|
14th International HIV Drug Resistance Workshop:
|
Cite as: Antivir Ther. 10, Suppl 1:xx (abstract no. ??)
where "xx" is the page number and "??" is the abstract number.
|
Plenary abstracts Abstracts P1 thru P2, Pages P1 to P4 |
|
| P1 | HOST GENETIC DETERMINANTS OF HIV TRANSMISSION AND PATHOGENESIS: SHOULD WE CARE? Antivir Ther. 10, Suppl 1:P3 (abstract no. P1) SK Ahuja Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/AIDS susceptibility. This susceptibility is even greater in individuals who also possess diseaseaccelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis.  Download Abstracts
|
| P2 | HCV RESISTANCE TO ANTIVIRAL AGENTS Antivir Ther. 10, Suppl 1:P4 (abstract no. P2) Giovanni Migliaccio and the HCV Antiviral Team Preliminary cross-resistance analysis indicates that structurally different inhibitors elicit distinct resistance profiles and might therefore be used in combination therapy. This pleanry talk will review advances in the emerging field of HCV antiviral resistance, focusing specifically on in vitro studies with prototypical inhibitors of the NS5B polymerase. Download Abstracts
|
|
Session 1: Clinical implications of resistance Abstracts 1 thru 37, Pages S1 to S39 |
|
| 1 | INFANT NEVIRAPINE RESISTANCE CAN BE SUBSTANTIALLY REDUCED AFTER SINGLE DOSE NEVIRAPINE BY AVOIDING MATERNAL NEVIRAPINE DOSING AND PROVIDING INFANTS WITH ZIDOVUDINE IN ADDITION TO SINGLE DOSE NEVIRAPINE AFTER BIRTH Antivir Ther. 10, Suppl 1:S3 (abstract no. 1) SH Eshleman1, DR Hoover2, SE Hudelson1, S Chen1, A Mwatha3, SA Fiscus4, JB Jackson1, NI Kumwenda1 and T Taha1 Nevirapine resistance in infants who became HIV-1 infected despite antiretroviral prophylaxis was significantly reduced by avoiding pre-delivery maternal nevirapine and providing infants with nevirapine+zidovudine. In NVAZ, the overall transmission rates at 6–8 weeks were not statistically different for this regimen (no maternal nevirapine, infants receive nevirapine+zidovudine, 15.3%) and the HIVNET 012 regimen (14.1%). By not exposing women to nevirapine, this regimen also prevents emergence of maternal nevirapine resistance, which could potentially compromise the efficacy of nevirapine prophylaxis in subsequent pregnancies or the efficacy of antiretroviral regimens for treatment of their HIV-1 infection. Download Abstracts
|
| 2 | SINGLE DOSE NEVIRAPINE COMBINED WITH A SHORT COURSE OF COMBIVIR FOR PREVENTION OF MOTHER TO CHILD TRANSMISSION OF HIV-1 CAN SIGNIFICANTLY DECREASE THE SUBSEQUENT DEVELOPMENT OF MATERNAL AND INFANT RESISTANT VIRUS Antivir Ther. 10, Suppl 1:S4 (abstract no. 2) JA McIntyre1, N Martinson1, GE Gray1 for the Trial 1413 Investigator Team, and DB Hall2, V Boltz3, S Palmer3, J Coffin3, J Mellors4, M Hopley5, T Kimura2, P Robinson2, DL Mayers2 SdNVP+CBV can significantly decrease the subsequent development of maternal and paediatric NNRTI resistant HIV-1 without risk of 3TC resistance. The optimal duration of CBV is uncertain and the two sdNVP+CBV arms remain open to accrual. Download Abstracts
|
| 3 | SHORT-COURSE COMBIVIR (CBV) SINGLE DOSE NEVIRAPINE REDUCES BUT DOES NOT ELIMINATE THE SELECTION OF NEVIRAPINE-RESISTANT HIV-1: IMPROVED DETECTION BY ALLELE-SPECIFIC PCR Antivir Ther. 10, Suppl 1:S5 (abstract no. 3) S Palmer1, V Boltz1, F Maldarelli1, N Martinson2, J McIntyre2, G Gray2, Investigators for the trial 14133, M Hopley4, T Kimura5, D Mayers5, P Robinson5, J Coffin1 and J Mellors6 Short-course CBV (4 or 7 days) reduced the selection of NVP-resistant variants following sdNVP from 75% to 27% of women as determined by allele-specific RT-PCR. The selection of low-frequency NVP-resistant variants in the CBV arms was not detected by standard genotype. The impact of these low-frequency NVP-resistant variants on future treatment options is unknown. The optimal duration of CBV to eliminate the selection of NVP-resistant needs to be established. Download Abstracts
|
| 4 | PATTERNS OF VIRAL LOAD AND DRUG RESISTANCE IN BREAST MILK AND BLOOD FROM WOMEN TREATED WITH SINGLEDOSE NEVIRAPINE TO REDUCE MOTHER-TO-CHILD TRANSMISSION OF HIV-1 Antivir Ther. 10, Suppl 1:S6 (abstract no. 4) DA Lehman1,3, MH Chung4, BA Richardson2, GC John-Stewart4,5 and J Overbaugh1,3 Compared to the Thai-CDC short-course zidovudine regimen, single-dose NVP results in sustained suppression of breast milk viral loads during the first 3 weeks postpartum. However, the benefits of this suppression may be counterbalanced with a high prevalence of resistance. Download Abstracts
|
| 5 | PREDICTORS OF DEATH, AND RESPONSE TO THERAPY IN PATIENTS WITH MULTI (THREE)-CLASS DRUG RESISTANT (MDR) HIV IN THE UK Antivir Ther. 10, Suppl 1:S7 (abstract no. 5) D Grover1, L Allen2, S G Edwards1, H Green3, A Copas2, S Forsyth1 and D Pillay2,4 on behalf of the UK Collaborative Group on HIV Drug Resistance and UK Collaborative HIV Cohort Study (UK CHIC) Resistance test-guided treatment is associated with virological and immunological benefit in this group of advanced patients. Undertaking a treatment interruption after MDR diagnosis was associated with an increased risk of death compared to continued or change of therapy. Download Abstracts
|
| 6 | DETERMINATION OF PHENOTYPIC CLINICAL CUTOFFS FOR ATAZANAVIR AND ATAZANAVIR/RITONAVIR FROM AI424-043 AND AI424-045 Antivir Ther. 10, Suppl 1:S8 (abstract no. 6) EP Coakley1, C Chappey1, JF Maa2, S Wang2, M Bates2, V Wirtz2 and D Seekins2 In these PI-experienced study populations the overall treatment responses to ATV and ATV/r were good. Optimum responses to ATV were observed at FCs <2.2 in the 043 cohort and to ATV/r at FCs <5.2 in the 045 cohort. Download Abstracts
|
| 7 | CLINICAL VALIDATION OF ATAZANAVIR/RITONAVIR GENOTYPIC RESISTANCE SCORE IN PI-EXPERIENCED PATIENTS Antivir Ther. 10, Suppl 1:S9 (abstract no. 7) S Vora1, A-G Marcelin6, H Günthard2, P Flandre7, HH Hirsch3, P Vernazza4, H Furrer5, B Masquelier8, A Zinkernagel2, G Peytavin6, V Calvez6, B Hirschel1, L Perrin1, S Yerly1, and the Swiss HIV Cohort Study (SHCS) Most PI-experienced patients switched to ATV/RTV containing HAART had a virological response. The ATV/RTV resistance score predicts reduced response in patients with at least three mutations of a set of seven to eight mutations. Download Abstracts
|
| 8 | VIROLOGICAL RESPONSE TO ATAZANAVIR/RITONAVIR-BASED REGIMENS: RESISTANCE MUTATIONS SCORE AND PHARMACOKINETIC PARAMETERS (Cmin, Cmax, AUC) (REYAPHAR STUDY) Antivir Ther. 10, Suppl 1:S10 (abstract no. 8) I Pellegrin1, M Vray2, D Neau3, HJA Fleury1, MH Schrive1, M-C Saux4, J-L Pellegrin3, E Lazaro3, J-M Ragnaud3, D Breilh4 Monitoring of atazanavir/ritonavirbased HAART should take into account both number of baseline atazanavir/ritonavir resistance-related mutations (<6 versus ≥6) and GIQ. Download Abstracts
|
| 9 | INITIATIVES FOR DEVELOPING AND COMPARING GENOTYPE INTERPRETATION SYSTEMS STEP 1: EXTERNAL VALIDATION OF EXISTING RULES-BASED ALGORITHM FOR ABACAVIR AND ddI EVALUATED ON VIROLOGICAL RESPONSE Antivir Ther. 10, Suppl 1:S11 (abstract no. 9) D Costagliola1, A Cozzi-Lepri2, C Dalban1, B Cheng3, on behalf of the Standardization and Clinical Relevance of HIV Drug Resistance Testing Project from the Forum for Collaborative HIV Research These results raise the question of external validation of existing interpretation systems and emphasize the need for collaborative work to improve existing systems both by increasing the sample size and by developing innovative statistical approaches. Download Abstracts
|
| 10 | RESISTANCE AFTER SINGLE DOSE NEVIRAPINE PROPHYLAXIS VARIES BY VIRAL SUBTYPE IN INFANTS FROM SUB-SAHARAN AFRICA Antivir Ther. 10, Suppl 1:S12 (abstract no. 10) SH Eshleman1, DR Hoover2, SE Hudelson1, S Chen1, LA Guay1, A Mwatha3, SA Fiscus4, F Mmiro5, P Musoke5, JB Jackson1, NI Kumwenda1, and T Taha1 Nevirapine resistance was more frequent in Malawian infants with subtype C than in Ugandan infants (mostly with other subtypes) 6–8 weeks after single dose nevirapine. This is consistent with the higher frequency of nevirapine resistance observed in these trials among mothers with subtype C than with A or D. Further studies are needed to evaluate whether the higher frequency of nevirapine resistance observed in Malawian infants after single dose nevirapine reflects effects of HIV subtype, or other factors. Download Abstracts
|
| 11 | RESISTANCE MUTATIONS ARISE IN THE MAJORITY OF WOMEN PROVIDED SINGLE-DOSE NVP AND APPEAR TO DIFFER IN EMERGENCE AND PERSISTENCE Antivir Ther. 10, Suppl 1:S13 (abstract 11) JA Johnson1, J-F Li1, L Morris2, N Martinson3, G Gray4, J McIntyre4 and W Heneine1 The finding of K103N and Y181C in an additional 43% of women with previously undetectable resistance suggests that resistant viruses emerge in the majority of women receiving SD-NVP. The disproportionately high numbers of K103N and its detection up to 36 weeks post-NVP suggests that in adults with HIV-1 subtype C this mutation has a selective advantage over Y181C and persists longer. These data emphasize the importance of sensitive assays to better assess the clinical implications of drug-resistant variants. Download Abstracts
|
| 12 | HIGH FREQUENCY OF NEVIRAPINE RESISTANT MUTATIONS IN THE HIV QUASI SPECIES FOUND IN NVP-TREATED PARTICIPANTS OF AN MTCT UGANDAN COHORT Antivir Ther. 10, Suppl 1:S14 (abstract no. 12) R Troyer1, M Lalonde1, F Kyeyune2, K Demers2, M Kamya3, C Whalen1, P Mugyenyi2, F Bajunirwe4 and E Arts1,2 These analyses suggest that NVP resistant mutations can be detected in over 75% of the NVP-treated infected mothers and infants. Prominence of these mutations in the quasispecies of HIV-infected mothers and infants 6 weeks post-partum and single-dose NVP treatment is of concern for prevention of MTCT and future treatment of NVP-containing treatment regimens in Uganda. Download Abstracts
|
| 13 | INCREASED SENSITIVITY OF DETECTION OF K103N RESISTANCE VARIANTS BY REAL-TIME PCR IN RNA AND DNA AFTER SINGLE-DOSE NEVIRAPINE Antivir Ther. 10, Suppl 1:S15 (abstract 13) S Loubser1, P Balfe2, G Sherman3, S Hammer2, L Kuhn2 and L Morris1 Real-time PCR detection of K103N was more sensitive than genotyping. An additional 73% (n=15) of RNA samples previously identified as wild-type by genotyping had detectable K103N. Cross-sectional analysis showed that K103N was detectable in RNA in the majority of women 6 weeks post-sdNVP which declined over time and was present in a minority at 48 weeks. In DNA, K103N was detectable in ~50% of samples at 6 weeks post-sdNVP and was essentially absent at 48 weeks. Download Abstracts
|
| 14 | IN VITRO PHENOTYPIC SUSCEPTIBILITY TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS OF HIV-2 ISOLATES WITH Q151M MUTATION IN THE REVERSE TRANSCRIPTASE GENE Antivir Ther. 10, Suppl 1:S16 (abstract no. 14) F Damond1, G Collin1, S Matheron1, A Taieb2, P Campa3, G Peytavin1, A Bènard2, S Delarue1, G Chêne2, F Brun-Vèzinet1, D Descamps1 and the French ANRS HIV-2 Cohort (ANRS CO 05) In HIV-2 isolates, Q151M mutation alone impacts only the phenotypic susceptibility to d4T and ABC. A decrease in susceptibility to all NRTIs was observed when Q151M was selected with V111I, mutation of unknown impact on HIV-1 resistance. Clinical relevance of these phenotypic susceptibility results needs to be evaluated in HIV-2 treated patients. Download Abstracts
|
| 15 | RARE SELECTION OF K65R MUTATION IN NAÏVE PATIENTS FAILING A FIRST-LINE ABACAVIR/LAMIVUDINE HAART CONTAINING REGIMEN. Antivir Ther. 10, Suppl 1:S17 (abstract no. 15) D Descamps1, S Delarue1, M Ait-Khaled2, C Craig3, G Collin1, F Brun-Vézinet1 Minority species harbouring K65R are uncommon and at very low frequency in patients experiencing virological failure, while receiving a first line ABC/3TC HAART containing regimen. These results show that the co-selection of L74V with K65R and of M184V with K65R mutations in these patients was rare. Indeed, the selection of L74V in a patient with baseline K65R suggests that M184V/L74V is the preferred ABC/3TC resistance pathway. The clinical significance of mutations present at ≤1% on first failure, of the same order as found in a patient at baseline, remains undetermined. Download Abstracts
|
| 16 | VIROLOGICAL RESPONSE TO ANTIRETROVIRAL THERAPY IN THE SETTING OF THE K65R MUTATION Antivir Ther. 10, Suppl 1:S18 (abstract 16) AB Nevins1, SY Rhee1, WJ Fessel2, M Horberg2, A Scarsella3, SY Lee3, RW Shafer1, AR Zolopa1 Among this cohort of highly treatment-experienced patients with the K65R mutation, response to subsequent antiretroviral therapy was robust in spite of the presence of multiple resistance mutations in many of these cases. This response appeared independent of specific prior RT inhibitor use or specific components of the new regimen. Download Abstracts
|
| 17 | INTENSIFICATION OF A FAILING REGIMEN WITH AZT MAY CAUSE SUSTAINED VIROLOGICAL SUPPRESSION IN THE PRESENCE OF THE K65R MUTATION Antivir Ther. 10, Suppl 1:S19 (abstract no. 17) S Staszewski, B Dauer, A Mueller, C Rottmann, T Lennemann, M Stuermer In these patients with the K65R mutation and no TAMS, AZT was added to regimens in which genotypic testing showed resistance to all their drugs. AZT was the only active drug, however, this addition was enough to achieve sustained viral load reductions to below 50 copies/ml. Download Abstracts
|
| 18 | PATTERNS OF RESISTANCE MUTATIONS IN PATIENTS FAILING ON A DIDANOSINE (DDI) AND TENOFOVIR (TNF) CONTAINING REGIMENS Antivir Ther. 10, Suppl 1:S20 (abstract no. 18) JM Gatell, A León, JL Blanco, J Mallolas, E Martinez, ED Lazzari, T Pumarola, M Larrousse, A Milincovic, M Lonca, M Laguno, A Biglia, JM Miró and F Garcí These results argue against the use of TDF-ddI plus a NRTI or a NNRTI not only in naïve patients but also in previously suppressed patients. Conversely combinations including lopinavir/ritonavir seem to be virologically safer. Download Abstracts
|
| 19 | GENOTYPIC RESISTANCE IN PATIENTS WITH PERSISTENTLY DETECTABLE LOW-LEVEL VIRAEMIA TREATED WITH TRIPLE NUCLEOSIDE ANTIRETROVIRAL THERAPY Antivir Ther. 10, Suppl 1:S21 (abstract no. 19) C Amiel1, E Marechal Da Silva2, V Schneider1, S Thevenet1, F Clavel3 and W Rozenbaum2 Among patients failing triple nucleoside therapy, the T215F/K219E resistance pathway, as opposed to the T215Y/L210W pathway, appears to be highly prevalent in patients retaining low VL levels. Whether this relates to the replicative capacity or the resistance properties of these viruses needs to be further investigated. That could influence the moment when a treatment must be modified in a failing patient. Download Abstracts
|
| 20 | TWENTY-FOUR-WEEK EFFICACY AND RESISTANCE PROFILE OF A ZIDOVUDINE/LAMIVUDINE/TENOFOVIR DF COMBINATION THERAPY IN ANTIRETROVIRAL-NAÏVE PATIENTS Antivir Ther. 10, Suppl 1:S22 (abstract no. 20) B Masquelier1, D Neau1, S Boucher1, V Lavignolle-Aurillac2, MH Schrive1, P Recordon-Pinson1, JM Ragnaud1, H Fleury1 The virological response in our study demonstrates the antiviral efficacy of the ZDV/3TC/TDF combination therapy. The presence of ZDV in the combination could have prevented the selection of K65R. This combination therapy could be of interest when other antiretroviral classes cannot be prescribed. Download Abstracts
|
| 21 | RATE OF VIROLOGICAL FAILURE AND RESISTANCE MUTATIONS IN ANTIRETROVIRAL-EXPERIENCED PATIENTS SHIFT TO A QD SIMPLIFICATION REGIMEN WITH DIDANOSINE, TENOFOVIR AND EFAVIRENZ (EFADITE TRIAL) Antivir Ther. 10, Suppl 1:S23 (abstract no. 21) L Valer1, A Barrios1, P Domingo2, P Labarga3, E Negredo4, J Vilaró-Rodríguez2, V Estrada5, V Asensi6, D Morales7, J Gálvez7, J Santos8, J-A Terrón9, E Casas10, M Riera11, A Vergara12, E Pérez Guzmán13, MJ Galindo14, I Maida1, L Martín-Carbonero1, P Barreiro1, T García-Benayas1, M Núñez1, F Blanco1, J González-Lahoz1, B Clotet2 and V Soriano1 In patients on HAART with complete virus suppression, simplification to a QD regimen with ddI-TDF-EFV provides virological responses at 12 months similar to those seen in patients who do not change therapy. While improvements in lipid abnormalities and treatment adherence might favour this simplification regimen, concerns on CD4 declines (particularly with high ddI doses) may discourage its use. While most patients failing virologically develop drug resistance to EFV, mutation K65R was the most frequent change for NRTI. Download Abstracts
|
| 22 | ASSOCIATION BETWEEN NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS RESISTANCE MUTATIONS AND LEVEL OF RESIDUAL HIV-1 VIRAEMIA UNDER ANTIRETROVIRAL TREATMENT IN PATIENTS EXPERIENCING VIROLOGICAL FAILURE Antivir Ther. 10, Suppl 1:S24 (abstract no. 22) B Roquebert1, C Dalban2, M Wirden1, R Tubiana2, MA Valantin2, M Bonmarchand3, A Simon3, C Katlama2, D Costagliola2, V Calvez1 and AG Marcelin1 Among the main NRTI resistance mutations, only the 184 mutation was associated with the level of viraemia: the M184V mutation with reduced viraemia and the M184I mutation with elevated viraemia. Download Abstracts
|
| 23 | INFLUENCE OF NEW REVERSE TRANSCRIPTASE MUTATIONS ON VIROLOGICAL RESPONSE TO DIDANOSINE IN THE DIDANOSINE ADD ON JAGUAR STUDY Antivir Ther. 10, Suppl 1:S25 (abstract no. 23) AG Marcelin1, P Flandre2, J Pavie3, N Schmidely4, M Wirden1, MC Bernard4, JM Molina3 and V Calvez1 With a stringent criterion, four mutations (H208Y, R211A/D/G/K/S, L214F, L228H/M/R) appear to be associated with virological response to ddI therapy. Taking account of these mutations, in addition to the GS, this may improve the classification of patients defined as not resistant to ddI and to better discriminate them. Nevertheless, this approach should be further investigated in other studies or databases. Download Abstracts
|
| 24 | RELATION BETWEEN THE ANTIRETROVIRAL ACTIVITY OF DIDANOSINE (DDI) AND THE NUMBER OF REVERSE TRANSCRIPTASE (RT) MUTATIONS: DINAM STUDY Antivir Ther. 10, Suppl 1:S26 (abstract no. 24) JL Blanco, A Biglia, M Arnedo, E de Lazzari, J Mallolas, E Martinez, M Lonca, M Laguno, M Larrousse, A Leon, A Milinkovic, F Garcia, JM Miro, JA Arnaiz, T Pumarola, JM Gatell ddI retains significant antiretroviral activity when the number of RT, TAMs or NAMs is less than four except when both the 74V and 65R are present. Download Abstracts
|
| 25 | MUTATION PATTERNS ASSOCIATED WITH RESISTANCE TO TENOFOVIR IN DRUG-NAÏVE PERSONS NEWLY DIAGNOSED WITH HIV Antivir Ther. 10, Suppl 1:S27 (abstract no. 25) DE Bennett, L McCormick, W Wheeler, R Kline Mutation patterns associated with tenofovir susceptibility occurred infrequently among this newly diagnosed population, but these data demonstrate that K65R and other relevant combinations of mutations are being transmitted in the US. In areas with a high prevalence of transmission of HIV with mutations associated with reduced tenofovir susceptibility, pre-exposure prophylaxis with tenofovir could be less effective. Studies should evaluate the extent to which resistant HIV could affect prevention of transmission by pre-exposure prophylaxis. Download Abstracts
|
| 26 | PREVALENCE AND IMPACT OF PROTEASE CODON 33 MUTATIONS/POLYMORPHISMS IN TREATMENT-NAÏVE AND TREATMENT-EXPERIENCED PATIENTS ENROLLING IN CLINICAL TRIALS Antivir Ther. 10, Suppl 1:S28 (abstract no. 26) MJ Kozal1, K Huppler Hullsiek2, R Leduc2, RM Novak3, RD MacArthur4, J Lawrence5, and JD Baxter6 for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) At protease codon 33, the prevalences of polymorphisms 33V and 33I were similar for PI-naïve and PI-experienced patients (<3%), but the prevalence of 33F was significantly different (0.2% vs 30.2%). In the treatment-experienced cohort, the differences between those with and without 33F in phenotypic fold-change for amprenavir, indinavir, and ritonavir persist after adjustment for the presence of other major PI mutations and PI drug exposure history. Given the availability of newer PIs that may select for 33F, monitoring for the presence of this mutation should be ongoing for both treatment-naïve and treatment-experienced patients. Download Abstracts
|
| 27 | NON-RESPONSE TO TIPRANAVIR IS ASSOCIATED WITH PRE-TREATMENT RESISTANCE CHARACTERIZED BY TIPRANAVIR PHENOTYPE OR GENOTYPIC TIPRANAVIR SCORE Antivir Ther. 10, Suppl 1:S29 (abstract no. 27) H Valdez1, DB Hall1, VM Kohlbrenner1, CA Boucher2, J Schapiro3, J Baxter4, J Scherer1, S McCallister1, DL Mayers1 IC50 fold change of <3 or a low TPV score predicted a response to TPV. Reduced susceptibility or high TPV score were associated with a greater non-response rate, however the majority of patients still responded to TPV. Download Abstracts
|
| 28 | DEVELOPMENT OF ATAZANAVIR RESISTANCE MUTATIONS IN A CLINICAL SETTING AMONG PATIENTS WITHOUT EVIDENCE OF PRE-EXISTING PROTEASE MUTATIONS Antivir Ther. 10, Suppl 1:S30 (abstract no. 28) C Salama, D Caplivski None of the patients taking ritonavir-boosted atazanavir developed significant new protease mutations upon virological failure. Two patients developed a G73S mutation after failing unboosted atazanavir. This mutation may play a role in atazanavir resistance. Two nelfinavir-experienced patients developed mutations linked to prior nelfinavir use (D30N, N88D). None of the patients developed I50L, N88S, or any other significant protease mutation. Download Abstracts
|
| 29 | FDA ANALYSIS OF THE EFFECT OF BASELINE PROTEASE GENOTYPE ON VIROLOGICAL RESPONSE TO ATV/RTV VS LPV/RTV IN THE TREATMENT-EXPERIENCED SUBJECTS IN STUDY AI424045 Antivir Ther. 10, Suppl 1:S31 (abstract no. 29) K Struble and LK Naeger Both the number and type of baseline PI mutations affected response rates in treatment-experienced subjects. Genotypic analysis of baseline isolates showed that the presence of mutations M46I/V/L, I54V/L/M/A/T, A71V/T/I, V82A/T/F/S, I84V, or L90M at baseline reduced response rates in both the ATV/RTV and LPV/RTV treatment arms. Response rates were similar (63–65%) between ATV/RTV and LPV/RTV-treated subjects with zero to four PI-associated mutations at baseline. Response rates were reduced for both treatments if five or more PI-associated mutations were present at baseline; 0% (0/9) for ATV/RTV compared to 28% (5/18) for LPV/RTV. Analysis by both number and type of baseline primary PI mutation showed ATV/RTV response rates were reduced to <30% if three or more primary PI mutations including changes at M36, M46, G73, V82, I84, or L90 were present at baseline. LPV/RTV response rates were reduced to <30% if three or more primary PI mutations including changes at M46 or V82 were present at baseline. Download Abstracts
|
| 30 | GENOTYPIC PROTEASE EVOLUTION IN ANTIRETROVIRAL-EXPERIENCED PATIENTS RECEIVING LOPINAVIR/R-CONTAINING REGIMENS Antivir Ther. 10, Suppl 1:S32 (abstract no. 30) D Costagliola1, D Descamps2, L Bocket3, C Tamalet4, M Wirden5, B Montès6, J Izopet7, P Palmer8, V Schneider9, A Ruffault10, V Ferré11, G Peytavin2, H Fleury12, F Brun-Vézinet2, B Masquelier12 and the ANRS AC11 Resistance Study Group In contrast with the very rare selection of mutations observed in naïve patients receiving a failing LPV-containing regimen, we observed a rapid increase of resistance to LPV after 6 months of a failing regimen in ARV-experienced patients, mainly explained by the increased frequency of mutations 33F, 63P and 82A. Download Abstracts
|
| 31 | IMPACT OF BASELINE PROTEASE DRUG MUTATIONS ON VIROLOGICAL RESPONSE TO FOSAMPRENAVIR/RITONAVIR-BASED REGIMENS IN ANTIRETROVIRAL-EXPERIENCED PATIENTS (ZEPHIR STUDY) Antivir Ther. 10, Suppl 1:S33 (abstract no. 31) I Pellegrin1,G Coureau2, D Neau3, D Lacoste3, E Lazaro3, HJA Fleury1, MH Schrive1, F Dabis2, JL Pellegrin3, D Breilh4 and the GECSA In highly experienced patients, FosAPV/r-score was predictive of virological response (<4 vs ≥4 mutations) at month 3. We found that L90M PI-mutation was associated with failure. Download Abstracts
|
| 32 | HIV DRUG RESISTANCE PREDICTORS OF CLINICAL DISEASE PROGRESSION IN PATIENTS UNDERGOING RESISTANCE TESTING IN CLINICAL PRACTICE Antivir Ther. 10, Suppl 1:S34 (abstract no. 32) S Di Giambenedetto, M Colafigli, C Pinnetti, A Bacarelli, A Cingolani, E Tamburrini, R Cauda and A De Luca Development of resistance to multiple classes, in particular with NNRTI resistance and =3 UPAM, predicts clinical progression in patients failing HAART. Download Abstracts
|
| 33 | DIFFERENT INCIDENCE OF PROTEASE RESISTANCE IN PATIENTS FAILING TREATMENT ON AN INITIAL RITONAVIR-BOOSTED SAQUINAVIR (SAQUINAVIR/R) REGIMEN VERSUS THOSE WITH PRIOR EXPOSURE TO DUAL-NUCLEOSIDES AND UNBOOSTED SAQUINAVIR Antivir Ther. 10, Suppl 1:S35 (abstract no. 33) J Ananworanich1, S Sirivichayakul2, S Ubolyam1, T Cheunyam1, M Schutz3, W Snowden3, P Cardiello1, D Cooper1,4, B Hirschel5, K Ruxrungtham1,2 Virological failure was rare and primary protease mutations were absent from a cohort of formerly treatment-naïve patients despite virological failure on once daily SQV/r. By contrast, virological failure occurred in 14% of patients who had received unboosted before boosted SQV. In these patients, primary resistance mutations were frequently detected. Download Abstracts
|
| 34 | THE LEVEL OF PERSISTENT VIRAEMIA BELOW 50 COPIES/ML IS ASSOCIATED WITH SUBSEQUENT REBOUND TO ABOVE 50 HIV RNA COPIES/ML FOR NELFINAVIR-TREATED SUBJECTS BUT NOT LOPINAVIR/RITONAVIR-TREATED SUBJECTS Antivir Ther. 10, Suppl 1:S36 (abstract no. 34) M King1, S Palmer2, A Wiegand2, F Maldarelli2, S Brun1, D Kempf1, G Hanna1, J Coffin2, and J Mellors3 Among subjects with HIV RNA <50 copies/mL for at least 36 weeks who had samples tested by SCA, a higher risk of subsequent virological failure (confirmed rebound >400 copies/mL) was observed among NFV-treated vs LPV/r-treated subjects. Week 60 SCA values were significantly associated with subsequent HIV RNA rebound >50 copies/mL for NFV-treated subjects but not for LPV/r-treated subjects. Download Abstracts
|
| 35 | EMERGENCE OF DRUG RESISTANCE MUTATIONS DURING TREATMENT INTERRUPTION IN PATIENTS WITH UNDETECTABLE VIRAL LOADS Antivir Ther. 10, Suppl 1:37(abstract no. 35) MA Winters1, D Weng-Cherng2, K Henry3, P Tebas4, H Valdez5, M Wantman2, DA Katzenstein1 for the ACTG A5102 Team Rapid return of detectable viral load after TI was associated with strains containing DRM. We found no strong association between type of HAART and DRM at breakthrough. The presence of DRM in PBMC DNA was associated with but not required for emergence of DRM-containing strains at breakthrough. Download Abstracts
|
| 36 | DEVELOPMENT OF RESISTANCE IN INJECTION DRUG USERS (IDUS) RECEIVING HAART WITHIN A DIRECTLY OBSERVED THERAPY (DOT) PROGRAM Antivir Ther. 10, Suppl 1:S38 (abstract no. 36) H Tossonian1, J Raffa1, B Rashidi1, M Viljoen2, M MacLean2, F Duncan2 S MacDonald2, M Khara2, H Culbert2, S DeVlaming2, B Conway1 PI and NNRTI-based DOT regimens both produced lasting virological suppression in over 65% IDUs. However, drug resistance (including loss of susceptibility to NRTIs) was more frequent with breakthrough on NNRTIs. As these are non-randomized data, there is now an urgent need for a randomized trial comparing NNRTI and PI-based regimens in this population, to compare the risks and benefits of these two approaches in a rigorous manner. Download Abstracts
|
| 37 | CLINICALLY RELEVANT BREAKPOINTS FOR VIRCO®TYPE HIV-1 PHENOTYPIC RESISTANCE INFORMATION Antivir Ther. 10, Suppl 1:S39 (abstract no. 37) B Winters2, R Harrigan3, J Montaner3, M Perez-Elias4, M Miller5, S Emery6, F van Leth7, P Robinson8, JD Baxter9, B Gazzard10, A Pozniak10, D Castor11, S Hammer12, A Rinehart and L Bacheler1 Clinically relevant breakpoints for Virco®TYPE HIV-1 phenotypic resistance information have been defined based on virological outcome in treated patients using a consistent approach and definition across all drugs. CCO definitions based on fractions of the wild type virological response are applicable to diverse patient populations. CCOs should enhance the clinical utility of Virco®TYPE in the selection of optimal antiretroviral treatment regimens for HIV-1+ subjects. Download Abstracts
|
|
Session 2: New resistance technologies and interpretations Abstracts 38 thru 57, Pages S41 to S62 |
|
| 38 | A PROMISING METHOD FOR MIXED POPULATION GENOTYPING OF DRUG-RESISTANT HIV-1 Antivir Ther. 10, Suppl 1:S43 (abstract no. 38) MJ Moser1, EL Beaty1, M Ruckstuhl2, M Kozlowski2, RF Schinazi2 and JR Prudent1 The RT× assay appears to be a rapid method for determining mixed population HIV-1 genotypes. Further experiments on HIV-1 viral RNA from infected individuals will be needed to further understand the potential of the method. Download Abstracts
|
| 39 | EVALUATION OF MULTICODE-RT×® REAL-TIME PCR SYSTEM FOR DETECTION OF SUBPOPULATIONS OF K65R AND M184V HIV-1 MUTANT VIRUSES Antivir Ther. 10, Suppl 1:S44 (abstract no. 39) ES Svarovskaia1, MJ Moser2, JR Prudent2, MD Miller1 and K Borroto-Esoda1 The MultiCode-RT× RT-PCR system represents a highly specific, convenient and sensitive assay for use in the early detection of low-levels of drug-resistant viruses. Plasma samples from treatment-naïve patients showed no detectable K65R or M184V mutations. Download Abstracts
|
| 40 | EARLY AND ISOLATED REVERSION OF TRANSMITTED RT K65R IN A MULTI-DRUG RESISTANT INFECTION DETECTED USING A NOVEL QUANTITATIVE ALLELE-SPECIFIC PCR Antivir Ther. 10, Suppl 1:S45 (abstract no. 40) RE Atchison1, TJ Liegler1, J Javier1, E Fiss2, FM Hecht3, T Myers2 and RM Grant1 The spread partner appears to have acquired a multi-drug resistant HIV-1, with rapid and isolated reversion of K65R but not nnRTI resistance mutations. This may be due to the high fitness cost associated with K65R. Rises in isolated primary nnRTI resistance in some communities may be due, in part, to failed detection of mutations conferring resistance to other classes of drugs. Allele specific PCR assays could be useful for primary resistance surveillance, estimation of relative fitness, detection of resistance after changing drugs, and monitoring clinical trials of chemoprophylaxis. Download Abstracts
|
| 41 | OPTIMIZATION OF THE OLIGONUCLEOTIDE LIGATION ASSAY (OLA), A RAPID AND INEXPENSIVE TEST FOR DETECTION OF HIV-1 DRUG-RESISTANT MUTATIONS, FOR NON-B SUBTYPES Antivir Ther. 10, Suppl 1:S46 (abstract no. 41) IA Beck1, C Crowell1, R Kittoe1, H Bredell2, W Janssens3, M Jacobs4, I Lorenzana5, G Alemnji6 and LM Frenkel1 The OLA designed for HIV-1 subtype B had indeterminate results in 6.6% of non-B subtypes specimens, compared to 2–3% in subtype B specimens. Modification of the oligonucleotide probes for common polymorphisms shared among specimens with indeterminate results can increase the rate of detection, making the OLA suitable to evaluate HIV-1 non-B subtypes for drug-resistance mutants. Download Abstracts
|
| 42 | RESISTANCE GENOTYPING USING A NOVEL LONG RANGE AMPLICON SYSTEM, HIV-1 LR-GENETANKER™ COMPLETE Antivir Ther. 10, Suppl 1:S47 (abstract no. 42) JT Huong1, DA Burns1, BD Kirkpatrick1, RT Prince1, M Holodniy2 and RM Lloyd Jr1 The use of LR RT-PCR amplification for potential co-linear sequence linkage is plausible. Comparative protease and reverse transcriptase gene resistance associated mutation results between the HIV-1 LR-GeneTanker Complete genotyping method and the TRUGENE HIV-1 Genotyping Assay were highly concordant. The MuTanker Polymorphic Comparator Tool was useful in the identification of unique viral variants across separated gene regions, in addition to locations of drug susceptibility, which suggests multiple divergent pathways while on antiviral therapy. Download Abstracts
|
| 43 | COMPARATIVE EVALUATION OF THE TRUGENE HIV-1 ENVELOPE (GP41) GENOTYPING ASSAY ON CLINICAL SAMPLES Antivir Ther. 10, Suppl 1:S48 (abstract no. 43) C Cabrera1, S Marfil1, E Poveda2, T Puig1, A Bonjoch1, R Ziermann3, V Soriano2, B Clotet1 and L Ruiz1 The new Bayer TRUGENE HIV-1 envelope (gp41) genotyping assay seems to be a useful tool for the recognition of enfurvirtide resistance mutations in clinical samples. Our data suggest that the Bayer assay is more sensitive than our in-house method to detect mixture populations at crucial positions conferring enfuvirtide resistance. Assay performance is generally not affected by the presence of distinct HIV-1 subtypes belonging to group M. Download Abstracts
|
| 44 | EVALUATION OF DRIED BLOOD SPOTS FOR HIV-1 DRUG RESISTANCE TESTING Antivir Ther. 10, Suppl 1:S49 (abstract no. 44) JG García-Lerma1, A McNulty1, C Jennings2, D Bennett1, J Fitzgibbon3, R Morack2, M Ussery3, TM Folks1, ML Kalish1 and W Heneine1 Our results show the feasibility of using this DBS method for drug resistance testing, despite the need to amplify a large fragment. Longterm storage at -20ºC appears to preserve nucleic acids in DBS. The frequent contribution of proviral DNA to DBS sequences highlights the need for a wider evaluation of the concordance of resistance genotypes between plasma and DBS. Download Abstracts
|
| 45 | COMPARISON OF WHOLE BLOOD, PLASMA, AND PBMC HIV-1 RESISTANCE GENOTYPING AND MATCHED DRIED SAMPLES USING SAMPLETANKER™ A NOVEL DRIED TRANSPORTATION MATRIX Antivir Ther. 10, Suppl 1:S50 (abstract no. 45) RM Lloyd Jr1, DA Burns1, JT Huong1, BD Kirkpatrick1 RL Mathis1, M Holodniy2, ML Tanner3 and PM Feorino1 Accuracy and reproducibility of results from plasma, whole blood and PBMC were comparable to the TRUGENE product insert specifications for FDA approved plasma genotyping. Concordance of protease and reverse transcriptase gene RAM results between liquid and dried SampleTanker samples demonstrate potential utility for resistance testing in studies using whole blood. Download Abstracts
|
| 46 | ASSESSMENT OF THE ANTIVIROGRAM® PERFORMANCE OVER TIME INCLUDING A REVISED DEFINITION OF BIOLOGICAL TEST CUT-OFF VALUES Antivir Ther. 10, Suppl 1:S51 (abstract no. 46) Y Verlinden1, H Vermeiren1, P Lecocq1, L Bacheler2, P McKenna1, M Vanpachtenbeke1, LI Laenen-Horvat1, M Van Houtte1 and LJ Stuyver1 The quarterly FC values for the wild-type viruses remained close to the reference mean, allowing to conclude that the Antivirogram® assay was stable over the period under study. The new BCOs reflect the combination of (i) the stability of the Antivirogram® assay; (ii) an up-to-date ‘normal range’ of phenotypic susceptibility to antiretroviral agents; (iii) any assay fluctuation over time. Download Abstracts
|
| 47 | A NEW PILOT REPLICATIVE CAPACITY ASSAY USING CLINICAL ISOLATES Antivir Ther. 10, Suppl 1:S52 (abstract no. 47) A Ruffault1, L Havard1, O Guist’hau1, A Maillard1, JM Chapplain2, C Arvieux2 and C Michelet2 This study shows a low replication capacity in multidrug-resistant isolates. In contrast the three isolates obtained from ARV-experienced patients with treatment interruption shows RC closed to untreated patients. To ensure the reproducibility of the assay (1) normalise inoculum is essential and (2) RC reference value must be defined for each experiment. Download Abstracts
|
| 48 | ENZYME-BASED ASSAY FOR TDM OF HIV PROTEASE INHIBITORS Antivir Ther. 10, Suppl 1:S53 (abstract no. 48) B Yu1, EI Afonina1, PR Harrigan2, CS Alexander2, S Langridge2, JW Erickson1 and SV Gulnik1 E-TDM represents a simple and inexpensive alternative for LC-MS, and can be used for the determination of total PI concentration in multiple PI-exposed patients. Download Abstracts
|
| 49 | MUTATIONS ASSOCIATED WITH DIDANOSINE RESISTANCE DETERMINED FROM 444 MATCHED GENOTYPE-PHENOTYPE PAIRS Antivir Ther. 10, Suppl 1:S54 (abstract no. 49) N Shulman1, R Bosch2, S Fiscus3, D Katzenstein1 and J Eron3 for DACS 227 A didanosine resistance score was derived from genotype-phenotype correlation that is presently being used to analyse the 8 week virological response to didanosine monotherapy in ACTG 175 and 307. Download Abstracts
|
| 50 | EVOLUTIONARY AND PHENOTYPICAL CHARACTERIZATION OF NOVEL NRTI-ASSOCIATED MUTATIONS Antivir Ther. 10, Suppl 1:S55 (abstract no. 50) T Sing1, V Svicher2, N Beerenwinkel3, F Ceccherini-Silberstein2, I Savenkov1, K Korn4, CF Perno2, H Walter4 and T Lengauer1 The dichotomy between early and late mutations reflects their respective impact on phenotype. Moreover, novel mutations might serve as valuable genotypic markers. In particular, tenofovir-containing regimes might be less favorable in the presence of 214F due to increased TDF cross-resistance conferred by the 214F-induced NAM1. While some novel mutations may be considered in future updates of rules-based algorithms, we found that their effects were already captured by geno2pheno prior to this study. Download Abstracts
|
| 51 | FLEXIBLE SEMIPARAMETRIC METHODS FOR RELATING PATTERNS OF MULTIPLE HIV-1 GENOTYPE MUTATIONS TO PHENOTYPE RESPONSES Antivir Ther. 10, Suppl 1:S56 (abstract no. 51) J Schumi1 and V De Gruttola1 The method proposed allows the investigation of the impact of resistance mutations in the presence of others and may suggest mechanisms by which resistance occurs or is reversed through the accumulation of mutations. The analyses presented here use population level average phenotypes, not serial genotypes on individuals, but the approach could be extended to handle longitudinal genotype data or incorporation of covariates such as treatment history. The methods also allow for analysis of specific mutations instead of the wild-type/mutation dichotomy. Download Abstracts
|
| 52 | TREATMENT HISTORY AND ADHERENCE INFORMATION SIGNIFICANTLY IMPROVES PREDICTION OF VIROLOGICAL RESPONSE BY NEURAL NETWORKS Antivir Ther. 10, Suppl 1:S57 (abstract no. 52) BA Larder1, D Wang1, A Revell1, R Harrigan2, J Montaner2, S Wegner3 and C Lane4 Treatment history data significantly improved the accuracy of ANN in predicting virological response possibly acting as a surrogate for minority mutant populations. ANN models trained using data from highly adherent patients were significantly more accurate than those trained with data from less adherent patients. Initial combined ‘treatment history/ adherent’ models achieved an intermediate level of performance, possibly due to the relatively small training set and large number of input variables. Combined models trained using a reduced mutation set showed improved performance. Download Abstracts
|
| 53 | GLOBAL NEURAL NETWORK MODELS ARE SUPERIOR TO SINGLE CLINIC MODELS AS GENERAL QUANTITATIVE PREDICTORS OF VIROLOGICAL TREATMENT RESPONSE Antivir Ther. 10, Suppl 1:S58 (abstract no. 53) S Wegner1, BA Larder2, D Wang2, A Revell2, R Harrigan3, J Montaner3 and C Lane4 Global ANN models can perform as accurately as local models, trained with data from a single clinic, in predicting response for patients from that clinic. Global models appear superior to local models for other clinics, suggesting that they may be the most powerful way to exploit ANN as a generally available treatment decision-making tool. Download Abstracts
|
| 54 | THE USE OF MACHINE LEARNING AND CAUSAL INFERENCE METHODOLOGY TO INTERPRET THE ASSOCIATION BETWEEN DRUG-RESISTANCE MUTATIONS AND TREATMENT RESPONSE Antivir Ther. 10, Suppl 1:S59 (abstract no. 54) ML Petersen1, SE Sinisi1, S Rhee2, RA Shafer2, JW Fessel3 and MJ van der Laan1 Use of the deletion/substitution/addition algorithm estimates the effects of HIV genotype on treatment responses with minimal a priori assumptions about which mutations are relevant and dataadaptively explores interactions between mutations. Combination of this algorithm with direct effect methodology from the causal inference statistical framework generates a set of mutation-specific effect estimates that can be used to inform current genotype interpretation systems. Download Abstracts
|
| 55 | HAART OUTCOME PREDICTION USING STATISTICAL LEARNING METHODS Antivir Ther. 10, Suppl 1:S60 (abstract no. 55) I Savenkov1, N Beerenwinkel2, T Sing1, M Däumer3, R Kaiser3 and T Lengauer1 Logistic regression with genetic barriers constitutes a powerful model for HAART outcome prediction characterized by robustness, interpretability, and high prediction accuracy. This model has been integrated into the geno2pheno system and is available at http://www.geno2pheno.org. Its predictions may be useful for designing individualized HIV combination therapies. Download Abstracts
|
| 56 | COMPARISON OF THE PERFORMANCE OF GENOTYPE-BASED HIV-1 RESISTANCE ANALYSIS SYSTEMS TO PREDICT VIROLOGICAL RESPONSE Antivir Ther. 10, Suppl 1:S61 (abstract no. 56) B Winters1, K Van Der Borght1 and L Bacheler2 1 Virco BVBA, Mechelen, Belgium 2 VircoLab, Inc Durham, NC, USA The results indicate that there is a benefit of interpreting phenotypical information as a continuous variable. In patients that exhibit some level of resistance to their regimen, phenotypical information provides added value to the genotype alone in predicting virological response. Download Abstracts
|
| 57 | 'COMMON LAW' APPLIED TO TREATMENT DECISIONS FOR DRUG RESISTANT HIV Antivir Ther. 10, Suppl 1:S62 (abstract no. 57) M Prosperi1, M Zazzi2, C-F Perno3, S Di Giambenedetto4, J Baxter5, L Ruiz6, P Clevenbergh7,G Ulivi1, A Antinori3 and A De Luca4; for the ARCA cohort, INMI cohort, Argenta, Gart, Havana and Viradapt Study Groups CBR and k-NearestNeighbor algorithm are highly predictive when a proper similarity function between cases is chosen. However, only very large and redundant data sets (or with data well distributed in attribute space and noise free) can assure good predictions for any case. Download Abstracts
|
|
Session 3: Resistance to new antiretroviral agents Abstracts 58 thru 78, Pages S63 to S85 |
|
| 58 | 1-(ß-D-DIOXOLANE)THYMINE (DOT) IS A TK-DEPENDENT ORALLY BIOAVAILABLE NUCLEOSIDE WITH SPECIFIC ACTIVITY AGAINST HIV-1 RESISTANT VARIANTS Antivir Ther. 10, Suppl 1:S65 (abstract no. 58) RF Schinazi, G Asif, M Detorio, B Hernandez-Santiago, M Ruckstuhl, V Yadav, KL Rapp, M Bennett, J Grier, M-Y Xie, J Lennerstrand, M Kozlowski, S Lutz, SJ Hurwitz and CK Chu DOT was markedly effective against numerous clinically relevant drug resistant mutants including HIV containing MDR and T69S insert mutations. Its pharmacological properties are unique for a nucleoside analogue. Thus, additional biological studies are warranted to determine the full potential of DOT for the treatment of HIV. Download Abstracts
|
| 59 | PROPERTIES OF IN VITRO GENERATED HIV-1 VARIANTS RESISTANT TO THE CCR5 ANTAGONISTS SCH 351125 AND SCH 417690 Antivir Ther. 10, Suppl 1:S66 (abstract no. 59) JM Strizki1, L Wojcik1, AJ Marozsan2, SE Kuhmann2, W Huang3, J Whitcomb3, C Petropoulos3 and JP Moore2 1) Resistance to CCR5 inhibitors emerges slowly in culture and is associated with the sequential accumulation of multiple mutations in gp120. 2) Resistant viruses generally remain CCR5-tropic in primary cells; although CXCR4-tropic variants were detected in one culture 3 culture. 3) Resistant viruses showed cross-resistance to other CCR5 inhibitors but were sensitive to other drug classes. 4) Mutational patterns differed among individual resistant viruses and were not always associated with V3-loop changes. Download Abstracts
|
| 60 | DIFFERENTIAL IMPACTS OF V1-V2 AND V3 MUTATIONS ON RESISTANCE TO A CCR5 INHIBITOR Antivir Ther. 10, Suppl 1:S67 (abstract no. 60) DE Mosier1, A Ramos1, R Nedellec1, R Offord2 and O Hartley2 The order in which mutations were introduced thus had a profound impact on the phenotype of the virus and the sensitivity of PSCRANTES. Moreover, certain combinations of mutations were lethal. The operational mutational pathways leading from R5 to X4 were few (<10% of possible pathways), and invariably led to intermediates with high sensitivity to PSC-RANTES. These results indicate that concerns about CCR5 inhibitors selecting for resistance via coreceptor switching may be overstated. Download Abstracts
|
| 61 | CLONAL ANALYSIS DETECTS PRE-EXISTING R5X4-TROPIC VIRUS IN PATIENT DEMONSTRATING POPULATION-LEVEL TROPISM SHIFT ON 873140 MONOTHERAPY Antivir Ther. 10, Suppl 1:S68 (abstract no. 61) K Kitrinos1, C LaBranche1, M Stanhope1, H Madsen1 and J Demarest1 The data indicate that the change in tropism at the population level observed on day 10 was the result of the emergence of pre-existing dual-tropic virus(-es) that were present but below the limits of detection on day 1. R5-tropic virus remained the dominant species at all timepoints and no X4-tropic only virus was detected. Population and clonal viruses were equally sensitive to 873140. Viruses present in a subject’s quasispecies, which are below the limits of detection with currently available tropism assays, may become detectable following monotherapy with a CCR5 antagonist. Download Abstracts
|
| 62 | NATURAL MUTATIONS IN THE HIV-1 V3 LOOP CONFER ALTERED SENSITIVITY TO ENTRY INHIBITORS AND CORRELATE TO CO-RECEPTOR AVIDITY AND FITNESS Antivir Ther. 10, Suppl 1:S69 (abstract no. 62) M Lobritz, A Marozsan, D Moore, E Fraundorf, K Demers and E Arts These findings suggest that natural polymorphisms at sites 318 and 319 in the V3 loop have significant effects on sensitivity to entry inhibitors, efficiency of host cell entry and fitness. Download Abstracts
|
| 63 | UNIQUE RESPONSE OF TIPRANAVIR TO MULTI-DRUG RESISTANT HIV-1 PROTEASES SUGGESTS NEW WAYS OF COMBATING DRUG RESISTANCE Antivir Ther. 10, Suppl 1:S70 (abstract no. 63) S Muzammil1, LW Kang2, AA Armstrong2, A Jakalian3, PR Bonneau3, V Schmelmer4, LM Amzel2 and E Freire1,2 The current study suggests a unique binding characteristic of tipranavir by which it maintains a high inhibitory potency against protease mutants by either gaining or sustaining minimal loss in binding enthalpy. Download Abstracts
|
| 64 | KINETIC CHARACTERIZATION OF THE POTENT ACTIVITY OF TMC114 ON WILD-TYPE HIV-1 PROTEASE Antivir Ther. 10, Suppl 1:S71 (abstract no. 64) I Dierynck1, IM Keuleers1, M De Wit1, A Tahri1, DL Surleraux1, A Peeters1 and K Hertogs1 1Tibotec, Mechelen, Belgium Using SPR we have shown that TMC114 binds with very high affinity to wild-type HIV- 1 protease. These data provide insights in the molecular mechanism of interactions of protease inhibitors with varying potency against wild-type and resistant HIV. The kinetics of the interaction between TMC114 and multi-drug resistant protease mutants are currently under investigation. Download Abstracts
|
| 65 | MARAVIROC (UK-427,857)-RESISTANT HIV-1 VARIANTS, SELECTED BY SERIAL PASSAGE, ARE SENSITIVE TO CCR5 ANTAGONISTS AND T-20 Antivir Ther. 10, Suppl 1:S72 (abstract no. 65) M Westby, J Mori, C Smith-Burchnell, M Lewis, M Mosley, F Perruccio, R Mansfield, P Dorr and M Perros Maraviroc did not select in vitro for HIV-1 variants cross-resistant to other entry inhibitors, notably other CCR5 antagonists. We propose that SCH-C, SCH-D and GK873140 bind to similar regions of CCR5 to Maraviroc but hold the receptor in different conformations that are sufficient to inhibit entry of MVC-resistant variants. Download Abstracts
|
| 66 | STUDIES WITH 873140, A NOVEL CCR5 ANTAGONIST, DEMONSTRATE SYNERGY WITH ENFUVIRTIDE AND POTENT INHIBITION OF ENFUVIRTIDE-RESISTANT R5-TROPIC HIV-1 Antivir Ther. 10, Suppl 1:S73 (abstract no. 66) CC LaBranche1, D Davison2, RG Ferris1, GW Koszalka2, JF Demarest1, LR Boone1 and ML Greenberg2 The data from these studies predict that 873140 will be effective against enfuvirtideresistant R5-tropic HIV-1. In addition, these in vitro experiments demonstrate synergism and, importantly, the absence of antagonism between 873140 and enfuvirtide, suggesting that these agents would be suitable for use in combination. This study suggests that entry inhibitors used in combination may provide new therapeutic approaches for the treatment of ART-experienced individuals. Download Abstracts
|
| 67 | EVOLUTION OF ENFUVIRTIDE RESISTANCE IN LONGITUDINAL SAMPLES OBTAINED AFTER CONTINUED ENFUVIRTIDE DOSING POST-VIROLOGICAL FAILURE Antivir Ther. 10, Suppl 1:S74 (abstract no. 67) T Melby1, R DeMasi1, GD Miralles1, G Heilek-Snyder2 and ML Greenberg1 Continued treatment with ENF following VF resulted in additional decreases in susceptibility to ENF concomitant with genotypic changes, primarily at the previously established ENF resistance loci and in the HR-2 region. These results suggest that ENF continues to exert selective pressure on HIV-1 following VF. Site-directed mutagenesis and viral fitness studies will be needed to determine the impact of the observed genotypical changes on virus replication and susceptibility to ENF. Download Abstracts
|
| 68 | IMPACT OF MUTATIONS IN HR2 OF HIV-1 ENV GP41 ON SUSCEPTIBILITY TO ENFUVIRTIDE Antivir Ther. 10, Suppl 1:S75 (abstract no. 68) SA Stanfield-Oakley1, SM Mosier1, DK Davison1, R Medinas, G Heilek-Snyder2, N Cammack2 and ML Greenberg1 Mutations N126K and S138A in HR2 were most often associated with modest effects on susceptibility to ENF, though differential effects were noted for individual envelopes. These results contrast with the more evident loss of ENF activity conferred by HR1 mutations. Accumulation of gp41 mutations in HR1 and HR2 may lead to incremental losses of ENF susceptibility. The effect of HR2 mutations may not be limited to ENF sensitivity. Download Abstracts
|
| 69 | GENOTYPICAL AND PHENOTYPICAL EVOLUTION OF VIRUS ENVELOPE THROUGH 48 WEEKS OF T-1249 TREATMENT IN THE T1249-105 STUDY Antivir Ther. 10, Suppl 1:S76 (abstract no. 69) T Melby1, Y Zhang1, N Cammack2, ML Greenberg1 and GD Miralles1 In patients harbouring ENF-resistance who undergo subsequent T1249 treatment, T-1249 resistance developed concurrent with additional and/or alternative substitutions in HR1 and in HR2, particularly at positions 126 and 138. Decreases in susceptibility to T-1249 were often accompanied by the loss of measurable residual ENF susceptibility. Taken together, these findings suggest that T1249 exerts significant additional selective pressure on HIV-1 in relation to enfuvirtide. Download Abstracts
|
| 70 | MULTI-TARGETING HIV-1 ENTRY BY AMINOGLYCOSIDE-ARGININE CONJUGATES (AACS) AND THE MECHANISMS OF HIV-1 AACS RESISTANCE Antivir Ther. 10, Suppl 1:S77 (abstract no. 70) A Lapidot and G Borkow The role of the V3 domain in the interaction of gp120 with CXCR4 has not been directly demonstrated; variable domains such as V1/V2 and V3 of gp120 can both contribute to the interaction with CXCR4 coreceptor. Therefore, mutations in NeoR6 resistant isolates may confer resistance by allowing the interaction of gp120 with CXCR4 in such a way that NeoR6 interference would be minimized. The mechanism of the dual functions of NeoR6, inhibiting HIV-1 entry by binding CXCR4 coreceptor and inhibiting the fusion process is being further investigated. The AACs may thus represent a novel family of fusion inhibitors. Download Abstracts
|
| 71 | MECHANISM OF CELLULAR RESISTANCE TO ANTI-CD63 INHIBITION OF HIV INFECTION Antivir Ther. 10, Suppl 1:S78 (abstract no. 71) H Chen, D Rojo, J von Lindern, N Liburd, MR Ferguson and WA O’Brien CD63 and CD4/CCR5 are associated in discrete membrane domains (TEMs), and this association is required for HIV infection. The interaction is most critical when expression of CD4 and CCR5 is limiting, as in primary MØ, but downregulation of CD63 in high CD4 expressing cells still affects HIV susceptibility. Defining specific mechanisms of efficient viral entry may identify desirable antiviral targets. Download Abstracts
|
| 72 | EFFECTS OF M184V MUTATION IN MULTI-DIDEOXYNUCLEOSIDE ANALOG RESISTANT HIV-1 REVERSE TRANSCRIPTASE ON REMOVAL OF ß-D-DIOXOLANE-GUANINE MONOPHOSPHATE FROM BLOCKED PRIMER Antivir Ther. 10, Suppl 1:S79 (abstract no. 72) J Lennerstrand1,3, N Hassani Espili1, A Pavlova1, CK Chu2, G Asif3 and RF Schinazi3 The 69S-SG mutants demonstrated the lowest and 151M mutants the highest level of resistance for DXG-TP compared with d4T-TP and tenofovir- DP. The M184V mutation reduced levels of ATP mediated excision of incorporated DXG-MP, in a similar manner as for d4T-MP and tenofovir with the 69SSG mutant. However, increased non-ATP-dependent resistance was seen for DXG-TP (and d4T-TP) when the M184V mutation was added to the 151M mutant. Besides the effect of the M184V mutation, these in vitro findings indicate that DXG resistance mainly involves binding discrimination and only modest ATP dependent excision. Download Abstracts
|
| 73 | A PLACEBO-CONTROLLED TRIAL OF THE ADDITION OF THE NRTI ALOVUDINE (AT DOSES OF 2 MG OR LESS PER DAY) TO HAART IN HIGHLY TREATMENT-EXPERIENCED PATIENTS WITH DETECTABLE VIRAL LOADS (VL) Antivir Ther. 10, Suppl 1:S80 (abstract no. 73) J Ghosn, A-M Quinson, C Katlama, L Cotte, C Piketty, N Dorleacq, M-L Bravo, D Mayers and H Valdez At a dose of 2 mg, 4 weeks of alovudine provided a significant VL reduction in patients harboring isolates with a median of four TAMs. Download Abstracts
|
| 74 | ANTIVIRAL PROFILE OF BILR 355 BS AGAINST A LARGE PANEL OF CLINICAL ISOLATES WITH MUTATIONS CONFERRING RESISTANCE TO CURRENTLY AVAILABLE NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) Antivir Ther. 10, Suppl 1:S81 (abstract no. 74) PR Bonneau1, PA Robinson2, Y Lie3, N Parkin3, R van Leeuwen4 and R Bethell1 The susceptibility of clinical isolates to BILR 355 BS was tested. Results show that it maintains potent antiviral activity against a majority of isolates containing mutations associated with NNRTI treatment failures, supporting its continued development for treatment of NNRTI-resistant HIV. Download Abstracts
|
| 75 | CONTEXT DEPENDENT EFFECTS OF MUTATIONS ASSOCIATED WITH RESISTANCE TO INHIBITORS OF HIV-1 INTEGRASE STRAND TRANSFER Antivir Ther. 10, Suppl 1:S82 (abstract no. 75) DJ Hazuda and the MRL HIV-1 Drug Discovery Team These results are consistent with the observation that distinct secondary mutations appear to be selected in the context of different primary mutations. A striking example of these phenomena was observed with two different primary mutations at residue155: N155S selected in vitro and N155H observed in rhesus macaques. The secondary mutation A91R selected after prolonged administration of L-870812 in rhesus macaques was shown to enhance resistance when combined with N155H while having little or no affect in the context of N155S. These analyses provide further evidence to support previous studies suggesting it is possible to identify InSTIs which exhibit distinct resistance profiles and limited cross resistance. Download Abstracts
|
| 76 | DIVALENT METAL ION CHELATING SMALL MOLECULES AS NOVEL HIV INTEGRASE INHIBITORS Antivir Ther. 10, Suppl 1:S83 (abstract no. 76) O Jegede1,2, J Weber1, R Rajagopalan3, WJ Wawro Sr3, JS Babu3 and ME Quiñones-Mateu1 A new generation of drugs targeting HIV integrase enzyme (for example, ß-diketo acid derivatives) are currently being evaluated in clinical trials. Here, we have identified three novel IN inhibitor candidates with different pharmacophores, which may be needed to combat HIV strains resistant to the first line of IN inhibitors. Ongoing (i) enzymatic IN assays (ii) quantification of viral integration and 2-LTR-circle forms and (iii) in vitro development of antiviral resistance to the active compounds will help us to further understand the intracellular antiviral mechanism(s) of these promising agents. Download Abstracts
|
| 77 | PL-100 AND ITS DERIVATIVES, A NOVEL CLASS OF POTENT HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE INHIBITORS: RESISTANCE PROFILE AND PHARMACOKINETICS Antivir Ther. 10, Suppl 1:S84 (abstract no. 77) JJ Wu1, G Sévigny1, BR Stranix1, S Dandache1, M Petrella1, M Ge1, G Milot1, J Yelle1, C Panchal1, N Parkin2, JM Schapiro3 and MA Wainberg4 The combination of a favourable cross-resistance profile, and improved solubility and pharmacokinetics confirms the potential of PPL-100 as a novel PI for treatment of patients infected with PIresistant HIV-1 strains. Download Abstracts
|
| 78 | IMPLICATIONS OF SUBSTRATE SHAPE ON INHIBITOR BINDING AND DRUG RESISTANCE: THE CRYSTAL STRUCTURE OF RO1 IN COMPLEX WITH HIV-1 PROTEASE Antivir Ther. 10, Suppl 1:S85 (abstract no. 78) M Prabu-Jeyabalan1, N King1, E Nalivaika1, G Heilek-Snyder2, N Cammack2 and C Schiffer1 The protease-inhibitor interactions derived from this crystal structure correlates with the results obtained biochemical and viral assays. Compliance of RO1 with the structure and substrate envelope shows why neither I50V nor D30N are selected. Furthermore, deviations from the substrate envelope may result in the emergence of the V32I mutation. Thus, this complex validates our theory and further emphasizes the necessity for inhibitors to fit within the substrate envelope to avoid resistance. Download Abstracts
|
|
Session 4: Mechanisms of HIV drug resistance Abstracts 79 thru 109, Pages S87 to S119 |
|
| 79 | RNASE H DOMAINS OBTAINED FROM TREATMENT-EXPERIENCED PATIENTS INCREASE RESISTANCE TO AZT Antivir Ther. 10, Suppl 1:S89 (abstract no. 79) GN Nikolenko1, KA Frankenberry1, S Palmer1, F Maldarelli1, JW Mellors2, JM Coffin1 and VK Pathak1 These results indicate that RNase H domains that confer substantial resistance to AZT are selected in response to NRTI therapy. The selected RNase H domains may reduce the rate of RNA degradation and, in the context of TAMs, increase AZT resistance in a synergistic manner. These studies indicate the need to include the RNase H domain in future genotypical and phenotypical analyses of NRTI resistance. Download Abstracts
|
| 80 | AN HIV-1 RNASE H INHIBITOR SYNERGIZES WITH THREE DIFFERENT CLASSES OF RT POLYMERASE INHIBITORS IN AN IN VITRO REVERSE TRANSCRIPTION ASSAY Antivir Ther. 10, Suppl 1:S90 (abstract no. 80) MD Miller1, B Feuston1, V Munshi1, K Getty1, J Krueger1, DJ Hazuda1, MA Parniak2, D Lewis1, JA Grobler1 and CA Shaw-Reid1 When tested in an assay that requires RNase H activity and both RNA- and DNA-dependent DNA polymerase activities, the DKA showed synergistic inhibition with each of the polymerase inhibitors. Though a definitive answer to this question must await the availability of a specific RNase H inhibitor with potent antiviral activity in cell culture, our findings to date indicate that a small molecule RNase H inhibitor does not confer resistance to AZT in vitro. Download Abstracts
|
| 81 | SUSCEPTIBILITY MEASUREMENTS USING RESISTANCE TEST VECTORS WITH OR WITHOUT PATIENT-DERIVED C-TERMINUS OF RT, RNASEH AND INTEGRASE ARE LARGELY CONCORDANT Antivir Ther. 10, Suppl 1:S91 (abstract no. 81) S Gupta, S Fransen, EE Paxinos, CJ Petropoulos, C Chappey, W Huang and NT Parkin With rare exceptions, concordant measurements were obtained with recombinant viruses that express either the entire patient derived pol or only PR and incomplete RT fragments. In one sample, where enhanced NNRTI resistance was observed, molecular analysis revealed that domains in pol after codon 305 were essential for this resistance. Capturing the entire patient pol gene has the potential to retain protein-protein interactions from the native virus. Novel mutations within this region could induce enhanced NNRTI resistance by causing structural changes in the NNRTI-binding pocket of RT. Download Abstracts
|
| 82 | AZT RESISTANCE: WHY DO HIV-1 AND HIV-2 CHOOSE DIFFERENT PATHWAYS? Antivir Ther. 10, Suppl 1:S92 (abstract no. 82) PL Boyer1, SG Sarafianos2, E Arnold2 and SH Hughes1 Each RT prefers a pathway for AZT resistance that extends the properties of the wild-type enzyme. Viewed in this light, the development of the excision resistance mechanism by HIV-1 RT is an unfortunate coincidence based on the existence of a nascent ATP binding site that has no clear role in normal viral replication. Download Abstracts
|
| 83 | ATP ENHANCES THE INHIBITORY EFFECT OF NCRTIS (NUCLEOTIDE-COMPETING RT INHIBITORS) Antivir Ther. 10, Suppl 1:S93 (abstract no. 83) D Jochmans1, B Van Schoubroeck1, T Ivens1, P Dehertogh, B Kesteleyn1 and K Hertogs1 Some mutations in RT are known to increase the binding of ATP and thus cause zidovudine resistance; the importance of these mutations on NcRTI susceptibility is currently being investigated. Download Abstracts
|
| 84 | MECHANISTIC DIFFERENCES BETWEEN NOVEL NUCLEOTIDE-COMPETING REVERSE TRANSCRIPTASE INHIBITORS (NCRTIS) AND CLASSICAL CHAIN-TERMINATORS Antivir Ther. 10, Suppl 1:S94 (abstract no. 84) J Deval1, D Jochmans2, K Hertogs2 and M Götte1 NcRTIs are potent inhibitors of HIV-1 replication (EC50=30 nM) as previously shown in cell culture-based assays. Here we showed that NcRTI-1 can occupy the substrate binding site, in spite of structural differences with nucleoside triphosphates. This specific binding is primarily driven by the structure of the primer terminus, and not by the base composition of the template. Download Abstracts
|
| 85 | KINETIC MECHANISM BY WHICH THYMIDINE ANALOG MUTATIONS ANTAGONIZE K65R IN HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 10, Suppl 1:S95 (abstract no. 85) U Parikh, N Sluis-Cremer and J Mellors The WT susceptibility of HIV-1 encoding K65R to AZT results from the counteracting effects of K65R: increased discrimination and decreased excision. This provides further evidence that K65R broadly discriminates against NRTIs including AZT. K65R causes tenofovir resistance by decreasing the catalytic rate of TFV-DP incorporation, and the TAM67 pathway antagonizes K65R by partially restoring the catalytic rate. These kinetic data further support the model that K65R and TAMs have mutually antagonistic resistance mechanisms that can be exploited to optimize NRTI therapy. Download Abstracts
|
| 86 | THE LEVEL OF RT IN HIV-1 PARTICLES AFFECTS SUSCEPTIBILITY TO NNRTIS BUT NOT TO 3TC Antivir Ther. 10, Suppl 1:S96 (abstract no. 86) Z Ambrose1, JG Julias1,2, PL Boyer1, VN KewalRamani1 and SH Hughes1 These data indicate that the level of HIV-1 RT within virions affects susceptibility to NNRTIs and that HIV-1 may be able to decrease its susceptibility Download Abstracts
|
| 87 | SUBSTRATE DEPENDENT INHIBITION OR ACTIVATION OF HIV RNASE H ACTIVITY BY NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS) Antivir Ther. 10, Suppl 1:S97 (abstract no. 87) JQ Hang, Y Yang, Y Li, S Tsing, J Barnett, N Cammack and K Klumpp HIV reverse transcriptase (HIV-RT) contains two distinct protein domains catalysing DNA polymerase and RNase H activities. The binding of NNRTIs to the polymerase domain of HIV-RT can affect HIV RNase H activity, but the mechanism of this long range interaction is unclear. A systematic analysis of HIV RNase H inhibition by NNRTIs was performed using representative compounds and assessing NNRTI interference with different modes of HIV RNase H activity. Download Abstracts
|
| 88 | RELATIONSHIP BETWEEN MUTATIONS IN HIV-1 RNASE H DOMAIN AND NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS RESISTANCE MUTATIONS IN EXPERIENCED PATIENTS Antivir Ther. 10, Suppl 1:S98 (abstract no. 88) AG Marcelin1, B Roquebert1, I Malet1, M Wirden1, A Simon2, C Katlama3 and V Calvez1 These results reinforce the hypothesis that RNase H mutations could be selected during antiretroviral therapy. Whether these mutations have their own impact or are associated to clusters of mutations impacting NRTI therapy should be investigated. Download Abstracts
|
| 89 | ROLE OF THE ß7–ß8-LOOP IN THE 51KDA SUBUNIT OF HIV-1 REVERSE TRANSCRIPTASE IN PROTEIN STABILITY AND DRUG RESISTANCE Antivir Ther. 10, Suppl 1:S99 (abstract no. 89) N Sluis-Cremer1, J Radzio1, MJ Camarasa2, G Tachedjian3 and D Nissley4 Mutations at codons 132, 135 and 138 in the 51kDa subunit of HIV-1 RT can confer high-level resistance to delavirdine and nevirapine, and low level resistance to efavirenz. Download Abstracts
|
| 90 | ENHANCED PYROPHOSPHOROLYTIC-EXCISION OF CARBOVIR CONFERRED BY THE M184V AND L74V ABACAVIR-ASSOCIATED RESISTANCE MUTATIONS Antivir Ther. 10, Suppl 1:S100 (abstract no. 90) JF McCarville1, KL Weaver2, TA Broderick2, WH Miller3, LH Carter2, SA Short2, MR Underwood1, R Lanier1 and P Gerondelis1 Generally, these and some prior observations suggest that rescue of chain-termination, as a mechanism of NRTI resistance, is not limited to zidovudine and ATP-mediated excision. It is interesting that while we observed enhanced pyrophosphorolyticexcision of carbovir by RT with the M184V and L74V mutations, previous studies have shown that these mutations suppress ATP-mediated excision of zidovudine. The significance of this difference is unknown. These results also suggest that resistance to abacavir may result in part from the selection of mutations that allow RT to more readily excise carbovir via pyrophosphorolysis, and that this mechanism may play a role in the preferential selection of M184V and L74V by abacavir in vivo Download Abstracts
|
| 91 | IN VITRO RESISTANCE SELECTION WITH TENOFOVIR AND EMTRICITABINE Antivir Ther. 10, Suppl 1:S101 (abstract no. 91) NA Margot1, J Waters2 and MD Miller1 After extended in vitro passage with tenofovir and emtricitabine, no Q151M or T69 insertion virus was observed. A mixture of three viruses – M184I, K65R and K65R+M184V – was observed with the M184I occurring first. The initial presence of distinct M184I and K65R viral genomes may relate to the effect of the M184V/I mutation to increase susceptibility to tenofovir. In two clinical studies of patients treated with tenofovir and emtricitabine plus either efavirenz or lopinavir, 5 out of 434 patients (1.1%) have developed M184V/I while no patients have developed K65R, consistent with the in vitro observations of slower development of K65R with this combination. Download Abstracts
|
| 92 | SELECTION OF THE HIV-1 REVERSE TRANSCRIPTASE MUTATION K70E IN ANTIRETROVIRAL-NAÏVE SUBJECTS TREATED WITH TENFOVIR/ABACAVIR/LAMIVUDINE THERAPY Antivir Ther. 10, Suppl 1:S102 (abstract no. 92) L Ross1, P Gerondelis1, Q Liao1, B Wine1, M Lim1, M Shaefer1, A Rodriguez2, K Limoli3, W Huang3, NT Parkin3, J Gallant4, R Lanier1 The K70E RT mutation was selected in 10% of the antiretroviral-naïve subjects receiving ABC/3TC/TDF regimen with both baseline and post baseline (pre-therapy switch) genotype. This mutation was also previously reported to be selected in adefovir passage experiments and to be associated with adefovir resistance, and/or with selection in heavily antiretroviral-experienced subjects, it was also selected in one treatment-naïve patient treated with TDF/3TC/EFV, and in one antiretroviral-experienced subject treated with ABC/3TC/TDF/ddI. These data suggest an alternate pathway for tenofovir resistance, while the clonal data suggests antagonism and exclusivity between K65R and K70E at the genomic level. Download Abstracts
|
| 93 | ADEFOVIR-ASSOCIATED HIV-1 RT MUTATION K70E IN THE AGE OF TENOFOVIR Antivir Ther. 10, Suppl 1:S103 (abstract no. 93) R Kagan1, L Ross2, M Winters3, T Merigan3, P Heseltine1 and M Lewinski1 The K70E RT mutation is more prevalent in NRTI-resistant viruses and has become more common in clinical samples since the introduction of tenofovir into clinical use. It has been reported that K70E modestly reduces tenofovir susceptibility in recombinant viruses and decreases RT specific activity and processivity, whereas Y115F increases the fidelity of the RT enzyme. Thus the more frequent occurrence of Y115F in K70E viruses suggests a compensatory role. Download Abstracts
|
| 94 | MUTATIONS AT REVERSE TRANSCRIPTASE (RT) CODONS G196, Q207, H208, R211 AND L214 ARE ASSOCIATED WITH DRUG EXPERIENCE AND SPECIFIC RT MUTATION PATTERNS Antivir Ther. 10, Suppl 1:S104 (abstract no. 94) AM Geretti1, C Sabin1, D Dunn2 and G Nebbia1, on behalf of the UK Collaborative Group on HIV Drug Resistance, and the UK Collaborative HIV Cohort (CHIC) Study Group The strong positive association between H208Y and drug-experience, especially with lamivudine, zalcitabine and indinavir, and the presence of M184V and TAMs suggests a resistance or compensatory role for H208Y. Q207E/A, R211K, L214F, and to a lesser extent G196E, showed an overall negative association with drug-experience, were either positively (G196E, Q207E/A, R211K) or negatively (L214F) associated with M184V, and clustered with the TAM1 or TAM2 pathways. These findings suggest significant interactions occur between key reverse transcriptase resistance-mutations and changes at codons G196/Q207/H208/R211/L214. Further studies are warranted to determine the impact on virological responses. Download Abstracts
|
| 95 | DIFFERENCES IN ENHANCED SUSCEPTIBILITIES TO NNRTIS AND TO ZIDOVUDINE (ZDV) IN SITE DIRECTED MUTANTS (SDMS) BEARING K65R, L74V OR M184V Antivir Ther. 10, Suppl 1:S105 (abstract no. 95) C Chappey, E Coakley, K Limoli, J Whitcomb and N Parkin The non-TA NAMS K65R, L74V and M184V significantly enhance susceptibilities to NNRTIs and to ZDV. Discrete differences between these mutations exist such that EFV susceptibility is enhanced by K65R>L74V and M184V. ZDV susceptibility is enhanced by M184V>L74V>K65R. These observations may have relevance to models exploring the mechanisms of reverse transcriptase inhibitor HS. Download Abstracts
|
| 96 | INVOLVEMENT OF NOVEL HIV-1 REVERSE TRANSCRIPTASE MUTATIONS IN THE HIGHLY ORDERED REGULATION OF NRTI RESISTANCE Antivir Ther. 10, Suppl 1:S106 (abstract no. 96) F Ceccherini-Silberstein1, V Svicher1, T Sing2, M Santoro1, N Beerenwinkel2, F Gago4, A Bertoli1, F Forbici3, MC Bellocchi3, P Narciso3, A d’Arminio Monforte5, A Antinori3 and CF Perno1,3 Our study gives evidence of RT mutational patterns more complex than currently known, that regulate positively and/or negatively NRTI-resistance. This strongly suggests that mutations beyond those currently known to confer resistance should be considered to define more precise algorithms able to predict resistance to antiretroviral drugs. Download Abstracts
|
| 97 | THE COEXISTENCE OF K65R+L74V ON THE SAME HIV GENOME IS RARE BUT POSSIBLE AS EVIDENCED BY CLONING ANALYSIS Antivir Ther. 10, Suppl 1:S107 (abstract no. 97) M Henry, C Tourres, P Colson and C Tamalet Our data confirm that the presence of K65R+L74V double mutant is rare in clinics (0.4% in the studied population). However, patients harbouring this double mutant exhibit a high level plasma viral load (7130–1×106 copies/ml), which is in disagreement with the in vitro studies reporting that this double mutant is highly attenuated for replication and renders the reverse transcriptase dysfunctional. Our findings suggest possible compensatory mechanisms allowing for the coexistence of K65R+L74V, which remains to be established. In addition, surprisingly, this clonal analysis revealed that in two patients, K65R+T215Y which are known to be antagonistic can, in some rare cases, coexist in the same genome. Download Abstracts
|
| 98 | LONG-TERM FOSCARNET THERAPY REMODELS THYMIDINE ANALOGUE MUTATIONS AND REVERSES RESISTANCE TO ZIDOVUDINE. Antivir Ther. 10, Suppl 1:S108 (abstract no. 98) S Mathiesen1, E Dam3,2, B Roge4, AL Laursen4, J Gerstoft1 and F Clavel2 Development of PFA resistance in the context of concomitant PFA and nucleoside analogue pressure requires complex remodelling of TAMs. The unique genotypic and phenotypic changes seen in these viruses likely reflect the delicate trade-off involved in developing resistance to a pyrophosphate analogue while retaining pyrophosphate-mediated primer rescue. Download Abstracts
|
| 99 | STRUCTURAL AND FUNCTIONAL INSIGHTS INTO THE NELFINAVIR-RESISTANT HIV-1 PROTEASE Antivir Ther. 10, Suppl 1:S109 (abstract no. 99) M Kolli1, M Somasundaran1, M Prabu-Jeyabalan1, S Lastere2 and CA Schiffer1 The absence of any covariations between the protease and some of the substrates suggests that only some substrates are likely to co-evolve. The cleavage rate of p1–p6 is one of the slowest and is not optimized for efficient cleavage. A possible reduction in protease efficiency due to the presence of D30N/N88D could possibly drive the p1–p6 substrate to co-evolve and become optimized for more rapid hydrolysis. Download Abstracts
|
| 100 | N88D FACILITATES THE DEVELOPMENT OF MULTIDRUG RESISTANCE FOLLOWING NELFINVAIR TREATMENT FAILURE Antivir Ther. 10, Suppl 1:S110 (abstract no. 100) MA Winters1, SY Rhee1, M Horberg2, A Scarsella3, A Zolopa1, SY Lee3, WJ Fessel2, RW Shafer1 N88D occurs only in combination with other major PI-DRM — usually D30N. In combination with D30N, N88D increases NFV resistance and causes low-level cross-resistance to ATV and SQV. The fact that additional major PI-DRM occur only in the presence of D30N+N88D suggests that N88D facilitates the accumulation of mutations that are incompatible with D30N alone. Download Abstracts
|
| 101 | EVOLUTION OF PROTEASE GENOTYPES AND PHENOTYPES IN PATIENTS RECEIVING ATAZANAVIR-BASED SALVAGE THERAPY Antivir Ther. 10, Suppl 1:S111 (abstract no. 101) C Piketty1, C Chazallon2, S Lebel-Binay3, A-G Marcelin4, V Calvez4, L Gérard2, J-P Aboulker2 and F Clavel5 In patients with extensive PI cross-resistance, ATV treatment can provoke important increases in ATV resistance at a minimal evolutionary cost. These increases can be either produced by the emergence of the characteristic I50L mutation or by other, often remarkably small changes in PR genotypes. Download Abstracts
|
| 102 | ROLE OF HIV-1 PROTEASE RESIDUES 71 AND 89 IN PROTEASE INHIBITOR RESISTANCE OF SUBTYPE G VIRUSES Antivir Ther. 10, Suppl 1:S112 (abstract no. 102) LMF Gonzalez1, K Van Laethem2, AB Abecasis3, EAJM Soares1, K Deforche2, AM Vandamme2, R Camacho3 and MA Soares1 Our in vitro results support the hypothesis that 71T stabilizes 89I in the protease of subtype G isolates, previously evidenced in Bayesian network estimations. We confirm that the mutation 90M confers PI drug resistance also to subtype G strains. Finally, the association of 89I and 90M may further increase PI resistance to subtype G viruses when compared to 90M alone, highlighting novel mutational profiles for antiretroviral drug resistance in non-B subtypes. Download Abstracts
|
| 103 | CRYSTAL STRUCTURES OF FOUR MULTI-DRUG RESISTANT HIV-1 PROTEASES AND IMPLICATIONS FOR DRUG DESIGN Antivir Ther. 10, Suppl 1:S113 (abstract no. 103) LC Kovari1, JF Vickrey1, P Martin1, G Proteasa1, R Yedidi1, I Kovari1, J Martinez2, R MacArthur2, M Spaller3, Z Wawrzak4, MA Winters5 and TC Merigan5 The crystal structures of the four 'wide open' MDR HIV-1 proteases represent a new ensemble of targets for the design of novel protease inhibitors. This work was supported by NIH, amfAR, and the Michigan Technology Tri-Corridor (GM62990, 106457-34-RGGN, and MTTC1798). Download Abstracts
|
| 104 | INFERENCE OF EVOLUTIONARY FORCES DRIVING HIV-1 DRUG-RESISTANCE ACQUISITION UNDER HAART USING LONGITUDINAL HIV-1 PROTEASE GENE SAMPLES Antivir Ther. 10, Suppl 1:S114 (abstract no. 104) N Hasegawa1, W Sugiura2, M Matsuda2, K Mogushi1, H Tanaka1 and F Ren3 We found two main features concerning HIV-1 drug-resistance acquisition. First, our results strongly support that D30N and L90M are mutually exclusive during the evolutionary process. Second, the selective pressure exerted on the virus is highly variable over time when different drugs are administered. We obtained estimates of dN/dS>1 in the sP1, suggesting that the virus was undergoing adaptive evolution when nelfinavir was administered, but the fitness of the sP1 might be lower than that of the sP2 as the latter showed higher dS that means the virus had a higher replication rate. Download Abstracts
|
| 105 | SUBSTITUTION OF METHIONINE AT POSITION 89 OF THE PROTEASE GENE BY OTHER AMINO-ACIDS OCCURS DIFFERENTIALLY DURING SELECTION OF PARTICULAR RESISTANCE PATHWAYS IN SUBTYPE C-PATIENTS Antivir Ther. 10, Suppl 1:S115 (abstract no. 105) Z Grossman1, S Maayan2, D Averbuch2, V Istomin3, H Rudich1, D Ram1, E Mendelson1, K Deforche4 AM Vandamme4 and JM Schapiro5 The frequency of L89M is significantly reduced, as compared to drug-naïve or PI-naïve patients, in PI-treated patients carrying viruses with particular resistance-conferring mutations. L89M is progressively substituted, not only with L89L, but notably also with L89I (P<0.001). L89M may thus be associated with reduced fitness of these mutated viruses. Preferential selection of L90M in nelfinavir-treated C-patients, despite similar reduction in L89M, suggests that L89M generates a higher barrier for selection of D30N. The molecular mechanisms underlying these interactions remain to be elucidated. As resistancedevelopment pathways in different subtypes become more predictable, fine-tuning of treatment regimens may become feasible. Download Abstracts
|
| 106 | ANALYSIS OF INTERFERENCE AND CO-EVOLUTION BETWEEN PROTEASE INHIBITOR RESISTANT MUTATIONS AND GAG MUTATIONS Antivir Ther. 10, Suppl 1:S116 (abstract no. 106) T Ueda, L Myint, T Shiino, M Nishizawa, M Matsuda, W Sugiura Our study confirmed distinct evolutional interference between PI resistant mutations and gag sequences. We identified that the Y132FGag mutation may interfere with V82APR, L90MPR and I54VPR PI resistant mutations. Our results give a better understanding of the HIV drug resistance evolution pathway, and may be beneficial to the design of custom-made treatment protocols. Download Abstracts
|
| 107 | NOVEL HIV GAG BASED PROTEASE DRUG RESISTANCE MECHANISM CAUSED BY AN INCREASED PROCESSING OF THE NC/P1 CLEAVAGE SITE Antivir Ther. 10, Suppl 1:S117 (abstract no. 107) M Nijhuis1, N van Maarseveen1, P Schipper1, B Glass2, D Dulude3, D de Jong1, I Goedegebuure1, L Brakier-Gingras3, HG Kraeusslich2 and C Boucher1 We have identified that increased NC/p1 processing is the underlying mechanism explaining gag related HIV protease drug resistance in the absence of protease mutations. The improved processing at this site may allow the virus to tolerate an inhibitor-induced reduction in protease activity and may thus be a general principle in resistance to protease inhibitors. Download Abstracts
|
| 108 | REDUCED SUSCEPTIBILITY TO PROTEASE INHIBITORS (PI) IN THE ABSENCE OF PRIMARY PI RESISTANCE-ASSOCIATED MUTATIONS. Antivir Ther. 10, Suppl 1:S118 (abstract no. 108) N Parkin, C Chappey, E Lam, and C Petropoulos Although rare, reduced susceptibility to PIs in excess of fivefold in the absence of primary mutations in PR can be observed in clinical samples. Accumulation of secondary mutations and/or polymorphisms in PR, as well as changes in the C-terminal region of gag, are potential contributors to reduced PI susceptibility and may modulate response to PI treatment. Download Abstracts
|
| 109 | LOW RESOLUTION STRUCTURAL MAPPING OF HIV-1 VIF: ANOTHER TARGET TO CIRCUMVENT RESISTANCE. Antivir Ther. 10, Suppl 1:S119 (abstract no. 109) J Auclair1, M Somasundaran1,2** and C Schiffer1** We propose that Vif has a specific and unique tertiary structure along with specific oligomeric forms, suggesting that the protein undergoes a conformational change that exposes different binding interfaces to form higher order oligomers. In the absence of crystallographic data, pursuing our low resolution structural analyses will provide momentum for Vif-targeted structure-based drug designs, and a possible new target to circumvent resistance. Download Abstracts
|
|
Session 5: Epidemiology Abstracts 110 thru 141, Pages S123 to S154 |
|
| 110 | DETECTION OF MINOR POPULATIONS OF DRUG-RESISTANT HIV-1 IN ACUTE SEROCONVERTERS Antivir Ther. 10, Suppl 1:S123 (abstract no. 110) KJ Metzner1, P Rauch1, H Walter1, C Boesecke2, B Zöllner3, H Jessen2, K Schewe4, S Fenske5, H Gellermann5 and H-J Stellbrink3 The prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters can be frequently detected and may impact the success of antiretroviral therapy. In addition, the prevalence of drug-resistant HIV1 as detected by sequencing seems likely to yield an underestimation of the transmission rate of these variant viruses. Download Abstracts
|
| 111 | MULTI-DRUG RESISTANT HIV-1 ARE TRANSMITTED MORE FREQUENTLY THAN CURRENT ESTIMATES Antivir Ther. 10, Suppl 1:S124 (abstract no. 111) JA Johnson1, J-F Li1, A Brant1, D Bennett1, M Cong1, T Spira1, P Sandstrom2 and W Heneine1 Our analysis of transmitted viruses carrying resistance-related mutations found that all four resistance mutations examined were underestimated by conventional sequencing. Interestingly, amongst the previously undetected low-frequency variants, the increases in K70R and D67N were greater than the increases in L90M and M184V, suggesting that they are present in a higher percentage of drug-naïve persons than previously reported. The newlydetected mutations substantially increased the known proportion of transmitted MDR viruses and may explain the poorer than expected antiretroviral treatment responses in persons appearing to lack resistance mutations. Download Abstracts
|
| 112 | TRANSMISSION EVENTS WITHIN RISK GROUPS FOLLOWING PRIMARY HIV-1 INFECTION (PHI) IN QUEBEC (1998–2005) Antivir Ther. 10, Suppl 1:S125 (abstract no. 112) BG Brenner1, M Roger2, D Moisi, C Matte2, M Ntemgwa, JP Routy3, M Legault, H Charest4, MA Wainberg1 and the Quebec PHI Study Group The transmission of viral variants harbouring resistance mutations remains a relatively rare event. However, a major proportion (>50%) of newly transmitted infections may arise during the two year period following PHI. This establishes public health rationale for earlier initiation of treatment of HIV-infected individuals who would also benefit from lower set points in regard to plasma viraemia. Download Abstracts
|
| 113 | SELECTIVE TRANSMISSION OF DRUG RESISTANCE MUTATIONS Antivir Ther. 10, Suppl 1:S126 (abstract no. 113) DAMC van de Vijver1, AMJ Wensing1, B Åsjö2, M Bruckova3, L Bruun Jorgensen4, A Horban5, M Linka3, M Lazanas6, C Loveday7, E MacRae7, C Nielsen4, D Paraskevis8, M Poljak9, E Puchhammer- Stöckl10, L Ruiz11, JCC Schmit12, G Stanczak5, M Stanojevic13, A-M Vandamme14, J Vercauteren14 and CAB Boucher1 on behalf of the SPREAD Programme Complex multi-class and many resistance associated mutations appear to be less frequently transmitted. We suggest that this discrepancy could be due to different transmission fitness and reversion of drug resistance mutations. Based on this study, essential predictions can be made about the mutations that are potentially transmitted to newly infected individuals. Download Abstracts
|
| 114 | SUB-OPTIMAL RESPONSE TO HAART IN PATIENTS TREATED AT TIME OF PRIMARY HIV-1 INFECTION AND INFECTED WITH HIV RESISTANT STRAINS Antivir Ther. 10, Suppl 1:S127 (abstract no. 114) ML Chaix1, L Desquilbet2, J Cottalorda3, D Descamps4, C Deveau2, J Galimand1, C Goujard5, M Harzic6, B Masquelier7, I Pellegrin7, A Ruffault8, V Schneider9, C Tamalet10, M Wirden11, D Costagliola12, F Brun-Vezinet4, C Rouzioux1, L Meyer2 for the French PRIMO Cohort Study Group (ANRS CO 06) and the French ANRS-AC11 Resistance Study Group In this large cohort of HAART-treated PHI-patients, we demonstrate that the presence of drug resistance leads to sub-optimal response to early empirical therapy. Recent French guidelines recommend performing resistance test prospectively in patients with PHI with results available soon after HAART initiation. Download Abstracts
|
| 115 | SLOW REVERSION OF HIV TRANSMITTED DRUG RESISTANCE TO NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS IN SEMEN Antivir Ther. 10, Suppl 1:S128 (abstract no. 115) DM Smith1, JK Wong2, HT Mai1, JM Moreno1, TM Russell1, CC Ignacio1, SDW Frost1, D Richman1,3 and SJ Little1 Transmitted drug resistance can persist in the circulating viral population (HIV RNA) in both blood and semen for over three years. The persistence of drug resistant virus in the male genital tract may contribute to the high prevalence rates of transmitted drug resistance. Download Abstracts
|
| 116 | TRANSMITTED HIV DRUG RESISTANCE: EFFECT OF TREATMENT INTENSIFICATION IN LIMITING THE EPIDEMIC Antivir Ther. 10, Suppl 1:S129 (abstract no. 116) F Lewis1, SDW Frost2, D Pillay3, WC Mathews2, DD Richman2, SJ Little2 and AJ Leigh Brown1 The impact of reduced viral fitness on rate of transmission of drug resistant HIV implies that patient monitoring and treatment intensification in response to ARV failure have limited the epidemic of DR HIV transmission. Introduction of ARV therapy to infected populations without monitoring could lead to uncontrolled epidemics of DR HIV. Download Abstracts
|
| 117 | METHAMPHETAMINE USE IS ASSOCIATED WITH ONGOING HIGH-RISK SEXUAL BEHAVIOURS AMONG HIV-INFECTED INDIVIDUALS WITH DRUG-RESISTANT VIRUS Antivir Ther. 10, Suppl 1:S130 (abstract no. 117) PV Chin-Hong1, SG Deeks1, T Liegler2, MR Krone1, RM Grant1,2, FM Hecht1, E Vittinghoff1, TJ Coates3 and JN Martin1 Among HIV-infected patients with drug-resistant virus, methamphetamine and sildenafil use are associated with high-risk sexual behaviour with HIV-uninfected partners. Because of the public health ramifications of the transmission of drug-resistant HIV, novel approaches are urgently needed to diminish the abuse of these recreational drugs. Download Abstracts
|
| 118 | RISK GROUP PREDICTS THE PREVALENCE OF PRIMARY RESISTANCE AMONGST NEWLY DIAGNOSED HIV-INFECTED PATIENTS PRESENTING WITH ESTABLISHED INFECTION ACCORDING TO THE STARHS ALGORITHM Antivir Ther. 10, Suppl 1:S131 (abstract no. 118) AM Geretti1, C Booth1, WA Labbett1, G Murphy2 and M Johnson1 Unselected systematic testing detected a lower prevalence of primary resistance in newly diagnosed patients with established HIV-1 infection. Nonetheless, the prevalence of resistance was significant in this cohort. White homosexual males infected with B subtype virus were identified as the group with the highest risk of primary resistance. Download Abstracts
|
| 119 | MAPPING NEVIRAPINE AND EFAVIRENZ RESISTANCE USING BAYESIAN NETWORKS OF HIV-1 POL SEQUENCES OF SUBTYPES A, B, C, F AND G Antivir Ther. 10, Suppl 1:S132 (abstract no. 119) K Deforche1, R Camacho2, Z Grossman3, T Silander4, MA Soares5, RW Shafer6, K Van Laethem1, AP Carvalho2, B Wynhoven7, P Cane8, J Clarke9, J Snoeck1, S Sirivichayakul10, K Ariyoshi11, A Holguin12, H Rudich3, R Rodrigues13, MB Bouzas14, F Brun-Vézinet15, P Cahn14, LF Brigido13, V Soriano12, W Sugiura11, P Phanuphak10, L Morris16, J Weber9, D Pillay17, A Tanuri5, PR Harrigan7, JM Schapiro6, D Katzenstein6, R Kantor6 and AM Vandamme1 A Bayesian network technique was used to analyse the role of resistance mutations against efavirenz and nevirapine and interactions with background polymorphisms. The networks verified current knowledge, and found many similarities for nevirapine and efavirenz. We found no evidence of major differences in resistance evolution among the subtypes against these NNRTIs. Download Abstracts
|
| 120 | INFLUENCE OF PATIENT CHARACTERISTICS, YEAR OF INFECTION, CD4 CELL COUNT AND VIRAL LOAD ON THE PRESENCE OF PRIMARY HIV-1 DRUG RESISTANCE IN RECENTLY INFECTED PATIENTS Antivir Ther. 10, Suppl 1:S133 (abstract no. 120) J-P Routy1, MD de B Edwardes2, D Rouleau3, CL Tremblay3, M-R Boulassel1, B Brenner4, R Thomas5, B Trottier5, Cote P6, Baril JG6, R Leblanc1, C Tsoukas7 and MA Wainberg3 Patient characteristics, socio-demographic and education were not related to the presence of DR. In contrast, reduced viral load and being infected before the year 2000 were identified to be the most predictive factors associated with DR at the time of HIV infection. Download Abstracts
|
| 121 | EVOLUTION IN THE POPULATION AT RISK OF TRANSMITTING RESISTANT HIV DURING THE PERIOD 1995–2003 Antivir Ther. 10, Suppl 1:S134 (abstract no. 121) N Lohse1, N Obel1, G Kronborg2, LB Jørgensen3 and J Gerstoft4 The population risk of transmitting resistant HIV has decreased substantially from 1995 to 2003. This decrease contributes to the sustained low risk of transmitted resistance. Still approximately one third of individuals with VL >1000 copies/mL in care are potential carriers of resistant virus, suggesting a reduced transmission capacity among resistant viruses. Download Abstracts
|
| 122 | VIROLOGICAL AND IMMUNOLOGICAL EVOLUTION OF PATIENTS WHO ACQUIRED A MULTI-DRUG RESISTANT (MDR) VIRUS AT TIME OF PRIMARY INFECTION Antivir Ther. 10, Suppl 1:S135 (abstract no. 122) ML Chaix1, C Tamalet2, J Ghosn1, V Schneider3, C Deveau4, J Izopet5, I Pellegrin6, M Harzic7, JCottalorda8, C Delaugerre1, B Masquelier6, C Rouzioux1, L Meyer4, F Brun-Vezinet9, D Costagliola10 for the PRIMO Cohort Study Group (ANRS CO 06) and the AC11-ANRS Resistance Study Group None of these patients had a rapid progression to AIDS, even untreated ones. Empirical treatment may be sub-optimal resulting in an acquisition of additional mutations in these already MDR viruses. Download Abstracts
|
| 123 | PREVALENCE AND DETERMINANTS OF HIV-1 VARIANTS WITH MULTIPLE CLASS DRUG RESISTANCE: RESULTS FROM THE CANADIAN HIV STRAIN AND DRUG RESISTANCE SURVEILLANCE PROGRAM Antivir Ther. 10, Suppl 1:S136 (abstract no. 123) GC Jayaraman1, P Sandstrom1 and CP Archibald1 for the Canadian HIV Strain and Drug Resistance Surveillance Program This population-base study shows continuing transmission of MDR HIV, the prevalence of which is not diminishing over time. Further studies stemming out of this program will inform targeted research, programming and policy on HIV drug resistance testing and treatment. Download Abstracts
|
| 124 | SURVEILLANCE OF DRUG RESISTANCE AND HIV SUBTYPES IN NEWLY DIAGNOSED PATIENTS IN SPAIN DURING 2004 Antivir Ther. 10, Suppl 1:S137 (abstract no. 124) J Martinez-Picado1, C Gutiérrez2, C de Mendoza3, I Erkicia1, P Domingo4, X Camino5, MJ Galindo6, JL Blanco7, M Leal8, A Masabeu9, A Guelar10, JM Llibre11, N Margall4, J Iribarren5, S Gutierrez8, JF Baldoví6, JD Pedreira12, JM Gatell7, S Moreno1, B Clotet3, V Soriano2 and L Ruiz1 on behalf of the Maraton TV3 Study Group The current prevalence of primary RT and PI genotypical resistance in Spain is close to 4%. There is no evidence of an increase in the risk of being infected with drug-resistant viruses during the last 5 years. HIV-1 non-B subtypes were detected in 7% of patients, suggesting a slight increase with respect to older periods. Resistance and subtyping should be monitored continuously in drug-naïve patients in order to recognize as soon as possible any significant change. Download Abstracts
|
| 125 | A MODEL PROGRAM LINKING HIV RESISTANCE SURVEILLANCE AND SENTINEL HIV SEROSURVEILLANCE IN PERU Antivir Ther. 10, Suppl 1:S138 (abstract no. 125) JR Lama1, L Suarez2, A Laguna3, M Acuñña1, J Olson3, JL Sanchez4, C Celum5, J Sanchez1 and RM Grant6 The prevalence of HIV-1 drug resistance in Peru is low, reflecting the low treatment rates prior to 2004, the high frequency of wild-type drug failure among treated persons, and the high incidence of HIV-1 infection. These explanatory factors were all documented in a common and large sampling frame. The low baseline prevalence of drug resistance prior to nationwide treatment roll-out in Peru contrasts with developed countries, where high levels of nucleoside reverse transcriptase inhibitor resistance occurred prior to introduction of combination treatment. Nonetheless, 3 class primary drug resistance has occurred. Download Abstracts
|
| 126 | THE RELATIONSHIP BETWEEN RESISTANCE AND ADHERENCE AND THE ACCUMULATION OF MUTATIONS IN DRUG NAÏVE INDIVIDUALS STARTING HAART IS SPECIFIC TO INDIVIDUAL DRUG CLASSES Antivir Ther. 10, Suppl 1:S139 (abstract no. 126) PR Harrigan1, C Brumme1, B Sattha1, D Bangsberg2, J Montaner1 and RS Hogg1 Multiple 'secondary' (but not 'primary') mutations accumulated more quickly in individuals starting PI-based HAART. The relationship between resistance and non-adherence differs between the drug classes. The results are useful in modeling resistance in individuals starting new HAART. Download Abstracts
|
| 127 | HIV SEXUAL TRANSMISSION RISK BEHAVIOUR AND MULTIDRUG RESISTANT (MDR) HIV Antivir Ther. 10, Suppl 1:S140 (abstract no. 127) M Kozal1, R Amico2, J Chiarella1, D Cornman2, W Fisher3, J Fisher2 and G Friedland1 Patients with drug resistant HIV continue to engage in sexual risk behaviour. Of concern in this population during this time period ~11% of sexual risk events involved HIV with ≥2 ART class resistance. Events with MDR virus were rare and the proportion of partners exposed to MDR was ~1%. Download Abstracts
|
| 128 | PREVALENCE AND ANALYSIS OF A MULTI-DRUG RESISTANT HIV-1 PR AND RT GENOTYPE ASSOCIATED WITH RAPID PROGRESSION TO AIDS IN A LARGE CLINICAL DATABASE Antivir Ther. 10, Suppl 1:S141 (abstract no. 128) R Kagan1, G Blick2, P Heseltine1 and M Lewinski1 Bioinformatic analysis has identified a rare cluster of MDR HIV-1 in four patients in a large clinical database. Although a rare mutational signature was seen in A and B, differences in other genomic regions suggest a more complex epidemiologic link that may include viral recombination. Download Abstracts
|
| 129 | SYSTEMATIC COMPARISON OF PREVALENCE OF MUTATION IN LARGE DATABASE REVEALS RARELY SELECTED MUTATIONAL PAIRS Antivir Ther. 10, Suppl 1:S142 (abstract no. 129) P Cheung, C Woods and PR Harrigan The data confirm and extend the previously reported lack of co-selection of K65R and T215Y. The reduced prevalence (or complete lack) of co-selection of key mutational pairs may provide clues as to which HIV resistance pathways the virus finds difficult to exploit in vivo, and suggest structural constraints on HIV evolution which could potentially be exploited. Download Abstracts
|
| 130 | PATTERNS OF THYMIDINE ANALOGUE MUTATIONS (TAMS) IN SAMPLES SENT FOR ROUTINE HIV DRUG RESISTANCE TESTING Antivir Ther. 10, Suppl 1:S143 (abstract no. 130) DT Dunn, on behalf of UK Collaborative Group on HIV Drug Resistance The division of TAMs into two groups appears to be over-simplistic. Analyses of the relevance of TAMs to cross resistance to other drugs should also take account of the component mutations. Further analyses will investigate clustering of the mutations and determinants of different TAM pathways. Download Abstracts
|
| 131 | INTERACTIONS BETWEEN NEVIRAPINE RESISTANCE MUTATIONS AND NRTI RESISTANCE MUTATIONS Antivir Ther. 10, Suppl 1:S144 (abstract no. 131) K Deforche1, R Camacho2, Z Grossman3, T Silander4, MA Soares5, RW Shafer6, K Van Laethem1, AP Carvalho2, B Wynhoven7, P Cane8, J Clarke9, J Snoeck1, S Sirivichayakul10, K Ariyoshi11, A Holguin12, H Rudich3, R Rodrigues13, MB Bouzas14, F Brun-Vézinet15, P Cahn14, LF Brigido13, V Soriano12, W Sugiura11, P Phanuphak10, L Morris16, J Weber9, D Pillay17, A Tanuri5, PR Harrigan7, JM Schapiro6, D Katzenstein6, R Kantor6 and A-M Vandamme1 The analysis shows a different prevalence of the three most important nevirapine resistance mutations, depending on NRTI resistance mutations and NRTI treatment. The independent influence of AZT and D4T treatment may be due to reversion of resistance mutations. The analysis suggests interactions between NNRTI and NRTI resistance pathways, and in particular an antagonistic effect between 181C and 184V, in addition to earlier reported interactions between 184V and 215Y/F, and 181C and 215Y/F. Download Abstracts
|
| 132 | DIFFERENCES IN THE FREQUENCY OF MINOR SUBSTITUTIONS BETWEEN HIV-1 SUBTYPES AND THEIR POTENTIAL IMPACT ON THE GENETIC BARRIER FOR RESISTANCE TO PROTEASE INHIBITORS Antivir Ther. 10, Suppl 1:S145 (abstract no. 132) DAMC van de Vijver1, AMJ Wensing1,2, G Angarano3, B Åsjö4, C Balotta5, E Boeri6, R Camacho7, M-L Chaix8, D Costagliola9, ELM Op de Coul10, A de Luca11, I Maljkovic12, C de Mendoza13, I Derdelinckx14, Z Grossman15, O Hamouda16, A Hatzakis17, IM Hoepelman2, R Hemmer18 A Horban19, K Korn20, C Kücherer16, T Leitner21, C Loveday22, E MacRae22, L Meyer23, C Nielsen24, V Ormaasen25, L Perrin26, D Paraskevis17, E Puchhammer-Stöckl27, L Ruiz28, M Salminen29, JCC Schmit18, F Schneider18, R Schuurman1, V Soriano13, G Stanczak19, M Stanojevic30, A-M Vandamme14, K Van Laethem14, M Violin5, K Wilbe12, S Yerly26, M Zazzi31 and CAB Boucher1 on behalf of the SPREAD Programme Dissimilarities in the genetic barrier for protease inhibitor resistance are expected across subtypes. Studies are needed to investigate whether these may be clinically relevant. If confirmed, such differences should be taken into account in the initial choice of antiretroviral drug regimens. Download Abstracts
|
| 133 | SELECTION OF RESISTANCE FOLLOWING FIRST-LINE ANTIRETROVIRAL REGIMENS AMONG HIV-1 SUBTYPES Antivir Ther. 10, Suppl 1:S146 (abstract no. 133) R Kantor1, A DeLong1, RW Shafer2, AP Carvalho3, B Wynhoven4, P Cane5, S Sirivichayakul6, MA Soares7, J Snoeck8, H Rudich9, R Rodrigues10, A Holguin11, K Ariyoshi12, MB Bouzas13, P Cahn13, W Sugiura12, V Soriano11, LF Brigido10, Z Grossman9, L Morris14, AM Vandamme8, A Tanuri7, P Phanuphak6, J Weber15, D Pillay16, PR Harrigan4, R Camacho3, JM Schapiro2, J Hogan1 and DA Katzenstein2 While differences in resistance could be partly explained by specific drug exposure or duration, in real life data sets, HIV-1 subtypes evolved different degrees of drug resistance to first line regimens, which may affect decisions on initial and subsequent antiretroviral regimens. Download Abstracts
|
| 134 | HIGH PREVALENCE OF HIV-1 NON-B SUBTYPE RECOMBINANTS AND DIVERSE POLYMORPHIC PROFILES IN A UK CLINICAL COHORT – IMPLICATIONS FOR FUTURE RESISTANCE ANALYSIS Antivir Ther. 10, Suppl 1:S147 (abstract no. 134) E MacRae and C Loveday; on behalf of the ICVC Clinical Collaborative Research Group In a UK NB population, there was a high prevalence of new diverse recombinant viruses. Although few resistance mutations were significantly different between NB and B, there was disproportionate representation of polymorphisms including some currently described as resistance mutations for newer PIs. These data imply the need for specific NB mutational charts for analysis of resistance. Download Abstracts
|
| 135 | SUSCEPTIBILITY TO ARVS OF CRF01_AE, CRF02_AG AND SUBTYPE C VIRUSES FROM NAÏVE PATIENTS: COMPARATIVE GENOTYPICAL AND PHENOTYPICAL DATA Antivir Ther. 10, Suppl 1:S148 (abstract no. 135) HJ Fleury1, TA Toni2, NTH Lan3, PV Hung3, A Deshpande4, P Recordon-Pinson1, A Cheret 5, S Lebel-Binay5 and B Masquelier1 CRF01_AE, CRF02_AG and subtype C viruses are globally susceptible to ARVs but some CRF01_AE, CRF02_AG and subtype C strains may exhibit less susceptibility respectively to NNRTIs, a NRTI (ABC) and a PI (ATV). Download Abstracts
|
| 136 | A SENSITIVE PHENOTYPICAL ASSAY UNCOVERS LOW FREQUENCY NNRTI-RESISTANT HIV-1 RT VARIANTS IN SUBTYPES A, B, C AND D FROM CLINICAL SAMPLES Antivir Ther. 10, Suppl 1:S149 (abstract no. 136) DV Nissley1,2, J Julias1,2, T Flys3, S Hughes2, J Mellors4, JB Jackson3, J Strathern2 and SH Eshleman3 Phenotypical selection in the TyHRT system uncovers low frequency NNRTI-resistant variants that are not detected by standard HIV-1 genotyping methods. This system monitors NNRTI resistance independent of RT sequence bias in subtypes A, B, C and D and should prove a useful tool in the analysis of viral evolution, particularly for non-subtype B strains where less is known about the genetic correlates of resistance. Download Abstracts
|
| 137 | FREQUENCY AND PATTERNS OF SPECIFIC PR MUTATIONS IN BATSWANA SUBTYPE C PATIENTS WHO FAILED A NELFINAVIR-CONTAINING HAART REGIMEN Antivir Ther. 10, Suppl 1:S150 (abstract no. 137) F Doualla-Bell1,2, A Avalos1, T Gaolathe3, M Mine1, S Gaseitsiwe1, B Brenner2, N Ndwapi3, H Moffat3, I Thior1, M Essex4 and MA Wainberg2 Subtype C viruses from Botswana and Ethiopia seem to differ in regard to the likelihood of developing resistance via a D30N versus L90M pathway. The distinct substitution frequencies observed among viruses from these two regions may contribute to distinct pathways to NFV resistance. Download Abstracts
|
| 138 | DIFFERENT SUBSTITUTIONS UNDER DRUG PRESSURE AT PROTEASE CODON 82 IN HIV-1 SUBTYPE G COMPARED TO SUBTYPE B INFECTED INDIVIDUALS INCLUDING A NOVEL I82M RESISTANCE MUTATION Antivir Ther. 10, Suppl 1:S151 (abstract no. 138) R Camacho1, AR Godinho2, P Gomes1, A Abecasis1,3, A-M Vandamme3, C Palma1, AP Carvalho1, J Cabanas1 and J Gonçalves2 We observed significant differences in codon 82 usage between subtypes B and G including a novel I82M PI resistance mutation in subtype G. These differences can be explained by different genetic barriers to resistance in subtype B compared to subtype G. We expect an impact on response to protease inhibitors and especially to tipranavir where 82T and not 82A is conferring resistance. Moreover, the new mutation I82M should be included in the algorithms for interpretation of indinavir genotypical resistance. Download Abstracts
|
| 139 | HIV-1 SUBTYPE A1, C, F AND G STRAINS HAVE A HIGHER TIPRANAVIR MUTATION SCORE THAN SUBTYPE B STRAINS Antivir Ther. 10, Suppl 1:S152 (abstract no. 139) A-M Vandamme1, K Deforche1, K Van Laethem1 and R Camacho2 All non-B subtype sequences tested, whether PI naïve or experienced, displayed a significantly higher TPV mutation score than subtype B, with subtype G most affected. Consequently, TPV is expected to be less effective in patients carrying non-B subtype strains. Download Abstracts
|
| 140 | UTILISATION OF HIV-1 SUBTYPE SPECIFIC CONSENSUS SEQUENCES TO EXPLORE TREATMENT RELATED MUTATIONAL PATTERNS WITHIN AND BETWEEN SUBTYPES Antivir Ther. 10, Suppl 1:S153 (abstract no. 140) R Gifford1 and D Pillay1,2 on behalf of the UK Collaborative Group on HIV-1 Drug Resistance We provide evidence that viral subtype may influence the pattern of drug selected mutations. We also demonstrate that selection of NRTI resistant viral genomes is associated with codon bias at position 65 of RT, possibly due to complex and antagonistic relationship between resistance mutations at this position with those at others. Download Abstracts
|
| 141 | ANTIRETROVIRALS, AFRICA AND THE EVOLUTION OF DRUG-RESISTANT HIV: PREDICTIONS FOR BOTSWANA Antivir Ther. 10, Suppl 1:S154 (abstract no. 141) R Vardavas and S Blower The WHO’s surveillance system in Africa will only detect transmitted resistance by 2009 in countries like Botswana (that plan to achieve high treatment rates) if very fit/transmissible drug-resistant strains evolve. Download Abstracts
|
|
Session 6: HIV pathogenesis, fitness and resistance Abstracts 142 thru 166, Pages S155 to S181 |
|
| 142 | ULTRA-DEEP SEQUENCING OF HIV FROM DRUG RESISTANT PATIENTS Antivir Ther. 10, Suppl 1:S157 (abstract no. 142) JF Simons1, M Egholm1, J Lanza1, G Turenchalk1, B Desany1, M Ronan1, J Knight1, L Du1, J Leamon1, JM Rothberg1 and M Kozal2 We present a sequencing technology that produces 1000-fold more sequencing reads per run than traditional methods. Applying the technology to clinical HIV variants we achieve massive over-sampling (~20 000 000 bases/run) enabling the identification of low-level mutations. Our work suggests that ultra-deep sequencing, due to its sensitivity and quantitative nature, will greatly facilitate the investigations into viral genetic drift, natural selection and response to antiretroviral therapy. Download Abstracts
|
| 143 | FREQUENT POLYMORPHISMS AT PROTEASE AND RT SITES ASSOCIATED WITH DRUG RESISTANCE ARE DETECTED IN TREATMENT NAÏVE PATIENTS BY SINGLE GENOME SEQUENCING Antivir Ther. 10, Suppl 1:S158 (abstract no. 143) M Kearney1, S Palmer1, F Maldarelli1,M Polis2, J Mican2, R Stephens3, D Rock4, J Margolick6, J Mellors5 and J Coffin1 HIV variants with polymorphisms at drug resistance pre-exist frequently as minor species in treatment naïve individuals, even early after infection. Standard sequencing techniques have underestimated the frequency of these variants. The mechanisms responsible for the variable frequency of specific variants among individuals and their impact on treatment response need to be determined. Download Abstracts
|
| 144 | HIV DRUG RESISTANCE AND REPLICATIVE CAPACITY IN PRIMARY HUMAN MACROPHAGES Antivir Ther. 10, Suppl 1:S159 (abstract no. 144) D Perez-Bercoff, S Wurtzer and F Clavel The lower dNTP content of MDMs does not appear to affect the extent of HIV resistance to nucleoside analogues compared to tumor cell-based assays. The replicative capacity of RT mutants, however, is consistently lower in MDM than in tumour cells or PHA-stimulated PBMCs. Download Abstracts
|
| 145 | SUSCEPTIBILITY TO INHIBITORS OF CD4-ENV BINDING CORRELATES WITH MEMBRANE FUSION: IMPLICATIONS FOR HIV-1 ENTRY Antivir Ther. 10, Suppl 1:S160 (abstract no. 145) J Toma, T Wrin, C Chappey, S Fransen, E Lam, J Whitecomb, CJ Petropoulos and W Huang Susceptibility of HIV-1 to CD4-bs inhibitors correlates inversely with susceptibility to CD4 inhibitor and the efficiency of membrane fusion. Envelope molecular clones exhibiting differential susceptibility to CD4 inhibition were distinguished by alterations in gp120 glycosylation and length of variable regions. Based on these observations, we hypothesize that envelope conformations influence the degree of CD4-dependency that is required to mediate membrane fusion and virus entry. Download Abstracts
|
| 146 | REVERSION OF DRUG RESISTANT HIV PROTEASE MUTANTS IS PROHIBITED BY A REDUCTION IN REPLICATION CAPACITY OF THE INTERMEDIATE VARIANTS Antivir Ther. 10, Suppl 1:S161 (abstract no. 146) NM van Maarseveen, AMJ Wensing, D de Jong, M Taconis, CAB Boucher and M Nijhuis Despite a reduced RC of the viral population during PTI, persistence of primary resistance mutations in protease was observed during PTI. Changing of the primary resistance mutations in protease to wild type led to an even further decrease in RC, driving the virus into a fitness valley. The further reduced RC is blocking the route back to wild type, explaining why some drug resistant protease mutants can persist in vivo in absence of drug. Download Abstracts
|
| 147 | CHANGE IN PRO-POL ALLELE FREQUENCY IN CHRONIC HIV-1 INFECTION IS SLOW AND POSITION SPECIFIC Antivir Ther. 10, Suppl 1:S162 (abstract no. 147) F Maldarelli1, M Kearney1, S Palmer1, J Mican2, D Rock-Kress2, C Rehm2, J Mellors3 and J Coffin1 HIV-1 pro-pol variation is nonuniform. Slow or nondetectable change in allele frequency with time suggests relatively large replicating populations. In this context, the presence of rapidly changing alleles may represent sites of strong selective pressure. Download Abstracts
|
| 148 | RAPID DEPLETION OF LATENT HIV INFECTION IN VIVO Antivir Ther. 10, Suppl 1:S163 (abstract no. 148) G Lehrman1, IB Hogue1, S Palmer2, C Jennings3, CA Spina4, A Wiegand2, AL Landay3, RW Coombs5, DD Richman4, JW Mellors6, JM Coffin2, RJ Bosch7 and DM Margolis1,8 These findings suggest that intensified HAART and a clinically tolerable dose of VPA can induce expression and clearance of HIV within resting CD4+ T cells in vivo. Further studies of the effect of HDAC inhibitors such as VPA and of antivirals with novel mechanisms of action such as T-20 on persistent infection within the resting cell reservoir are warranted. Download Abstracts
|
| 149 | IDENTIFICATION OF A MAJOR RESTRICTION IN HIV-1 INTERSUBTYPE RECOMBINATION Antivir Ther. 10, Suppl 1:S164 (abstract no. 149) MPS Chin, TD Rhodes, J Chen, W Fu and W-S Hu These results support the hypothesis that mismatched sequences in the DIS region alter the formation of functional heterozygous virions, thereby lowering the observable recombination rate. This is the first measurement of recombination rate between different subtypes of HIV-1 and the first in vivo evidence demonstrating a major restriction in HIV-1 intersubtype recombination. These results have important implications for the generation of circulating intersubtype recombinants within the infected population and in virus evolution. Download Abstracts
|
| 150 | A SYSTEMATIC ANALYSIS OF THE FITNESS EFFECTS OF MUTATIONS ASSOCIATED WITH RESISTANCE TO PROTEASE INHIBITORS Antivir Ther. 10, Suppl 1:S165 (abstract no. 150) GJ Henderson1, N Parkin2 and R Swanstrom1 Differences in selective pressure acting on amino acid residues in PR reflect the biological effects of mutations at these positions. This comprehensive analysis confirms many assumptions about the effects of resistance associated mutations in PR, but also points out those mutations whose characteristics are not in accord with these assumptions, suggesting more complex interactions at these positions. Download Abstracts
|
| 151 | EMERGING POPULATIONS OF ENFUVIRTIDE RESISTANT HIV-1 CONTAIN MULTIPLE VARIANTS THAT COMPETE FOR DOMINANCE Antivir Ther. 10, Suppl 1:S166 (abstract no. 151) W Huang1, L Maroldo1,2, S Fransen1, J Toma1, JM Whitcomb1, C Chappey1, E Coakley1 and CJ Petropoulos1 ENF resistance was associated with the early emergence of multiple variants containing distinct mutations in HR1. G-I-E variants exhibiting the largest reductions in susceptibility were prevalent at d10 and predominated by d40. The apparent lack of differences in env infectivity suggest that selection for G-I-E variants was driven by ENF pressure, however the contribution of infectivity will require a more thorough analysis of potential compensatory mutations. Download Abstracts
|
| 152 | GENOTYPIC AND PHENOTYPIC EXPLANATION FOR FAILURE OF TRIPLE NRTI THERAPY WITH LAMIVUDINE, DIDANOSINE AND TENOFOVIR Antivir Ther. 10, Suppl 1:S167 (abstract no. 152) D Barnas1, H Bazmi1, C Bixby1, D Koontz1, J Jemsek2 and J Mellors1 The rapid failure of the triple NRTI regimen of 3TC+ddI+TFV results from 2 nucleotide changes in RT, which when combined, confer resistance to each drug. In virus having 184V, the 65R mutation reverses hypersusceptibility to TFV and increases resistance to ddI. Only 50% of sequences had both 65R and 184V, indicating that resistance to 3TC alone contributed to failure. The reason standard susceptibility testing of samples with 65R and184V has not shown TFV resistance is that the virus population likely consists of a mixture of TFV-hypersusceptible virus with 184V alone and TFV-resistant virus with 65R+184V. Download Abstracts
|
| 153 | CONTRIBUTION OF GAG-PROTEASE AND RT IN FITNESS CHANGES OBSERVED IN VIRUSES WITH MULTIPLE RESISTANCE Antivir Ther. 10, Suppl 1:S168 (abstract no. 153) E Dam1,2, S Lastère1,3, D Descamps1,3, O Launay4, X Duval5, C Dalban6, D Costagliola6 and F Clavel1 Remarkable diversity in gag-PR fitness was seen in this group of patients, contrasting with limited variations in RT fitness. This diversity suggests complex compensatory mechanisms for PR fitness, which could, in some viruses, involve HIV regions not examined by current assays. Download Abstracts
|
| 154 | FITNESS COST OF DRUG RESISTANCE MUTATIONS IS RELATIVE AND IS MODULATED BY OTHER RESISTANCE MUTATIONS: IMPLICATIONS FOR PERSISTANCE OF TRANSMITTED RESISTANCE Antivir Ther. 10, Suppl 1:S169 (abstract no. 154) M Cong, DE Bennett, W Heneine and JG García-Lerma We confirm by using controlled competition assays that resistance mutations confer a wide range of fitness costs which predicts different persistence times. We also demonstrate thatdemonstrate that the the fitness cost of individual resistance mutations is relative and can be decreased or enhanced by other impact of drug resistance mutations. Our results suggest that modulation of fitness cost of mutations will play a role in the rate of reversion and persistence of transmitted resistance mutations. Download Abstracts
|
| 155 | IN VITRO MICROBICIDE ACTIVITY OF THE NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) UC781 AGAINST NNRTI-RESISTANT HIV-1 Antivir Ther. 10, Suppl 1:S170 (abstract no. 155) MM Hossain and MA Parniak Transmission of NNRTI-resistant virus may not be a significant issue at current microbicide formulation levels of UC781 (minimum of 0.1% which is equivalent to 3 mM UC781 assuming complete solubility). Nonetheless, the reduced microbicidal activity of UC781 against NNRTI-resistant HIV-1 suggests that NNRTI-based microbicide formulations might best be developed as combination microbicides containing one or more additional antiviral agents. Download Abstracts
|
| 156 | THE PRESENCE OF SELECTED MUTATIONS INFLUENCE THE DISAPPEARANCE OF MAJOR PROTEASE RESISTANCE MUTATIONS DURING TREATMENT INTERRUPTION Antivir Ther. 10, Suppl 1:S171 (abstract no. 156) F Ceccherini-Silberstein1, M Santoro1, C Gori2, V Svicher1, M Santoro1, F Forbici2, N Esposito1, R Bellagamba2, R D’Arrigo2, M Zaccarelli2, A Cenci1, U Visco2, A Antinori2 and CF Perno1,2 Minor mutations play a crucial role in the appearance and stabilization of L90M at virological failure. Overall, the characterization of mutations more detrimental for viral fitness can be used in designing clinical strategies aimed to reduce the virus-related damage in highly drug-experienced patients. Download Abstracts
|
| 157 | NNRTI-RESISTANCE DETECTED IN RT-SHIV-INFECTED MACAQUES TREATED WITH SINGLE DOSE NEVIRAPINE Antivir Ther. 10, Suppl 1:S172 (abstract no. 157) Z Ambrose1, A Wiegand1, J Kimata3, F Maldarelli1, SH Hughes1, S Palmer1, JW Mellors4, JM Coffin1, JD Lifson2 and VNK Ramani1 Single dose NVP treatment in RTSHIV mne infected pigtail macaques results in antiviral resistance. Our results suggest that this macaque RTSHIV mne model will be useful for studies of NNRTIbased therapies and NNRTI resistance, including the selection, relative fitness and persistence of resistant variants. Download Abstracts
|
| 158 | USING MIXTURES OF AMINO ACIDS TO DETECT INDIVIDUAL-AND POPULATION-LEVEL SELECTION OF HIV-1 PROTEASE Antivir Ther. 10, Suppl 1:S173 (abstract no. 158) SDW Frost1, SL Kosakovsky Pond1, DM Smith1, DD Richman1,2 and AJ Leigh Brown Our results support a model in which the HIV-1 genome has been shaped by the averaging of bursts of positive selection across multiple individuals, with sites under positive selection at the population that are also highly diverse within individuals. Selection pressure by antiviral agents can lead to increased within-host diversity of minor resistance mutations. For large sequence datasets, analysis of mixtures of amino acids can provide detailed information on the selection pressures shaping HIV genetic variation. Download Abstracts
|
| 159 | REPLICATIVE CAPACITY AND DRUG SUSCEPTIBILITY OF VIRAL CLONES CARRYING DUPLICATION OF THE PTAPP MOTIF IN WILD-TYPE AND DRUG-RESISTANT PR-RT CONTEXTS Antivir Ther. 10, Suppl 1:S174 (abstract no. 159) S Lastere1,2, V Perrin2, E Dam2,3, F Brun-Vezinet1,2 and F Mammano2 The impact of duplication of PTAPP motif on viral RC depended on the PR-RT context. This duplication was not associated with changes in susceptibility to most PI and NRTI tested. These data argue against a role for PTAPP duplication in the development of drug resistance in treated patients. Download Abstracts
|
| 160 | E-184V STUDY: IMMUNOLOGICAL AND VIROLOGICAL CORRELATES OF HIV-1 REPLICATIVE CAPACITY Antivir Ther. 10, Suppl 1:S175 (abstract no. 160) N Gianotti1, S Menzo2, A Danise1, L Galli1, G Schira1, A Galli1, M Mammarella1, M Clementi1, A Lazzarin1 and A Castagna1 RC recovery is lower in patients treated with lamivudine monotherapy than in those undergoing TI. CD4+ decline observed during the study is at least partially explained by changes in HIV-1 RC. Download Abstracts
|
| 161 | CONCORDANCE OF HIV DRUG RESISTANCE GENOTYPING RESULTS FOR PAIRED PBMC AND PLASMA SPECIMENS FROM PERSONS NEWLY DIAGNOSED WITH HIV Antivir Ther. 10, Suppl 1:S176 (abstract no. 161) DE Bennett1, MA Winters2, RW Shafer2, W Heneine1, L McCormick1, J Johnson1, JG Garcia-Lerma1, I Zaidi1 and H Weinstock3 Our results show no meaningful differences between sequences from proviral DNA sequences from PBMC and plasma RNA sequences from individuals newly diagnosed with HIV, whether their infections were recent or chronic. These findings suggest that similar MAR could be identified regardless of whether plasma specimens or specimens that may include proviral DNA, such as dried blood spots, are used for HIV drug resistance surveillance in drug-naïve individuals. Download Abstracts
|
| 162 | HIV-1 RESISTANT STRAINS ACQUIRED AT TIME OF PRIMARY INFECTION MASSIVELY FUEL THE CELLULAR RESERVOIR Antivir Ther. 10, Suppl 1:S177 (abstract no. 162) J Ghosn1, C Delaugerre1, C Goujard2, C Deveau3, C Tamalet4, J Galimand1, I Pellegrin5, D Emilie6, B Hoen7, L Meyer3, C Rouzioux1 and ML Chaix1 for the PRIMO cohort study group (ANRS CO 06) In all the study patients, resistant HIV-strains acquired at time of primary infection established themselves as the dominant viral population, and massively fuelled the cellular reservoir at an early time-point in infection. Download Abstracts
|
| 163 | RELATIVE FITNESS AND INFECTIVITY OF A CLINICAL HIV-1 ISOLATE WITH A DELETION OF CODON 70 IN REVERSE TRANSCRIPTASE Antivir Ther. 10, Suppl 1:S178 (abstract no. 163) ZX Hu1, H Hatano1, M Wild2, R Kalayjian2, B Gripshover3 and DR Kuritzkes1 A codon 70 deletion enhanced replication kinetics and fitness of recombinant virus expressing patient-derived RT carrying L74V and Q151M mutations, and enhanced relative infectivity in the presence of ABC. It will be interesting to compare the effects of Δ70 on biochemical and kinetic properties of RT with those of other insertion/deletion mutations in this region. Download Abstracts
|
| 164 | NOVEL DETERMINANTS IN HIV-1 GAG REGULATE PROTEASE ACTIVITY AND VIRAL FITNESS IN A DRUG RESISTANT VARIANT Antivir Ther. 10, Suppl 1:S179 (abstract no. 164) S Koch1, P O’Brien1, S Rose1, S Pomeroy1, B Dunn1, J Sleasman2 and M Goodenow1 Novel positions in gag, specifically the C cleavage site, p7NC, and p6Pol, modulate drug resistant PR processing activity and subsequent virus replication. In addition, the functional linkage between Gag and PR supports evidence for physical interaction between the two regions. Download Abstracts
|
| 165 | GAG MUTATIONS IDENTIFIED IN WILD-TYPE HIV-1 THAT IMPACT VIRAL REPLICATION CAPACITY (RC) MAY REPRESENT CYTOTOXIC T-LYMPHOCYTE (CTL) ESCAPE MUTATIONS Antivir Ther. 10, Suppl 1:S180 (abstract no. 165) M Bates1, N Parkin1, D Richman2, S Little2, L Ross3 and C Chappey1 The observation that gag mutations impact RC in WT viruses was confirmed in a larger dataset, and the many of the same mutations were significant in viruses from patients known to be ART-naïve. Most mutations occurred at known CTL epitopes, suggesting that evasion of host immunity may provide the selective pressure to maintain gag mutations that impair RC in WT viruses; other mutations may represent unrecognized epitopes or sites with as yet unknown functional importance. Download Abstracts
|
| 166 | COMPREHENSIVE ANALYSES OF PLASMA AND CEREBROSPINAL FLUID (CSF) COMPARTMENTS FOR HIV DRUG RESISTANCE, VIRAL LOAD, AND CHEMOKINE/CYTOKINE LEVELS LINKED TO NEUROPSYCHIATRIC TESTING AND NMR SPECTROSCOPY FINDINGS IN HIV-INFECTED SUBJECTS TREATED AT A UNIVERSITY-BASED HIV CLINIC Antivir Ther. 10, Suppl 1:S181 (abstract no. 166) VA Johnson1,2, JD Hazelwood2, EZ Kovacs3, WC Summers2, W-J Chu4, JA Den Hollander2, BA Bush5, LB Nabors6, JM Kilby2, FC Kinney5, JL Raper2, BJ Shelton7, S Hartley8, A Madan8, KL Netson8, S Buchthal2 and DJ Benos3 HIV RNA levels were higher in plasma than CSF. Phylogenetic reconstruction of HIV pol sequences showed peripheral blood and CNS from each subject were most closely related to one another, but distinct suggesting viral compartmentalization occurs. Discordance in HIV drug resistance profiles between plasma and CSF was less apparent over time in one subject, suggesting equilibration can occur between these two viral compartments. Download Abstracts
|
This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1980, 2005. AEGiS.