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16th International HIV Drug Resistance Workshop:
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Cite as: Antivir Ther. 2007, 12: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 | OVERCOMING THE CHALLENGES OF THE CARIBBEAN HIV EPIDEMICS Antivir Ther. 2007, 12:P3 (abstract no. P1) N Adomakoh Over the last 5 years there has been a proliferation of multisectoral programmes across the region implementing the UNAIDS ‘three ones’ principle in an effort to provide comprehensive, well-coordinated prevention, treatment, care and support programmes. Successful implementation of treatment programmes has seen a large decline in deaths (56% reduction in the first year of the Barbados Programme) and increasing coverage of services. |
| P2 | ROLE OF GAG POLYPROTEINS AND PROTEOLYSIS IN HIV ASSEMBLY AND MATURATION Antivir Ther. 2007, 12:P4 (abstract no. P2) H-G Kräusslich HIV assembly is driven by the structural polyprotein Gag which consists of four globular domains and several intervening peptides. In the budding process, Gag layers associate with the plasma membrane of the infected cell in a perpendicular orientation giving a hexagonal arrangement with the N-terminal matrix (MA) domain closely apposed to the lipid bilayer. |
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Session 1: Resistance to new antiretroviral agents Abstracts 1 thru 13, Pages S3 to S15 |
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| 1 | IN VITRO CROSS-RESISTANCE STUDIES OF FIVE DIFFERENT CLASSES OF INTEGRASE INHIBITORS IN RECOMBINANT HIV-1 Antivir Ther. 2007, 12:S3 (abstract no. 1) C Ren, S May, T Miletti and J Bedard It is well documented that in vitro resistance development to different chemical series of integrase inhibitors involved specific mutational pathways. In this study, phenotypic analysis of recombinant viruses harbouring selected mutations within the integrase gene has demonstrated significant cross-resistance with the compounds investigated. |
| 2 | EFFECTS OF PROTEASE AND REVERSE TRANSCRIPTASE INHIBITOR-RESISTANCE MUTATIONS ON INTEGRASE POLYMORPHISM IN MULTIDRUG RESISTANCE CASES Antivir Ther. 2007, 12:S4 (abstract no. 2) H Suzuki, M Fujino, M Matsuda, H Yen, Y Iwantani and W Sugiura Accumulation of PI and RTI resistance mutations apparently affected integrase polymorphism to some extent. However, the data for MDR patients were encouraging in that no diketo-acid-related resistance mutation was observed in either the MDR or naïve group. |
| 3 | HIV-1 INTEGRASE SEQUENCE VARIATION AND COVARIATION Antivir Ther. 2007, 12:S5 (abstract no. 3) RE Myers1 and D Pillay1,2 This analysis of sequence variation within HIV-1 integrase highlights strains and subtypes of HIV-1 that may be less susceptible to integrase inhibitors and interactions between amino acid positions, determined by covariation, which should be examined by in vitro and structural methods. Our data suggest that baseline susceptibility in vivo and the barriers to emergence of resistance may differ between the group M subtypes. |
| 4 | SPECIFIC MUTATIONS RELATED TO RESISTANCE TO HIV-1 INTEGRASE INHIBITORS ARE ASSOCIATED WITH REVERSE TRANSCRIPTASE MUTATIONS IN HAART-TREATED PATIENTS Antivir Ther. 2007, 12:S6 (abstract no. 4) F Ceccherini-Silberstein1, I Malet2, L Fabeni1, V Svicher1, C Gori3, S Dimonte1, S Bono1, A Artese4, R D’Arrigo3, C Katlama2, A Antinori3, A d’Arminio Monforte5, V Calvez2, AG Marcelin2 and CF Perno3 The association between selected INI- and RTI-mutations supports the hypothesis of a tight interaction of these two HIV proteins, and a potential coevolution of some of their mutations. Beside theoretical implications, these results support the importance of IN-sequencing in RTI-treated patients starting INI-containing regimens. |
| 5 | LOW LEVEL OF BASELINE RESISTANCE TO INTEGRASE INHIBITORS L731,988 AND L870,810 IN RANDOMLY SELECTED SUBTYPE B AND NON-B HIV-1 STRAINS Antivir Ther. 2007, 12:S7 (abstract no. 5) K Van Baelen, M Clynhens, E Rondelez, V Van Eygen, P Van den Zegel, H Vermeiren, I Vandenbroucke and LJ Stuyver The IC50 and FC values for wild-type and integrase mutant viruses were in concordance with published data. Substantial genotypic variability was detected in clinical samples, but no significant FCs could be assigned. This assay contains the RT, RNaseH and IN genes, allowing the study of clinical significance towards naturally occurring polymorphisms and NRTI-, NNRTI- and INI-selected variants. |
| 6 | NOVEL, SMALL MOLECULE INHIBITORS OF HIV-1 INTEGRASE Antivir Ther. 2007, 12:S8 (abstract no. 6) JJ Wu, G Milot, S Dandache, K Gouveia, Y Xiao, J Yelle, G Sevigny, A Dubois, B Tian, V Perron, D Herbart and BR Stranix A novel series of pyrazolopyridine IN inhibitors have been developed. These compounds demonstrated potent inhibition against HIV-1 IN strand-transfer activity. More importantly, pyrazolopyridine compounds showed a potentially distinct mechanism of strand-transfer inhibition, which may lead to a different resistance profile from known competitive strand-transfer inhibitors currently under clinical development. |
| 7 | BIOCHEMICAL CHARACTERIZATIONS OF THE EFFECT OF MUTATIONS SELECTED IN HIV-1 INTEGRASE GENE ASSOCIATED WITH FAILURE TO RALTEGRAVIR (MK-0518) Antivir Ther. 2007, 12:S9 (abstract no. 7) I Malet1, O Delelis2, MA Valantin3, B Montes4, C Soulie1, M Wirden1, L Tchertanova2, G Peytavin5, J Reynes4, JF Mouscadet2, C Katlama3, AG Marcelin1 and V Calvez1 E92Q, G140S+Q148H and N155H integrase mutations, located near the catalytic site of the enzyme, have been identified in patients failing to raltegravir and led to an in vitro resistance. Finally these mutations led to strongly crippled enzymes when tested in vitro in the absence of raltegravir affecting the strand-transfer activity in all cases and the 3' processing in some cases. |
| 8 | RESISTANCE TO THE HIV-INTEGRASE INHIBITOR RALTEGRAVIR: ANALYSIS OF PROTOCOL 005, A PHASE II STUDY IN PATIENTS WITH TRIPLE-CLASS RESISTANT HIV-1 INFECTION Antivir Ther. 2007, 12:S10 (abstract no. 8) DJ Hazuda, MD Miller, BY Nguyen and J Zhao for the P005 Study Team These results suggest a single mutation may not have been sufficient to confer complete resistance in patients with these viruses. HIV-1 variants with N155 or Q148 mutations exhibited cross resistance to diverse InSTIs consistent with a mechanism that affects binding of the common pharmacophore within the integrase active site. |
| 9 | RESISTANCE AND CROSS-RESISTANCE TO FIRST GENERATION INTEGRASE INHIBITORS: INSIGHTS FROM A PHASE II STUDY OF ELVITEGRAVIR (GS-9137) Antivir Ther. 2007, 12:S11 (abstract no. 9) DJ McColl1, S Fransen2, S Gupta2, N Parkin2, N Margot1, S Chuck1, AK Cheng1 and MD Miller1 A variety of integrase mutations were observed following VF in patients treated with EVG, some of which have also been associated with resistance to RAL. Development of integrase mutations was associated with reduced susceptibility to both EVG and RAL in most subjects, suggesting potential cross-resistance between these drugs. Emergence of integrase mutations was also associated with reduced viral RC. |
| 10 | CHARACTERIZATION OF MARAVIROC RESISTANCE IN PATIENTS FAILING TREATMENT WITH CCR5-TROPIC VIRUS IN MOTIVATE 1 AND MOTIVATE 2 Antivir Ther. 2007, 12:S12 (abstract no. 10) J Mori1, M Mosley1, M Lewis1, P Simpson1, J Toma2, W Huang2, J Whitcomb2, G Ciaramella1 and M Westby1 These results validate the use of a reduced MPI as a phenotypic marker of maraviroc resistance in vivo and identify V3 loop mutations as likely conferring the resistance phenotype. |
| 11 | CCR5 BINDING PROPERTIES OF A CCR5 SMALL-MOLECULE INHIBITOR WITH HIGH ANTIVIRAL POTENCY AGAINST A MARAVIROC-RESISTANT HIV-1 STRAIN Antivir Ther. 2007, 12:S13 (abstract 11) A Jekle, R Kondru, C Ji, K-T Chuang, DC Swinney, D Rotstein, S Sankuratri, N Cammack and G Heilek Distinct differences in the binding dynamics of individual inhibitors translate into differences in the receptor conformation. Inhibitors with antiviral potency cause conformations that can are not recognized by wildtype HIV-1. Resistant viruses learned to bind to conformations of inhibitor-bound receptors. |
| 12 | MAPPING OF VICRIVIROC RESISTANCE MUTATIONS IN HIV-1 GP120 GENERATED BY IN VITRO SELECTION OF A PRIMARY HIV-1 ISOLATE IN PM-1 CELLS Antivir Ther. 2007, 12:S14 (abstract no. 12) RA Ogert, C Buontempo, L Wojcik, L Ba, P Buontempo, RO Ralston, JM Strizki and JA Howe HIV-1 resistance to vicriviroc in the QZ4589 isolate maps to multiple amino-acid changes in the C2-V5 region. Single mutations within the V3, C3, and V5 regions restored partial, but not complete susceptibility to vicriviroc. Introduction of the QZ4589 V3-loop region into a heterologous background did not confer resistance to the chimeric envelope. This finding demonstrates that changes in the V3-loop are context dependent and alone are insufficient to cause vicriviroc resistance. |
| 13 | IN VIVO EMERGENCE OF HIV-1 RESISTANCE TO THE CCR5 ANTAGONIST VICRIVIROC: FINDINGS FROM ACTG A5211 Antivir Ther. 2007, 12:S15 (abstract 13) AMN Tsibris1,2, RM Gulick3, Z Su4, MD Hughes4, C Flexner5, T Wilkin3, R Gross6, M Hirsch1,2, PR Skolnick7, E Coakley8, WL Greaves9 and DR Kuritzkes2,10 VF in subjects receiving a VCVcontaining regimen was associated with changes in the V3 loop in samples from five of nine subjects tested. In the subject with phenotypic evidence of VCV resistance, discontinuation of VCV was associated with return toward genotypically wild-type, VCV-susceptible, R5-only virus, suggesting a fitness advantage of wild-type over VCV-resistant virus. |
| 14 | PREDICTION OF HIV-1 CORECEPTOR USAGE BASED ON STRUCTURAL DESCRIPTORS OF THE gp120 V3 LOOP Antivir Ther. 2007, 12:S16 (abstract no. 14) O Sander1, T Sing1, I Sommer1, AJ Low2, PK Cheung2, PR Harrigan2, T Lengauer1 and FS Domingues1 The structural descriptor significantly improved prediction of coreceptor usage compared to a linear support vector machine trained on sequence data. For a given specificity of 0.95, a sensitivity of 0.77 was achieved, improving further to 0.80 when combined with a sequence-based representation using amino acid indicators. |
| 15 | STRUCTURAL BASIS FOR THE RESISTANCE PROFILE OF THE HIV-1 PROTEASE INHIBITOR PL-100 Antivir Ther. 2007, 12:S17 (abstract no. 15) JP Vacca1, MK Holloway1, TJ Allison1, CA Coburn1, JJ Wu2 and MA Wainberg3 The mutational profile of PL-100 can be deduced from a model and subsequent X-ray crystal structure of the inhibitor bound to HIV-1 protease. This information can aid in the understanding of the resistance profile of PPL-100 and the design of novel protease inhibitors. |
| 16 | IN VITRO HIV-1 RESISTANCE SELECTION TO GS-8374, A NOVEL PHOSPHONATE PROTEASE INHIBITOR: COMPARISON WITH LOPINAVIR, ATAZANAVIR AND DARUNAVIR Antivir Ther. 2007, 12:S18 (abstract 16) C Callebaut, K Stray, L Tsai, L Xu, W Lee and T Cihlar Direct comparison with several approved PIs suggests a higher genetic barrier for the selection of Protease mutations in the presence of GS-8374. The results indicate a direct role of specific Gag mutations in a selective resistance to GS-8374. Overall, this study further emphasizes the favourable properties of GS-8374 resulting from its unique mode of interaction with HIV protease. |
| 17 | IN VITRO ACTIVITY OF A NON-CONVENTIONAL (FOLDING) PROTEASE INHIBITOR ON HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 REPLICATION Antivir Ther. 2007, 12:S19 (abstract no. 17) M Lo Cicero1, AE Laface2, S Ferramosca1, F Sirianni1, E Cesana2, D Provasi3, G Tiana3, M Galli1, M Moroni1, A Clivio2, RA Broglia3,4 and S Rusconi1 An excellent therapeutic/toxic ratio was evidenced, with antiviral levels well below toxic concentrations. We noted a correspondence between the p24Ag ELISA and western blot. Different p24 production was evident, particularly between the infected control and the treatment with 83–92. The peptide inhibited a multiresistant isolate as compared to a conspicuous loss of ATV, which was not effective on the patient infected with this MDR virus. These evidences stand for a possible new approach for the inhibition of HIV-1 infection. |
| 18 | IN VITRO RESISTANCE PROFILE OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 TO TWO NEW HIV-1 PROTEASE INHIBITORS: CRS-074 AND CRS-075 Antivir Ther. 2007, 12:S20 (abstract no. 18) A Calazans1, E Xavier2, R Debom2, O Pacheco2, A Tanuri1 and R Brindeiro1 CRS-074 is one of most potent PI ever described (EC50=0.5 nM). Although CRS-074 presented high relative values of EC50 against resistant viruses, the absolute value of EC50 reached is still very low when compared to other PI against susceptible viruses. CRS-075 has an EC50 value comparable to the FDA-approved PI; moreover, CRS-075 highly effectiveness against resistant viruses demonstrated its potential as a future drug for second-line therapy. |
| 19 | HIGHLY POTENT PROTEASE INHIBITORS WITH NOVEL ESCAPE PATHWAYS Antivir Ther. 2007, 12:S21 (abstract no. 19) E Afonina1, SV Gulnik1, M Eissenstat1, H Yokoe1, B Yu1, NT Parkin2 and JW Erickson1 SPI-390 and SPI-457 represent a group of highly potent protease inhibitors and maintain nanomolar potency against worst-case scenario MDR HIV isolates. Selection of virus resistant to both compounds was a very slow process and required multiple passages with small incremental increases of concentration with the novel escape pathways. |
| 20 | IMPACT OF BASELINE PROTEASE MUTATIONS ON VIROLOGICAL RESPONSE TO DARUNAVIR–RITONAVIRCONTAINING THERAPY IN PROTEASE INHIBITOR-EXPERIENCED PATIENTS (PREDIZISTA STUDY) Antivir Ther. 2007, 12:S22 (abstract no. 20) I Pellegrin1, L Wittkop2, D Breilh3, P Merel1, B Winters4, M Bonarek5, D Neau5, D Bollens6, JL Pellegrin5, PM Girard6, HJA Fleury1, MC Saux3, R Thiébaut2 and L Morand-Joubert6 Sixty percent of heavy pretreated patients were considered as success at M3 on DRV/r-based HAART. DRV/r-score (built with this stringent endpoint) should be further investigated in order to define the individual impact of each retained mutation. Furthermore, their potential compensatory effect for associated major mutations, not retained in the present study population, should be elucidated. |
| 21 | IMPACT OF GAG CLEAVAGE SITE MUTATIONS ON THE VIROLOGICAL RESPONSE TO DARUNAVIR/RITONAVIR IN TREATMENT-EXPERIENCED PATIENTS IN POWER 1, 2 AND 3 Antivir Ther. 2007, 12:S23 (abstract no. 21) I Dierynck, S De Meyer, K Cao-Van, H Van Marck, E Lathouwers, K Thys, B Maes and M-P de Béthune Preliminary analyses on the pooled data of the POWER trials indicate that in treatment-experienced patients some baseline CS mutations in the Gag region have an impact on the virological response to darunavir/r at week 24. V128I was the only emerging CS mutation in the rebounder population, and seemed to be strongly correlated with the protease V32I mutation. The impact of the Gag CS mutations V128I, E428G, S451T and R452S on darunavir susceptibility will be further explored through site-directed mutagenesis. |
| 22 | RESISTANCE TO PYRIMIDINEDIONE HIV INHIBITORS REQUIRES MULTIPLE MUTATIONS IN BOTH REVERSE TRANSCRIPTASE AND ENVELOPE Antivir Ther. 2007, 12:S27 (abstract no. 22) RW Buckheit Jr and KM Watson The pyrimidinediones represent excellent therapeutic and microbicide development candidates based on their dual mechanism of action, high level of potency, lack of toxicity, and the inability of viruses resistant to one of the mechanisms of action to abrogate the activity of the second mechanism. The pyrimidinediones might be expected to provide the same level of protection in patients as the combination of Sustiva and Fuzeon, but in one small molecule. |
| 23 | NOVEL PATHWAYS TO NCRTI RESISTANCE SELECTED IN VITRO FROM HIV-1 STRAINS Antivir Ther. 2007, 12:S25 (abstract no. 23) D Jochmans, M Van Ginderen, I De Baere, S Hallenberger and G Kraus Different IVS methods reveal novel NcRTI resistance pathways via mutations in the active site of RT (A62V+A114S and V111G). This strengthens the hypothesis that NcRTIs inhibit HIV-1 RT by binding the active site and competing with incoming nucleotides. |
| 24 | CLONAL ANALYSIS OF SAMPLES FROM VIROLOGICAL RESPONDERS RECEIVING RACIVIR IN THE RCV 201 STUDY Antivir Ther. 2007, 12:S26 (abstract no. 24) A De La Rosa1, Robert Lloyd Jr2 and MJ Otto1 RCV effectively reduced viral loads in responders harbouring the M184V mutation and fewer than three TAMs at day 28. Clonal genotypic analysis of virus from responders indicate that the M184V mutation was found on all clones in addition to multidrug resistance associated mutations observed with first-line therapy failure. |
| 25 | CHARACTERIZATION OF A NOVEL S68 DELETION IN HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 2007, 12:S27 (abstract no. 25) RF Schinazi, M Ruckstuhl, KL Rapp, J Lennerstrand, M Bennett and M Detorio The S68 deletion demonstrated resistance to several clinically important NRTI. The Stanford database did not reveal matching sequences for the S68 deletions. Codon insertions and deletions have been associated with multidrug resistance (MDR) in clinical samples obtained from antiretroviral-treated individuals (67del, 69del, 69ins, 70del); however, the S68 deletion has never been reported. The novel S68 deletion may prove to be an important variable in NRTI MDR and improve treatment strategies. |
| 26 | ANTI-HCV ACTIVITY AND CELLULAR PHARMACOLOGY OF 2′-METHYLCYTIDINE ALONE AND IN COMBINATION WITH NON-TOXIC CONCENTRATIONS OF RIBAVIRIN IN THE HCV REPLICON SYSTEM Antivir Ther. 2007, 12:S28 (abstract no. 26) BI Hernandez-Santiago, L Bassit, J Grier and RF Schinazi NM107-TP levels in liver cells in the presence of non-toxic concentrations of RBV were 10- fold higher than the levels that inhibit HCV polymerase. Combination between NM107 and RBV at clinically relevant ratios resulted in additivity. These results suggest that NM107 (and NM283) can be used in combination with RBV for the treatment of HCV. |
| 27 | SYNERGY OF A HEPATITIS C VIRUS (HCV) NS4A ANTAGONIST, ACH-806, IN COMBINATION WITH HCV PROTEASE OR POLYMERASE INHIBITORS Antivir Ther. 2007, 12:S29 (abstract no. 27) DL Wyles, KA Kaihara and RT Schooley The HCV NS4A antagonist, ACH- 806 is synergistic with small molecular inhibitors of HCV replication representative of the compound classes currently being tested in clinical trials. Inhibitors which posses complementary actions in vitro (synergy) and have divergent resistance pathways should be prioritized for study in clinical trials of combination therapy for HCV. ACH-806 and other compounds with a similar mechanism of action represent attractive compounds to potentially combine with both protease and polymerase inhibitors. |
| 28 | R1206, A REPRESENTATIVE OF A NEW CLASS OF POTENT DIPHENYLETHER NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS BROADLY ACTIVE AGAINST NNRTI RESISTANT HIV-1 VARIANTS AND ACHIEVING HIGH SYSTEMIC EXPOSURES AND BENIGN SAFETY PROFILES IN ANIMAL SPECIES Antivir Ther. 2007, 12:S30 (abstract no. 28) K Klumpp, J Dunn, G Heilek, A Zhou, D Stefanidis, C-W Chen, JB Xu, J Hang, M Martin, J Davidson, S Harris, T Mirzadegan, A Paul, Y Li, G Su, T Silva, D Hirschfeld, X Han, S Swallow, N Cammack, H Vora, H Hogg and Z Sweeney R1206 represents a series of prodrugs for novel NNRTIs with high antiviral potency against wild-type and NNRTI-resistant HIV-1. R1206 is efficiently converted to the active parent RO-0335, achieving high oral bioavailability, high plasma exposures and benign safety pharmacology and toxicity profiles in acute and subchronic studies in rats and dogs. |
| 29 | α-SUBSTITUTED ACETANILIDES: HIV-1 NNRTIS WITH IMPROVED ACTIVITY AGAINST NNRTI-RESISTANT VIRUSES Antivir Ther. 2007, 12:S31 (abstract no. 29) MD Miller for the NNRTI Discovery Team The new structural classes of NNRTIs presented here include compounds with excellent antiviral potency against wild-type viruses as well as K103N, Y181C, and many other common NNRTI-resistant mutants. In addition, some of these compounds display good pharmacokinetic properties, suggesting this novel template may provide a source of new NNRTI candidates for clinical development. |
| 30 | IDX12899 ANTI-HIV-1 ACTIVITY AND RESISTANCE PROFILE IS SUPERIOR TO EFAVIRENZ Antivir Ther. 2007, 12:S32 (abstract no. 30) J Jakubik, M Seifer, L Gray, C Chapron, A Patty, C Dousson and DN Standring IDX12899 demonstrated potent antiviral activity in vitro, a higher genetic barrier to resistance compared to efavirenz, and enhanced activity in combination with other approved drugs, suggesting that IDX12899 is a promising second-generation NNRTI development candidate. Clinical evaluation of IDX12899 has been initiated. |
| 31 | STRATEGIC FLEXIBILITY OF THE NONNUCLEOSIDE RT INHIBITOR TMC278 EXPLAINS ITS POTENCY AGAINST DRUG-RESISTANT MUTANTS Antivir Ther. 2007, 12:S33 (abstract no. 31) K Das1, JD Bauman1, M Baweja1, AD Clark Jr1, PL Boyer2, AJ Shatkin1, PJ Lewi3, SH Hughes2 and E Arnold1 High-resolution structures of RT are critical for reliable description of inhibitor–protein interactions, better understanding of the effects of resistance mutations, and systematic structure-based drug design. The structures demonstrate the important role of strategic flexibility of TMC278 in evading the effects of drug resistance mutations. Incorporation of strategic flexibility into ligands appears to be an important consideration in designing drugs against rapidly evolving targets. |
| 32 | IMPACT OF BASELINE NNRTI MUTATIONS ON THE VIROLOGICAL RESPONSE TO TMC125 IN THE PHASE III CLINICAL TRIALS DUET-1 AND DUET-2 Antivir Ther. 2007, 12:S34 (abstract no. 32) J Vingerhoets1, A Buelens1, M Peeters1, G Picchio2, L Tambuyzer1, H Van Marck1, G De Smedt1, B Woodfall1 and MP de Béthune1 Thirteen mutations, mainly occurring in the presence of other NNRTI-RAMs were associated with a decreased response to TMC125. The decrease was function of the number of baseline TMC125-RAMs with the largest impact in the subgroup of patients with greater than three of those. Additional analyses will provide more insight into the role of these mutations, individually and combined, in resistance to TMC125. |
| 33 | IN VITRO SELECTION AND CHARACTERIZATION OF VIRUSES RESISTANT TO R1206, A NOVEL NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR Antivir Ther. 2007, 12:S35 (abstract no. 33) G Su1, Y Li1, A Paul2, J Hang1, S Harris1, H Hogg1, J Dunn1, N Cammack1, K Klumpp1 and G Heilek1 RO-0335 represents a series of novel NNRTIs with high antiviral potency against wild-type and NNRTI-resistant HIV-1. Passaging of wild-type HIV-1 in MT-4 cells under increasing drug pressure of RO-0335 identified the triple mutation V106A/F227C/M230L conferring resistance to RO-0335, whereas the individual mutations were not sufficient to confer significant levels of resistance. |
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Session 2: HCV/HBV drug resistance Abstracts 34 thru 35, Pages S39 to S40 |
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| 34 | DOES TREATMENT OF HEPATITIS B VIRUS REDUCE HEPATITIS DELTA VIRAEMIA IN HIV CO-INFECTED PATIENTS? Antivir Ther. 2007, 12:S39 (abstract no. 34) J Sheldon, B Ramos, P Ríos, J Martínez-Alarcón, C Toro and V Soriano In patients undergoing successful anti- HBV antiviral therapy there is an indirect benefit suppressing Delta virus replication, albeit not very efficient. Hypothetically, a significant and sustained reduction in serum HDV RNA may only be seen when a reduction in HBV cccDNA is achieved, which may require long periods of successful anti-HBV therapy. In our knowledge, this is the first evidence of benefit of potent anti-HBV nucleos(t)ide analogue therapy in chronic Delta hepatitis. |
| 35 | QUASISPECIES ANALYSIS IN NON-STRUCTURAL 5A (NS5A) REGION OF HEPATITIS C VIRUS (HCV) GENOTYPE 1B IN INTERFERON (IFN) OR COMBINED INTERFERON-RIBAVIRIN (IFN-R) THERAPY RESISTANCE Antivir Ther. 2007, 12:S40 (abstract no. 35) C Payan1,2, P Veillon1, H Le Guillou-Guillemette1, C Gaudy3, F Lunel1 and the Fontevraud Study Group These results suggested that detailed molecular analysis of the NS5A protein may be important to understand the resistance to IFN treatment in HCV 1b infection. |
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Session 3: Epidemiology Abstracts 36 thru 55, Pages S39 to S62 |
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| 36 | HIV-1 TRANSMISSION DYNAMICS IN RECENT SEROCONVERTERS: RELATIONSHIP WITH TRANSMISSION OF DRUG RESISTANCE AND VIRAL DIVERSITY Antivir Ther. 2007, 12:S43 (abstract no. 36) P Recordon-Pinson1, O Peuchant1, S Capdepont1, V Lavignolle2, D Neau2,3, P Morlat3, JL Pellegrin3, R Thiébaut2, F Dabis2, H Fleury1, B Masquelier1 and the ANRS CO3 Aquitaine Cohort The dynamics of HIV-1 transmission in this cohort in south-western France was clearly shown to be different in patients infected with B and non-B HIV-1 isolates. The high frequency of forward transmission events in subtype B-infected patients can lead to an overtransmission of drug resistant isolates with particular patterns and pleads for earlier antiretroviral therapy in recently infected patients and for increasing prevention efforts in developed countries. |
| 37 | POPULATION-BASED SURVEILLANCE SHOW TRANSMISSION CASCADES OF HIV-1 VARIANTS HARBOURING DRUG RESISTANCE Antivir Ther. 2007, 12:S44 (abstract no. 37) BG Brenner1,2, D Moisi1, M Roger3, JP Routy2, J Cox2, MA Wainberg1,2 and the Quebec Primary HIV Infection (PHI) Study Group In a North American setting offering universal access to health care, antiretroviral therapy and genotyping, the majority of new infections arise from untreated persons at early stages of infection, often unaware of their HIV serostatus. This may result in onward transmission of HIV drug-resistant infections. Prevention and diagnostic strategies, as well as routine genotyping, are needed for early stage infections. |
| 38 | EVOLVING WAVES OF SINGLE, DUAL AND TRIPLE CLASS RESISTANCE IN SAN FRANCISCO Antivir Ther. 2007, 12:S45 (abstract no. 38) S Blower1, R Smith1, J Okano1, E Bodine1 and J Kahn2 In San Francisco the severity of the epidemic has decreased since the introduction of therapy; levels of MDRHIV are likely to fall over the next five years. Initiating treatment earlier in individuals infected with wild-type strains could lead to sudden and dramatic decreases in levels of MDR. |
| 39 | SENSITIVE TESTING DEMONSTRATES A HIGH PREVALENCE OF TRANSMITTED DRUG RESISTANCE AMONG CONVENTIONALLY GENOTYPED WILDTYPE HIV-1 INFECTIONS Antivir Ther. 2007, 12:S46 (abstract no. 39) JA Johnson, J-F Li, X Wei, J Lipscomb, A Smith, and W Heneine The identification of resistance-associated mutations in drug-naïve persons previously diagnosed with wildtype virus infections increased the prevalence of transmitted drug resistance in this cohort from 20% to 33% (+65%). The considerable prevalence of low-frequency mutations and their equal occurrence in chronic infections demonstrate that a substantial proportion of transmitted drug-resistant variants decay and persist at low levels. These findings underscore the importance of sensitive baseline drug-resistance testing. |
| 40 | PREVALENCE OF MINORITY QUASISPECIES OF DRUG-RESISTANT HIV-1 IN PATIENTS WITH PRIMARY HIV-1 INFECTION IN ZURICH IN THE YEARS 2002–2006 Antivir Ther. 2007, 12:S47 (abstract no. 40) KJ Metzner1, P Rauch1, V von Wyl2, H Kuster2, H-J Stellbrink3, J Böni4, A Trkola2, R Weber2 and HF Günthard2 The prevalence of minority quasispecies of K103N and M184V variants is high in patients with PHI from Zurich, thus, the transmission rate of drug-resistant viruses is probably underestimated based on population sequencing. However, detection of minority quasispecies of drug-resistant HIV-1 was not associated with therapeutic failure in those patients within 0.8 to 4 years. |
| 41 | A LONGITUDINAL MOLECULAR ANALYSIS OF PRIMARY HIV DRUG RESISTANCE Antivir Ther. 2007, 12:S48 (abstract no. 41) J Brooks1, H Merks1, N Masse1, R Pilon1, G Jayaraman2, N Goedhuis2, C Archibald2, M Reckart3 and P Sandstrom1 Not only do clusters with DR persist over time, but new members to the cluster are more likely to have related DR patterns. Larger clusters are associated with more related infections over time. Targeting public health interventions toward clusters of related infections would identify a greater percentage of transmitted DR, and may have a much greater impact overall in reducing HIV transmission. |
| 42 | STABLE FREQUENCY OF HIV-1 TRANSMITTED DRUG-RESISTANCE OVER A DECADE (1996–2006) IN FRANCE IS LIKELY EXPLAINED BY THE INCREASE OF CHRONICALLY TREATED PATIENTS IN VIROLOGICAL SUCCESS Antivir Ther. 2007, 12:S49 (abstract no. 42) ML Chaix1, J Fichou2, C Deveau3, P Andre4, L Bocket5, T Bourlet6, D Descamps7, C Goujard8, J Izopet9, E Kohli10, B Masquelier11, M Ouka12, C Payan13, I Pellegrin11, JC Plantier14, S Rogez15, A Ruffault16, A Schmück17, V Schneider18, C Tamalet19, M Wirden20, C Rouzioux1, F Brun-Vezinet7, D Costagliola2 L Meyer3 and the ANRS AC11 Resistance Group, Cohort PRIMO, and FHDH Study Groups The frequency of acquired resistant virus at the time of primary infection was stable over time, over 5% for NRTI and NNRTI. One explanation for this stability may be the increasing number of treated patients in virological sucess. Early infection at the origin of transmission is not uncommon in French patients and successful therapy may prevent onward HIV transmission. |
| 43 | MOLECULAR EPIDEMIOLOGY AND PREVALENCE OF DRUG-RESISTANCE-ASSOCIATED MUTATIONS IN NEWLY DIAGNOSED HIV-1 PATIENTS IN CAMEROON Antivir Ther. 2007, 12:S51 (abstract no. S50) AD Nkengafac, S Tina, F Sua, T Mason, N Auyuketta and S Oben The identification of newly diagnosed individuals carrying resistance-associated mutations confirms that drug resistance transmission is a public health problem in Cameroon, with a possible impact on prevention, treatment and monitoring of HIV-1 infections. |
| 44 | INCREASING PREVALENCE OF HIV-1 NON-B SUBTYPES IN THE US AND IMPLICATIONS FOR PROTEASE INHIBITOR RESISTANCE MUTATION SCORES Antivir Ther. 2007, 12:S51 (abstract no. 44) R Kagan1, M Winters2, L Li1 and M Lewinski1 The prevalence of HIV-1 non-B subtypes is increasing in the tested population in the US. The higher frequency of tipranavir-score protease variants in non-B subtypes can result in more frequent predictions of tipranavir resistance in genotypic assays. The phenotypic and clinical consequences of these mutation patterns should be assessed and the need for subtype-specific mutation scores for non-B subtypes should be evaluated. |
| 45 | THE K65R MUTATION IS RARELY DETECTED AS A MINORITY QUASISPECIES IN THERAPY-NAÏVE, CHRONICALLY HIV-1-INFECTED PERSONS Antivir Ther. 2007, 12:S52 (abstract no. 45) KJ Metzner1, H Walter1, P Rauch1, P Braun2, H Knechten2, R Ehret2, M Mueller3, S Klauke4, J van Lunzen5 and B Ranneberg6 The K65R mutation is very uncommon in therapy-naïve, chronically infected patients. The prevalence of the K65R mutation as a minority quasispecies before ART seems not to be associated with virological therapy failure in patients initiating ART with Truvada and a third agent. |
| 46 | DRUG RESISTANCE AMONG HIV-INFECTED PREGNANT WOMEN RECEIVING ANTIRETROVIRALS FOR PROPHYLAXIS IN LIMBE, CAMEROON Antivir Ther. 2007, 12:S53 (abstract no. 46) AD Nkengafac, S Tina, F Sua, T Mason, N Auyuketta and S Oben PRMs occurred among 16.1% of relatively healthy HIV-1-infected mothers from Limbe in the South West Province of Cameroon receiving MTCT prophylaxis. |
| 47 | CHANGES IN THE REGIONAL PREVALENCE OF HIV-1 DRUG RESISTANCE-ASSOCIATED MUTATIONS AND IN THE PREVALENCE OF NON-CLADE B SUB TYPES IN ANTIRETROVIRAL THERAPY-NAÏVE HIV-INFECTED PATIENTS IN THE UNITED STATES FROM 2000–2006 Antivir Ther. 2007, 12:S54 (abstract no. 47) LL Ross, V Williams, B Wine, C Vavro, C Craig, D McClernon, M Tisdale, R Balu, T Lancaster, J Horton, K Pappa and ER Lanier By IAS-USA or Stanford definitions, the number of ART-naïve patients with DRM in this large US cohort increased from 2000–2006, with the greatest increase observed for NNRTI DRM. Regional differences in DRM prevalence were observed, with the highest in the south and west, albeit with yearly variation, suggesting that prescribing patterns may impact these results. Detection of dual-class DRM increased slightly over time. Subtype B was the most common subtype, although nonclade B subtypes increased slightly from 2001–2006. |
| 48 | FREQUENCY OF TRANSMITTED DRUG RESISTANCE AMONG ACUTE AND RECENTLY HIV-INFECTED PATIENTS IN NORTH CAROLINA IS SIMILAR TO REPORTS FROM MORE URBANIZED AREAS Antivir Ther. 2007, 12:S55 (abstract no. 48) C Hurt1, S McCoy2, M Kerkau3, J Nelson3, J Sebastian4, J Kuruc1, K McGee5, J Lennox6, C Pilcher7, C Hicks5 and J Eron1,3 TDR among acutely HIV-infected patients in North Carolina’s largely rural, heterosexual epidemic is similar to estimates from US metropolitan areas with different demographics. These findings have implications for initial regimen selection and secondary prevention efforts in non-urban HIV epicenters. |
| 49 | GEOGRAPHICAL AND TEMPORAL TRENDS OF TRANSMITTED HIV-1 DRUG RESISTANCE AMONG ANTIRETROVIRAL-NAÏVE SUBJECTS SCREENING FOR CLINICAL TRIALS Antivir Ther. 2007, 12:S56 (abstract no. 49) S Rahim, LM Fredrick, B da Silva, B Bernstein, M King and GJ Hanna Transmitted resistance to NNRTI was more frequent than to PI globally. Transmitted HIV-1 drug resistance was highest in North America. |
| 50 | FREQUENCY OF PI-RESISTANCE MUTATIONS FROM HIV-1 OF SUBTYPES B, C AND F IN A COHORT OF PATIENTS FAILING ARV THERAPY IN BRAZIL Antivir Ther. 2007, 12:S57 (abstract no. 50) M Arruda1, AF Pinto1, F Nobre2, R Mariano2, A Tanuri3 and R Brindeiro3 The evidence of different frequencies of resistance mutations to PI (primary and secondary) in proteases of different subtypes, herein posed, suggests that those viruses choose diverse mutational pathways against drug selective pressure, possibly due to their divergent molecular signatures (polymorphisms related to subtype). Novel PI-resistance polymorphisms shall be further addressed by analysis of the entire protease sequence divergences among different clades. |
| 51 | COMPARISON OF RESISTANCE ALGORITHMS TO DETERMINE PREVALENCE OF TRANSMITTED DRUG RESISTANCE Antivir Ther. 2007, 12:S58 (abstract no. 51) L Liu1, S May1, D Richman1,2, S Kosakovsky Pond1, S Frost1, S Little1 and D Smith1,2 The characterization of TDR rates depended on the method used to call a mutation as associated with resistance. Specifically, Stanford 60 was the most conservative. Estimates of TDR-based Stanford 30, IAS-USA and CPR were very close with the agreement being excellent across all drug classes (range of kappa: 0.84–0.97). The agreement between these three and Stanford 60 depended on the class of ARV with described resistance. |
| 52 | APPLICATION OF A BROADLY SENSITIVE GENOTYPING ASSAY USING DRIED BLOOD SPOTS FOR SURVEILLANCE OF HIV-1 DRUG RESISTANCE IN PEPFAR COUNTRIES Antivir Ther. 2007, 12:S57 (abstract no. 52) A McNulty1, K Diallo1, J Zhang2, S Kassim1, D Bennett3, J Aberle-Gasse4, T Kibuka5, JN Nkengasong1 and C Yang1 Our results indicate that DBS can be used as a sample collection method for DR surveillance in resource-limited settings. Our improved genotyping method amplifies a large HIV-1 subgenomic region encompassing almost the entire protease and 2/3 of RT region with high efficiency. This method has a broad sensitivity to cover multiple HIV-1 subtypes and recombinants and may find its wide utility in many PEPFAR countries. |
| 53 | STUDY OF ANTIRETROVIRAL RESISTANCE IN TREATED PATIENTS WITH VIROLOGICAL FAILURE (START STUDY): TEMPORAL TRENDS OF CLASS RESISTANCE EVALUATED IN PATIENTS FAILING LAST HAART Antivir Ther. 2007, 12:S60 (abstract no. 53) I Caramma1, M Violin1, R Velleca1, S Corvasce1, M Franzetti1, A Antinori2, S Bonora3, AP Callegaro4, A Capetti5, B Bruzzone6, A De Luca7, F Ceccherini-Silberstein8, N Gianotti9, F Maggiolo4, L Monno10, F Mazzotta11, V Micheli12, C Torti13, M Zazzi14, C Balotta1 for the START Study In the context of a moderate decrease of NRTI and PI mutations over time a noteworthy reduction of NRTI+PI combined resistance was observed in patients treated with these drugs. The marked decrease of M184I/V mutations may be the effect of an enhanced protection of 3TC or FTC containing regimens possibly due to boosted PIs in drug prescribing. |
| 54 | CHARACTERIZATION OF DRUG RESISTANCE IN A COHORT OF SUBJECTS ON ANTIRETROVIRAL THERAPY INFECTED WITH HIV-1 CRF02_AG AND AGK SUBTYPES IN MALI AND BURKINA FASO Antivir Ther. 2007, 12:S61 (abstract no. 54) N Machouf1,2, M Sylla3, A Chamberland3,4, C Boileau1, HA Traoré5, S Ag-Aboubacrine5, M Cissé6, S Koala7, J Drabo8, I Diallo8, A Traoré8, P Niamba8, D Tremblay-Sher3, Sélim Rashed3, VK Nguyen3 and CL Tremblay3,4 for the ATARAO Group While CRF02_AG is the dominant clade in the Burkina Faso/Mali region, isolates with subtype K RT were frequent in our cohort. The trend towards a more common TAM2 pathway for mutations in subtype K reverse transcriptase needs to be further evaluated in a larger cohort of non-B HIV-infected individuals. |
| 55 | HIV-1 DRUG RESISTANCE IS NOT A PREDICTOR OF INCREASED MORTALITY IN THE CONTEXT OF CLINICAL CARE Antivir Ther. 2007, 12:S62 (abstract no. 55) HM Truong1,2, S Chen3, W McFarland1,3, T Liegler1 and RM Grant1,2 HIV-1 drug resistance was not associated with increased mortality. Drug resistance, and by defacto resistance testing, is a surrogate marker for access to medical care and antiretroviral treatment. Matched analysis findings suggest even antiretroviral treatment that results in HIV-1 drug resistance does not increase mortality risk, in the context of having access to care which allows for adjustment of treatment regimens in response to resistance test results.HIV-1 drug resistance was not associated with increased mortality. Drug resistance, and by defacto resistance testing, is a surrogate marker for access to medical care and antiretroviral treatment. Matched analysis findings suggest even antiretroviral treatment that results in HIV-1 drug resistance does not increase mortality risk, in the context of having access to care which allows for adjustment of treatment regimens in response to resistance test results. |
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Session 4: Clinical implications of resistance Abstracts 56 thru 83, Pages S65 to S92 |
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| 56 | CXCR4-USING VIRUS DETECTED IN PATIENTS RECEIVING MARAVIROC IN THE PHASE III STUDIES MOTIVATE 1 AND 2 ORIGINATES FROM A PRE-EXISTING MINORITY OF CXCR4-USING VIRUS Antivir Ther. 2007, 12:S65 (abstract no. 56) M Lewis1, P Simpson1, S Fransen2, W Huang2, J Whitcomb2, M Mosley1, DL Robertson3, R Mansfield1, G Ciaramella1 and M Westby1 This detailed clonal analysis supports a pre-existing CXCR4-using virus as the most likely origin of on-treatment CXCR4-using virus. No evidence for coreceptor switching was identified whilst on therapy. The apparent loss of CCR5-tropic clones in the on-treatment samples is consistent with their strong in vivo inhibition by maraviroc. |
| 57 | DRUG RESISTANCE AT VIROLOGICAL FAILURE IN A RANDOMIZED, PHASE III TRIAL OF NRTI-, PI- AND NNRTI-SPARING REGIMENS FOR INITIAL TREATMENT OF HIV-1 INFECTION (ACTG 5142) Antivir Ther. 2007, 12:S66 (abstract no. 57) RH Haubrich1 , SA Riddler2, AG DiRienzo3, L Peeples3, KL Klingman4, KW Garren5, T George6, JF Rooney7, B Brizz8, D Havlir9, JW Mellors2 and the AIDS Clinical Trials Group 5142 Study Team NNRTI resistance was significantly more frequent at virological failure on LPV+EFV than EFV+two NRTI. Resistance mutations in two drug classes were more frequent with EFV+two NRTI, but virological failure was least likely on this regimen. These findings underscore the complexity of choosing initial treatment regimens. |
| 58 | DIFFERENCES IN THE TEMPORAL EMERGENCE OF PRIMARY AND SECONDARY NRTI AND PI DRUG-RESISTANCE MUTATIONS (DRMS) Antivir Ther. 2007, 12:S67 (abstract no. 58) SY Rhee, TF Liu, SP Holmes and RW Shafer The relationship between conditional probabilities and temporal emergence within a pair of DRMs is stronger for NRTI than PI DRMs suggesting that the pathway to developing multiple DRMs is more parsimonious for the NRTIs. Whereas secondary NRTI DRMs nearly always followed primary NRTI DRMs, secondary PI DRMs often preceded primary PI DRMs. The designation of PI DRMs as primary or secondary, therefore, refers more to their roles in causing resistance and not to the order in which they develop. |
| 59 | EXTENSIVE HIV-1 ANTIRETROVIRAL DRUG CLASS RESISTANCE IS ASSOCIATED WITH INFERIOR VIROLOGICAL AND CLINICAL OUTCOMES Antivir Ther. 2007, 12:S68 (abstract no. 59) S Napravnik, J Keys, B Stalzer and JJ Eron TC-DR is associated with inferior virological and clinical outcomes although therapy continues to provide some immunological benefit even in the presence of extensive HIV-1 drug resistance. |
| 60 | ACCUMULATION OF CLASS DRUG-RESISTANCE AMONG SURVIVORS AND NON-SURVIVORS IN A LARGE COHORT OF ANTIRETROVIRAL-NAÏVE INDIVIDUALS Antivir Ther. 2007, 12:S69 (abstract no. 60) VS Gill1,2, AJ Low1,2, R Joy1, PR Harrigan1,2 and V Lima1 In agreement with previous results, mean accumulated HIV drug-class resistance was highest between 50–95% adherence. Although most individuals did not have resistance to many categories of drugs even after years of exposure, mean accumulated HIV drug-class resistance was greater in non-survivors than survivors across all adherence strata, suggesting that resistance remains a risk factor for mortality. |
| 61 | CONTINUING EVIDENCE OF FAST HIV DISEASE PROGRESSION RELATED TO CLASS-WIDE RESISTANCE TO ANTIRETROVIRALS: A 6-YEAR FOLLOW-UP ANALYSIS OF A LARGE OBSERVATIONAL DATABASE Antivir Ther. 2007, 12:S70 (abstract no. 61) M Zaccarelli1, F Forbici2, P Lorenzini1, F Ceccherini-Silberstein2, V Tozzi1, MP Trotta1, P Marconi1, P Narciso1, CF Perno2 and A Antinori1 Despite the use of new antiretroviral drugs overcoming class resistance, class-wide resistance was confirmed to be associated with a significantly higher risk of death and disease progression also over prolonged follow-up. |
| 62 | INCREASING PREVALENCE OF TRIPLE-CLASS-EXPERIENCED PATIENTS AT SIX US SITES: DATA FROM THE CNICS (CFAR NETWORK OF INTEGRATED CLINICAL SYSTEMS) COHORT Antivir Ther. 2007, 12:S71 (abstract no. 62) S Jain1, C Mathews1, M Saag2, M Kitahata3, B Rodriguez4, J Kahn5, S Boswell6, WB Lober3, M Lederman4, S Sun1, S Frost1, RH Haubrich1, and the CNICS Study Team Over the past six years, there was a >10% increase in three-class experienced patients both among all patients and among those on therapy, but VF was decreasing. Sensitivity analysis indicated that trends were consistent across the six CNICS sites. New classes of ARV medications in development should improve treatment for the growing population of experienced patients in US clinics. |
| 63 | COMPILATION OF MUTATIONS ASSOCIATED WITH RESISTANCE TO NNRTIS DEDUCED FROM CLINICAL SAMPLES, IN VITRO ANALYSES AND BIBLIOGRAPHICAL STUDIES Antivir Ther. 2007, 12:S72 (abstract no. 63) LT Rimsky1, L Tambuyzer1, J Vingerhoets1, H Azijn1, M Staes2, G Picchio3, G Kraus1 and M-P de Béthune1 This list provides a thorough overview of the mutations involved, alone or in combination with others, in loss of susceptibility to NNRTIs. This list can be used to guide clinical and in vitro research on the mechanism of HIV-1 resistance to current and next generation NNRTIs. |
| 64 | NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) PLASMA CONCENTRATIONS DETERMINE DIFFERENT NNRTI-RESISTANCE PATTERN IN VIROLOGICAL RESPONDERS DURING TREATMENT INTERRUPTIONS Antivir Ther. 2007, 12:S73 (abstract no. 64) L Darwich1, R Bellido1, A Blanco1, L Ruiz1, A Esteve2, C Cabrera1, J Molto1,3, B Clotet1,3 and J Martinez-Picado1,4 The genotypic pattern of NNRTI-associated mutations emerged during the TI was different according to plasma drug concentrations of the preceding treatment period. Therefore, even in virological responders, drug concentrations close to the lowest limit of therapeutic range should be avoided, since the selection of major HIV-1 NNRTI-resistant variants could already happen during treatment periods with concentrations close to the lower clinical cut-off. Why different drug levels drive the virus to select different resistance pattern warrants further investigation. |
| 65 | PREVALENCE OF ETRAVIRINE-ASSOCIATED MUTATIONS IN CLINICAL SAMPLES WITH RESISTANCE TO NEVIRAPINE AND EFAVIRENZ Antivir Ther. 2007, 12:S74 (abstract no. 65) JM Llibre1, JR Santos1, T Puig2, J Moltó1, L Ruiz2 and B Clotet1,2 ETV will retain activity in most patients with resistance to first generation NNRTI. Complete resistance to ETV will be very rare, but low-to-intermediate resistance will be fairly common. These results emphasize the recommendation of withdrawing first generation NNRTI from non-suppressive antiretroviral regimens to avoid the accumulation of further mutations that would increase the degree of resistance to ETV. |
| 66 | IS THERE AN INTERMEDIATE RANGE OF CLINICAL RESPONSE TO NNRTI-BASED THERAPIES? Antivir Ther. 2007, 12:S75 (abstract no. 66) PR Harrigan1, J Montaner1, E Van Craenenbroeck2, M Van Houtte2, L Bacheler3, B Gazzard4, A Pozniak4, F van Leth5, P Robinson6, V Dias Lima1 and B Winters2 The data suggests the existence of a relatively small population in whom partial antiretroviral activity remains after the selection of some NNRTI resistance for first generation NNRTIs. The clinical relevance of this potential partial antiretroviral activity needs to be investigated further. |
| 67 | CORRELATES OF K65R EMERGENCE IN PATIENTS TREATED WITH TNV-CONTAINING THERAPY Antivir Ther. 2007, 12:S76 (abstract no. 67) S Yerly1, V von Wyl2, J Böni3, P Burgisser4, T Klimkait5, M Battegay5, H Furrer6, M Cavassini4, B Hirschel7, P Vernazza8, E Bernasconi9, M Rickenbach10, B Ledergerber2, H Günthard2 and the SHCS This analysis of a dataset from routine clinical practice confirms the protective effect of TAMs against the emergence of K65R, and further suggests that drug combinations including NNRTI and/or ddI with TNV favours the selection of this mutation. |
| 68 | IMPACT OF HIV-1 REVERSE TRANSCRIPTASE POLYMORPHISM R83K ON VIROLOGICAL RESPONSE IN DRUG-NAÏVE PATIENTS STARTING THYMIDINE-ANALOGUE-CONTAINING HAART Antivir Ther. 2007, 12:S77 (abstract no. 68) F Ceccherini-Silberstein1, V Svicher1, MM Santoro1, M Prosperi2, F Forbici3, A Bertoli1, C Mussini4, A De Luca5, G Palamara6, P Narciso3, A Antinori3, C Balotta7, A d’Arminio Monforte7, and CF Perno3 - ICoNA Study Group, INMI-Collaborative Group for Clinical Use of HIV Genotype Resistance Test Our study provides evidence that R83K at baseline correlates with a favourable virological response to TA-containing regimens, and with very limited TAMs development. Overall, data strongly support R83K as a ‘protective’ polymorphism interfering with the accumulation of TAMs, thus prolonging the benefits of antiretroviral regimens and consequently slowing down progression to AIDS. |
| 69 | CLINICAL AND GENOTYPIC FINDINGS IN HIV-INFECTED PATIENTS WITH THE K65R MUTATION FAILING STAVUDINE, LAMIVUDINE AND NEVIRAPINE FIRST-LINE ANTIRETROVIRAL THERAPY Antivir Ther. 2007, 12:S79 (abstract no. 69) C Hawkins1, B Chaplin2, J Idoko3, C Idehen4, I Adewole5, W Gashau6, R Murphy1, P Kanki2 and APIN Plus/Harvard PEPFAR Team The K65R mutation is surprisingly common among patients failing first-line ART in this West African setting. Similar to previous reports, a positive correlation with Q151M was observed. Although excellent, initial virological responses were demonstrated among patients switching to second-line ART, further follow- up is required to determine if the K65R mutation limits the long-term success of these TDF-containing regimens. |
| 70 | SELECTION OF RESISTANCE MUTATIONS IN A RANDOMIZED TRIAL TESTING AN INDUCTION MAINTENANCE STRATEGY WITH TRIZIVIR® PLUS EITHER EFAVIRENZ OR LOPINAVIR/r DURING THE INDUCTION PERIOD Antivir Ther. 2007, 12:S79 (abstract no. 70) J Mallolas, M Riera, P Domingo, H Knobel, E Pedrol, F Gutiérrez, P Barrufet, J Peraire, D Dalmau, E Ribera, A Ocampo, MA Muniaín, C Alonso, V Estrada, JR Blanco, J Cucurull, J Pich, E De Lazzari, JM Llibre, J Carmena, MJ Galindo and JM Gatell for the TRIZEFAL study group There was a trend towards an increased virological failure rate in the EFV arm during the maintenance phase, which is associated with selection of the 184V mutation with or without TAMs, and not explained by the presence of mutations at baseline. |
| 71 | VIRAL EVOLUTION IN HIV-1 REVERSE TRANSCRIPTASE IN PATIENTS RECEIVING A HOLDING REGIMEN WITH TRIZIVIR® AND TENOFOVIR WITH PERSISTENT VIRAL REPLICATION Antivir Ther. 2007, 12:S80 (abstract no. 71) JM Llibre1, A Bonjoch1, JA Iribarren2, MJ Galindo3, X Martínez-Picado4,5, P Arazo6, JR Santos1, P Domingo7 and B Clotet1,4 There is no further accumulation of retrotranscriptase mutations in patients with persistent viral replication on a holding regimen with TZV + TDF. This combination appears to be safe and maintain an immunological benefit seemingly at no cost for RT mutations over a 24-week period. |
| 72 | RATE OF ACCUMULATION OF THYMIDINE ANALOGUE MUTATIONS (TAM) IN PATIENTS LEFT ON VIROLOGICALLY FAILING REGIMENS CONTAINING ZIDOVUDINE (ZDV) OR STAVUDINE (d4T) Antivir Ther. 2007, 12:S81 (abstract no. 72) A Cozzi-Lepri1, AN Phillips1, J Martinez-Picado2, A d’Arminio Monforte3, C Katlama4, A-B Eg Hansen5, A Horban6, J Bruun7, B Clotet2 and J Lundgren8 for the EuroSIDA study group Pts who are kept on a virologically failing regimen containing ZDV/d4T experience a relatively slow accumulation of TAM. |
| 73 | TENOFOVIR-BASED BACKBONES IN SALVAGE THERAPY FOR ANTIRETROVIRAL-EXPERIENCED PATIENTS WITH L74V MUTATION AT FAILURE Antivir Ther. 2007, 12:S82 (abstract no. 73) MP Trotta1, M Zaccarelli1, S Bonfigli1, F Ceccherini-Silberstein2, A Ammassari1, U Visco-Comandini1, F Forbici1, G Antonucci1, CF Perno1 and A Antinori1 In patients with L74V mutation, addition of thymidine analogues to a TDF-based backbone in salvage regimen seems to have a beneficial virological effect. |
| 74 | IMPACT OF HIV-1 SUBTYPE IN SELECTING MUTATIONS ASSOCIATED WITH RESPONSE TO BOOSTED TIPRANAVIR IN HIV-1-INFECTED PROTEASE INHIBITOR EXPERIENCED PATIENTS Antivir Ther. 2007, 12:S83 (abstract no. 74) P Flandre1, AG Marcelin1, B Masquelier2, D Descamps3, J Izopet4, C Charpentier5, C Aloui6, G Peytavin3, M Lavignon7 and V Calvez1 on behalf of the TPV ANRS study group This study demonstrates the importance of HIV-1 subtype in identifying a set of mutations associated with VR to a TPV/r-based regimen. Large databases including patients with non-B subtype are now needed to identify specific genotypic scores according to different subtypes. |
| 75 | PROTEASE GENE MUTATIONS IN A TRIAL COMPARING FIRST-LINE LOPINAVIR/RITONAVIR MONOTHERAPY TO LOPINAVIR/RITONAVIR + ZIDOVUDINE/LAMIVUDINE (MONARK TRIAL) Antivir Ther. 2007, 12:S84 (abstract no. 75) C Delaugerre1, P Flandre2, ML Chaix1, P Dellamonica3, F Raffi4, H Jäger5, D Schürmann6, NgoVan7, M Norton8, I Cohen Codar7, JF Delfraissy9 and C Rouzioux1 Genetic barrier to the development of a major PI mutation was lower for lopinavir/ritonavir monotherapy compared to lopinavir/ritonavir + zidovudine/ lamivudine. Mutation L76V might be considered in further studies. All subjects who developed a major PI resistance mutation, continued on either lopinavir/ritonavir monotherapy or intensified with zidovudine/lamivudine had subsequent VL <400 c/ml. |
| 76 | SELECTIVE ADVANTAGE OF HIV PROTEASE MUTATIONS ASSOCIATED WITH RESISTANCE TO LOPINAVIR Antivir Ther. 2007, 12:S85 (abstract no. 76) A Molla1, L Lu1, M King1, R Woods2, T Pilot-Matias1, E Lam3, J Whitcomb3, B Bernstein1, G Hanna1 and D Kempf1 Single, double and triple mutants containing the most common LPV/r resistance mutations displayed low or no selective advantage over wt virus in the presence of LPV. These results may provide insight into the low incidence of PI resistance in clinical studies of LPV/r in PI-naïve patients. |
| 77 | RESISTANCE PROFILE AFTER VIRAL REBOUND ON ATAZANAVIR-CONTAINING THERAPY: FOCUS ON PROTEASE INHIBITOR-NAÏVE SUBJECTS IN THE IMPACT STUDY (BMS AI424-128) Antivir Ther. 2007, 12:S86 (abstract no. 77) A Zolopa1, W Towner2, D Butcher3, S Wang3, JF Maa3 and D Seekins3 In this cohort, the overall prevalence of I50L was 9.5%. Of 39 PI-naïve individuals, seven (two antiretroviral-naïve) developed primary PI substitutions, of whom all but one had maintained or increased susceptibility to essentially all PIs (except ATV). |
| 78 | MUTATIONS IN HIV-2 PROTEASE SELECTED BY PROTEASE INHIBITOR THERAPY Antivir Ther. 2007, 12:S87 (abstract no. 78) J Cavaco Silva1, J Cabanas1, MF Gonçalves1, K Van Laethem3, AM Vandamme3, P Gomes1,2 and RJ Camacho1,2 Several mutations selected by antiretroviral therapy were observed, showing that the pathways for HIV-2 protease drug resistance are different from those in HIV-1. The generation of large datasets will allow to further clarify HIV-2 resistance pathways. |
| 79 | GENOTYPIC RELATIONSHIPS BETWEEN TIPRANAVIR AND DARUNAVIR RESISTANCE IN PROTEASE-INHIBITOR EXPERIENCED PATIENTS Antivir Ther. 2007, 12:S88 (abstract no. 79) DB Hall1, J Scherer1, J Schapiro2, CAB Boucher3, J Baxter4, VM Kohlbrenner1 and D Mayers1* PI-associated mutations at 48V, 50V, and 54L are associated with susceptibility to TPV and reduced susceptibility to DRV. These mutations are selected against during TPV therapy, leading to increased susceptibility to DRV. The impact of archived mutations is unknown. Selection for mutations associated with TPV resistance (82L/T) is not associated with development of resistance to DRV. |
| 80 | IMPACT OF HIGH BASELINE RESISTANCE TO APPROVED PROTEASE INHIBITORS ON DARUNAVIR/r VIROLOGICAL RESPONSE IN TREATMENT-EXPERIENCED PATIENTS IN POWER 1, 2 AND 3 Antivir Ther. 2007, 12:S90 (abstract no. 80) S De Meyer1, G Picchio2, T Vangeneugden1, S Spinosa-Guzman1, E Lathouwers1 and M-P de Béthune1 The use of any of the approved PIs at screening had no or minimal impact on the darunavir/r virological response in treatment-experienced patients in POWER 1, 2 and 3. High baseline resistance to (fos)amprenavir had a larger relative impact on response as compared to the other PIs. |
| 81 | ANTIVIRAL EFFICACY AND EMERGENT PI SUBSTITUTIONS IN TREATMENT-NAÏVE SUBJECTS RECEIVING ATAZANAVIR ± RITONAVIR-BASED HAART IN SUBTYPE B AND NONTYPE B HIV-1 INFECTION Antivir Ther. 2007, 12:S90 (abstract no. 81) D McGrath, V Wirtz, R Yang, M Mathew, A Rightmire and S Schnittman for the BMS AI424089 Study Group Individuals infected with subtypes B or C demonstrated virological response to both ATV300/RTV and ATV400. Major IAS-defined PI substitutions were only observed on ATV400, and only in subtype B individuals with virological failure. |
| 82 | CURRENT GENOTYPIC INTERPRETATION SYSTEMS ARE COMPARABLE IN THEIR PREDICTIVE ABILITY AND HIGHLY DEPENDENT ON IDENTIFYING THE MOST ACTIVE PROTEASE INHIBITOR Antivir Ther. 2007, 12:S91 (abstract no. 82) SY Rhee1, WJ Fessel2, NM Marlowe3, CM Rowland3, A-M Vandamme4, K Van Laethem4, F Brun-Vezinet5, V Calvez6 and RW Shafer1 All four commonly used genotypic interpretation systems independently predicted virological response to a new salvage ARV regimen. For all four interpretation systems, the PI GSS was the strongest predictor of response. |
| 83 | POLYMORPHISM OF HIV-2 INTEGRASE GENE AND IN VITRO PHENOTYPIC SUSCEPTIBILITY OF HIV-2 CLINICAL ISOLATES TO INTEGRASE INHIBITORS: RALTEGRAVIR AND ELVITEGRAVIR Antivir Ther. 2007, 12:S92 (abstract no. 83) B Roquebert1, F Damond1, G Collin1, S Matheron1, A Taieb2, G Peytavin1, A Bénard2, P Campa3, G Chêne2, F Brun-Vézinet1, D Descamps1 and the French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2) This is the first study assessing the susceptibility of HIV-2 clinical isolates to INI. Despite 40% of heterogeneity between HIV-1 and HIV-2 IN genes, phenotypic susceptibility to the two available INI is similar to that observed for HIV-1 and showed no variation due to natural polymorphisms in HIV-2 IN. The Q151M MDR mutation also did not alter phenotypic susceptibility of HIV-2 to INI. This new class of antiretroviraI drugs represent a novel therapeutic option for HIV-2-infected patients. |
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Session 5: HIV pathogenesis, fitness and resistance Abstracts 84 thru 109, Pages S95 to S120 |
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| 84 | HOW HIV-1 SELECTS COPACKAGED RNAS: IMPLICATION FOR ANTIVIRAL STRATEGIES TARGETING RNA DIMERIZATION INITIATION SIGNAL Antivir Ther. 2007, 12:S95 (abstract no. 84) MD Moore1, W Fu2, O Nikolaitchik1, J Chen1, RG Ptak2 and W-S Hu1 Our results demonstrate that the base-pairing of the DIS is a major determinant in the selection of the copackaged RNA partner, and altering the base pairing of the DIS can change the proportion of heterozygous viruses in a viral population. However, blocking the base-pairing in DIS does not prevent dimer formation, and has little effect on virus replication in a single round assay. Therefore, viruses are likely to be able to escape from molecules interfering with DIS function. |
| 85 | INTERMITTENT ANTIRETROVIRAL PROPHYLAXIS WITH TENOFOVIR AND EMTRICITABINE PROTECTS MACAQUES AGAINST REPEATED RECTAL SHIV EXPOSURES Antivir Ther. 2007, 12:S96 (abstract no. 85) JG García-Lerma, R Otten, M Cong, E Jackson, R Janssen, TM Folks and W Heneine Two-dose PrEP given before and 24 h after virus exposure can be as effective as daily PrEP. Single-dose PreP is highly effective but not sufficient to achieve full protection, suggesting that the extended antiviral activity in the second 24 h dose also contributes to protection. These data highlight the importance of effectively blocking the early stages of virus replication and show the promise of intermittent PreP as a strategy for HIV prevention. |
| 86 | NO EVIDENCE OF DRUG RESISTANCE MUTATIONS IN A SEROCONVERTER EXPOSED TO TENOFOVIR DISOPROXIL FUMARATE (TDF) CHEMOPROPHYLAXIS IN AFRICA Antivir Ther. 2007, 12:S97 (abstract no. 86) RE Atchison1,2, L Peterson3, E Clark4, TJ Liegler2, W Cates3 and RM Grant1,2 There is no evidence of TDF-resistance mutations K65R or K70E in one adherent participant who seroconverted after 1 month of exposure to TDF chemoprophylaxis. Similarly, TDF resistance has not been observed in non-human primates who became infected despite TDF chemoprophylaxis. In contrast with treatment use, prevention use of antivirals may engender drug resistance rarely, or not at all, because the viral populations being inhibited are too small to readily generate resistant mutants. |
| 87 | DYNAMICS OF VIRUS REPLICATION AND ANTIVIRAL DRUG RESISTANCE IN A NEW RT-SHIV MACAQUE MODEL OF ANTIVIRAL THERAPY Antivir Ther. 2007, 12:S98 (abstract no. 87) S Palmer1, Z Ambrose1, M Kearney1, W Shao1, V Boltz1, J Kimata2, F Maldarelli1, JW Mellors3, S-L Hu4, JD Lifson5, VN KewalRamani1 and JM Coffin1 ART used in HIV-1-infected persons can effectively suppress RT-SHIVmne replication in macaques. Evolution of RT-SHIVmne antiviral resistance mimics what is observed in infected persons. Short-course EFV monotherapy selected EFV-resistant variants in two of three macaques; the macaque with the greatest pretherapy viral genetic diversity failed subsequent EFV-containing ART. This new animal model can be used to address questions about the appearance, selection, tissue origins and persistence of drug resistance that cannot be answered in human studies. |
| 88 | MOLECULAR CLONING AND REPLICATION CHARACTERIZATION OF A NEWLY TRANSMITTED, DUAL-TROPIC, MULTIDRUG-RESISTANT HIV-1 ASSOCIATED WITH RAPID DISEASE PROGRESSION Antivir Ther. 2007, 12:S99 (abstract no. 88) H Mohri and M Markowitz A multidrug-resistant infectious molecular clone that has been constructed exhibits high replication capacity, dual tropism and strong cytopathicity in vitro. This clone along with others under construction will enable us to probe for the relative contributions of structural and regulatory gene products in accounting for mechanisms of compensation, growth kinetics and cytopathicity. |
| 89 | EVOLUTION AND PERSISTENCE OF CTL-ASSOCIATED MUTATIONS IN NEWLY HIV-1-INFECTED INDIVIDUALS Antivir Ther. 2007, 12:S100 (abstract no. 89) M Kearney1,2, W Shao1, F Maldarelli1, J Margolick3, E Daar4, J Mellors5, V Rao2, J Coffin1 and S Palmer1 These data indicate that acute HIV-1 (subtype B) infection usually results from transmission of a single viral variant carrying mutations in CTL epitopes. Reversion of these mutations even in the absence of CTL selection was not observed. The transmission of multiple HIV-1 variants in one case resulted in high diversity in acute infection and differential evolution in pro-pol and env. |
| 90 | DIFFERENCES IN VIRAL LOAD AND REPLICATION CAPACITY IN INDIVIDUALS HARBOURING VIRUS WITH OR WITHOUT DRUG RESISTANCE Antivir Ther. 2007, 12:S100 (abstract no. 90) SJ Little1, NT Parkin2, C Chappey2, DM Smith1, DD Richman1,3 and SDW Frost1 The relative VL in individuals with transmitted versus transmitted and acquired drug resistance was similar (NNRTI, WT>PI>PI+NNRTI); however, the magnitude of the differences in VL were larger in individuals with transmitted resistance. NNRTI resistance is associated with a similar or higher viral load despite a lower RC. |
| 91 | ASSOCIATION BETWEEN RESISTANCE AND CD4-COUNT CHANGE IN PATIENTS ON ART WITH ONGOING VIRAEMIA Antivir Ther. 2007, 12:S102 (abstract no. 91) ZV Fox1,2, AM Geretti3, B Clotet4, A Cozzi-Lepri2, T Hill2, H Green5, CA Sabin2, B Ledergerber6, JD Lundgren1 and AN Phillips2 for the UK Collaborative Group on HIV Drug Resistance, EuroSIDA and the UK CHIC Study There was little evidence of a difference in CD4-count slopes for a given HIV RNA level (or a given HIV RNA change from the pre-ART value) according to the presence of mutations. Certain NNRTI mutations may be associated with greater CD4-count declines, but since this analysis has limited power due to the high variability of the CD4-count slopes, further analyses on a larger number of patients is required before any firm conclusions can be drawn. |
| 92 | LOW-LEVEL VIRAEMIA IN HIV-1-INFECTED PATIENTS CLASSIFIED AS ‘ELITE CONTROLLERS’ COMPARED TO PATIENTS ON SUPPRESSIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2007, 12:S103 (abstract no. 92) S Palmer1, A Wiegand1, T Miura2, B Block2, F Pereyra2, F Maldarelli1, M King3, B Bernstein3, G Hanna3, J Mellors4, B Walker2 and J Coffin1 As with patients on suppressive antiretroviral therapy, the majority of patients classified as elite controllers have low-level viraemia. The levels of viraemia below 50 copies/ml tended to be higher for elite controllers compared to those in persons on suppressive therapy. The mechanisms involved in the virus suppression in elite controllers remain to be elucidated. |
| 93 | SUSTAINED RESTRICTION OF VIRAL DIVERSITY FOLLOWING INTERRUPTION OF ANTIRETROVIRAL TREATMENT Antivir Ther. 2007, 12:S104 (abstract no. 93) B Joos1, M Fischer1, H Kuster1, JK Wong2, J Böni3, A Trkola1, R Weber1 and HF Günthard1 Rebounding virus during short treatment interruptions is homogeneous, suggesting mono- or oligoclonal origin during reactivation. Expansion of distinct lineages at different STI suggests stochastic reactivation of different clones of long-lived, latently infected cells rather than expansion of low-level-replicating viral populations. A prolonged delay in restoration of pretreatment viral diversity following treatment interruption implies a surprisingly sustained evolutionary bottleneck induced by punctuated antiretroviral therapy. The basis for this effect and potential consequences on disease course merits additional study. |
| 94 | SIMILAR DIVERSITY OF HIV-1 PRO-POL BEFORE AND AFTER INITIATION OF SUPPRESSIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2007, 12:S105 (abstract no. 94) F Maldarelli1, M Kearney1, S Palmer1, K Danley1, J Mican2, D Rock3, W Shao4, J Mellors5 and J Coffin1 HIV-1 pro-pol genetic diversity did not change significantly, even after 10,000-fold reduction in viraemia with therapy. These data imply that antiretroviral therapy, at least initially, does not select for a genetically restricted subset of viruses or infected cells. The similar virus population structure before and after therapy implies a common source of genetic diversity with or without drug suppression. This suggests HIV-1 diversity is similar in infected cell populations with long or short half-lives. |
| 95 | MAPPING EVOLUTIONARY PATHWAYS OF HIV-1 DRUG RESISTANCE USING CONDITIONAL SELECTION PRESSURE Antivir Ther. 2007, 12:S106 (abstract no. 95) Q Wang1,2, L Chen1,3 and C Lee1,2,3 1) Conditional Ka/Ks, measured without any temporal information, is actually a kinetic parameter that estimates the rates of HIV evolutionary pathways. 2) This parameter directly predicts the preferred order and relative rates of competing evolutionary pathways.... |
| 96 | STANDARD ART AND VALPROIC ACID HAVE LIMITED IMPACT ON PERSISTENT HIV INFECTION OF RESTING CD4+ T-CELLS Antivir Ther. 2007, 12:S109 (abstract no. 96) NM Archin1, J Eron1, S Palmer2, L Ngo1, A Hartmann Duff1, N Bandarenko1, J Schmitz1, A Wiegand2, JM Coffin2, AL Landay3, RJ Bosch4, MS Cohen1 and DM Margolis1 VPA therapy combined with standard ART depleted RCI in a minority of volunteers. However, in contrast to the observation that latent infection in patients treated with ART and prescribed VPA for concomitant conditions increased up to 16-fold in some patients (Siliciano, et al., J Infect Dis. 2007 Mar 15;195(6):833-6.), no patient in our prospective, monitored study was observed to have a significant increase in latent infection. VPA or more potent HDAC inhibitors may result in more uniform or rapid depletion of RCI if administered with intensified ART. |
| 97 | GENETIC DISTANCE OF REBOUND VIRAEMIA FROM PROVIRAL DNA AND THE SELECTION OF DRUG-RESISTANCE MUTATIONS IN HIV-1 RNA AFTER TREATMENT INTERRUPTION Antivir Ther. 2007, 12:S108 (abstract no. 97) S Dalai, M Winters, S Kassaye and D Katzenstein for the ACTG A5102 Team After TI, plasma RNA evolves from proviral DNA over a continuum of GD, largely through synonymous mutations. Significant drug-resistance mutations were associated with early rebound viraemia and a trend towards greater GD between DNA and RNA. Surprisingly, suppression on a PI regimen with subsequent TI was significantly associated with emergence of new drug-resistance mutations in viral RNA, compared to RTI regimens. SD is supported by the Howard Hughes Medical Institute Research Fellowship. |
| 98 | THE FIDELITY OF HIV-1 REVERSE TRANSCRIPTASE: IDENTIFICATION OF VARIANTS WITH INCREASED LEVELS OF MUTATION DURING REVERSE TRANSCRIPTION Antivir Ther. 2007, 12:S109 (abstract no. 98) DV Nissley1,2, JL Shenk2, Z Ambrose3, JN Strathern2 and N Sluis-Cremer4 In order to identify error-prone RT variants, we carried out a screen for HIV-1 RT fidelity variants using a coupled reverse transcription/fidelity assay. In this assay RT activity is monitored via a reverse transcription indicator gene and fidelity is measured by reversion of point mutations in a second marker. |
| 99 | RELATIVE FITNESS AND TENOFOVIR RESISTANCE LEVELS OF K70E AND K65R HIV-1 RT MUTANTS FAVOURS SELECTION OF K65R OVER K70E VIRUSES IN THE PRESENCE OF TENOFOVIR Antivir Ther. 2007, 12:S110 (abstract no. 99) ES Svarovskaia1, D Goodman1, J Ly2, A Eastoak-Siletz2, K White2, G LaFlamme2, NA Margot2, MD Miller2 and K Borroto-Esoda1 The higher levels of tenofovir resistance observed for K65R versus K70E allow for the predominant selection of K65R over the K70E mutant virus despite the greater reduction in replication fitness of the K65R mutant compared to K70E. |
| 100 | ANTI-HIV ACTIVITY AND RESISTANCE PROFILES OF ENTECAVIR COMPARED TO CLEVUDINE Antivir Ther. 2007, 12:S113 (abstract no. 100) V Zennou, M Keilman, E Murakami, MJ Otto and P Furman We have confirmed that WT HIV-1 virus is sensitive to entecavir and that the M184V mutation confers resistance. In addition, we showed that certain nucleoside-resistant HIV variants remain sensitive to entecavir and that clevudine does not inhibit HIV in vitro. Thus, clevudine may be useful in treating HIV-HBV-coinfected patients. |
| 101 | PRIOR EMERGENCE OF K103N AFTER SINGLE-DOSE NEVIRAPINE PREDICTS DETECTION OF K103N AFTER EXPOSURE TO SINGLE-DOSE NEVIRAPINE IN A SUBSEQUENT PREGNANCY Antivir Ther. 2007, 12:S112 (abstract no. 101) TS Flys1, A Mwatha2, LA Guay1, C Nakabiito3, D Donnell2, P Musoke3, F Mmiro3, JB Jackson1 and SH Eshleman1 Detection of K103N after an initial nevirapine exposure and pre-nevirapine viral load independently predict detection of K103N after repeat use of single-dose nevirapine. This association could reflect maternal factors (for example, absorption or clearance of the drug), viral factors (for example, properties of viral strains that influence fitness of K103N-containing variants), or establishment of a reservoir of resistant variants after the initial exposure. |
| 102 | DIFFERENTIAL CORECEPTOR USE BY DUAL-TROPIC HIV-1 ENVELOPES IMPACTS CORECEPTOR INHIBITOR SUSCEPTIBILITY Antivir Ther. 2007, 12:S115 (abstract no. 102) J Toma, J Whitcomb, S Fransen, J Reeves, N Parkin, C Petropoulos and W Huang Examination of 30 dual-tropic Envs revealed a broad range of infectivity on U87.CD4.CCR5 or U87.CD4.CXCR4 cells. Envs that used CXCR4 poorly (dual-R) had V3 loop sequences similar to those of R5-tropic Envs and distinct from efficiently CXCR4-utilizing dualtropic Envs from the same patient. Dual-R Envs had a decreased or lack of ability to induce syncytia in MT2 cells. Infection of U87.CD4.CCR5 or U87.CD4.CXCR4 cells by dual-tropic psuedoviruses could be inhibited by CCR5 or CXCR4 inhibitors, respectively. Infection of U87.CD4.CCR5.CXCR4 cells and PBMCs by dual-R clones was blocked by a CCR5 inhibitor, but not a CXCR4 inhibitor. Conversely, infection mediated by dual-Envs that exhibited efficient use of CXCR4 but not CCR5 was blocked by a CXCR4 inhibitor, not a CCR5 inhibitor. Dual- Envs that efficiently utilized both CCR5 and CXCR4 were not inhibited well by either CCR5- or CXCR4-inhibitors in a single-cycle assay on U87.CD4.CXCR4.CCR5 cells, or multiple-cycle infection in PBMCs. |
| 103 | IMPACT OF HR1 ENFUVIRTIDE RESISTANCE MUTATIONS ON SENSITIVITY TO HR2-DIRECTED NEUTRALIZING ANTIBODIES Antivir Ther. 2007, 12:S114 (abstract no. 103) AP Barry, SA Stanfield-Oakley, SM Mosier and ML Greenberg In most cases examined, ENF HR1- resistance mutations led to increased sensitivity to neutralizing antibodies consistent with an impact of these mutations on the structure and/or lifetime of fusion intermediates critical to viral entry. The effects on neutralization sensitivity were often background dependent (as seen with ENF resistance), highlighting the importance of genetic background. The increased sensitivity to neutralizing antibodies may have implications for viral fitness of ENF-resistant viruses. |
| 104 | SPECIFIC T-20-SELECTED MUTATIONAL PATHWAYS IN HIV-1 GP41 ARE SIGNIFICANTLY CORRELATED WITH A GAIN OF CD4+ T-CELL COUNT DESPITE VIROLOGICAL FAILURE Antivir Ther. 2007, 12:S115 (abstract no. 104) V Svicher1, S Aquaro1,2, R D’Arrigo3, F Ceccherini-Silberstein1, G Di Perri4, S Lo Caputo5, R Bellagamba3, U Visco-Comandini3, A Antinori3, P Narciso3 and CF Perno1,3 T-20 is the driver of a revolutionary concept in anti-HIV therapy by favouring the appearance of mutational patterns able to decrease HIV-1 cytopathic effect and/or enhance immune response. The mechanism( s) of action seem to be related to viral or cellular functions not strictly associated to virus replicative cycle, and thus without any significant effect upon viral load. |
| 105 | EXPLORING PLASMA-VIRUS-DERIVED GAG–PROTEASE INTERRELATIONSHIPS IN DRUG RESISTANCE AND FITNESS LANDSCAPE Antivir Ther. 2007, 12:S116 (abstract no. 105) A Kohli1, C Parry1,2 and D Pillay1,2 We confirm that gag mutations coexisting with protease mutations enhance PI resistance. We show that the persistence of these gag mutations in absence of drug pressure is highly dependant on coexpression with the corresponding protease. The linkage of MA mutations with those in the C-terminal portion of gag and in protease, suggest that the fitness landscape of a multiply mutated protease should be considered in the context of the full-length gag protein. |
| 106 | COMPENSATION OF RESISTANCE-ASSOCIATED LOSS OF REPLICATIVE CAPACITY BY GAG IS RESTRICTED TO THE NC-P1-P6 DOMAINS Antivir Ther. 2007, 12:S117 (abstract no. 106) E Dam1,2,3, JL Faudon1, O Launay4, X Duval5, D Costagliola6, D Descamps7 and F Clavel3 During evolution of resistance, the changes in Gag that compensate for resistance-associated loss of RC are restricted to the NC-p1-p6 region, emphasizing that PR cleavage events in this region are rate-limiting. Interestingly, changes in Gag not only affect RC, but also strongly contribute to resistance. |
| 107 | INTERPRETATION OF DRUG-SUSCEPTIBILITY AND REPLICATIONCAPACITY RESULTS FROM SUBTYPE C HIV-1 PROTEASE/RT IS NOT INFLUENCED BY THE SUBTYPE OF THE RESISTANCE TEST VECTOR Antivir Ther. 2007, 12:S118 (abstract no. 107) SS Choe, E Stawiski, and NT Parkin Subtype C patient-derived PR/RT drug susceptibility measurements are not significantly affected by testing in a subtype B versus subtype C RTV. The lower RC values observed for subtype C samples does not appear to be a result of mismatched (subtype B) gag and pol sequences. Our data suggest that subtype C PR/RT sequences have an inherently reduced RC. |
| 108 | ANTIRETROVIRAL RESISTANCE AND NEUROPSYCHOLOGICAL PERFORMANCE AMONG HIV-INFECTED INDIVIDUALS Antivir Ther. 2007, 12:S119 (abstract no. 108) GK Hightower1, SL Letendre1, ER Cachay1, M Cherner1, S Gibson1, R Ellis1, DD Richman1,2, CC Ignacio1 and DM Smith1,2 These data indicate that HIV DR may have a protective effect on NP. Since these findings were also demonstrated among those with primary drug resistance, the effect is most likely independent of antiretroviral use. One potential mechanism of this effect is that drug-sensitive or wild-type virus may have an increased replication capacity leading to greater neuroinflammation, generation of neurotoxins and brain injury than DR virus. Although these retrospective investigations were nested in a well characterized cohort and were appropriately controlled, the study cohort was relatively small and the observations will need to be validated in larger prospective studies. |
| 109 | CHARACTERIZATION OF THE Q151M AND V111I MUTATIONS OF HIV-2 REVERSE TRANSCRIPTASE Antivir Ther. 2007, 12:S122 (abstract no. 109) M Bennett1, M Detorio1, J Lennerstrand1, F Brun-Vézinet2, D Descamps2 and RF Schinazi1 The 151M mutation alone resulted in high resistance to a large number of NRTI in HIV-2 above and beyond those found for HIV-1. These findings demonstrate for the first time that the Q151M mutation alone is sufficient to confer HIV-2 multidrug resistance in RT assays and in cell culture. |
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Session 6: Mechanisms of drug resistance Abstracts 110 thru 133, Pages S123 to S146 |
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| 110 | COMPETITION WITH THE NUCLEIC ACID SUBSTRATE CAN PRESENT AN OBSTACLE IN THE DEVELOPMENT OF RNASE H ACTIVE SITE INHIBITORS Antivir Ther. 2007, 12:S123 (abstract no. 110) G Beilhartz1, E Tchesnokov1, A Bermingham2, B O’Keefe2, J Beutler2, S LeGrice2 and M Götte1 Our findings point to intrinsic biochemical problems in the development of RNase H active site inhibitors. The data suggest that the competition with the nucleic acid substrate is difficult to overcome with small molecules that bind in close proximity to the metal binding sites of the RNase H active site. The incoming primer/template can displace the bound tropolone, because most contacts between HIV-1 RT and its nucleic acid substrate involve the polymerase domain of the enzyme. VU447 is a prototype compound that appears to be able to bypass this problem. These findings point to an allosteric mechanism of action. |
| 111 | HIV-1 REVERSE TRANSCRIPTASE MUTATIONS A371V AND Q509L DECREASE DNA-DEPENDENT RNASE H CLEAVAGE AND INCREASE THE RATE OF AZT-MP EXCISION Antivir Ther. 2007, 12:S124 (abstract no. 111) J Brehm, D Koontz, N Sluis-Cremer and J Mellors These results show that mutations in the connection and RNase H domains of RT can delay the degradation of RNA template and increase the efficiency of AZT-MP excision. |
| 112 | PROBING THE MECHANISM BY WHICH CONNECTION DOMAIN MUTATIONS ENHANCE AZT RESISTANCE: MUTATIONAL ANALYSIS OF THE RNASE H PRIMER GRIP Antivir Ther. 2007, 12:S125 (abstract no. 112) KA Delviks-Frankenberry, GN Nikolenko, R Barr and VK Pathak These results demonstrate that mutations in the RNase H primer grip region can significantly enhance AZT resistance, and support the hypothesis that mutations in the connection and RNase H domains can increase resistance by altering the RNase H primer grip region, changing interactions between RT and the template- primer complex, and/or shifting the balance between the polymerase and RNase H activities. |
| 113 | SILENT MUTATIONS AT RT CODONS 65 AND 66 ARE VERY STRONGLY ASSOCIATED WITH TREATMENT AND DRUG RESISTANCE AND ARE IMPLICATED IN REVERSE TRANSCRIPTION EFFICIENCY Antivir Ther. 2007, 12:S126 (abstract no. 113) PR Harrigan1, T Chihwei Sheen2, B Wynhoven1, P Lecocq3, G Tachedjian4 and N Sluis-Cremer2 The data provide the first evidence for an RNA-level mechanism of direct relevance to drug resistance. Silent mutations at K65 and/or K66 are selected as strongly as TAMS; it is actually unusual to have a D67N mutation in the absence of a concomitant silent mutation at codons 65 and/or 66. |
| 114 | IN VITRO MOLECULAR CHARACTERIZATION OF THE DEVELOPMENT OF THE K65R AND M184V MUTATIONS IN SUBTYPE C HIV-1 Antivir Ther. 2007, 12:S127 (abstract no. 114) D Coutsinos, CF Invernizzi, H Xu, BG Brenner and MA Wainberg The more rapid emergence of K65R in subtype C RT appears to be based on the pol gene coding sequence. In contrast, the emergence of M184V is not favoured by the pol gene coding sequence. |
| 115 | FOSCARNET SELECTS FOR A D113V MUTATION WITHIN THE Q151M CLUSTER THAT SUPPRESSES ZIDOVUDINE RESISTANCE Antivir Ther. 2007, 12:S128 (abstract no. 115) K Van Laethem1,2, C Pannecouque1, B Scarth3, M Götte3 and A-M Vandamme1 The results of this study show that mutations conferring decreased susceptibility to foscarnet can reverse resistance to zidovudine in the context of the Q151M complex. Thus, zidovudine resensitization effects are not restricted to mutational patterns that are associated with the excision reaction. Biochemical studies are underway to elucidate how the D113V mutation may affect nucleotide binding and incorporation, and the excision reaction. Given its strategic position in the RT structure, changes at this residue will likely affect both the forward and the reverse reaction. |
| 116 | FOSCARNET SALVAGE THERAPY EFFICACY IS ASSOCIATED WITH THE PRESENCE OF THYMIDINE-ASSOCIATED MUTATIONS (TAMS) IN HIV-INFECTED PATIENTS Antivir Ther. 2007, 12:S129 (abstract no. 116) C Charpentier1, D Laureillard2, A Si-Mohamed1, M Karmochkine2, L Bélec1, L Weiss1 and C Piketty1 These findings are the first to suggest that the virological response to foscarnet, used as salvage therapy in multi class experienced patients, may differ according to the number of TAMs present in RT gene. The use of zidovudine, in combination with foscarnet, for HIV patients infected with viruses harbouring three or more TAMs at baseline appears to predict optimal response to foscarnet salvage therapy. |
| 117 | THE COMBINATION OF ZIDOVUDINE AND AMDOXOVIR PREVENTS THE SELECTION OF THYMIDINE ANALOGUE MUTATIONS IN PRIMARY HUMAN LYMPHOCYTES Antivir Ther. 2007, 12:S130 (abstract no. 117) KL Rapp, M Ruckstuhl and RF Schinazi The combination of ZDV and DAPD suppressed the appearance of clinically relevant mutations while the combination of the two dioxolane nucleosides D-FDOC and DAPD enhanced the appearance of the K65R mutation. Based on these results, a combined modality of ZDV and DAPD is currently being evaluated in HIV-infected persons. We also found that growing viruses with drugs that select for the same mutation is contraindicated since resistant virus emerges faster. |
| 118 | REPLICATION CAPACITY AND RELATIVE FITNESS OF ABACAVIRRESISTANT HIV MUTANTS Antivir Ther. 2007, 12:S131 (abstract no. 118) Z Hu1, R Lanier2 and DR Kuritzkes1 The 74V mutation impaired viral growth more than any other single mutant tested, but in the presence of ABC conferred a greater resistance and fitness than TAM-1 mutations. These findings help explain why ABC selects for 74V rather than TAMs in the absence of ZDV and for 74V rather than 65R in the absence of tenofovir. |
| 119 | A NOVEL IN VITRO SYSTEM FOR COMPARATIVE PROTEASE INHIBITORS (PI) SUSCEPTIBILITY PHENOTYPING USING PROTEASE, GAG AND PROTEASE/GAG SEQUENCES FROM CLINICAL ISOLATES Antivir Ther. 2007, 12:S132 (abstract no. 119) AN Martins1, PA Brindeiro2, CM Abreu1, MB Arruda1, A Tanuri1 and RM Brindeiro1 The phenotyping matrix system developed was capable of distinguishing different PI-susceptibility behaviours of proteases from clinical isolates when they were coexpressed with their co-evoluted p6Gag. The specific results herein found during the proof-of-concept suggest an antagonic effect of p6 late-domain duplications and the resistance mutation profiles on proteases, related to phenotypic resistance to PI. |
| 120 | EFAVIRENZ ALTERS THE INTERACTION BETWEEN HIV-1 REVERSE TRANSCRIPTASE AND TEMPLATE/PRIMER Antivir Ther. 2007, 12:S133 (abstract no. 120) J Radzio, C-W Sheen and N Sluis-Cremer When EFV was added to the energy transfer experiments, E decreased to 0.68 from residue 449 and increased to 0.77 from residue 560. These data provide direct evidence that EFV binding to the RTs alters the precise positioning of the T/P in the DNA binding tract of RT, and we hypothesize that these changes significantly contribute to the mechanism by which EFV inhibits both nucleotide incorporation and AZT excision. |
| 121 | MUTATIONS IN THE CORECEPTOR BINDING REGION OF THE HIV-1 ENVELOPE CONFER RESISTANCE TO THE CCR5 INHIBITOR SCH-C (SCH 351125) Antivir Ther. 2007, 12:S134 (abstract no. 121) W Huang1, L Wojcik2, J Toma1, S Fransen1, N Parkin1, J Whitcomb1, J Strizki2 and C Petropoulos1 Mutations in the coreceptor-binding region conferred resistance to SCH-C, indicating that these residues may play a critical role in envelope/CCR5 interactions and in determination of resistance to CCR5 antagonists. Accumulated mutations in multiple domains of envelope outside of V3 were required for high-level resistance to SCH-C, suggesting that CCR5 antagonist-resistant variants can evolve using different pathways in addition to those involving primarily mutations in V3 loop. |
| 122 | HIV-1 ISOLATES RESISTANT TO CCR5 ANTAGONISTS DEMONSTRATE INCREASED AFFINITY FOR THE DRUG-BOUND CORECEPTOR Antivir Ther. 2007, 12:S135 (abstract no. 122) PJ Buontempo, L Wojcik, C Buontempo, J Strizki and R Ralston Measurement of HIV infection by flow cytometry was sensitive and reproducible. Analysis of the virus inhibitor dose response data provided estimates of the underlying affinity and cooperativity constants and allowed quantitative comparisons between viruses and inhibitors. Viral susceptibility to CCR5 entry inhibitors was associated with decreased affinity for the coreceptor in the presence of the compound. |
| 123 | STRUCTURAL ANALYSIS OF THE FUSION INHIBITOR TRI-1144 IN COMPLEX WITH AN HR1 CONTAINING THE ENFUVIRTIDE RESISTANCE MUTATION N43D SUGGESTS A MECHANISM FOR ACTIVITY AGAINST FI-RESISTANT VIRUS Antivir Ther. 2007, 12:S136 (abstract no. 123) X Bai1, KL Wilson1, DK Davison1, R Medinas1, SA Freel1, L Jin1, SA Stanfield-Oakley1, Z Wang2, ML Greenberg1 and JJ Dwyer1 We have determined the structure of TRI-1144 in complex with a wild-type HR1 and an HR1 containing the ENF-resistance mutation N43D. We show that the inhibitory action of TRI-1144 is likely analogous to that of ENF and other HR2 fusion inhibitors. In addition to the higher binding affinity of TRI-1144, it is apparent that the helix-promoting motifs may also be ameliorating the structural impact of the N43D resistance mutation. |
| 124 | LOW GENETIC BARRIER TO NUCLEOSIDE ANALOGUE RESISTANCE IN HIV-2 Antivir Ther. 2007, 12:S137 (abstract no. 124) RA Smith, DJ Anderson, CL Pyrak, NB Kiviat, GS Gottlieb and BD Preston These data show that equivalent mutations in HIV-1 and HIV-2 RT can have differing effects on substrate analogue susceptibility. Importantly, as few as two amino acid replacements in HIV-2 are sufficient for robust dual resistance to AZT+3TC. This finding raises the possibility that many HIV-2-infected patients will experience rapid drug failure and poor responsiveness to salvage therapy. |
| 125 | CIRCUMVENTING DRUG RESISTANCE: USING THE SUBSTRATE ENVELOPE HYPOTHESIS TO DEVELOP ROBUST NOVEL HIV-1 PROTEASE INHIBITORS Antivir Ther. 2007, 12:S138 (abstract no. 125) MNL Nalam1, A Ali1, K Reddy1, M Altman2, S Chellappan3, R Bandaranayake1, SG Anjum1, TM Rana1, MK Gilson3, B Tidor2 and CA Schiffer1 This design effort of novel HIV-1 protease inhibitor validates the substrate envelope hypothesis that it is possible to avoid susceptibility to drug-resistant variants by designing inhibitors to fit within the substrate recognition region of the active site. |
| 126 | CRYSTAL STRUCTURE OF LYSINE SULPHONAMIDE INHIBITOR REVEALS THE DISPLACEMENT OF THE CONSERVED FLAP WATER MOLECULE IN HIV-1 PROTEASE Antivir Ther. 2007, 12:S139 (abstract no. 126) MNL Nalam1, R Bandaranayake1, A Peeters2, THM Jonckers2, I Dierynck2 and CA Schiffer1 The crystal structure of a lysine sulphonamide inhibitor in complex with HIV-1 protease demonstrates that although there has been extensive investigation of competitive inhibitors of HIV-1 protease there still remain novel manners by which the active site of the enzyme may be filled, thereby avoiding cross-resistance with other more similar HIV-1 PIs. |
| 127 | A NOVEL GENETIC PATHWAY INVOLVING L76V AND M46I LEADING TO LOPINAVIR/R RESISTANCE Antivir Ther. 2007, 12:S140 (abstract no. 127) M Nijhuis1, AMJ Wensing1,2, W Bierman3, D de Jong1, WJM van Rooyen1, R Kagan4, C Jaspers2, K Schurink2, L Lu5, T Pilot-Matias5, A Molla5, MA van Agtmael3 and CAB Boucher1 Failure to respond to lopinavir in naïve patients can occur through a novel genetic pathway involving L76V+M46I. The role of the other associated mutations needs to be investigated. Further research is warranted to identify which factors favour this pathway. |
| 128 | UNRAVELLING THE COMPLEX RESISTANCE PATHWAYS OF DARUNAVIR USING BIOINFORMATICS RESISTANCE DETERMINATION (BIRD) Antivir Ther. 2007, 12:S141 (abstract no. 128) H Van Marck1, I Dierynck1, G Kraus1, S Hallenberger1, T Pattery2, G Muyldermans2, H Van Vlijmen1, K Hertogs1 and M-P de Béthune1 The BIRD approach allowed for the analysis of the impact of individual PI-RAMS in a background of multiple PI-RAMs on the in vitro susceptibility of HIV-1 to darunavir and confirmed the importance of the darunavir-RAMs V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, and I84V (V11I and L89V were not assessed in this study). Interplays between V32I-I84V and L10F-I50V-A71V were revealed in the darunavir resistance pathways. |
| 129 | CLINICALLY RELEVANT RESENSITIZATION OF PROTEASE INHIBITORS (PIS) SAQUINAVIR AND ATAZANAVIR (ATV) BY L76V MUTATION IN MULTIDRUG-RESISTANT HIV-1-INFECTED PATIENTS Antivir Ther. 2007, 12:S142 (abstract no. 129) P Braun1, H Walter2, D Hoffmann3, M Däumer4, R Ehret1, K Korn1, B Thiele5, T Berg6, M Stürmer7, F Wiesmann1 and R Kaiser4 L76V was detected under LPV-, (f)APV- and DRV-containing regimens. ATV- and SQV containing regimens were more successful than others when L76V was present. This can be explained by the modelling experiments. It seems to be advantageous to keep selective pressure by LPV or APV upon the L76V. |
| 130 | INTERFERENCE BETWEEN GAG NON-CLEAVAGE SITE MUTATION P453L AND HIV-1 PROTEASE NON-DRUG RESISTANCE MUTATION E35D Antivir Ther. 2007, 12:S143 (abstract no. 130) J Shibata1,2, F Ren1, M Nishizawa2, M Fujno2, Y Iwatani2, M Matsuda2, H Miura2, H Tanaka1 and W Sugiura2 The viral growth advantage of the combined mutations, Gag P453L and protease E35D, initially determined by bioinformatic analysis, was confirmed by in vitro growth kinetic assay. Our finding indicates the importance of non-cleavage and non-drug resistance mutations in acquiring and selecting for drug-resistant viruses. |
| 131 | SIGNATURE SUBSTRATE MUTATIONS ASSOCIATED WITH HIV-1 PROTEASE INHIBITOR RESISTANCE Antivir Ther. 2007, 12:S144 (abstract no. 131) M Kolli1, E Stawiski2, C Chappey2, N Parkin2 and CA Schiffer1 Drug resistance in HIV-1 protease is frequently associated with cleavage site mutations. Often particular protease mutations have unique signature substrate mutations. The extent to which these cleavage site mutations impact both protease activity and viral fitness is not fully known. Further experimentation along these lines will provide new insights into the mechanisms of drug resistance. |
| 132 | INCREASE OF CLEAVAGE SITE MUTATIONS IN THE GERMAN HIV-1 SEROCONVERTER STUDY OVER TIME Antivir Ther. 2007, 12:S145 (abstract no. 132) J Verheyen1, O Hamouda2, S Somogy2, U Schuldenzucker3, G Poggensee2, E Litau1, H Pfister1, D Hoffmann4, R Kaiser1 and C Kücherer2 Therapy-associated CS mutations in therapy-naïve viruses are most frequent in viruses with major PR mutations. However, frequencies of these mutations rose after 2000 in drug-sensitive viruses coinciding with the widespread use of PIs in antiretroviral therapy. The maintenance of CS mutations 436R and 437V in absent of major PR mutations may be due to compensatory fixation within gag and potentially decrease the genetic barrier of first-line PI therapies. |
| 133 | CHANGES IN HIV GAG AND PROTEASE CANNOT EXPLAIN PERSISTENT VIRAEMIA IN THE MAJORITY OF PATIENTS FAILING FIRST-LINE LOPINAVIR/RITONAVIR THERAPY Antivir Ther. 2007, 12:S146 (abstract no. 133) M Nijhuis1, P Schipper1, M King2, B Bernstein2, G Hanna2 and CAB Boucher1 Persistent viraemia in these eight patients cannot be explained by mutations in HIV Gag with only one subject developing low-level lopinavir resistance. The potential role of Gag mutations in lopinavir treatment failure requires further investigation. |
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Session 7: New resistance technologies and interpretations Abstracts 134 thru 159, Pages S149 to S174 |
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| 134 | PREVALENCE OF LOW ABUNDANT DRUG-RESISTANT VARIANTS BY ULTRA-DEEP SEQUENCING IN CHRONICALLY HIV-INFECTED ANTIRETROVIRAL (ARV)-NAÏVE PATIENTS AND THE IMPACT ON VIROLOGICAL OUTCOMES Antivir Ther. 2007, 12:S150 (abstract no. 134) BB Simen1, K Huppler Hullsiek2, RM Novak3, RD MacArthur4, JD Baxter5, C Huang1, C Lubeski1, GS Turenchalk1, MS Braverman1, B Desany1, JF Simons1, JM Rothberg1, M Egholm1 and MJ Kozal6 Ultra-deep sequencing identified a significantly larger proportion of chronically infected ARV-naïve patients harbouring drug-resistant variants than standard resistance genotyping. For those who initiated ART within the NNRTI arm of FIRST, the risk of virological failure was significantly greater for participants with low abundant NNRTI-resistant variants identified by ultra-deep sequencing than for those without NNRTI resistance identified. |
| 135 | COMPARISON OF TRADITIONAL PLASMID-BASED CLONAL SEQUENCING TO 454 ULTRA-DEEP SEQUENCING FOR HIV CLINICAL ISOLATES WITH REVERSE TRANSCRIPTASE (RT) MUTATIONS AT K65R AND L74V Antivir Ther. 2007, 12:S150 (abstract no. 135) R Lanier1, A Moffatt2, C Stone3, D Irlbeck1, E Rouse1, J Horton1, L Ross1, L Du4, B Taillon4, M Egholm4 and C Craig3 These results suggest that 454-sequencing yields similar data to clonal analysis, but provides additional depth; linkage information is currently limited to shorter regions with 454. Both methods revealed low levels of K65R at baseline and L74V at Week 12, but 454 was able to detect L74V at baseline, K65R at week 24, and K65R+L74V on the same clones post-baseline. |
| 136 | ULTRA-DEEP PYROSEQUENCING OF MINORITY VARIANTS IN PLASMA SAMPLES FROM ARV-TREATED PERSONS AND FROM UNTREATED PERSONS WITH T215 REVERTANTS Antivir Ther 2007, 12:S151 (abstract no. 136) Y Mitsuya1, C Wang1, P Jayakumar1, B Gharizadeh2, M Ronaghi2 and RW Shafer1 With appropriate analysis, UDPS is a reliable method for characterizing genetic diversity and detecting minor DRMs in plasma HIV-1 samples. The absence of T215Y/F in samples containing T215 revertants suggests that these variants may be out-competed once a more fit revertant emerges. |
| 137 | DNA BAR CODING AND PYROPHOSPHATE SEQUENCING REVEALS RARE HIV DRUG RESISTANCE MUTATIONS OF POTENTIAL CLINICAL SIGNIFICANCE Antivir Ther 2007, 12:S152 (abstract no. 137) C Hoffmann1, N Minkah1, J Leipzig1, GP Wang1,2, P Tebas2 and FD Bushman1 Methods for sensitive characterization of HIV resistance alleles have been reported previously, but only the method reported here has the ability to determine the sequence of the full genomic region at risk for resistance mutations for multiple HIV populations in a single experiment. The DNA bar coding method should allow substantial reductions in the cost per genotype, since many samples can be analysed in parallel – in other studies, we have used as many as 42 bar codes in a single sequencing run. |
| 138 | REAL-TIME PCR TESTING ALLOWS FOR SENSITIVE DRUG RESISTANCE SCREENING AND MUTATION LINKING IN HIV-1 Antivir Ther. 2007, 12:S153 (abstract no. 138) JA Johnson, J Lipscomb, J-F Li, X Wei and W Heneine We demonstrate that direct sequencing of mutation-specific amplicons following real-time PCR testing provided a simple strategy to further identify and link both high- and low-frequency mutations. Combining sensitive screening with mutation-specific linking can be a powerful and easy approach for studying the dynamics and clinical consequences of drug resistance mutations in HIV-1. |
| 139 | DETECTION LIMIT OF X4 MINORITY VIRUS IN ABUNDANT R5-TROPIC VIRUS POPULATIONS IN STANDARD GENOTYPIC AND PHENOTYPIC ASSAYS Antivir Ther. 2007, 12:S154 (abstract no. 139) I Vandenbroucke, V Van Eygen, E Rondelez, K Van Baelen and LJ Stuyver The detection of the minority X4 variant was possible in the majority of test conditions. As theoretically anticipated, the success rate decreased with decreasing viral loads and minority template input. It might be unrealistic to expect detection of minority variants below 1% at 5 log IU/ml, with decreasing chance of success at even lower viral load. Establishing cut-offs for X4 minority species will be multifactorial (input volumes, VL, detection limits, PCR drift and resampling issues). |
| 140 | NOVEL ANTI-HIV-1 SCREENING SYSTEM BASED ON INTACT RECOMBINANT VIRUSES EXPRESSING SYNTHETIC FIREFLY AND RENILLA LUMINESCENT PROTEINS Antivir Ther. 2007, 12:S155 (abstract no. 140) J Weber and ME Quiñones-Mateu We have developed an antiretroviral drug screening method based in dual infections with X4 and R5 viruses expressing different luminescent proteins. This assay allows the simultaneous detection of compounds interacting with both HIV-1 coreceptors. More important, this screening design does not require a prior knowledge of all anti-HIV targets, providing an exciting opportunity to identify HIV inhibitors directed against known and novel proteins, of both viral and cellular origin. |
| 141 | NOVEL ELECTROPHORETIC-TAG-BASED IN VITRO ASSAY TO QUANTIFY DIMERIZATION OF P66 AND P51 SUBUNITS OF HIV-1 REVERSE TRANSCRIPTASE (RT) Antivir Ther. 2007, 12:S156 (abstract no. 141) S Gupta, R Dua, P Nhonthachit, S Fransen, D McCann, CJ Petropoulos, NT Parkin and W Huang The eTag-based dimerization assay is a useful tool for screening potential dimerization inhibitors of RT and for furthering our understanding of the effect of connection domain mutations on RT dimerization. |
| 142 | DEVELOPMENT OF A DNA MICROARRAY TO DETECT MUTATIONS ASSOCIATED WITH HIV-1 INTEGRASE INHIBITOR RESISTANCE AND SITES CRITICAL FOR LEDGF/p75 BINDING Antivir Ther. 2007, 12:S158 (abstract no. 142) M Lataillade, J Chiarella and MJ Kozal DNA microarrays are a promising technology that can survey large regions of PR, RT and IN for resistance mutations, and aa positions critical for LEDGF/p75 binding and integration. The highly conserved nature of the LEDGF/p75 binding sites signifies the importance of these positions for interaction between the host protein LEDGF/p75 and IN. |
| 143 | HIGH CONCORDANCE BETWEEN HIV-1 DRUG RESISTANCE GENOTYPES GENERATED FROM PLASMA AND DRIED BLOOD SPOTS IN ANTIRETROVIRAL-EXPERIENCED PATIENTS Antivir Ther. 2007, 12:S158 (abstract no. 143) S Masciotra1, C Garrido2, AS Youngpairoj1, A McNulty1, N Zahonero2, A Corral2, W Heneine1, C de Mendoza2 and JG García-Lerma1 We demonstrate a high concordance between resistance genotypes from plasma and DBS. We also show that resistance testing from DBS can achieve sensitive levels similar to those seen using plasma. Our results indicate that DBS may represent a feasible alternative to plasma for drug resistance testing in treated persons. This specimen type may be particularly useful for resistance surveillance in resource-limited settings where the use of antiretroviral drugs continues to increase. |
| 144 | FACTORS DETERMINING EFFICACY OF HIV-1 DRUG RESISTANCE GENOTYPING FROM DRIED BLOOD SPOTS WITHIN AN INTERNALLY-CONTROLLED ASSAY SYSTEM Antivir Ther. 2007, 12:S159 (abstract no. 144) AJ Buckton1, SL Bissett1, RE Myers1, S Beddows1 and D Pillay1,2 Expanding access to antiretroviral therapy, particularly in the developing world, necessitates the development of robust laboratory testing procedures to monitor drug resistance, using DBS testing. A number of different DBS methodologies have recently been developed for HIV drug resistance genotyping. A consensus as to optimal collection matrices, nucleic acid extraction techniques and amplification strategies is required. These studies provide further insight into the most appropriate molecular testing procedures for HIV DBS drug resistance genotyping and highlight the importance of filter paper selection and extraction method. |
| 145 | PERFORMANCE OF A POPULATION-BASED HIV-1 TROPISM PHENOTYPIC ASSAY AND CORRELATION WITH V3 GENOTYPIC PREDICTION TOOLS IN RECENT HIV-1 SEROCONVERTERS Antivir Ther. 2007, 12:S160 (abstract no. 145) C de Mendoza1, K Van Baelen2, E Poveda1, E Rondelez2, N Zahonero1, L Stuyver2, C Garrido1, J Villacian2 and V Soriano1, on behalf of the Spanish HIV Seroconverter Study Group A significant proportion (16.4%) of recent HIV-1 seroconverters harbours X4 or X4R5 viruses. Drug resistance mutations do not seem to influence coreceptor usage. Concordance of genotypic and phenotypic tools for HIV tropism assessment is relatively good (>80%), although SVM is the most accurate tool. This information is relevant for the selection of candidates to receive CCR5 antagonists in places where phenotypic tropism assays may not be feasible. |
| 146 | EVALUATION OF SEVEN DIFFERENT BIOINFORMATIC TOOLS TO PREDICT HIV-1 TROPISM IN NON-B SUBTYPES AND CONCORDANCE WITH A PHENOTYPIC ASSAY Antivir Ther. 2007, 12:S161 (abstract no. 146) C Garrido1, V Roulet2,3, N Chueca4, N Zahonero1, A Aguilera5, K Skrabal2,3, E Poveda1, S Carlos4, F García4, JL Faudon2, C de Mendoza1 and Vi Soriano1 Most genotypic tools predict quite well coreceptor usage in HIV-1 non-B subtypes, although overall results tend to be better in subtype B. |
| 147 | A SENSITIVE ASSAY FOR THE DETERMINATION OF VIRAL TROPISM SUITABLE FOR CLINICAL MANAGEMENT OF HIV SUBTYPE B AND NON-B INFECTED INDIVIDUALS TREATED WITH CORECEPTOR ANTAGONISTS: PHENOSCRIPT® ENV Antivir Ther. 2007, 12:S162 (abstract no. 147) V Roulet1,2,3, J-L Faudon1, S Rochas1,2, J-L Labernardière2,3, F Mammano3, S Lebel-Binay2 and K Skrabal1,2 Given the efficiency of PHENOSCRIPT® ENV, our assay is suitable for the clinical management (selection and follow-up) of HIV-infected individuals treated with coreceptor antagonists. It can be used to assign tropism of viral populations across diverse viral subtypes. |
| 148 | IMPROVED HIV-1 CORECEPTOR USAGE PREDICTION USING INDEXED BLAST-BASED LOCAL SMOOTHING KERNEL METHODS, RULES AND DECISION TREES WITH GRID MULTIPLE STATISTICAL VALIDATION Antivir Ther. 2007, 12:S163 (abstract no. 148) I Fanti1, A De Luca2, M Zazzi3, G Ulivi1, A Micarelli1 and MCF Prosperi1 BLAST-LSK on V3 alone provided a simple model which performed significantly better or equal compared to more complex state-of-the-art models. RBs and DTs gave powerful and interpretable tools improving also performances. Multiple k-fold-cross-validation – made possible through grid computing – allowed robust methodology comparisons. |
| 149 | CURRENT IMPLEMENTATIONS OF HIV GENOTYPING ALGORITHMS ARE INADEQUATE FOR THE PREDICTION OF X4 CORECEPTOR USAGE IN CLINICAL ISOLATES FROM POPULATION-BASED V3 SEQUENCES: APPROACHES TO IMPROVEMENT Antivir Ther. 2007, 12:S164 (abstract no. 149) A Low1, D Chan1, W Dong1, T Sing2, R Swanstrom3, M Jensen4, S Pillai5, B Good6, V Dias Lima1 and PR Harrigan1 Current default implementations of coreceptor prediction algorithms are not yet adequate for predicting HIV X4 coreceptor phenotype in clinical samples, particularly those X4 phenotypes with low CXCR4 RLU signals. Significant improvements can be made to genotypic predictors, including training on clinical samples, using clinical data to improve predictions, optimizing cutoffs and/or a quantitatively assessing of genotype signal strength to improve detection of minority species. |
| 150 | PREDICTION OF PHENOTYPIC SUSCEPTIBILITY TO THE THREE MAJOR HIV DRUG CLASSES FROM PHYSIOCHEMICAL PROPERTIES OF THE PRIMARY ENZYMATIC STRUCTURE USING ARTIFICIAL NEURAL NETWORKS (ANNS) Antivir Ther. 2007, 12:S165 (abstract no. 150) J Kjær1,2, L Høj2, Z Fox1 and JD Lundgren1 Based on the physiochemical properties of the PR and RT amino acid sequences, ANNs predict the phenotypic susceptibility to drugs inhibiting these viral enzymes to an extent comparable to that obtained from routine phenotypic susceptibility testing. An advantage of this approach is that the ANNs can interpolate between the various physiochemical properties it was trained on, and hence do not require updating to predict susceptibility from novel mutational patterns. |
| 151 | MARKOV MODELS OF VIRAL EVOLUTION TRAINED ON CLINICAL PATIENT DATA Antivir Ther. 2007, 12:S166 (abstract no. 151) RK Belew1, DJ Looney2 and JK Wong3 Patient treatment history and virological data can improve predictions of underlying viral genotype. A methodology is presented that will allow the precision of similar models to improve as increased volumes of data become available. |
| 152 | DEVELOPMENT OF COMPUTATIONAL MODELS FOR PREDICTION OF VIROLOGICAL RESPONSE IN A PROSPECTIVE CLINICAL STUDY Antivir Ther. 2007, 12:S167 (abstract no. 152) BA Larder1, D Wang1, A Revell1, J Montaner2, R Harrigan2, S Wegner3 and HC Lane4 These results suggest that the combination of outputs from different modelling methods may provide the most accurate predictions of virological response. The accuracy of the predictions for the new drugs was particularly encouraging. These models are now being used in combination in an international, multicentre clinical trial of the RDI system. |
| 153 | REPRESENTING COMPLEX REGIMEN DATA IN THE CNICS (CFAR NETWORK OF INTEGRATED CLINICAL SYSTEMS) COHORT Antivir Ther. 2007, 12:S168 (abstract no. 153) SDW Frost1, C Mathews1, M Saag2, M Kitahata3, B Rodriguez4, J Kahn5, S Boswell6, WB Lober3, M Lederman4, S Sun1, AFY Poon1, S Jain1, RH Haubrich1 and the CNICS Study Team The large number of possible combinations of antiviral agents makes treating each regimen individually infeasible, yet lumping regimens into a small number of classes defined a priori may risk losing information. Our approach of representing regimens as trees avoids information loss, can help to identify clusters of regimens and temporal trends in extremely large observational databases, and can be used as input for methods of predicting virological response on therapy. |
| 154 | INFERRING VIROLOGICAL RESPONSE FROM GENOTYPE: WITH OR WITHOUT PREDICTED PHENOTYPES? Antivir Ther. 2007, 12:S169 (abstract no. 154) A Altmann1, T Sing1, H Vermeiren2, B Winters2, E Van Craenenbroeck2, Koen Van der Borght2, SY Rhee3, RW Shafer3, E Schülter4, R Kaiser4, Y Peres5, A Sonnerborg6, W Jeffrey Fessel7, F Incardona8, M Zazzi9, L Bacheler10, H Van Vlijmen2 and T Lengauer1 Traditional summation scoring of treatment regimens can be improved. Predicted phenotypes as inputs were among the most sensitive non-hybrid approaches, while being easiest to interpret (a single number per drug). Combining information on genotype and predicted phenotype into hybrid approaches can improve predictive performance, as compared to purely genotype- or phenotype-based approaches. |
| 155 | ASSESSMENT OF THE PERFORMANCE OF THE virco®TYPE SYSTEM IN AN INDEPENDENT CLINICAL DATASET Antivir Ther. 2007, 12:S170 (abstract no. 155) B Winters1, J Montaner2, PR Harrigan2, B Gazzard3, A Pozniak3, K Van Der Borght1, J Villacian1 and L Bacheler4 The results confirm, in an unseen clinical outcome dataset, the higher accuracy of the virco®TYPE system in predicting 8 week outcome initially observed in the dataset used for CCO development. The virco®TYPE system compared favourably with the other algorithms at week 24 although the CCOs were developed on week 8 outcome. |
| 156 | PREDICTION OF CLINICAL RESPONSE RATE BY PHENOTYPIC FOLD CHANGE USING KAPLAN–MEIER ESTIMATE IN THE AI424-045 STUDY Antivir Ther. 2007, 12:S171 (abstract no. 156) D Seekins and JF Maa KM methodology provides a detailed and simplified way of estimating clinical response rates compared to frequency analysis. The probability of clinical response assessed by KM method using baseline phenotypic data provides clinicians a continuous assessment tool that may be useful in guiding treatment decisions. Further validation of this methodology from other datasets is suggested. |
| 157 | PROOF-OF-PRINCIPLE EVALUATION OF PREDICTIVE PERFORMANCE FOR THERAPY OUTCOME OF BASELINE ESTIMATED FITNESS AND GENETIC BARRIER TOWARDS RESISTANCE IN A CLINICAL COHORT OF HIV-1-TREATED PATIENTS Antivir Ther. 2007, 12:S172 (abstract no. 157) K Deforche1, A Cozzi-Lepri2, K Theys1, B Clotet3, R Camacho4, J Kjaer5, K Van Laethem1, AN Phillips2, Y Moreau1, JD Lundgren5 and A-M Vandamme1 for the EuroSIDA Study Group Despite the small sample size, the NFVfitness landscape and genetic barrier on this landscape captured genotypic features associated with therapy response that may have been missed by expert rules for NFV, while, for AZT, fitness landscapes were less predictive of virological failure at 3 months than rule-based predictions. This observation warrants to be assessed for boosted PI strategies on a population with larger sample size. |
| 158 | DETERMINING THE PREVALENCE OF TRANSMITTED DRUG-RESISTANT HIV AMONG RECENT VERSUS ESTABLISHED HIV INFECTIONS: A POPULATION-BASED APPROACH Antivir Ther. 2007, 12:S173 (abstract no. 158) A Ajua, F Taku, S Abiye, and M Suzenne In Cameroon, transmitted drug resistance is occurring within all three drug classes and across different population groups. The results suggest that the prevalence rates may be higher among recent versus established infections. Given the public health implications of transmitting drug-resistant HIV, it is important to continue population-based drug resistance surveillance to guide optimum prevention and treatment of HIV infection. |
| 159 | THE ASSOCIATION BETWEEN HIV-1 GENOTYPE AND HIV-1 RNA LEVEL IN ACTG 398 Antivir Ther. 2007, 12:S174 (abstract no. 159) G DiRienzo1, S Hammer2 and J Mellors3 Using valid statistical approaches for variable selection and model selection, we identify and quantify the association between known resistance mutations for drugs in ACTG 398 regimens and week 24 HIV-1 RNA. |
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