINDING ENERGY AGAINST RESISTANCE MUTATIONS Antivir Ther. 2008, 13(Suppl 3):A3 (abstract no. 1) BD Welch1, JP Redman1, S Paul2, MJ Root2 and MS Kay1 Our D-peptide trimer is a broad and potent inhibitor of HIV entry that has been designed to prevent or delay the development of resistance. This inhibitor addresses limitations associated with enfuvirtide and is a strong candidate for the prevention and treatment of HIV/AIDS. |
| 2 | RESISTANCE TO CCR5mAb RoAb3952 IS ASSOCIATED WITH A SHIFT IN BINDING FROM THE EXTRACELLULAR DOMAIN 2 TO THE N TERMINUS OF CCR5 Antivir Ther. 2008, 13(Suppl 3):A4 (abstract no. 2) A Jekle1, M Chhabra1, E Chow1, S Meier1, S Sankuratri1, M Brandt2, N Cammack1 and G Heilek1 Using high titred, genetically diverse viruses and CD8-depleted human PBMCs, we were able to select virus strains resistant to the CCR5mAb RoAb3952. Resistance to RoAb3952 was associated with a change in the binding properties of the virus; RoAb3952-sensitive virus still required binding to ECL2 of CCR5 for viral entry, whereas RoAb3952-resistant virus was capable of efficiently using the N-terminal loop of CCR5 for viral entry in the presence of an antibody that binds to CCR5 ECL2. |
| 3 | NOVEL RESISTANCE PROFILE OF THE POTENT NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITOR 3′-AZIDO2′, 3′-DIDEOXYGUANOSINE Antivir Ther. 2008, 13(Suppl 3):A5 (abstract no. 3) J Meteer1, D Koontz1, KL Rapp2, M Detorio2, M Ruckstuhl2, RF Schinazi2 and JW Mellors1 AZG selects a novel combination of mutations in the polymerase and RNase H domains of RT that do not include classical thymidine analogue mutations (TAMs). These findings are consistent with the lack of cross-resistance of viruses containing TAMs to AZG and inefficient excision of AZG-5′-monophosphate by RT with TAMs. This study also provides further evidence that the primary determinant for the selection of TAMs is the base structure and not the 3′-azido group on the ribose sugar. |
| 4 | HEXADECYLOXYPROPYL TENOFOVIR (CMX157) HAS ENHANCED POTENCY IN VITRO AGAINST NRTI-RESISTANT HIV RELATIVE TO TENOFOVIR AND A FAVOURABLE PRECLINICAL PROFILE Antivir Ther. 2008, 13(Suppl 3):A6 (abstract no. 4) ER Lanier, B Lampert, L Trost, G Painter and M Almond CMX157 is substantially more potent than tenofovir in vitro, possibly due to higher active anabolite levels in target cells. Toxicology and toxicokinetic data reveal high systemic exposure with no indication of nephrotoxicity. CMX157 is being developed for treatment of HIV. |
| 5 | IN VITRO CROSS-RESISTANCE PROFILE, ANTIVIRAL ACTIVITY, SAFETY AND PHARMACOKINETICS IN HIV-1-INFECTED PATIENTS OF IDX899, A NOVEL HIV-1 NNRTI WITH HIGH BARRIER TO RESISTANCE Antivir Ther. 2008, 13(Suppl 3):S7 (abstract no. 5) R Murphy1, C Zala2, JJ Jakubik3, XJ Zhou3, K Pietropaolo3, C Chapron3, L Hubbard3, M Seifer3, DN Standring3, J Sullivan-Bolyai3, B Belanger3 and D Mayers3 |
| 6 | LONGITUDINAL ANALYSIS OF RESISTANCE TO THE HIV-1 INTEGRASE INHIBITOR RALTEGRAVIR: RESULTS FROM P005 A PHASE II STUDY IN TREATMENT-EXPERIENCED PATIENTS Antivir Ther. 2008, 13(Suppl 3):A8 (abstract no. 6) MD Miller, RM Danovich, Y Ke, M Witmer, J Zhao, C Harvey, B-Y Nguyen and D Hazuda on behalf of the P005 Study Team These studies define four distinct evolutionary patterns for RAL resistance and provide evidence for ongoing selective pressure and a clear preference to evolve to pathways associated with higher level resistance. Whether differential effects on resistance and replication capacity associated with these patterns have consequences for clinical outcomes remains to be examined. |
| 7 | LOSS OF RALTEGRAVIR SUSCEPTIBILITY IN TREATED PATIENTS IS CONFERRED BY MULTIPLE NON-OVERLAPPING GENETIC PATHWAYS Antivir Ther. 2008, 13(Suppl 3):A9 (abstract no. 7) S Fransen1, S Gupta1, R Danovich2, D Hazuda2, M Miller2, M Witmer2, CJ Petropoulos1, NT Parkin1 and W Huang1 This is the first study that demonstrates the selection of distinct resistance pathways in raltegravir-treated patients using clonal analysis. Combinations of drug resistance mutations differentially affected raltegravir susceptibility and RC depending on the patterns of mutations that were selected. |
| 8 | HIV-1 GAG POLYMORPHISMS DETERMINE TREATMENT RESPONSE TO BEVIRIMAT (PA-457) Antivir Ther. 2008, 13(Suppl 3):A10 (abstract no. 8) S McCallister1, J Lalezari2, G Richmond3, M Thompson4, R Harrigan5, D Martin6, K Salzwedel6 and G Allaway6 Using a genotype assay, treatment response to bevirimat is associated with baseline amino acid polymorphisms at Gag positions 369, 370 or 371 on SP-1; lower baseline CD4+ T-cell count may be a surrogate for these Gag changes. The Gag data were confirmed by phenotypic assay and a new prospective clinical study to verify these findings is underway. |
| 9 | RESISTANCE MUTATIONS IN HIV-1 INTEGRASE SELECTED WITH RALTEGRAVIR OR ELVITEGRAVIR CONFER REDUCED SUSCEPTIBILITY TO A DIVERSE PANEL OF INTEGRASE INHIBITORS Antivir Ther. 2008, 13(Suppl 3):A11 (abstract no. 9) O Goethals, R Clayton, E Wagemans, M Van Ginderen, A Vos, P Geluykens, K Dockx, V Smits, G Meersseman, D Jochmans, S Hallenberger and K Hertogs The Q148R mutation is selected by both raltegravir and elvitegravir and conferred resistance to a diverse panel of INIs. Additionally, mutations selected with elvitegravir (E92Q and T66I) conferred significant resistance to many INIs with a small reduction in susceptibility to raltegravir. We suggest that Q148R, E92Q and T66I be considered as RAMS conferring resistance to a diverse panel of INIs. |
| 10 | VIROLOGICAL AND IMMUNOLOGICAL OUTCOMES IN A COHORT OF PATIENTS FAILING INTEGRASE INHIBITORS Antivir Ther. 2008, 13(Suppl 3):A12 (abstract no. 10) H Hatano1, H Lampiris1, W Huang2, R Hoh1, S Gupta2, S Fransen2, JN Martin1, C Petropoulous2 and SG Deeks1 Although experience from clinical trials suggests that the majority of patients receiving the newer antiretroviral agents do well, there remains a subset of individuals for whom these drugs will not work because of preexisting resistance or non-adherence. There may, however, be a residual clinical benefit despite lack of viral suppression. This benefit may be due in part to alterations in viral fitness, as suggested by changes after removal of raltegravir in a single individual. Notably, this latter observation is consistent with observations from the SIV-infected macaque model, where removal of integrase inhibitors in animals harbouring the N155H mutation was associated with initial stable viraemia followed by rapid increase in viraemia as the mutations waned. |
| 11 | VIROLOGICAL EVOLUTION IN HIV TREATMENT-EXPERIENCED PATIENTS WITH RALTEGRAVIR-BASED SALVAGE REGIMENS Antivir Ther. 2008, 13(Suppl 3):A13 (abstract 11) C Katlama1, F Caby1, RM Andrade1, L Schneider1, A Canestri1, N Ktorza1, R Tubiana1, MA Valantin1, M Wirden2, I Mallet2 and V Calvez2 In our experience, the majority of patients in virological failure to RAL-based regimens showed low viraemia for a prolonged period without exacerbation. The presence of RAL-resistance mutations was associated to the highest viral replication rates. A longer follow-up of such patients will allow a better understanding of the evolution of RAL resistance profile. |
| 12 | MUTATIONAL PATTERNS IN THE HIV-1 INTEGRASE RELATED TO VIROLOGICAL FAILURES ON RALTEGRAVIR-CONTAINING REGIMENS Antivir Ther. 2008, 13(Suppl 3):A14 (abstract no. 12) D Da Silva1,2, I Pellegrin1,2, G Anies1,2, D Breilh1,2, L Wittkop3 , P Morlat1, M Dupon1,2, D Neau1,2, JL Pellegrin1,2, H Fleury1,2 and B Masquelier1,2 Complex and diverse genetic profiles can be associated to VF on RAL-containing regimens, including dynamics of replacement of mutational profiles. This genetic evolution deserves further molecular investigation in order to better characterize the resistance to RAL. |
| 13 | INTEGRASE INHIBITOR RESISTANCE INVOLVES COMPLEX INTERACTIONS AMONG PRIMARY AND SECONDARY RESISTANCE MUTATIONS: A NOVEL MUTATION L68V/I ASSOCIATES WITH E92Q AND INCREASES RESISTANCE Antivir Ther. 2008, 13(Suppl 3):A15 (abstract 13) D Goodman1, R Hluhanich2, J Waters1, NA Margot2, S Fransen3, S Gupta3, W Huang3, N Parkin3, K Borroto-Esoda1, ES Svarovskaia1, MD Miller2 and DJ McColl2 Evolution of INI resistance involves complex interactions among both primary and secondary drug-selected mutations. Evidence for mutual exclusion of the E92Q and Q148R mutations was demonstrated by clonal analysis. Viruses containing E92Q or N155H mutations had reduced relative fitness; their combination further reduced viral fitness and enhanced resistance to INIs. Novel secondary EVG-selected mutations, L68V and L68I, were shown to be strongly linked to E92Q and enhanced resistance to INI, but did not affect relative viral fitness. Acquisition of higher phenotypic drug resistance is a significant factor in the evolution of INI resistance pathways. |
| 14 | PRE-EXISTING MUTATIONS IN THE U5 VIRAL DNA END OF THE HIV-1 LTR DO NOT AFFECT RESPONSE TO THE INTEGRASE INHIBITOR ELVITEGRAVIR: DATA FROM STUDY GS-US-183-0105 Antivir Ther. 2008, 13(Suppl 3):A16 (abstract no. 14) ES Svarovskaia1, RM Hluhanich2, D Goodman1, NA Margot2, DJ McColl2, MD Miller2 and K Borroto-Esoda1 Among this highly treatment-experienced population, ~10% of patients examined had sequence variation within the first 16 nucleotides of the U5 viral ends prior to treatment with EVG. The observed polymorphic changes did not appear to affect susceptibility or clinical response to EVG. Additionally, patients did not develop detectable changes in the U5 viral ends in cases of virological failure. |
| 15 | STRUCTURAL BASIS FOR THE RESISTANCE PROFILE OF THE HIV-1 PROTEASE INHIBITOR PL-100 Antivir Ther. 2008, 13(Suppl 3):A17 (abstract no. 15) A Voet1, F Christ2, M De Maeyer1, Z Debyser2 and L Vandekerckhove3 The current resistance mutations against DKAs allow mapping of the strand transfer inhibitors to a model of integrase and to better understand the organization of the functional integrase complex and the different binding sides of DKAs and LEDGF/p75. S-1360 lacks the hydrophobic moiety across from the DKA pharmacophore, produces a different resistance pattern and is not sensitive to mutations in the C-terminal part of integrase. Better understanding of the integrase viral DNA-inhibitor complex is highly important for the development of new generation integrase inhibitors. |
| 16 | SMALL-MOLECULE INHIBITORS OF HIV-1 INTEGRASE Antivir Ther. 2008, 13(Suppl 3):A18 (abstract 16) JJ Wu, G Milot, F Beaulieu, J-E Bouchard, Y Xiao, S Dandache, K Gouveia, A Forte, S Garde, Z Wang, M Ge, T Oudanonh and BR Stranix A novel series of vitamin B6-based integrase inhibitors has been developed. These compounds demonstrate potent inhibition against HIV-1 integrase strand transfer activity, antiviral activity and specificity against HIV-1 integrase in cellular assays. |
| 17 | RALTEGRAVIR RESISTANCE MUTATIONS AFFECT STRONGLY THE INTEGRASE ACTIVITIES AND THE REPLICATIVE CAPACITY OF VIRUSES HARBOURING SUCH MUTATIONS Antivir Ther. 2008, 13(Suppl 3):A19 (abstract no. 17) AG Marcelin1, I Malet1, O Delelis2, MA Valantin3, B Montes4, L Tchertanov2, C Soulie1, M Wirden1, G Peytavin1, J Reynes4, C Katlama3, JF Mouscadet2 and V Calvez1 These results show that recombinant viruses with raltegravir resistance mutations have a very low RC. This is in accordance with biochemical results showing that these mutated IN have both 3′-processing and strand transfer altered activities and with the high difficulty to select such mutations using in vitro passages under raltegravir progressive pressure. Discrepancy between in vitro low RC and in vivo high level of HIV viral load rebound after selection of raltegravir mutations raises the question of other genetic determinants located outside of the IN gene that could be needed to get failure and resistance to raltegravir. |
| 18 | VIROLOGICAL RESPONSE AND RESISTANCE IN MULTI-EXPERIENCED PATIENTS TREATED WITH RALTEGRAVIR Antivir Ther. 2008, 13(Suppl 3):A20 (abstract no. 18) F Ceccherini-Silberstein1,2, D Armenia1, R D’Arrigo2, V Micheli3, L Fabeni1, P Meraviglia3 , A Capetti3, M Zaccarelli2, MP Trotta2, P Narciso2, A Antinori2 and CF Perno1,2 Raltegravir showed an extraordinary potent antiretroviral and immunological efficacy in the large majority of multi-experienced patients. In a minority of patients, a rapid resistance to raltegravir emerged and correlated with later virological outcome, thus confirming the importance of associating this new integrase inhibitor to other active drugs to maintain long-term efficacy. |
| 19 | HIV DNA VIRAL LOAD EVOLUTION UNDER A RALTEGRAVIR-BASED THERAPY Antivir Ther. 2008, 13(Suppl 3):A21 (abstract no. 19) C Charpentier1,2, C Piketty3, D Laureillard3, P Tisserand1, L Weiss2,3, L Bélec1,2 and A Si-Mohamed1 Our data showed no drastic effect of RAL on total HIV DNA level as only a median decrease of -0.48 log10/106 cells was observed at W12. However, when HIV DNA was reported to the proportion of CD4+ T-cell count, a correlation was found with the magnitude of HIV RNA decrease. Thus, these findings may suggest that newly CD4+ T-cells generated during treatment may integrate less of HIV DNA copies. |
| 20 | GENOTYPIC ANALYSIS OF PATIENTS ENROLLED IN STUDY AVX-201 AND TREATED WITH APRICITABINE FOR 24 WEEKS Antivir Ther. 2008, 13(Suppl 3):A22 (abstract no. 20) S Cox, J Southby and S Moore No additional mutations developed in patients treated with apricitabine either during a 21-day period of functional monotherapy, nor up to 24 weeks in combination with an optimized background. The M184V mutation was maintained in the majority of patients where a genotype could be obtained. No development of K65R, L74V, TAMs or other NAMs was seen. |
| 21 | IN VITRO SELECTION AND CHARACTERIZATION OF VIRUSES RESISTANT TO RO-5028, A NOVEL NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR Antivir Ther. 2008, 13(Suppl 3):A23 (abstract no. 21) H Javanbakht, Y Li, Z Sweeney, E Chow, J Hang, J Dunn, D Saito, N Cammack, K Klumpp and G Heilek Passaging of HIV-1 HXB2 in MT4 cells under increasing drug pressure of RO-5028 in three independent experiments has identified two diverse resistant pathways independent of those seen with efavirenz and etravirine. Notably RO-5028 passage 13 resistance viruses contain mutations that are less prevalent when compared with high prevalent mutations such as K103N, Y181C and G190A. R0-5028 is a potent candidate for the potential treatment of NNRTIs naïve and pretreated patients. |
| 22 | INCREASED PHENOTYPIC SUSCEPTIBILITY TO ETRAVIRINE IN HIV-1 WITH NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR RESISTANCE Antivir Ther. 2008, 13(Suppl 3):A27 (abstract no. 22) J Benhamida, E Coakley, NT Parkin and C Chappey Resistance to NRTIs is associated with increased etravirine susceptibility, causing hypersusceptibility when NNRTI resistance mutations are absent or few and reducing the level of resistance in combination with multiple NNRTI mutations. The clinical relevance of this phenomenon is unknown but deserves further study and may affect the derivation of genotype algorithms for prediction of reduced etravirine susceptibility. |
| 23 | NUCLEOSIDE-ASSOCIATED MUTATIONS CAUSE HYPERSUSCEPTIBILITY TO ETRAVIRINE Antivir Ther. 2008, 13(Suppl 3):A25 (abstract no. 23) G Picchio1, J Vingerhoets2, N Parkin3, H Azijn2 and MP de Bethune2 Among the HIV-1 isolates studied, HS to etravirine was mainly observed among those carrying NAMs and/or M184V. K103N-containing isolates did not exhibit HS to etravirine; nevertheless, FC values were below the PhenoSense clinical cut-off for etravirine (2.9). The potential effect of HS on response to etravirine deserves further investigation. |
| 24 | AN UPDATE OF THE LIST OF NNRTI MUTATIONS ASSOCIATED WITH DECREASED VIROLOGICAL RESPONSE TO ETRAVIRINE: MULTIVARIATE ANALYSES ON THE POOLED DUET-1 AND DUET-2 CLINICAL TRIAL DATA Antivir Ther. 2008, 13(Suppl 3):A26 (abstract no. 24) J Vingerhoets1, M Peeters1, H Azijn1, L Tambuyzer1, A Hoogstoel1, S Nijs1, MP de Béthune1 and G Picchio2 A comprehensive analysis of baseline resistance data from DUET-1 and DUET-2 identified three additional mutations resulting in a list of 16 etravirine RAMs (V90I, A98G, L100I, K101E/H/P, V106I, E138A, V179D/F/T, Y181C/I/V and G190A/S). Weighting these mutations improved the correlation between genotypic and phenotypic resistance interpretations. Decreased virological response was a function of the number of baseline etravirine RAMs with the largest effect observed in the subgroup of patients with three or more RAMs. |
| 25 | ANTIVIRAL ACTIVITY, SAFETY AND PHARMACOKINETICS OF IDX899, A NOVEL HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR WITH HIGH BARRIER TO RESISTANCE, IN TREATMENT-NAÏVE HIV-1-INFECTED PATIENTS Antivir Ther. 2008, 13(Suppl 3):A27 (abstract no. 25) R Murphy1, C Zala2, XJ Zhou3, K Pietropaolo3, J Sullivan-Bolyai3, B Belanger3 and D Mayers3 IDX899, dosed at 800 mg QD for 7 days was well tolerated and demonstrated potent HIV-1 antiviral activity. Our results support further evaluation of IDX899 at lower doses as well as longer studies of combination therapy to assess durability of antiviral response and long-term safety. |
| 26 | IN VITRO CROSS-RESISTANCE PROFILE FOR A NEXT-GENERATION NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR: IDX899 Antivir Ther. 2008, 13(Suppl 3):A28 (abstract no. 26) JJ Jakubik, C Chapron, L Hubbard, M Seifer and DN Standring IDX899 has previously been shown to be active against most of the resistance mutations produced by first-generation NNRTIs. The present study of NNRTI-selected mutants suggests that IDX899 has less in vitro cross-resistance than efavirenz and TMC125. |
| 27 | PRECLINICAL PROFILE OF R7180, A PRODRUG OF THE NOVEL NNRTI RO-5028, WITH HIGH ANTIVIRAL POTENCY AGAINST WILD-TYPE AND NNRTI-RESISTANT VIRUSES Antivir Ther. 2008, 13(Suppl 3):A29 (abstract no. 27) K Klumpp, J Dunn, G Su, Y Li, A Zhou, D Stefanidis, S Chanda, M Martin, S Harris, T Mirzadegan, A Paul, H Javanbakht, JQ Hang, A Briggs, JB Xu, M Irwin, M Fielden, S Swallow, N Cammack, Z Sweeney and G Heilek R7180 represents a series of prodrugs for novel NNRTIs with high antiviral potency against wild-type and NNRTI-resistant HIV-1. R7180 is efficiently converted to the active parent RO-5028, achieving high oral bioavailability and well-tolerated in toxicity studies where high plasma exposures were achieved, therefore supporting further development of R7180 for the treatment of HIV infection. |
| 28 | HIV-1 SUSCEPTIBILITY TO THE MATURATION INHIBITOR BEVIRIMAT IS MODULATED BY NATURAL POLYMORPHISMS AT POSITIONS 369–371 IN GAG SPACER PEPTIDE 1 Antivir Ther. 2008, 13(Suppl 3):A30 (abstract no. 28) K Van Baelen1, K Salzwedel2, H De Wolf1, Y Verlinden1 and LJ Stuyver1 Using a Gag-PR phenotypic and genotypic assay, three levels of susceptibility to bevirimat were observed for a set of 20 patient-derived virus isolates. Reduced susceptibility correlated with polymorphisms at Gag residues 369–371 in SP1. The 11 viruses containing polymorphisms all had the highest FC values. Testing of additional virus isolates should help to further clarify the role of individual polymorphisms in bevirimat susceptibility. |
| 29 | ROLE OF GAG POLYMORPHISMS IN HIV-1 SENSITIVITY TO THE MATURATION INHIBITOR BEVIRIMAT Antivir Ther. 2008, 13(Suppl 3):A31 (abstract no. 29) K Salzwedel1, M Reddick1, C Matallana1, C Finnegan1, C Adamson2, M Sakalian1, D Stanley1, D Martin1, S McCallister1, E Freed2 and G Allaway1 We have identified naturally occurring polymorphisms at Gag positions 369, 370 and 371 in SP1 that reduce the susceptibility of viruses to bevirimat in vitro. These polymorphisms are distinct from previously described resistance mutations in that they have not been observed in resistance selection experiments in vitro and, in contrast to resistance mutations, the effect of the polymorphisms on bevirimat activity appears to be MOI-dependent. The fact that bevirimat is active against the polymorphic viruses under conditions of low viral replication in vitro may help explain why some patients respond to bevirimat despite being infected by virus bearing these polymorphisms. |
| 30 | NEW PHENOTYPING ASSAY DEMONSTRATES ROLE OF GAG-SP1 POLYMORPHISMS IN HIV-1 SENSITIVITY TO THE MATURATION INHIBITOR BEVIRIMAT Antivir Ther. 2008, 13(Suppl 3):A32 (abstract no. 30) F Hamy1, S Louvel1, K Salzwedel2 and T Klimkait1,3 The in vitro replicative system deCIPhR reproducibly assessed in vitro susceptibility to the maturation inhibitor bevirimat using clinical virus samples. The level of in vitro bevirimat sensitivity was closely related to the presence or absence of polymorphisms at Gag residues 369/370/371. This supports the clinical correlation observed between the presence of these polymorphisms and patient response to bevirimat. These results suggest that the deCIPhR assay may have utility in further defining the determinants of bevirimat response. |
| 31 | PHENOTYPIC AND GENOTYPIC DETERMINANTS OF RESISTANCE TO DARUNAVIR: ANALYSIS OF DATA FROM TREATMENT-EXPERIENCED PATIENTS IN POWER 1, 2, 3 AND DUET-1 AND 2 Antivir Ther. 2008, 13(Suppl 3):A33 (abstract no. 31) S De Meyer1, I Dierynck1, E Lathouwers1, B Van Baelen1, T Vangeneugden1, S Spinosa-Guzman1, M Peeters1, G Picchio2 and M-P de Béthune1 Analyses of a larger clinical dataset confirmed the previously defined phenotypic and genotypic determinants of DRV resistance. An updated DRV RAMs list was defined, containing 10 of the 11 2006 DRV RAMs and one new mutation, T74P. |
| 32 | THE NON-CONVENTIONAL (FOLDING) PROTEASE INHIBITOR BLOCKS THE HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 REPLICATION WITHOUT EVIDENCE OF RESISTANCE DURING IN VITRO PASSAGE Antivir Ther. 2008, 13(Suppl 3):A34 (abstract no. 32) S Ferramosca1, M Lo Cicero1, AE Laface2, F Sirianni1, E Cesana2, D Provasi3, G Tiana3, M Galli1, M Moroni1, A Clivio2, RA Broglia3,4 and S Rusconi1 The capacity to escape selection of resistance after several in vitro passages suggests that primary and/or secondary mutations on the protease gene able to overcome the inhibition of BRU 83–92 are likely to be incompatible with the regular activity of the enzyme. Resistance to protease inhibitors require specific or multiple mutations in discrete regions of the protease and BRU seems to avoid them so far. These data support the investigation of this peptide in the clinical setting. |
| 33 | HIGHLY POTENT HIV PROTEASE INHIBITORS WITH SUBSTITUTED OXINDOLES IN P2′ Antivir Ther. 2008, 13(Suppl 3):A35 (abstract no. 33) SV Gulnik, EI Afonina, H Yokoe, B Yu, T Guerassina, AM Silva, JW Erickson and M Eissenstat HIV PIs containing enamino-oxindole substituents in P2′ are highly active against WT and MDR HIV isolates. |
| 34 | DEFINING THE STRUCTURAL AND FUNCTIONAL ROLES OF MUTATIONS IN GP120 ASSOCIATED WITH THE EMERGENCE OF HIV-1 CLINICAL RESISTANCE TO THE CCR5 ANTAGONIST VICRIVIROC Antivir Ther. 2008, 13(Suppl 3):A39 (abstract no. 34) JA Howe, N Murgolo, Y Hou, L Ba, P Buontempo, J Strizki and R Ogert While no consistent pattern of resistance mutations to VCV has been identified, results from the two patients’ isolates suggest that mutations in the V3 loop and C4 region can be important determinants of the resistant phenotype. We identified mutations in the stem and tip region of the V3 loop that were associated with resistance level and other likely compensatory changes in the V3 stem, base and C4 region that affected viral infectivity. It will be necessary to analyze a larger number of clinical isolates in order to understand more fully the genotypic and phenotypic characteristics of VCV susceptibility. |
| 35 | NUCLEOSIDE ANALOGUES TARGETED AGAINST NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR-RESISTANT HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 2008, 13(Suppl 3):A40 (abstract no. 35) BC Vu1, PL Boyer, MA Siddiqui2, Z Ambrose3, VE Marquez2 and SH Hughes1 Analysis of viral DNA isolated from infected cells by real-time PCR indicates the compounds are targeting early steps in viral DNA synthesis. In vitro studies with purified wild-type RT suggest incorporation of C4′-methyl-2-deoxyadenosine triphosphate is efficiently incorporated into viral DNA, but poorly extended. These C4′-modified nucleoside analogues warrant further studies to assess clinical potential. |
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Session 2: MECHANISMS OF HIV DRUG RESISTANCE Abstracts 36 thru 67, Pages A41 to A62 |
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| 36 | MECHANISM BY WHICH THE HIV INTEGRASE ACTIVE-SITE MUTATION N155H CONFERS RESISTANCE TO RALTEGRAVIR Antivir Ther. 2008, 13(Suppl 3):A41 (abstract no. 36) JA Grobler, KA Stillmock, MD Miller and DJ Hazuda The integrase active-site mutation N155H confers resistance to raltegravir primarily by perturbing the arrangement of the active-site magnesium ions and not by affecting the affinity of the metals or by affecting direct contacts of the inhibitor with the enzyme. These studies lay a foundation for determining the roles of additional mutations in the N155H resistance pathway and for establishing the mechanisms by which other pathways confer resistance to InSTIs. |
| 37 | STRUCTURAL EXPLANATIONS TO ALTERED DRUG RESISTANCE PATHWAYS IN HIV-1 NON-CLADE B PROTEASES Antivir Ther. 2008, 13(Suppl 3):A42 (abstract no. 37) RM Bandaranayake1, C Ng1, M Kolli1, M Prabu-Jeyabalan1, M Nalam1, J Kakizawa2, A Heroux3, NM King1, W Sugiura2 and CA Schiffer1 Structural data indicate that sequence polymorphisms in HIV-1 CRF01_AE cause significant structural changes within the protease when compared with clade B protease. Calorimetric data suggest that wild- type CRF01_AE protease might have lower affinity for NFV and DRV. This weakened affinity may permit the alternative pathway for NFV resistance via N88S, which is a mutation outside the active site. |
| 38 | HOW HEPATITIS C VIRUS NS3-4A PROTEASE R155K/T STRAINS CAN DISCRIMINATE VX-950 AND ITMN-191 BUT AFFECT DIFFERENTIALLY SCH-503034 Antivir Ther. 2008, 13(Suppl 3):A43 (abstract no. 38) J Courcambeck1, M Bouzidi1, G Roche1, G Pèpe2 and P Halfon1 These data provide new insights into the understanding of the molecular mechanisms of HCV drug escape, potential virological breakthrough and bring predictive potential cross-resistance phenomena with future PIs. |
| 39 | STRUCTURAL BASIS FOR K65R FUNCTION: TENOFOVIR RESISTANCE, REDUCED NUCLEOTIDE INCORPORATION AND EXCISION ANTAGONISM Antivir Ther. 2008, 13(Suppl 3):A44 (abstract no. 39) K Das1,2, R Bandwar1,2, KL White3, JY Feng3, SG Sarafianos1,2, S Tuske1,2, X Tu1,2, AD Clark, Jr1,2, PL Boyer4, BL Gaffney2, RA Jones2, MD Miller3, SH Hughes4 and E Arnold1,2 The R65+R72 platform interfaces with M184 and TAMs at two distinct sites. If the K65R and M184V mutations co-exist, the side chains of R72 and V184 would stack like walls on either side of the ribose ring of a bound dNTP, which further stabilizes the pocket and may explain the lower rate of dNTP incorporation and excision by the double-mutant that results in partial TFV resensitization. The K70R TAM, if it were to coemerge with K65R, would add additional restrictions to the R65+R72 platform that might be detrimental for dNTP binding, ATP binding (for excision) and/or nucleotide incorporation, which may explain the rare appearance of K65R+K70R mutations. Other TAMs, such as T215Y, which enhance binding of ATP for excision, are antagonistic with K65R because the R65+R72 platform would hinder the proper positioning of the phosphates of ATP, thus decreasing excision and leading to no enhancement of resistance. |
| 40 | ZIDOVUDINE RESISTANCE RELATED CONNECTION MUTATIONS IN HIV-1 REVERSE TRANSCRIPTASE CAUSE SELECTIVE DISSOCIATION FROM RNASE H COMPETENT COMPLEXES Antivir Ther. 2008, 13(Suppl 3):A45 (abstract no. 40) GL Beilhartz1, M Ehteshami1, B Scarth1, E Tchesnokov1, B Wynhoven2, R Harrigan2 and M Götte1 Selective dissociation of transiently formed hybrids from RNase H competent complexes provides a mechanism for the increase in AZT excision associated with connection mutations N348I and A360V. The combination of diminished RNase H cleavage and increased processivity renders the use of both PPi and ATP advantageous, whereas classic TAMs solely enhance the ATP-dependent reaction. |
| 41 | Q509L IN HIV-1 REVERSE TRANSCRIPTASE INCREASES ZIDOVUDINE RESISTANCE BY PROMOTING POLYMERASE-COMPETENT VERSUS RNASE H COMPETENT BINDING ON RNA/DNA TEMPLATE/PRIMERS WITH SHORT DUPLEX LENGTHS Antivir Ther. 2008, 13(Suppl 3):A46 (abstract no. 41) J Brehm, J Mellors, N Sluis-Cremer The Q509L mutation does not have a direct effect on RT RNase H catalytic activity, but increases AZT resistance by promoting RT binding to RNA/DNA T/P duplexes <18 nucleotides in a polymerase-competent mode that favours excision rather than an RNase H competent mode that favours further cleavage and T/P dissociation. These findings provide new insights into the mechanism by which mutations in the C-terminal domain of RT confer nucleoside reverse transcriptase inhibitor resistance. |
| 42 | EVOLUTION OF REVERSE TRANSCRIPTASE CONNECTION DOMAIN MUTATIONS IN PATIENTS ON ANTIRETROVIRAL THERAPY Antivir Ther. 2008, 13(Suppl 3):A47 (abstract no. 42) V von Wyl1, P Bürgisser2, S Yerly3, J Böni4, T Klimkait5, R Kouyos1, B Ledergerber1, H Günthard1 and the Swiss HIV Cohort Study (SHCS) The CD mutation N348I does not seem to emerge in the absence of M184V, and contrary to earlier reports was not associated with TAMs. Thus, at this point sequencing of the CD does not seem mandatory. |
| 43 | DELAYED CHAIN-TERMINATION PROTECTS THE HEPATITIS B VIRUS DRUG ENTECAVIR FROM EXCISION BY HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 2008, 13(Suppl 3):A48 (abstract no. S50) E Tchesnokov1, A Obikhod2, RF Schinazi2 and M Götte1 The results of this study demonstrate that ‘delayed chain-termination’ at position n+3 is the dominant mechanism of action of ETV. The combined data provide a rationale for the development of ETV-like, delayed chain-terminators as anti-HIV compounds that can evade the excision mechanism. |
| 44 | CO-EVOLVED PROTEASE SUBSTRATE CLEAVAGE SITE MUTATIONS ENHANCE PROTEASE INHIBITOR PHENOTYPIC RESISTANCE Antivir Ther. 2008, 13(Suppl 3):A49 (abstract no. 44) M Kolli1, EW Stawiski2, C Chappey2, NT Parkin2 and CA Schiffer1 Enhanced PI resistance in HIV-1 is associated with the presence of Gag CS mutations. These studies suggest that substrate co-evolution might contribute to PI susceptibility in highly specific ways based on the particular combinations of mutations and inhibitors. |
| 45 | CLONAL ANALYSIS OF PROTEASE AND GAG SEQUENCES FROM HIV-1 SUBTYPE C INFECTED PATIENTS FAILING A PROTEASE INHIBITOR Antivir Ther. 2008, 13(Suppl 3):A50 (abstract no. 45) J Ledwaba, V Pillay and L Morris Population sequencing underestimates the diversity of PI resistance mutations within minority populations following Kaletra administration. Mutations found in the gag cleavage sites are likely to compensate the mutated PR, but might also contribute to PI resistance in those patients who have wild-type PR. |
| 46 | IMPACT OF GAG MUTATIONS ON SELECTION OF DARUNAVIR RESISTANCE MUTATIONS IN HIV-1 PROTEASE Antivir Ther. 2008, 13(Suppl 3):A51 (abstract no. 46) AG Marcelin1, S Lambert-Niclot1, A Canestri2, C Soulie1, M Wirden1, R Tubiana2, A Cheret3, C Katlama2, P Flandre4 and V Calvez1 In these PI-treated patients suffering treatment failure of a darunavir-containing regimen, mutations in the gag region NC-P1/TFP-P6/P6* might influence the selection of darunavir resistance mutations; in particular, the I437T/V gag mutation that confers resistance to PI reduces the selection of darunavir resistance mutations in protease. |
| 47 | GAG NC/P1 PROTEASE RESISTANCE MUTATIONS CAN CAUSE SELECTION OF ADDITIONAL NC/P1 CHANGES TO OPTIMIZE CLEAVAGE EFFICIENCY AND REPLICATIVE CAPACITY Antivir Ther. 2008, 13(Suppl 3):A52 (abstract no. 47) NM van Maarseveen1, PJ Schipper1, D de Jong1, CAB Boucher1,2 and M Nijhuis1 The results from this study clearly demonstrate that there is an optimum rate for HIV-1 gag cleavage. When enhanced gag processing due to PI resistance mutations in NC/p1 reduces RC, HIV-1 can modulate the NC/p1 sequence by selection of additional changes to restore gag cleavage and RC. |
| 48 | RELEVANCE OF HIV GAG CLEAVAGE SITE MUTATIONS IN FAILURES OF PROTEASE INHIBITOR THERAPIES Antivir Ther. 2008, 13(Suppl 3):A53 (abstract no. 48) J Verheyen1, A Altmann2, E Knops1, E Schülter1, N Sichtig1, S Reuter3, G Fätkenheuer1, H Pfister1 and R Kaiser1 Therapy-associated HIV CS mutations were frequently selected under PI therapies and PI-resistant viruses were rarely found without CS mutations. Furthermore, CS mutations were found in PI failures without predicted PI resistance probably pointing to an underestimated genotypic PI resistance. This is especially supported by the fact that outcomes of LPV therapies were predicted more exactly by bioinformatic methods using HIV pol and gag genes. |
| 49 | MUTATIONS SELECTED BY THERAPY IN HIV-2 REVERSE TRANSCRIPTASE Antivir Ther. 2008, 13(Suppl 3):A54 (abstract no. 49) J Cavaco Silva1, AC Miranda1, J Cabanas1, A Mercês1, E Valadas2 MJ Aleixo3, T Branco4, J Vera5, I Germano6, K Mansinho1, K Van Laethem7, AM Vandamme7, P Gomes1,8,9 and RJ Camacho1,8 Several mutations selected by antiretroviral therapy were observed in this population of HIV-2-infected patients. Some of them were not previously reported. Further studies are needed to clarify their real effect on nucleoside reverse transcriptase inhibitor (NRTI) resistance. |
| 50 | MUTATIONS IN THE REVERSE TRANSCRIPTASE CONNECTION AND RNASE H DOMAINS EXHIBIT DUAL RESISTANCE TO NUCLEOSIDE AND NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Antivir Ther. 2008, 13(Suppl 3):A55 (abstract no. 50) GN Nikolenko, KA Delviks-Frankenberry, A Jere and VK Pathak These experiments demonstrate that specific mutations in the connection and RNase H domains exhibit dual resistance to NRTIs and NNRTIs. These studies indicate that the C-terminal domains of RT significantly contribute to antiviral drug resistance and their inclusion in genotypic and phenotypic analysis of clinical antiviral drug resistance could significantly enhance the accuracy of predicting drug resistance. |
| 51 | PREVALENCE OF K65R IN DIFFERENT HIV-1 SUBTYPES AND ITS ASSOCIATION WITH THYMIDINE ANALOGUE MUTATIONS AND NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR RELATED MUTATIONS Antivir Ther. 2008, 13(Suppl 3):A56 (abstract no. 51) Z Grossman1, K Theys2, AP Carvalho3, D Ram1, K Deforche2, H Rudich1, J Vercauteren2, P Libin2, E Mendelson1, RJ Camaho3,4, I Levy5 and A-M Vandamme2 Differences in prevalence of K65R in B, C and G subtypes can only partly be explained by different treatment history and by differences in pre-existing reverse transcriptase mutations. In particular, the subtype-specific pathways of association with TAM accumulation and with NNRTI-related mutations should be further investigated. |
| 52 | INTRACELLULAR FACTORS THAT DECREASE HIV-1 RNASE H ACTIVITY AND INCREASE THE RATE OF ZIDOVUDINE 5′MONOPHOSPHATE EXCISION STUDIED FOR RNA AND DNA TEMPLATE DEPENDENCY Antivir Ther. 2008, 13(Suppl 3):A57 (abstract no. 52) A Malmsten1, M Bennett2, E Orenstein2, GR Bluemling2, M Ruckstuhl2, RF Schinazi2 and J Lennerstrand1,2 Low intracellular pH or differences between physiological and enzymatic assay Mg2+ levels are, besides other parameters, likely to play a role when measuring AZT resistance. These initial results indicate that these factors are involved in a mechanism promoting enhanced excision with RNA template dependency, and possibly also involve RNase H activity. |
| 53 | A NEW CLASS OF TIGHT BINDING NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS INHIBIT THE BURST AND STEADY-STATE PHASES OF WILD-TYPE AND Y188L HIV-1 REVERSE TRANSCRIPTASE ACTIVITY Antivir Ther. 2008, 13(Suppl 3):A58 (abstract no. 53) V Leveque, Tony Giannetti, Y Li, J Deval, S Harris, N Cammack and K Klumpp These data suggest a correlation between the HIV-RT binding affinity of compounds within a new amide series of NNRTIs and their ability to inhibit the burst amplitude and steady-state phases of nucleotide incorporation by HIV-RT. The mechanism of inhibition of tight-binding compounds from a new series of NNRTIs may therefore be different as compared with first-generation NNRTIs. |
| 54 | IDENTIFICATION OF LAMIVUDINE (3TC) AS A NOVEL SUBSTRATE FOR HUMAN ORGANIC CATION TRANSPORTERS 1, 2 AND 3 Antivir Ther. 2008, 13(Suppl 3):A59 (abstract no. 54) G Minuesa1, C Volk2, V Gorboulev2, I Erkizia1, B Clotet1, M Pastor-Anglada3, H Koepsell2 and J Martinez-Picado1,4 3TC is a newly identified substrate for hOCTs, which are expressed both in kidney and immune cells. ABC, AZT, TDF and FTC have a high-affinity interaction with hOCTs, suggesting a putative role of NRTIs as modulators of hOCTs physiological functions. Finally, inhibition of 3TC uptake at low concentrations of ABC and AZT might have implications for 3TC pharmacokinetics. |
| 55 | HIV-1 REVERSE TRANSCRIPTASE CONNECTION DOMAIN MUTATIONS REDUCE TEMPLATE RNA DEGRADATION AND ENHANCE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR EXCISION Antivir Ther. 2008, 13(Suppl 3):A60 (abstract no. 55) GN Nikolenko1*, KA Delviks-Frankenberry1*, PL Boyer2, SH Hughes2, JM Coffin3, A Jere1 and VK Pathak1 Overall these studies provide strong support for the model that cn domain mutations increase AZT resistance by reducing the degradation of the RNA template, thus providing additional time for RT to catalyse AZT-MP excision. |
| 56 | THE FIDELITY OF HIV-1 REVERSE TRANSCRIPTION: REVERSE TRANSCRIPTASE VARIANTS WITH ALTERED MUTATION LEVELS DURING REPLICATION Antivir Ther. 2008, 13(Suppl 3):A61 (abstract no. 56) DV Nissley1,2, JL Shenk2, Z Ambrose3, JN Strathern2 and N Sluis-Cremer3 We identified HIV-1 RT variants that have increased mutation frequencies, altered mutation spectrum and base specificity, and effects on viral replication. These fidelity variants expand the repertoire of enzyme–nucleic acid interactions that influence the quality of replication. Some of these variants may prove useful in distinguishing the contributions of RT and RNA polymerase to HIV-1 diversity. These variants also make it possible to compare the evolution of drug resistance in low fidelity viruses with that of wild type. |
| 57 | SYNONYMOUS MUTATIONS ARE INVOLVED IN THE HIGHLY ORDERED REGULATION OF NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR RESISTANCE Antivir Ther. 2008, 13(Suppl 3):A62 (abstract no. 57) V Svicher1, C Alteri1, A Laganà2, G Pigola2, S Dimonte1, C Mussini3, F Forbici4, A Ferro2, P Narciso4, A Antinori4, F Ceccherini-Silberstein1,4 and CF Perno1,4 Besides well-known amino acid mutations, synonymous mutations strongly modulate the evolution of drug resistance. Their knowledge can be crucial for a better understanding of HIV-1 drug resistance mechanisms. |
| 58 | SILENT MUTATIONS AT REVERSE TRANSCRIPTASE CODONS 65 AND 66 IN B AND C STRAINS FOUND IN BRAZIL ARE VERY STRONGLY ASSOCIATED WITH TREATMENT AND THESE SIGNATURES CAN IMPACT ON ZIDOVUDINE MUTATION ACQUISITION IN VITRO Antivir Ther. 2008, 13(Suppl 3):A63 (abstract no. 58) LMF Gonzalez, AFN Pinto, AN Martins, RS Aguiar, AO Afonso, RM Brindeiro and A Tanuri Our findings corroborate and extend Harrigan’s work for subtype B isolates. Additionally, subtype C isolates seem to carry K66K/K65K silent mutations as a natural polymorphism of these variants. These findings can predict a faster selection of TAMs in subtype C, owing to the favourable RNA template for the excision reaction catalysed by TAMs. The in vitro study using a recombinant virus derived from HBX2 shows subtype-specific differences during antiretroviral drug selection in vitro. This could suggest that these silent mutations, as well as specific polymorphisms found in subtype C isolates, can lead to important differences in the biological behaviour of the patients infected with different HIV-1 variants under antiretroviral therapy. |
| 59 | IN VITRO SELECTION AND CHARACTERIZATION OF MARAVIROC-RESISTANT HIV TYPE 1 Antivir Ther. 2008, 13(Suppl 3):A64 (abstract no. 59) J Wei, PA Hogan, RL Paulman, MS Jones, MK Mankowski, JD Russell and RG Ptak Although a classical shift in IC50 was not observed in susceptibility studies with passage-15 virus, the clear pattern of increasing mutations in gp120 and the ability of passage-18 virus to replicate to significant levels in 40 µM maraviroc (~40,000-fold above the IC50) demonstrate a novel maraviroc resistance genotype and phenotype based on HIV-1 JR-CSF. The results from this study expand existing knowledge of maraviroc resistance. The reagents generated will be useful for studying the antiviral activity of other CCR5 antagonists. |
| 60 | ESCAPE OF HIV-1 FROM A CCR5 ANTAGONIST CAN REDUCE ENVELOPE-MEDIATED ENTRY Antiviral Therapy 2008; 13 Suppl 3:A65 (abstract no. 60) W Huang1, L Wojcik2, J Toma1, S Fransen1, E Stawiski1, J Whitcomb1, N Parkin1, J Strizki2 and C Petropoulos1 Variants resistant to the CCR5 antagonist SCH-C can exhibit decreased viral infectivity. Reduced infectivity was associated with mutations in co-receptor-binding regions, including the V3 and C4 domains. Amino acid substitutions in regions associated with co-receptor binding, but distinct from V3, can compensate for the loss of infectivity of resistant virus. These findings may provide important insight into co-receptor binding and resistance to CCR5 antagonists, including vicriviroc and maraviroc. |
| 61 | DUAL MODES OF RESISTANCE TO AN HIV-1 FUSION INHIBITOR Antivir Ther. 2008, 13(Suppl 3):A66 (abstract no. 61) HK Steger and MJ Root The data show that similar antiviral agents that inhibit with the same mechanism and with comparable potencies can give rise to vastly different mechanisms of resistance. HIV-1 escape from 5-Helix inhibition involves a complex interplay between binding affinity, Env plasticity and viral fitness that has important implications for the development of inhibitors that target transient intermediate states of HIV-1 entry. |
| 62 | DISSECTION OF THE CONTRIBUTIONS OF PROTEASE AND CLEAVAGE SITE MUTATIONS TO PROTEASE INHIBITOR RESISTANCE: A CASE OF MULTIDRUG-RESISTANT VIRUS ASSOCIATED WITH RAPID PROGRESSION TO AIDS Antivir Ther. 2008, 13(Suppl 3):A67 (abstract no. 62) E Afonina1, M Markowitz2, H Yokoe1, H Mohri2, SV Gulnik1 and JW Erickson1 Generated recombinant viruses allowed us to analyse the relative contributions of cleavage site and protease mutations to phenotypic resistance to PIs and replication capacity. Although no or minimal resistance to all PIs was observed for virus containing only cleavage site mutations, their combination with PR mutations resulted in a synergistic effect. The presence of cleavage site mutations contributed to an improved replication capacity of mutant virus. |
| 63 | NATURAL VARIATION OF INTEGRASE SEQUENCES FROM SUBTYPE B AND CRF02-AG HIV-1 ANTIRETROVIRAL-NAÏVE PATIENTS AND POSSIBLE EFFECT ON SUSCEPTIBILITY TO INTEGRASE INHIBITORS Antivir Ther 2008; 13 Suppl 3:A68 (abstract no. 63) AG Marcelin1, I Malet1, L Tchertanov2, A Maiga1, C Soulie1, A Derache1, M Wirden1, C Katlama3, JF Mouscadet2 and V Calvez1 These results suggest that virological response to IN inhibitors, according to the subtype, needs to be carefully studied in clinical trials. The fact that most variations were found in clusters suggests that some of them could be linked together through compensatory mechanisms. |
| 64 | EVALUATING THE ‘SUBSTRATE ENVELOPE’ HYPOTHESIS: STRUCTURAL ANALYSIS OF NOVEL HIV-1 PROTEASE INHIBITORS DESIGNED TO BE ROBUST AGAINST RESISTANCE Antivir Ther. 2008, 13(Suppl 3):A69 (abstract no. 64) M Nalam1, A Ali1, KK Reddy1, M Altman2, S Chellappan3, S Anjum1, T Rana1, M Gilson3, B Tidor2 and C Schiffer1 This is the first systematic analysis performed on a large number of HIV protease–inhibitor complexes. The study shows that, although HIV-1 protease possesses intrinsic structural plasticity, there are some subtle interactions that distinguish nanomolar inhibitors from picomolar inhibitors. Modern drug design ignores the molecular basis for function, resulting in the rapid evolution of drug resistance. With the substrate envelope hypothesis, we have shown that inhibitors can be designed that are less susceptible to resistance. |
| 65 | NINETY NINE NOT ENOUGH? CHARACTERIZATION OF HIV-1 PROTEASE MUTANTS WITH INSERTIONS IN THE FLAP REGION Antivir Ther. 2008, 13(Suppl 3):A70 (abstract no. 65) M Kozísek1,2, K Grantz Sasková1,2, P Rezácocvá1,3, J Brynda1,3, NM van Maarseveen4, D De Jong4, CAB Boucher4, RM Kagan5, M Nijhuis4 and J Konvalinka1,2 Prevalence of protease insertions is very low but increasing over time, which could be a concern because they confer high-level resistance to most clinically relevant PIs. Enlargement of the protease substrate-binding site together with impaired flap dynamics could account for the weaker PI binding by the insertion mutants. These protease insertions could therefore represent an additional mechanism of HIV PI resistance development. |
| 66 | HIV p7/p1 CLEAVAGE-SITE MUTATIONS ARE SELECTED BY THE IMMUNE SYSTEM AND/OR BY ANTIRETROVIRAL THERAPY Antivir Ther. 2008, 13(Suppl 3):A71 (abstract no. 66) J Verheyen1, F Schweitzer1, E Harrer2, E Knops1, S Müller2, M Däumer3, K Eismann2, S Bergmann2, H Pfister1, R Kaiser1 and T Harrer2 A variety of CS mutations could be detected in therapy-naïve HIV. Different selective pressures contribute to the occurrence of CS mutation 436R. Our data indicate that, in addition to drug therapy, immune selection may influence the development of CS mutations. |
| 67 | MULTIPLY DRUG-RESISTANT (MDR) VARIANTS OF HIV-1 CAN EXIST WITHIN CELLS AS REPLICATION-DEFECTIVE QUASISPECIES AND BE RESCUED BY SUPERINFECTION Antivir Ther. 2008, 13(Suppl 3):A72 (abstract no. 67) Y Quan, BG Brenner, C Liang and MA Wainberg Cells that harbour defective viruses can produce infectious progeny after superinfection by another defective virus, because of probable recombination during second rounds of infection. These results demonstrate that defective HIV variants possibly represent an important component of the HIV-1 reservoir in terms of both wild-type and drug-resistant viral progeny. |
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Session 3: HIV pathogenesis, fitness and resistance Abstracts 68 thru 86, Pages A75 to A94 |
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| 68 | SINGLE CELL ANALYSIS OF HIV DNA FROM INFECTED PATIENTS Antivir Ther. 2008, 13(Suppl 3):A75 (abstract no. 68) S Palmer1,2, F Maldarelli2, M Kearney2, W Shao2, D Rock3, J Mellors4, J Albert1 and J Coffin5 Results from two chronically infected patients indicate that most infected mononuclear cells in blood contain only one copy of HIV DNA, implying a limited potential for recombination in this population. The genetic similarity between HIV populations in PBMCs and plasma implies ongoing exchange between these compartments, even following suppressive therapy. |
| 69 | CORRELATIONS BETWEEN TRANSMITTED HIV-1 DRUG RESISTANCE MUTATIONS AND THE HUMAN LEUKOCYTE ANTIGEN ALLELES OF THERAPY-NAïVE HIV PATIENTS Antivir Ther. 2008, 13(Suppl 3):A76 (abstract no. 69) F Schweitzer1,2, SM Mueller3, M Daeumer4, R Kaiser2, M Oette5,6, T Lengauer7 and T Harrer3 on behalf of the RESINA-study group Our data suggest that the HLA system seems to play a role in the evolution of drug resistance mutations, even in treatment-naïve patients. |
| 70 | HIV-1 RECOMBINATION IN PATIENTS INFECTED WITH MULTIPLE HIV-1 VARIANTS FROM THE SAME DONOR Antivir Ther. 2008, 13(Suppl 3):A77 (abstract no. 70) M Kearney1, W Shao1, F Maldarelli1, J Margolick2, E Daar3, J Mellors4, J Coffin5 and S Palmer1,6 These findings show that recombination contributes substantially to HIV diversity in acute infection and facilitates rapid, independent evolution of different regions of the HIV genome. |
| 71 | THE SELECTION, TRANSMISSION AND PERSISTENCE OF DRUG-RESISTANT HIV-1 IN INFANTS PROPHYLAXED WITH SINGLE-DOSE NEVIRAPINE VARIES BY THE TIMING OF INFECTION Antivir Ther. 2008, 13(Suppl 3):A78(abstract no. 71) MA Micek1,2, AJ Blanco1, IA Beck3, S Dross3, E Matediane4, L Mantunha1, P Montoya1,2, I Jani4, J Kasper1, K Siedel3, S Gantt2,3, L Jamisse4, S Gloyd1,2 and LM Frenkel2,3 The selection, transmission and persistence of rNVP-HIV-1 in infants following sdNVP varies by the timing of their infection. Resistant viruses are generally selected when infection is well-established prior to birth. In contrast, acute HIV-1 infection during NVP pressure results in virus populations composed of mixed, wild-type, or mutant genotypes, corresponding possibly to virus acquisition slightly prior, immediately prior, or after nevirapine dosing. |
| 72 | INTENSIFICATION WITH EFAVIRENZ OR LOPINAVIR/RITONAVIR DOES NOT REDUCE RESIDUAL HIV-1 VIRAEMIA IN PATIENTS ON STANDARD ANTIRETROVIRAL THERAPY Antivir Ther. 2008, 13(Suppl 3):A79 (abstract no. 72) F Maldarelli1, A Wiegand1, S Palmer1, N Urban1, M Kearney1, J Coffin2, and J Mellors3 Antiretroviral intensification with lopinavir/ritonavir or efavirenz did not decrease the level of residual viraemia. This result is inconsistent with the idea that persistent viraemia results from ongoing, complete cycles of viral replication. New therapeutic approaches will be required to eliminate HIV-1 reservoirs. |
| 73 | TREATMENT-EMERGENT GAG CLEAVAGE SITE MUTATIONS DURING VIROLOGICAL FAILURE OF RITONAVIR-BOOSTED PROTEASE INHIBITORS Antivir Ther. 2008, 13(Suppl 3):A80 (abstract no. 73) A Garcia-Diaz1, Z Fox1, UB Dragsted2, J Kjaer3, N Clumeck2, A Philips1, JD Lundgren2,4 and AM Geretti1 The prevalence and patterns of CS mutations differed in drug-naïve and PI-experienced individuals. Mutations in p7/p1 and p1/p6 were more frequent in PI-experienced persons, with A431V, I437V and P453L found exclusively in treatment-experienced patients. Whether CS mutations independently contribute to risk of VF should be further explored. |
| 74 | GAG–PROTEASE INTER-RELATIONSHIPS IN DRUG RESISTANCE AND VIRAL FITNESS Antivir Ther. 2008, 13(Suppl 3):A81 (abstract no. 74) CM Parry, A Kohli and D Pillay We demonstrate a complete restoration of replication capacity for a highly mutated Protease by full-length Gag and also a poorly studied region of Gag containing no cleavage site mutations; this suggests a complex inter-relationship between Gag and Protease, and also within Gag, to yield replication competent virus with high-level resistance. We encourage the use of full-length Gag in future studies of protease resistance. |
| 75 | SPONTANEOUS MUTATIONS IN HIV-1 V3 ENVELOPE OF SLOW AND FAST PROGRESSORS ARE CAPABLE TO INFLUENCE THE BINDING TO CCR5 AND CXCR4 CORECEPTORS Antivir Ther. 2008, 13(Suppl 3):A82 (abstract no. 75) M Bellini1, M Lo Cicero1, M Airoldi2, S Ferramosca1, P Vitiello1, M Galli1, M Moroni1, F Maggiolo2, J Martinez-Picado3, J Dalmau3 and S Rusconi1 The different mutation pattern between V3 of the two progressors influenced the binding affinity towards the coreceptors. The presence of an aspartic residue instead of a glycine on the tip was able to change the stability and modify the chemophysical properties when present at position 27. Our data will be useful to study the mechanism of interaction between gp120 and coreceptors. |
| 76 | FITNESS PROGRESSION AND PHENOTYPIC SUSCEPTIBILITY TO RALTEGRAVIR OF HIV-1 INTEGRASE ARE NOT RESTRICTED IN LONG-TERM HAART-TREATED PATIENTS Antivir Ther 2008; 13 Suppl 3:A83 (abstract no. 76 MJ Buzón1, S Marfil1, MC Puertas1, E Garcia1, B Clotet1, J Blanco1, C Cabrera1 and J Martinez-Picado1,2 Long-term drug pressure with PR and RT inhibitors is not enough to restrict fitness progression of IN. Additionally, HIV-1 IN from longitudinal samples obtained from patients treated with IN inhibitor-sparing regimens showed no evidence of genotypic and phenotypic resistance to raltegravir. These data suggest that current antiretroviral regimens do not preclude either IN fitness or efficacy of raltegravir. |
| 77 | RELATIVE FITNESS OF RALTEGRAVIR RESISTANCE MUTANTS IN HIV-1 INTEGRASE Antivir Ther. 2008, 13(Suppl 3):A84 (abstract no. 77) Z Hu, W Sun, T Yu, F Giguel and DR Kuritzkes Mutations Q148H/R/K or N155H impaired viral fitness compared with WT. Although the 148H mutation substantially impaired replication when present by itself, fitness was partially restored by the presence of additional INSTI resistance mutations at positions E138K and G140S. E92Q and G163R, but not L74M, restored fitness of the N155H mutants. It will be interesting to compare the effects of L74M on strand transfer activity and the 3′ processing properties of IN with those of other mutations in this region. |
| 78 | TRACKING HIV-1 INTEGRASE POLYMORPHISMS FROM THE PRE-ANTIRETROVIRAL THERAPY ERA UP TO THE INTRODUCTION OF INTEGRASE INHIBITORS Antivir Ther. 2008, 13(Suppl 3:A85 (abstract no. 78) H Ji1, N Masse1, H Merks1, R Pilon1, M Ofner2, C Archibald2, M Rekart3, P Sandstrom1 and J Brooks1 The HIV-1 IN gene is intrinsically polymorphic with some INI-resistance-associated mutations present in samples collected in the pre-ART era. Increasing levels of nucleotide and amino acid sequence polymorphisms over time may be due to the influence of ART. Further characterization of these observations is ongoing. |
| 79 | SUSTAINING LAMIVUDINE/EMTRICITABINE, ABACAVIR, ZIDOVUDINE OR ATAZANAVIR FROM A PREVIOUS TREATMENT SHOWS A CLINICAL BENEFIT Antivir Ther. 2008, 13(Suppl 3):A86 (abstract no. 79) M Rosen-Zvi1, E Schülter2, A Altmann3, S Sierra-Aragon2, M Zazzi4, A Sönnerborg5, M Oette6, T Lengauer3 and R Kaiser2 on behalf of the EuResist group Significant clinical advantage of drug maintenance was seen for lamivudine/emtricitabine, abacavir, zidovudine or atazanavir. It is unclear whether this is a mechanistic effect or a consequence of biased clinical practice. |
| 80 | MORE FREQUENT DETECTION OF LOPINAVIR RESISTANCE BY SINGLE GENOME SEQUENCING AT VIROLOGICAL FAILURE OF LOPINAVIR/RITONAVIR MAINTENANCE THERAPY IN THE OK04 STUDY Antivir Ther. 2008, 13(Suppl 3):A87 (abstract no. 80) JE McKinnon1, R Delgado2, JR Arribas3, F Pulido2 and JW Mellors1 Viral variants encoding major LPV resistance mutations were detected more frequently at virological rebound on LPV/RTV therapy by SGS than standard population genotyping. The clinical significance of such low frequency variants warrants further study. |
| 81 | DIVERSITY OF THE PERSISTENT RESERVOIR OF HIV-1 ASSOCIATED WITH LOW-LEVEL VIRAEMIA DURING COMBINED ANTIRETROVIRAL THERAPY Antivir Ther. 2008, 13(Suppl 3):A88 (abstract no. 81) H Mens1, TL Benfield1, LB Jørgensen2, J Gerstoft3 and TL Katzenstein3 The diversity of the persistent reservoir of HIV-1 was found to be significantly higher in patients experiencing LLV >200 copies/ml than in patients with no LLV or LLV between 20–200 copies/ml. This correlation suggests a link between population diversity and number of potentially virus-producing cells on therapy. Factors driving the differences in diversity will be discussed. |
| 82 | RECOGNITION OF PROTEASE BY HIV-1-SPECIFIC CYTOTOXIC T-LYMPHOCYTE IS INFLUENCED BY PROTEASE INHIBITOR RESISTANCE MUTATIONS Antivir Ther. 2008, 13(Suppl 3):A89 (abstract no. 82) SM Mueller1, B Schatz1, K Eismann2, S Bergmann2, H Walter3, B Schmidt3, K Korn3, M Schmucker1, B Spriewald3, E Harrer3 and T Harrer1 for the German Competence Network on HIV/AIDS Prospective studies will be needed to explore whether CTL targeting drug resistance mutations in the HIV-1 protease influence the emergence of resistance to protease inhibitors. The interaction between the CTL response and the development of drug resistance mutations could have important clinical implications for the sequencing of protease inhibitors in antiretroviral therapy, the understanding of drug resistance pathways and the design of therapeutic vaccines. |
| 83 | INTERACTIONS BETWEEN REPLICATION CAPACITY AT THE END OF STRUCTURED TREATMENT INTERRUPTION (STI) AND PRE-STI CD4+ COUNT AS PREDICTORS OF CLINICAL OUTCOME AFTER STI Antivir Ther. 2008, 13(Suppl 3):A90 (abstract no. 83) AC Paquet1, JM Weidler1, J Lawrence2, R Kim3, JD Baxter3, Y Lie1, E Coakley1, CJ Petropoulos1, MP Bates1 and C Chappey1 These data suggest that multiple subpopulations of HIV-infected patients with different immunologic outcomes after STI can be defined by their baseline CD4 count and the RC of their dominant circulating virus. The impact of viral RC on immunologic recovery appears to be different depending on the immune recovery potential of the host. |
| 84 | MODELLING THE HIV FITNESS LANDSCAPE UNDER INDINAVIR TREATMENT PRESSURE USING OBSERVED EVOLUTION IN LONGITUDINAL SEQUENCE DATA Antivir Ther. 2008, 13(Suppl 3):A91 (abstract no. 84) RZ Sangeda1, K Deforche1, K Theys1, P Libin1, J Vercauteren1, R Camacho2, K Van Laethem1 and A-M Vandamme1 This study suggests that drug fitness landscapes can be modelled from longitudinal data, even when epistatic interactions are learned from selective pressure with other drugs acting on the same HIV protein, thus enabling their use for drugs with limited sequence information and mainly used in salvage therapy. Even though the landscapes are subtype-neutral with respect to resistance evolution, they remain fitness landscapes for drug selective pressure and can not capture fitness differences between subtypes. The fact that the correlation was worse when excluding IDV-learned epistatic interactions may indicate that IDV causes protease changes that are not captured by any other PI selective pressure. |
| 85 | HIV NEF IN LONG-TERM NON-PROGRESSORS ARE DEFECTIVE IN THE SERINE/THREONINE KINASE BINDING SITE (RR), THE GLUTAMIC ACID CLUSTER AND THE PROTEASE CLEAVAGE SITE (CAW\LEA) AS WELL AS IN MOTIFS IMPORTANT FOR MHC CLASS I DOWN-REGULATION AND RETENTION Antivir Ther. 2008, 13(Suppl 3):A92 (abstract no. 85) S Trapp1, M Däumer2, J von Lunzen3, S Staszewski4, JK Rockstroh5, S Mauss6, RE Schmidt7, G Fätkenheuer8, J Jiang9, M Robbiani9, S Awerkiew1, VV Kartashev10, TK Poplavskaja10, H Walter11, H Pfister1 and R Kaiser1 We conclude that both cohorts of LTNP show mutations in motifs that were described as important for viral infectivity. It could be that those mutations contribute to a low viral load and slow disease progression. |
| 86 | DYNAMICS OF EMERGENCE OF CXCR4-USING HIV IN CLINICAL SAMPLES AS DETECTED BY TROFILE AND MT-2 ASSAYS Antivir Ther. 2008, 13(Suppl 3):A93 (abstract no. 86) AB van ‘t Wout1, E Coakley2, J Reeves2, CJ Petropoulos2, H Schuitemaker1 and W Huang2 The detection of X4 variants in patients’ plasma (enhanced Trofile) or PBMC (MT-2 assay) is highly concordant. Clonal analysis revealed distinct phenotypes of dual-tropic variants possibly representing Env with different efficiencies of CXCR4 usage during evolution from the R5 to X4 phenotype. |
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Session 4: New resistance technologies and interpretations Abstracts 87 thru 118, Pages A95 to A128 |
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| 87 | DYNAMIC HIV-1 ESCAPE FROM VICRIVIROC THERAPY IN VIVO Antivir Ther. 2008, 13(Suppl 3):A97 (abstract no. 87) AMN Tsibris1,2, R Arnaout3,4, B Korber5,6, C Russ7, C-C Lo5, B Gaschen5, T Leitner5, R Paredes2,3,8, ZSu9, MD Hughes9, RM Gulick10, W Greaves11, E Coakley12, C Flexner13, C Nusbaum7, B Birren7 and DR Kuritzkes2,3 V3 loop forms associated with VCV escape, either through CXCR4 use or the emergence of high-level VCV resistance, exist prior to therapy. Minor variants present at <1% of the starting population emerge rapidly in response to VCV treatment and contribute to virological failure. |
| 88 | RESPONSE TO VICRIVIROC IN HIV-INFECTED, TREATMENT-EXPERIENCED INDIVIDUALS USING AN ENHANCED VERSION OF THE TROFILE HIV CO-RECEPTOR TROPISM ASSAY [TROFILE (ES)]: REANALYSIS OF ACTG 5211 RESULTS Antivir Ther. 2008, 13(Suppl 3):A98 (abstract no. 88) Z Su1, JD Reeves2, A Krambrink1, E Coakley2, M Hughes1, C Flexner3, T Wilkin4, P Skolnik5, W Greaves6, D Kuritzkes7, R Gulick4 and the ACTG 5211 Team Reanalysis of key study endpoints based on Trofile (ES) demonstrates improved antiretroviral activity of VCV and indicates that Trofile (ES) is an improved screening tool for determining patient eligibility for CCR5 antagonist therapy. |
| 89 | IMPROVED DETECTION OF X4 VIRUS BY V3 GENOTYPING: APPLICATION TO PLASMA RNA AND PROVIRAL DNA Antivir Ther. 2008, 13(Suppl 3):A99 (abstract no. 89) A Moores1, A Thielen2, W Dong1, A Low1, C Woods1, M Jensen3, B Wynhoven1, D Chan1, C Glascock1 and PR Harrigan1 Fully automated analyses of multiple V3 sequence assessments detect a much greater proportion of X4 samples than previously possible, regardless of the genotype algorithm used. Using this approach, most patients with X4 virus can be screened out, at a cost of approximately $300–400 per assay. The ability to measure tropism from proviral DNA suggests the possibility of screening for those with suppressed pVL who may wish to switch to CCR5 antagonists for tolerability or other reasons. |
| 90 | IMPROVED GENOTYPIC PREDICTION OF HIV-1 CORECEPTOR USAGE BY INCORPORATING V2 LOOP SEQUENCE VARIATION Antivir Ther. 2008, 13(Suppl 3):A100 (abstract no. 90) A Thielen1, PR Harrigan2, AJ Low2, A Moores2, A Altmann1, K Bozek1, E Heger3, N Sichtig3, R Kaiser3 and T Lengauer1 Mutations in V2 as well as additional features have been shown to be associated with CXCR4 usage and confirm the influence of V2 for coreceptor usage in a large dataset of genotype–phenotype pairs. Incorporation of this information into genotypic predictors leads to modest but significant improvements in prediction quality on an independent clinical dataset. |
| 91 | INFERRING VIRAL TROPISM FROM GENOTYPE WITH MASSIVELY PARALLEL SEQUENCING: QUALITATIVE AND QUANTITATIVE ANALYSIS Antivir Ther. 2008, 13(Suppl 3):A101 (abstract no. 91) MP Däumer1, R Kaiser2, R Klein1, T Lengauer3, B Thiele1 and A Thielen3 Combining genotypic prediction with ultradeep sequencing results in a fast and accurate alternative to phenotypic assays. The detection of X4 viruses in all isolates suggests that coreceptor usage as well as fitness of minorities is important for therapy outcome. The high sensitivity of this technology in combination with a quantitative description of the viral population may allow implementing meaningful cutoffs for predicting response to CCR5 antagonists in the presence of X4 minorities. |
| 92 | INITIATIVES FOR DEVELOPING GENOTYPE INTERPRETATION SYSTEMS: DERIVATION AND VALIDATION OF A DIDANOSINE INTERPRETATION SYSTEM USING LARGE DERIVATION AND LARGE VALIDATION DATASETS Antivir Ther. 2008, 13(Suppl 3):A102 (abstract no. 92) L Assoumou1,2, A Cozzi-Lepri3, F Brun-Vézinet4, V DeGruttola5, D Kuritzkes6, A Phillips3, A Zolopa7, V Miller8 and D Costagliola1,2 on behalf of the Standardization and Clinical Relevance of HIV Drug Resistance Testing Project from the Forum for Collaborative HIV Research We derived and validated a genotypic score including mutations that both positively and negatively impact virological response and which contains five mutations never reported in previous studies. Assessment of this new score on external datasets would help to conclude on the role of these new mutations. |
| 93 | ASSESSING THE VARIABILITY IN BUILDING GENOTYPIC SCORE IN PATIENTS RECEIVING A DIDANOSINE-CONTAINING REGIMEN: BASELINE CHARACTERISTICS VERSUS STATISTICAL METHODOLOGY Antivir Ther. 2008, 13(Suppl 3):A103 (abstract no. 93) L Assoumou, A Houssaïni, D Costagliola and P Flandre on behalf of the Standardization and Clinical Relevance of HIV Drug Resistance Testing Project from the Forum for Collaborative HIV Research This study shows that baseline characteristics (geographical origin) contribute to a larger variability in building genotypic score than the statistical method used. |
| 94 | IMPROVED INTERPRETATION AND CLINICAL VALIDATION OF SUBSTITUTIONS IN HIV-1 PROTEASE PREDICTING THE VIROLOGICAL RESPONSE TO DARUNAVIR/RITONAVIR Antivir Ther. 2008, 13(Suppl 3):A104 (abstract no. 94) A De Luca1, S Di Giambenedetto1, F Marando2, R Maserati3, N Gianotti4, P Narciso5, A Antinori5, G Di Perri6, F Baldanti3, M Zazzi7, CF Perno2 and MM Santoro2 for the TMC114-C226 and the ARCA study groups The validated DRVnew score showed improved predictive capacity of VR. The absence of correlation for some ‘classical’ DRV mutation requires more investigation. |
| 95 | A RIGOROUS STATISTICAL LEARNING METHOD FOR THE ESTIMATION AND VALIDATION OF WEIGHTED DRUG SUSCEPTIBILITY SCORES APPLIED TO IN VIVO VIROLOGICAL OUTCOME PREDICTION IN ATAZANAVIR/RITONAVIRCONTAINING HAART Antivir Ther. 2008, 13(Suppl 3):A105 (abstract no. 95) S Di Giambenedetto1, MCF Prosperi1,2, L Bracciale1, AP Callegaro3, F Maggiolo4, A Di Garbo5, B Bruzzone6, S Bonora5, F Baldanti7, D Francisci8, S Menzo9, G Colao10, M Zazzi11, L Monno12 and A De Luca1 GSS and PSS scores correlate significantly with VR. CV results in more precise assessment than only multivariable P-values. GSSnew led to potentially misleading mutation interpretation probably due to limited sample size and confounders. Existing and new algorithms outperformed GSSbasic. We foresee in PSS an alternative weighted score to catch fine interpretations of resistance/hypersusceptibility roles of mutations. |
| 96 | A COMBINATION OF BIOINFORMATIC TOOLS CAN BE ACCURATELY USED FOR THE SCREENING OF CORECEPTOR USAGE IN CLINICAL SAMPLES Antivir Ther. 2008, 13(Suppl 3):A106 (abstract no. 96) N Chueca1, L Martin1, M Alvarez1, A Peña2, V Guillot1, V Garcia-Casas1, R Sanchez3, J Hernandez-Quero2, MC Maroto1 and F Garcia1 An algorithm combining four distinct bioinformatics tools, SVM, geno2pheno, PSSM and C4.5, might improve the prediction of HIV tropism and can be used as a screening tool in clinical practice. In our experience, using this strategy, the number of specimens requiring further phenotypic testing will be substantially reduced. |
| 97 | LOW RATE OF TIPRANAVIR AND DARUNAVIR RESISTANCE MUTATIONS IN PI-EXPERIENCED PATIENTS USING THE NEW INTERPRETATION SCORES – IMPLICATIONS FOR PI SEQUENCING Antivir Ther. 2008, 13(Suppl 3):A107 (abstract no. 97) C Garrido, E Poveda, A Corral, C de Mendoza and V Soriano Most PI-experienced patients retain full susceptibility to TPV and DRV, according to the latest genotypic interpretation scores. Moreover, the extent of cross-resistance between DRV and TPV is low, which may permit sequential rescue interventions. |
| 98 | PRELIMINARY RESULTS OF A PROSPECTIVE CLINICAL STUDY OF THE HIV RESISTANCE RESPONSE DATABASE INITIATIVE’S COMPUTATIONAL MODELS AS A TREATMENT DECISION TOOL Antivir Ther. 2008, 13(Suppl 3):A108 (abstract no. 98) BA Larder1, D Wang1, AD Revell1, D Coe1, C Torti2, JSG Montaner3, M Harris3 and HC Lane4 These preliminary results indicate that the models are able to predict virological response to highly active antiretroviral therapy with accuracy in clinical practice, that the system affects treatment decision-making and would be widely used if made available. The clinical pilot study continues and an international, multi-centre prospective controlled clinical trial of the RDI system is planned. |
| 99 | IMPROVEMENT OF GENOTYPIC ALGORITHMS TO PREDICT HIV-1 TROPISM IN TREATMENT-EXPERIENCED PATIENTS – CORRELATION WITH TROFILE RESULTS Antivir Ther. 2008, 13(Suppl 3):A109 (abstract no. 99) E Poveda1, E Seclén1, MM González1, C Garrido1, C de Mendoza1, R Sánchez2, P Mallaina2 and V Soriano1 The use of webPSSMx4r5-8 showed the best correlation with Trofile to identify X4-variants compared with other genotypic tools, and might assist with therapeutic decisions for using CCR5 antagonists in HIV patients. |
| 100 | CROSS-SECTIONAL VERSUS CUMULATIVE INTERPRETATION OF HIV-1 DRUG RESISTANCE MUTATIONS Antivir Ther. 2008, 13(Suppl 3):A110 (abstract no. 100) S Yerly1, P-A Michel2, S Emler2, V Von Wyl3, H Günthard3, B Hirschel4, L Perrin1 and L Kaiser1 Cumulative analysis of drug resistance mutations provides an additional tool that improves resistance interpretation as compared with cross-sectional analysis, in particular when multiple drug regimens have been used or antiretroviral drugs have been stopped. This approach takes into account previous failing drug regimens and archived mutations. However, limitations of the cumulative approach may potentially arise from compensatory or antagonistic mutations not necessarily present on a given viral genome. |
| 101 | AUTOMATIC IDENTIFICATION OF RESISTANCE-ASSOCIATED MUTATIONS USING TECHNIQUES FROM HUMAN LANGUAGE TECHNOLOGIES Antivir Ther. 2008, 13(Suppl 3):A111 (abstract no. 101) BY Cheng and JG Carbonell Contrary to a previous study, we developed an automatic method to identify resistance-associated mutations for phenotype prediction that can match the performance of human experts without special treatment history data. This method can remove the human bottleneck in statistical prediction systems relying on human-selected mutations. |
| 102 | DETERMINATION OF HIV-1 CORECEPTOR USAGE IN GERMAN PATIENTS – COMPARISON OF GENOTYPIC METHODS WITH THE TROFILE PHENOTYPIC ASSAY Antivir Ther. 2008, 13(Suppl 3):A112 (abstract no. 102) M Obermeier1, N Sichtig2, P Braun3, M Däumer4, H Walter5, C Noah6, E Wolf7, H Müller8, M Stürmer9, R Kaiser2 and A Thielen10 We conclude that geno2pheno coreceptor is a suitable tool to predict HIV-tropism for using CCR5 receptor blocker in clinical practice. Although only a small number of proviral DNA samples were tested, this method seems promising to conduct tropism testing in patients with undetectable plasma viral load. |
| 103 | EVALUATION OF THE GENOTYPIC PREDICTION OF HIV-1 CORECEPTOR TROPISM IN A CLINICAL SETTING Antivir Ther. 2008, 13(Suppl 3):A113 (abstract no. 103) P Recordon-Pinson1, C Soulié2, G Anies1, P Flandre3, D Descamps4, J Cottalorda5, B Montes6, C Tamalet7, V Schneider8, C Amiel8, V Ferré9, L Morand-Joubert10, D Desbois11, M Macé12, A Vabret13, A Ruffault14, H Fleury1, F Brun-Vézinet4, J Izopet15, AG Marcelin2, J Reynes6 , V Calvez2, B Masquelier1 and the ANRS AC11 Resistance Study Group Bioinformatic tools can predict coreceptor usage with acceptable concordances with a phenotypic test. The combination of several algorithms can be used for increasing the detection of X4 or D/M viruses. Follow-up data on maraviroc therapy will be of interest to compare the predictivity of genotypic and phenotypic tests on virological response. |
| 104 | DIRECT SEQUENCING OF V3 COULD BE A VALUABLE ALTERNATIVE TO PHENOTYPIC ASSAYS FOR THE ROUTINE ASSESSMENT OF HIV-1 TROPISM Antivir Ther. 2008, 13(Suppl 3):A114 (abstract no. 104) S Raymond1,2,3, P Delobel1,4, M Mavigner1, M Cazabat1,3, C Souyris1,3, K Sandres-Sauné1,2,3, L Cuzin4, B Marchou2,4, P Massip2,4 and J Izopet1,2,3 The genotypic determination of HIV-1 coreceptor usage based on direct sequencing of V3 could be an efficient, simple alternative to phenotypic assays. This test is indicated before the use of CCR5 antagonists and in the event of therapeutic failure. |
| 105 | DETECTION OF LOW-ABUNDANCE DRUG-RESISTANT HIV VARIANTS IN TREATMENT-EXPERIENCED SUBJECTS Antivir Ther. 2008, 13(Suppl 3):A115 (abstract no. 105) T Le1, J Chiarella1, BB Simen2, B Hanczaruk2, M Egholm2, ML Landry1, K Dieckhaus3 and MJ Kozal1,4 Low-abundance drug-resistant HIV variants in ARV-experienced individuals with viraemia on ART are common. The overall burden of resistance in an ARV-experienced individual is often greater than that reflected in standard genotypes, with NRTI, NNRTI and PI low-abundance resistance variants all being identified in individuals. |
| 106 | MINORITY QUASISPECIES OF DRUG-RESISTANT HIV-1 LEADING TO EARLY THERAPY FAILURE IN TREATMENT-NAïVE AND ADHERENT PATIENTS Antivir Ther. 2008, 13(Suppl 3):A116 (abstract no. 106) SG Giulieri1, SA Knoepfel2, P Rauch2, HF Günthard3, M Cavassini1 and KJ Metzner2 Minority quasispecies of drug-resistant viruses detected at baseline can rapidly outgrow and represent the major virus population subsequently leading to early therapy failure. Sensitive assays for key mutations might be a useful tool before starting ART. |
| 107 | DEVELOPMENT AND APPLICATION OF A BROADLY SENSITIVE GENOTYPING ASSAY FOR SURVEILLANCE OF HIV-1 DRUG RESISTANCE IN PEPFAR COUNTRIES Antivir Ther. 2008, 13(Suppl 3):A117 (abstract no. 107) A McNulty1, K Diallo1, J Zhang1,2, B Titanji3, S Kassim1, D Bennett4, J Aberle-Gasse5, T Kibuka6, PM Ndumbe3, JN Nkengasong1 and C Yang1 Our results indicate that this broadly sensitive genotyping assay can successfully be used to amplify and genotype both plasma and DBS specimens from individuals infected with diverse HIV-1 subtypes and CRFs. The assay is likely to be useful for HIV drug resistance surveillance in PEPFAR and other developing countries. |
| 108 | PRESENCE OF MINOR DRUG-RESISTANT MUTATIONS IN HIV-1 SUBTYPE C PATIENTS FAILING ANTIRETROVIRAL THERAPY Antivir Ther. 2008, 13(Suppl 3):A118 (abstract no. 108) C Wallis1, W Stevens1,2, M Papathanasopolous1, BB Simen3, M Braverman3, M Egholm3, V Pillay4, L Morris4, T Ndung’u5, M Gordon5 and J Sakwa6 Ultra Deep sequencing of HIV-1 subtype C samples provided good-quality sequences and detected several minority drug resistance mutations in patients failing ARVs. The presence of the K65R mutation previously not detected using standard population-based sequencing needs to be further investigated to determine the effect it and other minority mutations may have on future ARV treatment strategies. |
| 109 | EVALUATION OF HIV-1 TROPISM USING A NEW AND SENSITIVE SYSTEM BASED ON RECOMBINANT VIRUSES Antivir Ther. 2008, 13(Suppl 3):A119 (abstract no. 109) N González1, M Pérez-Olmeda1, J García-Pérez2, E Mateos1, A Cascajero1, A Álvarez1, S Spijkers1, S Sánchez-Palomino3 and J Alcamí1 We describe a new system to assess HIV tropism based on the generation of chimeric replication-competent viruses that increases the sensitivity for detecting minority populations in comparison with available commercial tests. |
| 110 | EXPLORING ETRAVIRINE RESISTANCE AMONG RECENT ROUTINE CLINICAL SAMPLES SUBMITTED FOR RESISTANCE TESTING Antivir Ther. 2008, 13(Suppl 3):A120 (abstract no. 110) L Bacheler1, K Van Der Borght2, E Van Craenenbroeck2, B Winters2 and P Lecocq2 Most RCS, including those with evidence of resistance to first generation NNRTIs, had low ETR FC values, suggesting they might benefit from treatment with etravirine as part of a HAART regimen. |
| 111 | NO EFFECT OF SUBTYPE ON SUSCEPTIBILITY AND VIROLOGICAL RESPONSE TO TPV/R FOR TREATMENT-EXPERIENCED PATIENTS Antivir Ther. 2008, 13(Suppl 3):A121 (abstract no. 111) R Bethell1, DB Hall2, J Baxter3, J Schapiro4, C Boucher5 and J Scherer6 Phenotypic susceptibility to TPV/r is not reduced among non-B subtypes studied. Although genotypic scores show higher baseline results for non-B than B samples, non-B patients do not have inferior responses, suggesting that this difference is not clinically significant. Further investigation and analysis will be necessary to develop a full understanding of the role of resistance-associated polymorphisms in response to non-B subtype viruses. TPV/r is a viable treatment option for treatment-experienced subtype B and non-B patients. |
| 112 | DYNAMICS OF THE M184V MUTATION BY ALLELE-SPECIFIC PCR (AS-PCR) IN PATIENTS RECEIVING LAMIVUDINE OR EMTRICITABINE MONOTHERAPY OR UNDERGOING TREATMENT INTERRUPTION (TI) Antivir Ther. 2008, 13(Suppl 3):A122 (abstract no. 112) A Bestetti1, A Soria1, L Galli1, A Danise1, S Sala1, S Bossolasco1, M Sampaolo2, A Bigoloni1, A Galli1, M Clementi2, A Lazzarin1, A Castagna1 and P Cinque1 3TC or FTC monotherapy, including FTC once weekly, was associated with steady rates of M184V over 24 weeks. The association between slow M184V decay and smaller loss of CD4+ T-cells cells, observed in TI patients, supports the hypothesis that virus harbouring this mutation might be less pathogenic on CD4+ T-cells irrespective of VL. |
| 113 | IN SILICO IDENTIFICATION OF PHYSIOCHEMICAL PROPERTIES AT MUTATING POSITIONS RELEVANT TO REDUCED SUSCEPTIBILITY TO AMPRENAVIR Antivir Ther. 2008, 13(Suppl 3):A123 (abstract no. 113) L Høj1, J Kjær1, O Winter2, A Cozzi-Lepri3 and JD Lundgren1,4 We have mathematically identified the important physiochemical properties that drive the change in IC50 FC to amprenavir, although the approach maybe missing properties with high collinearity. Applying this approach to other antiviral inhibitors will provide cost effective in silico knowledge about the physiochemical changes to the affected enzymes and could serve as input for computer-assisted drug designs and improvement of existing drug compounds. |
| 114 | DETECTION OF MIXTURES OF HEPATITIS C VIRUS GENOTYPES Antivir Ther. 2008, 13(Suppl 3):A124 (abstract no. 114) RM Lloyd Jr1, M Holodniy2, RL Mathis1, PM Feorino1 and WA O’Brien1 HCV-infected patients may have mixed genotypes, reflecting multiple exposures. At present, the ability to detect HCV genotype mixtures may be important for treatment, and if anti-HCV therapies are developed which differ in response rates based on HCV genotype. |
| 115 | IN VITRO ANALYSIS OF SYNERGISM/ANTAGONISM EFFECT OF DIFFERENT NUCLEOSIDE/NUCLEOTIDE ANALOGUES COMBINATIONS ON THE INHIBITION OF HIV-1 REPLICATION Antivir Ther. 2008, 13(Suppl 3):A125 (abstract no. 115) M Perez-Olmeda1, J Garcia-Perez1, E Mateos1, S Spijkers1, MC Ayerbe2, A Carcas3 and J Alcami1 The results of this new, viable and reproducible method in vitro to evaluate combination of two drugs allow to define synergistic, additive or antagonistic effects among different NRTI combinations. The results suggest that combined therapy, including TDF with thymidine analogues, may be considered for future therapeutics options in failing patients. In contrast to antagonistic combinations such as TDF+ddI or 3TC+ddI that would explain the virological failure happening in clinical studies when these combinations were used. |
| 116 | DEVELOPMENT OF A GENOTYPING ASSAY FOR HIV-1 INTEGRASE COMPATIBLE WITH GLOBALLY AVAILABLE IN VITRO DIAGNOSTIC PLATFORMS Antivir Ther. 2008, 13(Suppl 3):A126 (abstract no. 116) SD Pandit, H Kapur, and AJ Uzgiris Although the clinical utility of genotyping from plasma in the range of 50–400 RNA copies/ml has not been established, the sensitivity of this new assay may allow more routine analysis of samples of research interest. Results with samples collected in Beijing in 2005 and 2007 suggest that some HIV-positive populations in China may diverge from previously reported IN polymorphism patterns in addition to grouping with relatively rare subtypes or circulating recombinant forms. |
| 117 | VALIDATION OF A GENOTYPIC AND PHENOTYPIC RECOMBINANT VIRUS ASSAY TO DETERMINE RESISTANCE AGAINST HIV-1 INTEGRASE INHIBITORS Antivir Ther. 2008, 13(Suppl 3):A127 (abstract no. 117) K Van Baelen, E Rondelez, V Van Eygen, V Smits, P Van den Zegel and LJ Stuyver A genotypic and phenotypic IN resistance assay was successfully validated, and constitutes a first step in the construction of validated databases in support of the development of an IN resistance predictive algorithm. Since the amplicon contains the RT, RNase H and IN genes, the assay can also be used to study the clinical significance of naturally occurring polymorphisms and nucleoside reverse transcriptase inhibitors-, non-nucleoside reverse transcriptase inhibitors- and INI-selected variants, as well as the interaction between RT and IN. |
| 118 | TECHNICAL VALIDATION OF AN ENHANCED SENSITIVITY TROFILE HIV CORECEPTOR TROPISM ASSAY FOR SELECTING PATIENTS FOR THERAPY WITH ENTRY INHIBITORS TARGETING CCR5 Antivir Ther. 2008, 13(Suppl 3):A128 (abstract no. 118) L Trinh, D Han, W Huang, T Wrin, J Larson, L Kiss, E Coakley, CJ Petropoulos, NT Parkin, JM Whitcomb and JD Reeves These validation experiments demonstrate that Trofile (ES) is accurate, precise, reproducible, and has improved sensitivity to detect low levels of CXCR4-using variants in env clone mixtures and patient env populations compared with standard Trofile. These data support adoption of Trofile (ES) as the assay of choice for coreceptor tropism determination of patient virus populations. |
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Session 5: Clinical implications of resistance Abstracts 119 thru 134, Pages A131 to A146 |
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| 119 | EMERGENCE OF DRUG RESISTANCE AFTER FAILURE OF FIRST-LINE HAART IS ASSOCIATED WITH INTENSITY OF VIROLOGICAL MONITORING: A SYSTEMATIC ANALYSIS OF COHORT AND TRIAL DATA SPECIFICALLY ADDRESSING THE WHO PUBLIC HEALTH APPROACH TO ANTIRETROVIRAL THERAPY Antivir Ther. 2008, 13(Suppl 3):A131 (abstract no. 119) RK Gupta1, A Hill2, AW Sawyer3, A Cozzi-Lepri1, A Phillips1, V von Wyl4, S Yerly5, HF Gunthard4 and D Pillay1 Genotypic resistance to lamivudine, NRTIs (TAMs) and NNRTIs appears substantially higher in infrequently monitored patients as compared with those more intensively monitored. Our data supports the use of sequential drug combinations with non-overlapping resistance profiles in order to maximize the clinical benefit of ART rollout in the context of limited monitoring. |
| 120 | LOW FREQUENCY K103N MUTATIONS ARE STRONGLY ASSOCIATED WITH INADEQUATE VIROLOGICAL RESPONSES TO NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR BASED THERAPY Antivir Ther. 2008, 13(Suppl 3):A132 (abstract no. 120) G Hunt1, A Coovadia2, EJ Abrams3, G Sherman4, T Meyers5, J Ledwaba2, S Hammer6, L Morris1 and L Kuhn7 Approximately 10% of women participating in this study had K103N mutations detected pretreatment, irrespective of their reported prior exposure to sd-NVP for prevention of mother-to-child transmission. These K103N mutations were shown to be strongly associated with inadequate virological responses to NNRTI-based therapy. |
| 121 | DETERMINATION OF PHENOTYPIC CLINICAL CUT-OFFS FOR ETRAVIRINE: POOLED WEEK 24 RESULTS OF THE DUET-1 AND DUET-2 TRIALS Antivir Ther. 2008, 13(Suppl 3):A133 (abstract no. 121) M Peeters1, S Nijs1, J Vingerhoets1, L Tambuyzer1, B Woodfall1, M-P de Bethune1 and G Picchio2 Response in the ETR arms of the DUET trials decreased with increasing baseline ETR FC. The highest response rate was observed in the group of patients with ETR FC=3 (lower CCO). The robust responses observed in a substantial number of patients with baseline ETR FC>13 (intermediate CCO) and the low number of observations in this subgroup did not allow for the determination of a high CCO. These CCOs provide phenotypic guidance for use of ETR in treatment-experienced HIV-1-infected patients. |
| 122 | BIOLOGICAL AND CLINICAL CUT-OFF ANALYSES FOR ETRAVIRINE IN THE PHENOSENSE™ HIV ASSAY Antivir Ther. 2008, 13(Suppl 3):A134 (abstract no. 122) E Coakley1, C Chappey1, J Benhamida1, G Picchio2, L Tambuyzer3 J Vingerhoets3 and M-P de Béthune3 In models accounting for the activity of background therapy a LCCO for etravirine was observed at FC 2.9. In this highly treatment experienced population etravirine HS was common, being observed in approximately one third of samples. |
| 123 | THE CASTLE STUDY 48 WEEK RESULTS: THE IMPACT OF HIV SUBTYPES AND BASELINE RESISTANCE ON TREATMENT OUTCOMES AND THE EMERGENCE OF RESISTANCE Antivir Ther. 2008, 13(Suppl 3):A135 (abstract no. 123) M Lataillade1, J-M Molina2, A Thiry1, M Mancini1 and D McGrath1 for the BMS AI424138 Study Group At baseline, CASTLE had many HIV subtypes and frequent NRTI, NNRTI and PI substitutions, although phenotypic resistance was rare. ATV/r and LPV/r regimens achieved consistent response rates regardless of subtype or number of baseline PI substitutions. The emergence of non-polymorphic PI substitutions was infrequent with both regimens. |
| 124 | MUTATIONS SELECTED BY OTHER PROTEASE INHIBITORS PREDICT DURABLE RESPONSE TO TIPRANAVIR IN TREATMENT-EXPERIENCED PATIENTS Antivir Ther. 2008, 13(Suppl 3):A136 (abstract no. 124) DB Hall1, J Baxter2, J Schapiro3, CAB Boucher4, C Tilke5 and J Scherer5 Patients with at least one of the mutations 24I, 50L/V, 54L and 76V demonstrated significantly improved virological response rates to TPV/r-based therapy at week 8 and had strong associations with decreased phenotypic resistance to TPV. The improved response rates decreased over time, but a significant benefit of having these mutations remained throughout the 48 week period. |
| 125 | COMPARABLE IN VITRO SUSCEPTIBILITY AND VIROLOGICAL OUTCOME TO DARUNAVIR IN PATIENTS INFECTED WITH SUBTYPE B AND NON-SUBTYPE B HIV ISOLATES PARTICIPATING IN THE ARTEMIS PHASE III TRIAL Antivir Ther. 2008, 13(Suppl 3):A137 (abstract no. 125) I Dierynck1, S De Meyer1, E Lathouwers1, C Vanden Abeele1, T Van De Casteele1, S Spinosa-Guzman1, G Picchio2 and MP de Béthune1 In vitro susceptibility to DRV was comparable across HIV-1 subtypes in a broad panel of primary isolates in PBMCs and in clinical isolates from the ARTEMIS trial. Accordingly in ARTEMIS, once-daily DRV/r 800/100 mg was highly effective, irrespective of HIV-1 subtype. These results confirm the broad activity of DRV. |
| 126 | RE-EVALUATION OF RESISTANCE ALGORITHMS FOR LOPINAVIR/RITONAVIR IN THE TITAN TRIAL Antivir Ther. 2008, 13(Suppl 3):A138 (abstract no. 126) A Hill1, AG Marcelin2 and V Calvez2 The analysis identified more sensitive ‘efficacy advantage cut-off levels’ for four lopinavir genotypic algorithms, below those currently used, at which there is significant efficacy advantage for treatment with darunavir/ritonavir versus LPV/r in the TITAN trial. |
| 127 | WEEK 96 FINAL ANALYSIS OF RESISTANCE MUTATIONS IN PROTEASE GENE AND IN CLEAVAGE SITE OF GAG PROTEIN FOR PATIENTS FAILING ON A FIRST-LINE LOPINAVIR/RITONAVIR SINGLE-DRUG REGIMEN IN THE MONARK TRIAL Antivir Ther. 2008, 13(Suppl 3):A139 (abstract no. 127) J Ghosn1,2, C Delaugerre1, ML Chaix1, P Flandre3, J Galimand1, I Cohen-Codar4, F Raffi5, M Norton6, JF Delfraissy2 and C Rouzioux1 Patients (14/15) for whom results are currently available had at least one substitution in cleavage site of Gag at baseline. Changes in cleavage site of Gag between baseline and failure occurred in 6/15 patients. Interestingly, most of these changes were not associated with the emergence of major PI resistance mutations. |
| 128 | THE RATE OF ACCUMULATION OF NNRTI RESISTANCE IN PATIENTS KEPT ON A VIROLOGICALLY FAILING REGIMEN CONTAINING NNRTI: A EuroSIDA STUDY Antivir Ther. 2008, 13(Suppl 3):A140 (abstract no. 128) A Cozzi-Lepri1, B Clotet2, R Paredes2, J Kjær3, AN Phillips1 and JD Lundgren3,4 Whereas the average rate of accumulation of NNRTI mutations was appreciable (1/2.2 years) etravirine-specific mutations accumulated more slowly (1/4 years), leading to an 8% mean reduction in etravirine activity per year. More sensitive viruses accumulated NNRTI resistance mutations faster. |
| 129 | FAILING THERAPY WITH EFAVIRENZ RESULTS IN SIGNIFICANTLY FEWER MUTATIONS LIMITING TO ETRAVIRINE THAN FAILING THERAPY WITH NEVIRAPINE: ON-TREATMENT ANALYSES FROM THE CPCRA FIRST STUDY Antivir Ther. 2008, 13(Suppl 3):A141 (abstract no. 129) RD MacArthur1, K Huppler Hullsiek2, G Peng2, M van den Berg-Wolf3, LR Crane1, RM Novak4, L Chen2 and MJ Kozal5 on behalf of the CPCRA 058 Study Team, the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the International Network for Strategic Initiative in Global HIV Trials (INSIGHT) The use of efavirenz resulted in less NNRTI, NRTI or any class resistance than the use of nevirapine. Emergent major NNRTI mutations at VF differed by NNRTI used; the mutation patterns suggest that subsequent suppression of HIV RNA with etravirine-containing regimens may be more successful if initial therapy with efavirenz is used rather than nevirapine. |
| 130 | HIV-1 GENOTYPE ALGORITHMS FOR PREDICTION OF ETRAVIRINE SUSCEPTIBILITY: NOVEL MUTATIONS AND WEIGHTING FACTORS IDENTIFIED THROUGH CORRELATIONS TO PHENOTYPE Antivir Ther. 2008, 13(Suppl 3):A142 (abstract no. 130) J Benhamida, C Chappey, E Coakley and NT Parkin Existing etravirine genotype interpretation rules underestimate phenotypic RS. The improved scoring system with weighted mutations reduced this type of discordance and should be tested in additional validation studies. The sensitizing effects of NRTI mutations on etravirine resistance or the effects of other potent drugs that are co-administered in clinical studies could be responsible for differences between scoring systems that are based on clinical response or phenotypic susceptibility. |
| 131 | HIV DRUG RESISTANCE AT BASELINE OF THE FIRST HIGHLY ACTIVE ANTIRETROVIRAL THERAPY TRIAL IN VIETNAM (ANRS 1210): CORRELATION WITH POOR IMMUNOLOGICAL AND VIROLOGICAL RESPONSES Antivir Ther. 2008, 13(Suppl 3):A143 (abstract no. 131) HJ Fleury1, NTH Lan2, NH Chi3, NV Ngai4, VT Nhung5, TTX Lien5, M Maynart5, C Chazallon6, JP Aboulker6 and JY Follezou7 The resistance at baseline has clearly impaired the efficacy of the HAART regimen of this first antiretroviral trial in Vietnam. Some hypotheses can be raised up to tentatively explain the presence of DRMs at baseline: circulation in HCMC of HIV-1 isolates with DRMs, denied ARV treatment before inclusion in ANRS 1210 and close contaminant relationships between patients of IDU group. |
| 132 | THYMIDINE ANALOGUE MUTATION PATTERNS FROM HIV-INFECTED MEXICAN CHILDREN AFTER MULTIPLE ANTIRETROVIRAL DRUG FAILURE Antivir Ther. 2008, 13(Suppl 3):A144 (abstract no. 132) ML Cabrera-Ruiz1, R Rodriguez-Diaz2, L Fuentes-Romero2, L Xochihua-Diaz1, P Villalobos-Acosta3, R Muñoz-Hernández4, N Pavia-Ruz3 and LE Soto-Ramirez2 TAM development in children is significantly related to the time on AZT/d4T exposure. Pattern 1 is more frequent in males and not frequently related to TDF resistance, while pattern 2 is more frequent in females and always correlate with TDF resistance. |
| 133 | CLASS-WIDE RESISTANCE TO ANTIRETROVIRAL DRUGS IS PREDICTIVE OF SHORTER SURVIVAL IN PATIENTS WHO ACHIEVED UNDETECTABLE HIV RNA AFTER TREATMENT FAILURE Antivir Ther. 2008, 13(Suppl 3):A145 (abstract no. 133) M Zaccarelli1, V Tozzi1, P Lorenzini1, F Forbici1, U Visco-Comandini1, F Ceccherini-Silberstein2, P Narciso1, R D’Arrigo1, CF Perno1 and A Antinori1 Our findings suggest that extended resistance to >1 drug class could be overcome by GRT-guided therapy but remains a strong marker of HIV progression, even in patients who achieve viral suppression. Thus, extended class resistance is a marker of advanced disease and should be prevented in order to improve survival. |
| 134 | RESPONSE TO TREATMENT AND RESISTANCE PATTERNS IN HIV-2-INFECTED PATIENTS LIVING IN BISSAU, WEST AFRICA Antivir Ther. 2008, 13(Suppl 3):A146 (abstract no. 134) B Rodés1, C Toro1, R Colombatti2, A Simón1, F Riccardi2, C Vieira2, A Coin2 and V Soriano1 Complete viral suppression of HIV-2 in monoinfected or coinfected patients is not readily achieved and sustained over 1 year with triple antiretroviral regimens and drug resistance develops rapidly. In this study, K65R was selected in the absence of tenofovir in patients failing abacavir±didanosine. Selection of potent drug combinations and treatment strategies for HIV-2 merits a differential consideration from HIV-1. |
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Session 6: Epidemiology Abstracts 135 thru 153, Pages A149 to A167 |
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| 135 | EVALUATION OF TRANSMITTED HIV DRUG RESISTANCE USING THE WHO HIV DRUG RESISTANCE THRESHOLD SURVEY MODEL IN FOUR CENTRAL AFRICAN COUNTRIES Antivir Ther. 2008, 13(Suppl 3):A149 (abstract no. 135) AF Aghokeng1, L Vergne2, A Atem-Tambe1, M Tongo1, MN Peyou3, C Butel2, E Delaporte2, E Mpoudi-Ngole1, M Peeters2 and the OCEAC HIVDR Study Group Although we found a moderate prevalence in Douala, the overall prevalence of transmitted HIVDR among newly infected individuals was low in Chad and Cameroon. This study also highlighted the difficulties of carrying out the WHO generic protocol in field reality. |
| 136 | ARE PATIENTS WITH ACUTE HIV-1 INFECTION THE MAJOR SOURCE OF HIV TRANSMISSION IN FRANCE? A 5-YEAR SURVEY IN THE ANRS PRIMO NETWORK Antivir Ther 2008, 13(Suppl 3):A150 (abstract no. 136) ML Chaix1, J Galimand1, D Descamps2, P Frange1, C Deveau3, M Wirden4, A Signori-Schmuck5, V Schneider6, S Rogez7, C Delaugerre8, J Cottalorda9, C Charpentier10, L Bocket11, V Avettand-Fenoel1, F Brun-Vezinet2, B Masquelier12, V Calvez4, D Costagliola13, C Rouzioux1, L Meyer3 and the ANRS PRIMO Cohort and the ANRS AC11 Resistance Study Group At least 30% of PHI in France form phylogenetic clusters, indicating that these individuals may contribute to HIV transmission. A better understanding of HIV transmission dynamics is important to design effective preventive and public health interventions, especially for improving both HIV diagnosis of PHI and chronic infections. |
| 137 | EPIDEMIOLOGICAL TRENDS IN GENOTYPIC RESISTANCE MUTATIONS IN RELATION WITH ANTIRETROVIRAL EXPOSURE Antivir Ther 2008, 13(Suppl 3):A151 (abstract no. 137) A Jaén1, E Buira2, A Giménez2, T Pumarola3, T Puig4, J Niubó5, M Xercavins1, D Podzamczer5, B Clotet4, JM Gatell3 and D Dalmau1 on behalf of CHRN group study In our cohort, triple-class drug resistance dropped almost by half over time and NRTI class resistance decreased at the expense of TAMs. Reduction in specific mutations are related to changes in antiretroviral use. These results may reflect the efficacy of new drugs, new regimens and/or changes in drug prescription. |
| 138 | VIROLOGICAL CHARACTERIZATION OF HIV STRAINS IN RECENT SEROCONVERTERS IN SPAIN Antivir Ther. 2008, 13(Suppl 3):A152 (abstract no. 138) C de Mendoza1, C Rodriguez2, A Aguilera3, F Garcia4, P Leiva5, E Poveda1, F Gutierrez6, L Ruiz7, E Caballero8, N Zahonero1, C Garrido1 and V Soriano1 on behalf of the Spanish HIV Seroconverter Study Group The rate of drug-resistant HIV has slightly increased since 2005 in Spain, being currently 15.1%. PI- and multidrug-resistant viruses have become more frequent in recent years. The presence of X4 viruses does not seem to be associated with transmission of drug resistance mutations. |
| 139 | THE PREVALENCE OF MULTIDRUG RESISTANCE AMONG TREATED PATIENTS IN NORTH AMERICA AND ITS IMPACT ON MORTALITY Antivir Ther. 2008, 13(Suppl 3):A153 (abstract no. 139) SG Deeks for the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the IeDEA The prevalence of limited class resistance declined over time while the prevalence of high-level MDR remained stable, at least through 2005. The overall mortality rates in those with resistance was high; this was particularly true for those with NNRTI resistance. Individuals who had no evidence of resistance at the time of genotypic testing also had high mortality rates, presumably as this was a marker of non-adherence. |
| 140 | PREVALENCE OF RESISTANCE MUTATIONS IN ANTIRETROVIRAL-NAÏVE CHRONICALLY HIV-INFECTED PATIENTS IN 2006/2007: A FRENCH NATIONWIDE STUDY Antivir Ther. 2008, 13(Suppl 3):A154 (abstract no. 140) D Descamps1, B Montes2, ML Chaix3, S Pakianather4, F Barin5, G Dos Santos6, A Krivine7, C Delaugerre8, J Izopet9, AG Marcelin10, A Maillard11, L Morand-Joubert12, C Pallier13, JC Plantier14, C Tamalet15, V Calvez10, B Masquelier16, F Brun-Vézinet1, D Costagliola4,10 and the ANRS AC-11 Resistance Group In France in 2006/2007, the prevalence of transmitted drug-resistant variants was around 10%. The proportion of non-B subtypes increased from 33% in 2001 to 42% in 2006/2007. Interestingly, prevalence of transmitted drug resistance was comparable in B and non- B subtypes. Prevalence of resistance was similar according to the 2007 International AIDS Society (IAS) list of mutations without taking into account etravirine resistance mutations. |
| 141 | PROFILING RESISTANCE-RELATED MUTATIONS ACCORDING TO THE CLADE ASSIGNMENT IN A BRAZILIAN POPULATION Antivir Ther. 2008, 13(Suppl 3):A155 (abstract no. 141) P Munerato1, MC Sucupira1, MPR Oliveros1,2, DFC Souza3, AA Pereira3, LA Inocêncio3 and RS Diaz1 Resistance mutations were differently selected in distinct clades in Brazil. According to the TAM profile, cross-resistance to tenofovir will be more prevalent in clade B than in C. It can be predicted that failures to nevirapine will result in more cross-resistance to etravirine than failures to efavirenz, according to the resistance pathway described above. Using viral load as a viral fitness surrogate marker, there is an initial decrease of fitness from selection of resistance mutations, but the viral fitness is restored as the number of mutations increases. |
| 142 | PREVALENCE AND PATTERNS OF ANTIRETROVIRAL DRUG RESISTANCE AT LOW PLASMA HIV RNA LOAD LEVELS Antivir Ther. 2008, 13(Suppl 3):A156 (abstract no. 142) AM Geretti1, A Phillips1, S Kaye2, C Booth1, A Garcia1 and N Mackie2 on behalf of the UK Resistance Database and CHIC Study The likelihood of detection of resistance mutations was highest at VL>300 copies/ml and up to 10,000 copies/ml. Detection remained significant, although reduced, at VL<300 copies/ml and declined progressively as the VL increased >10,000 copies/ml. Resistance testing at low-VL yields useful information. |
| 143 | INJECTION DRUG USERS HAVE A HIGHER PROBABILITY OF DEVELOPING RESISTANCE THAN NON-INJECTION DRUG USERS REGARDLESS OF ADHERENCE OR INITIAL TREATMENT REGIMEN Antivir Ther. 2008, 13(Suppl 3):A157 (abstract no. 143) VS Gill1,2, VD Lima1, KA Fernandes1 and PR Harrigan1,2 Even after accounting for baseline parameters and adherence, the estimated probability of developing resistance was higher among IDUs than non- IDUs across all prescription refill and UDL strata (with the exception of resistance to NRTIs other than lamivudine). |
| 144 | VIROLOGICAL OUTCOME AND ANTIRETROVIRAL DRUG RESISTANCE IN THE NATIONAL ANTIRETROVIRAL THERAPY PROGRAM IN CAMEROON Antivir Ther. 2008, 13(Suppl 3):A158 (abstract no. 144) C Montavon1, C Kouanfack2, C Laurent1, A Aghokeng3, A Kenfack2, A Bourgeois4, S Koulla-Shiro2, E Delaporte1,4, E Mpoudi-Ngole3 and M Peeters1 Virological failure and drug resistance were relatively low, however, 69% and 18% of the patients with HIVDR mutations were resistant to two or three drugs, respectively, from their regimen. Importantly, only 1/4 and 3/4 of VL failure were associated with drug resistance at month 12 and month 24, respectively. This study underlines the importance of VL but highlights the risk of switching to second-line treatments too early in non-adherent patients in the absence of genotypic drug resistance testing. |
| 145 | PREDICTING THE EFFECTS ON RESISTANCE OF LACK OF VIRAL LOAD MONITORING IN RESOURCE-LIMITED SETTINGS Antivir Ther. 2008, 13(Suppl 3):A159 (abstract no. 145) A Phillips1, D Pillay1,2, A Miners3, D Bennett4, CF Gilks4 and JD Lundgren5 For patients on the first-line regimen of stavudine, lamivudine and nevirapine, the benefits of viral load monitoring compared with clinical (or CD4+ T-cell count) monitoring are relatively modest. Development of cheap and robust versions of these assays is important, but widening access to ART (with or without laboratory monitoring) is currently the highest priority. |
| 146 | CHANGES IN REGIONAL PREVALENCE, CLADE AND EPIDEMIOLOGY OF HIV-1 DRUG RESISTANCE MUTATIONS AND CLADE AMONG ANTIVIRAL THERAPY-NAÏVE PATIENTS IN THE UNITED STATES FROM 2000 TO 2007 Antivir Ther. 2008, 13(Suppl 3):A160 (abstract no. 146) LL Ross, L Dix, B Wine, C Vavro, J Horton and KA Pappa Although some have predicted that prevalence of HIV RM in ART-naïve subjects could be on the decline, in this large US cohort, RM increased from 2000 to 2007, using either IAS-USA or Stanford definitions; the greatest increase was observed for NNRTI RM (15% of subjects in 2007 by IAS-USA). Regional differences in RM prevalence were observed, with the highest in the south and west. Detection of dual-class RM increased slightly over time, although triple-class RM were rare (<1%). Subtype B is still the most common subtype, although non-clade B subtypes increased slightly from 2001 to 2007. |
| 147 | TEMPORAL TREND IN NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) TRANSMITTED DRUG RESISTANCE: RELATIONSHIP WITH CHRONICALLY INFECTED POTENTIAL TRANSMITTER POPULATION Antivir Ther. 2008, 13(Suppl 3):A161 (abstract no. 147) JP Routy1, B Brenner2, N Machouf3, R Thomas3, B Trottier3, JG Baril4, D Rouleau5, C Tremblay5, R LeBlanc6, A Dascal7, J Bruneau5, M Roger5 and MA Wainberg2 In contrast to NRTIs and PIs, the transmission of variants conferring resistance to NNRTIs has increased over the past decade. This increase of NNRTI transmitted DR cannot be fully explained by the influence of the CI patients harbouring DR, as VL reached very low levels making transmission unlikely. Globally, these results indicate that transmission of DR variants may occur through clustering events observed during early stage infection, fuelling the DR epidemic. |
| 148 | PREVALENCE OF DRUG RESISTANCE ASSOCIATED MUTATIONS IN NEWLY DIAGNOSED HIV/AIDS PATIENTS IN JAPAN FROM 2003 TO 2007 Antivir Ther. 2008, 13(Suppl 3):A162 (abstract no. 148) S Yoshida1, H Gatanaga2, T Itoh3, M Fujino4, M Kondo5, K Sadamasu6, T Kaneda7, F Gejyo8, T Shirasaka9, H Mori10, M Ueda11, N Takata12, R Minami13, W Sugiura4,7 and the Japanese Drug Resistance HIV-1 Surveillance Network The prevalence of transmitted drug- resistant HIV cases in Japan increased 1.7-fold from 2003 to 2007. Continuous surveillance is required to understand the epidemiological status of this transmission and to consider strategies to prevent transmission of drug- resistant virus. |
| 149 | IMPACT OF CLUSTERING ON THE TRANSMISSION OF HIV-1 VARIANTS HARBOURING DRUG RESISTANCE Antivir Ther. 2008, 13(Suppl 3):A163 (abstract no. 149) BG Brenner1, M Roger2, JP Routy3, D Moisi1, MA Wainberg1 and the Quebec Primary HIV Infection (PHI) Study Group The majority of new infections arise from untreated persons at early stages of infection, often unaware of their serostatus. This may result in onward transmission of HIV drug-resistant infections. Improved prevention and diagnostic strategies, as well as routine genotyping, are needed for early stage infection. |
| 150 | ANTIRETROVIRAL DRUG RESISTANCE PATTERNS FROM PATIENTS FAILING THE NATIONAL ROLL-OUT PROGRAMME IN SOUTH AFRICA Antivir Ther. 2008, 13(Suppl 3):A164 (abstract no. 150) C Wallis1, W Stevens1,2, F Venter3 and I Sanne4 The HIV-1 subtype C ARV drug resistance pattern remains consistent with that presented previously. The occurrence of both the nucleoside reverse transcriptase inhibitor (NRTI) mutations K65R and Q151M remain at a constant frequency and their presence may impact on future treatment strategies containing tenofovir. Continued monitoring of PR resistance is important as the number of patients accessing Kaletra increases to determine the impact of the subtype C polymorphisms. |
| 151 | NOVEL AMINO ACIDS AT RESISTANCE POSITIONS CAN INDICATE TRANSMISSION OF DRUG-RESISTANT VARIANTS Antivir Ther. 2008, 13(Suppl 3):A165 (abstract no. 151) AMJ Wensing1, DAMC van de Vijver2, D Frentz1, E Bowles1, R Boulme3, R Schuurman1 and CAB Boucher1,2 on behalf of the WATCH investigators group Novel amino acids at resistance positions are more frequently found in antiretroviral-naïve patients infected with drug-resistant HIV as compared with wild-type virus. The detection of novel amino acids at major resistance positions may serve as an indicator for transmitted drug-resistant viruses. |
| 152 | SURVEILLANCE OF TRANSMITTED HIV-1 DRUG RESISTANCE IN NEWLY DIAGNOSED HIV-1-INFECTED PATIENTS FROM SHANDONG PROVINCE, CHINA Antivir Ther. 2008, 13(Suppl 3):A166 (abstract no. 152) J Zhang1,2, D Kang1, J Fu1, X Sun1, B Lin1, J Nkengasong2 and C Yang2 Our analysis of 47 drug-naïve DBS specimens from newly diagnosed HIV-1 patients collected from Shandong Province, China in 2006 indicates that prevalence of transmitted DR viruses in this population is low, <5%. Phylogenetic analysis indicated that the HIV-1 epidemic is characterized by multiple subtypes and CRFs co-circulating. Continued monitoring of the transmitted drug resistance in recently HIV-1-infected populations is warranted to inform the effectiveness of treatment guidelines. |
| 153 | DRUG RESISTANCE IN NEWLY HIV DIAGNOSED INDIVIDUALS: TRANSMISSION RATE, CLUSTERS AND PERSISTENCE Antivir Ther. 2008, 13(Suppl 3):A167 (abstract no. 153) S Yerly1, T Junier2, E Boffi3, HF Günthard4, E Zdobnov2, B Hirschel3 and L Kaiser1 In a Swiss urban area, resistant strains accounted for 6.2% of newly diagnosed HIV infections. Chains of transmission could be identified in one-third of these cases. In the absence of drug pressure, transmitted drug-resistant strains are persistently detectable for at least two years in the vast majority of individuals. These observations strongly support the need to perform systematic drug resistance testing in any newly HIV diagnosed individual. |
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Session 7: HBV drug resistance Abstracts 154 thru 156, Pages A171 to A173 |
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| 154 | AMINO ACID PATTERNS OF HEPATITIS B VIRUS (HBV) REVERSE TRANSCRIPTASE FROM UNTREATED AND TREATED CHRONICALLY HBV-INFECTED PATIENTS IN SOUTHEASTERN FRANCE Antivir Ther. 2008, 13(Suppl 3):A171 (abstract no. 154) P Colson1,2, C Tamalet1,2, I Ravaux3, I Poizot-Martin4, J Moreau5 and R Gerolami6 Our data underline the substantial variability of HBVrt and the association of drug-selected aa. They also suggest that drug-selected patterns might differ according to the HBV genotype. |
| 155 | HBV GENOTYPE CONSTRAINS THE SELECTION OF LAMIVUDINE RESISTANCE PROFILE IN MONOINFECTED AND HIV-COINFECTED PATIENTS Antivir Ther. 2008, 13(Suppl 3):A172 (abstract no. 155) V Svicher1, C Gori2, M Trignetti1, R Longo3, V Micheli4, G Rizzardini4, R Salpini1, M Bellocchi1, GM De Sanctis6, F Ceccherini-Silberstein1,2, A Spanò3 and CF Perno1,2 The genotype of HBV, which in a fashion is similar to or even more pronounced than HIV, plays a key role in driving both RT and HBsAg evolution under lamivudine treatment. Coinfection with HIV is also relevant in the selection of HBV-mutational pathways. HBV genotype can thus be relevant for therapeutic sequencing, immunological response and disease progression. |
| 156 | USE OF NUCLEOS(T)IDE ANALOGUES FOR TREATING CHRONIC HEPATITIS B VIRUS (HBV) INFECTION MAY RESULT IN THE SELECTION OF HBV VACCINE ESCAPE MUTANTS Antivir Ther. 2008, 13(Suppl 3):A173 (abstract no. 156) L Yuen1,2, P Revill1, S Locarnini1,2, J Sheldon3 and V Soriano3 Although previously identified vaccine escape mutations were uncommon in this international series of chronic hepatitis B patients failing NA therapy, an association between lamivudine-associated resistance mutations and vaccine escape mutants was observed. Similar associations for adefovir- and tenofovir-associated resistance mutations have not been identified to date. Two patients coinfected with genotype A with the lamivudine-selected triple HBV mutations had no previous treatment history with this drug, suggesting increased likelihood of transmission among vaccinated individuals, particularly in the setting of HIV infection. |
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Session 8: HCV drug resistance Abstracts 157 thru 158, Pages A177 to A178 |
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| 157 | AMINO ACID POLYMORPHISM AND DRUG RESISTANCE-ASSOCIATED SUBSTITUTIONS WITHIN HEPATITIS C VIRUS NS3 PROTEASE FROM PROTEASE INHIBITOR-NAÏVE CHRONICALLY INFECTED PATIENTS Antivir Ther. 2008, 13(Suppl 3):A177 (abstract no. 157) P Colson1,2, R Gerolami3, N Brouk1,2, F Lembo1,2 and C Tamalet1,2 We identified substantial amino acid polymorphism within the NS3 protease from HCV chronically infected patients with differences according to the HCV genotype and subtype. Moreover, we described the natural presence of aa conferring reduced susceptibility to HCV-PIs. Further studies are needed to confirm and assess the extent of primary resistance to HCV-PI, which would represent a concern for its future use. |
| 158 | A NOVEL HEPATITIS C VIRUS NS3/4A PROTEASE ASSAY
USING A BACTERIOPHAGE LAMBDA-BASED GENETIC SCREEN Antivir Ther. 2008, 13(Suppl 3):A178 (abstract no. 158) S Franco, M Parera, B Clotet and MA Martínez Compared with other protease assay methods, this assay has the following advantages: safe, highly sensitive, highly specific, easy quantification and rapid generation of different protease cleavage substrates using molecular cloning and expression. Characterization of the proteolytic activities of individual NS3/4A proteases should provide clues for understanding HCV-host interactions, as well as assisting in the development of new classes of NS3/4A protease inhibitors. |
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