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15th International HIV Drug Resistance Workshop:
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Cite as: Antivir Ther. 2006, 11:xx (abstract no. ??)
where "xx" is the page number and "??" is the abstract number.
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Plenary abstracts Abstracts P1 thru P2, Pages P3 to P4 |
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| P1 | NEW ACHIEVEMENTS IN HEPATITIS C VIRUS RESEARCH AND THEIR IMPLICATIONS FOR ANTIVIRAL THERAPY Antivir Ther. 2006, 11:P3 (abstract no. P1) R Bartenschlager Hepatitis C viruses (HCV) comprise a group of positive- strand RNA viruses that together with the flaviviruses and the pestiviruses belong to the Flaviviridae family. As a major cause of acute and chronic liver disease that currently affects 170 million people worldwide and for which no selective therapy exists HCV has received much attention. |
| P2 | HBV DRUG RESISTANCE Antivir Ther. 2006, 11:P4 (abstract no. P2) S Locarnini The hepatitis B virus (HBV) has evolved a unique life cycle that results in the production of enormous viral loads during active replication without actually killing the infected hepatocyte directly. Most of the disease process of hepatitis B is the result of an inadequate or inappropriate host immune response. |
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Session 1: HBV/HCV drug resistance Abstracts 1 thru 13, Pages S3 to S15 |
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| 1 | SELECTIVE EXCISION OF NON-OBLIGATE CHAIN-TERMINATORS BY THE HEPATITIS C VIRUS NS5B POLYMERASE Antivir Ther. 2006, 11:S3 (abstract no. 1) J Deval, CM D’Abramo and M Götte The results of this study suggest that the phosphorolytic removal of incorporated pyrimidine analogues is an important factor that can diminish the inhibitory effects of these compounds. Our findings provide a rational for the development of purine analogues as antiviral drugs, despite the fact that these compounds compete with high intracellular concentrations of ATP and GTP. |
| 2 | SYNERGY OF SMALL MOLECULAR INHIBITORS OF HEPATITIS C VIRUS REPLICATION DIRECTED AT DIFFERENT VIRAL TARGETS Antivir Ther. 2006, 11:S4 (abstract no. 2) DL Wyles, K Kaihara and RT Schooley Small molecular inhibitors of the HCV protease and polymerase show antiviral activity in our genotype 1 replicon system. Combinations of inhibitors targeting different viral proteins act synergistically; while combinations targeting the same viral protein are additive. Synergistic combinations of HCV inhibitors are likely to produce greater viral load decreases in vivo and substantially increase the resistance barrier. These effects should result in the increased durability and efficacy of small molecule-based HCV antiviral therapy. This system provides a useful approach for the in vitro testing of antiviral combinations in anticipation of rationally designed clinical studies of combination chemotherapy directed at HCV. |
| 3 | SELECTION AND CHARACTERIZATION OF HEPATITIS C VIRUS REPLICON VARIANTS DUALLY RESISTANT TO THUMB AND PALM BINDING NON-NUCLEOSIDE POLYMERASE INHIBITORS Antivir Ther. 2006, 11:S5 (abstract no. 3) S Le Pogam, H Kang, SF Harris, V Leveque, AM Giannetti, S Ali, WR Jiang, S Rajyaguru, G Tavares, C Oshiro, T Hendricks, K Klumpp, J Symons, MF Browner, N Cammack and I Nájera These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme. Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple resistant mutants. |
| 4 | SELECTION AND CHARACTERIZATION OF MUTATIONS CONFERRING RESISTANCE TO A HCV RNA DEPENDENT RNA POLYMERASE INHIBITOR IN VITRO Antivir Ther. 2006, 11:S6 (abstract no. 4) A Molla, L Lu, P Krishnan, R Pithawalla, T Dekhtyar, T Ng, W He, T Pilot-Matias, W Jiang, Y Liu, G Koev, K Stewart, D Larson, T Bosse, W Kati, R Wagner, D Kempf and H Mo This study suggested that single amino acid substitutions at any of several positions could result in reduced susceptibility to A-848837. However, combination of this inhibitor with IFN or protease inhibitor may be synergistic in controlling HCV replication. |
| 5 | ROBUST SUPPRESSION OF VIRAL REPLICATION IN HCV INFECTED CHIMPANZEES BY A NUCLEOSIDE INHIBITOR OF THE NS5B POLYMERASE Antivir Ther. 2006, 11:S7 (abstract no. 5) DB Olsen1, SS Carroll1, M-El Davies2, L Handt3, K Koeplinger4, R Zhang4, S Ludmerer1, M MacCoss, DJ Hazuda1 Currently approved therapies to treat infection by hepatitis C virus (HCV) consist of combinations of pegylated interferon a and ribavirin which have limited utility in patients infected with genotype 1 viruses. The development of agents that can enhance both the efficacy and tolerability of HCV therapy is therefore highly desired and much effort has recently focused on direct antiviral agents targeting the virally encoded RNA-dependent RNA polymerase (RdRp), NS5B, and protease, NS3. |
| 6 | SeqHepB: A SEQUENCE ANALYSIS PROGRAM AND RELATIONAL DATABASE SYSTEM FOR HEPATITIS B VIRUS MUTATIONS IN HBV MONO- AND HIV-HBV CO-INFECTED PATIENTS Antivir Ther. 2006, 11:S8 (abstract no. 6) A Bartholomeusz, L Yuen, A Ayres and S Locarnini Chronic hepatitis B is a disease with a complex natural history, and this complexity increases with the use of antiviral agents and also in co-infection with HIV. The SeqHepB system is an important tool that will enable the physician to individualize patient management, to cope with the explosion of antiviral drug-resistant associated HBV mutations, and should prove to be a useful therapeutic guide in clinical settings as new antiviral agents and combinations thereof, are implemented into patient care. |
| 7 | DEVELOPMENT OF A NEW HIGH THROUGHPUT PHENOTYPING TEST TO EVALUATE THE DRUG SUSCEPTIBILITY OF HBV STRAINS ISOLATED FROM PATIENTS: PHENOSCRIPT-HBV® Antivir Ther. 2006, 11:S9 (abstract no. 7) L Barraud1, S Durantel1, A Ollivet1, D Durantel2, S Lebel-Binay1, K Skrabal1, JL Faudon3, G Avenard1 and F Zoulim2 We have developed a high throughput technique using a new whole HBV genome amplification method that allows phenotyping of the overall population found in patients, in a quick and sensitive way. This method should allow a better monitoring of patients receiving antiviral therapy, as well as the screening and the optimization of new drugs against HBV. |
| 8 | CHANGING PREVALENCE OF ADEFOVIR- AND LAMIVUDINE ASSOCIATED MUTATIONS IN CLINICAL HBV SAMPLES SUBMITTED TO A NATIONAL REFERENCE LABORATORY Antivir Ther. 2006, 11:S10 (abstract no. 8) R Kagan, J Platt, H Hamdan, R Chen and M Lewinski Adefovir-associated mutations are emerging in the clinical population while lamivudine-associated mutations are declining and tenofovir and entecavir resistance is not yet evident. BCP mutations, associated with improved interferon response of HbeAG(+) virus, were more prevalent in subtype C. The precore mutation, which may improve replicative capacity of lamivudine-resistant HBV, did not correlate with lamivudine mutations. Continued surveillance of clinical sequences may aid in the detection of emerging mutational patterns to HBV antivirals and combination therapies. |
| 9 | TENOFOVIR DISOPROXIL FUMARATE (TDF) AND ADEFOVIR DIPIVOXIL (ADV) ARE EFFECTIVE IN CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IN SUBJECTS WHO ARE CO-INFECTED WITH HIV: HBV AND HIV DRUG RESISTANCE RESULTS OF ACTG PROTOCOL A5127 Antivir Ther. 2006, 11:S11 (abstract no. 9) VA Johnson1,2, JD Hazelwood2, J Andersen3, AB Miller2, T Liu3, B Alston-Smith4, CL Brosgart5, JF Rooney5, B Polsky6 and MG Peters7 for the ACTG Protocol A5127 Team Both TDF and ADV were effective for HBV. No known or novel TDF- or ADV-associated HBV drug resistance mutations were detected during TDF or ADV therapy of HBV-infected subjects with HIV co-infection. |
| 10 | DEVELOPMENT OF A RAPID PHENOTYPIC SUSCEPTIBILITY ASSAY FOR HCV POLYMERASE INHIBITORS Antivir Ther. 2006, 11:S12 (abstract no. 10) E Penuel, D Han, K Favero, E Lam, Y Liu, NT Parkin We have developed a prototype transient transfection, luciferase-based phenotypic susceptibility assay for patient-derived NS5B polymerase. Approximately 50% of patient samples can be assayed for drug susceptibility. Several reported resistance mutations previously identified by in vitro selection also occur as natural polymorphisms in patient samples with reductions in susceptibility to NS5B polymerase inhibitors. We expect that the use of phenotypic susceptibility assays will be crucial for complete understanding of HCV drug resistance. |
| 11 | RIBAVIRIN TREATMENT, BUT NOT INTERFERON PHARMACOKINETICS, IS ASSOCIATED WITH SUPPRESSION OF VIRAL REBOUNDS DURING HIGH DOSE INTERFERON-α-2a THERAPY OF HEPATITIS C INFECTION Antivir Ther. 2006, 11:S13 (abstract 11) SDW Frost1, L Ruffini2, DD Richman1,3 and G Lake-Bakaar4 Viral rebounds, which may arise due to resistance to interferon, may occur even during sustained interferon levels, and are suppressed by ribavirin. Our models can fit complex viral dynamic data, with fewer convergence problems suffered by previous models, and may be important in the clinical evaluation of new antiviral agents. |
| 12 | HIGH GENOTYPIC AND PHENOTYPIC RESOLUTION OF HCV NS3/4A PROTEASE QUASISPECIES: MUTATIONS ASSOCIATED WITH DRUG RESISTANCE IN TREATMENT-NAÏVE PATIENTS Antivir Ther. 2006, 11:S14 (abstract no. 12) S Franco, B Clotet and MA Martínez Our findings revealed the presence of protease resistance mutations in HCV therapy naïve patients. Although a high number of protease variants were identified in the three patients studied, 52.6% of these variants displayed a catalytic efficiency comparable to that showed by the master proteases. Different selective forces are acting in different infected individuals and affect the HCV protease amino acid diversification. |
| 13 | CHARACTERIZATION OF RESISTANT HCV REPLICON-CONTAINING CELLS SELECTED WITH PSI-6130 Antivir Ther. 2006, 11:S15 (abstract 13) P Furman1, L Stuyver1, T McBrayer1, C Niu1, M Keilman1, E Murakami1, H Bao1, A De La Rosa1, W-R Jiang2, J Symons2 and M J Otto1 The HCV NS5B S282T mutation, which is associated with resistance to several 2'-Cmethyl analogs, remained sensitive to PSI-6130 in both replicon and RdRp assays. Sequencing the RdRp of resistant replicons isolated by passaging in the presence of PSI-6130 failed to identify resistant mutations. However, reduced cellular dCK activity was observed. |
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Session 2: Resistance to new antiretroviral agents Abstracts 14 thru 32, Pages S19 to S37 |
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| 14 | MOLECULAR DETERMINANTS OF RESISTANCE TO THE gp41-DIRECTED NEUTRALIZING ANTIBODY D5: INSIGHTS FROM A CRYSTAL STRUCTURE OF D5 Fab BOUND TO 5-helix Antivir Ther. 2006, 11:S19 (abstract no. 14) MD Miller for the HIV Antibody Discovery Team The human monoclonal antibody D5-IgG1 binds to the heptad repeat 1 (HR1) region of the HIV-1 gp41 protein and blocks entry of diverse HIV isolates from multiple subtypes. D5 is thought to block entry by preventing gp41 folding into a “trimer-of-hairpins” conformation in a mechanism analogous to that of T20. We now present data that define the D5 epitope, demonstrate that HR1 is the physiologic target of D5, and begin to address the binding correlates of neutralization. |
| 15 | IDENTIFICATION AND CHARACTERIZATION OF NOVEL REVERSE TRANSCRIPTASE INHIBITORS Antivir Ther. 2006, 11:S20 (abstract no. 15) O Jegede1,2, A Khodyakova1, M Chernov1, A Gudkov1 and ME Quiñones-Mateu1 Our cell-based drug screening system proved to be efficient to discover new antiretroviral agents, allowing us to expand the screening or our small molecule library. To this point, we have identified three novel NNRTI, one of them active against common NNRTI-resistant viruses. Interestingly, we identified three small molecules related to NcRTI-1, which selected for a different RT mutation profile. Ongoing experiments will help us to further characterize these compounds with the intention to begin phase I studies in the near future. |
| 16 | THE IN VITRO RESISTANCE PROFILE OF NcRTI-1 IS COMPLEMENTARY WITH THE RESISTANCE PROFILE OF TENOFOVIR AND ZIDOVUDINE Antivir Ther. 2006, 11:S21 (abstract 16) D Jochmans, M Van Ginderen, I De Baere, P Dehertogh, S Hallenberger and K Hertogs In vitro, we identified a novel HIV RT mutational pattern A62V+P133H, associated with NcRTI-1 resistance and reversal of zidovudine resistance. Together with the main pattern of M184V+Y115F-associated resistance and K65R-associated hypersusceptibility, these data indicate that the resistance profile of NcRTIs fits favorably with the resistance profiles of zidovudine and tenofovir. It could be hypothesized that these in vitro findings will translate in favourable synergies in the clinic. |
| 17 | IMPACT OF BASELINE K103N OR Y181C ON THE VIROLOGICAL RESPONSE TO THE NNRTI TMC125: ANALYSIS OF STUDY TMC125-C223 Antivir Ther. 2006, 11:S22 (abstract no. 17) J Vingerhoets, K Janssen, J Welkenhuysen-Gybels, M Peeters, K Cao-Van, L Tambuyzer, B Woodfall and MP de Béthune These data showed that TMC125 retained activity in the presence of multiple NNRTI mutations, including K103N and Y181C, where current NNRTIs were not expected to be active. The presence of Y181C, in combination with other NNRTI mutations, seemed to be associated with higher FC values for TMC125 and decreased virological response. Additional data are required to confirm these findings. |
| 18 | CHARACTERIZATION OF SUSCEPTIBILITY PROFILES FOR THE CCR5 ANTAGONIST VICRIVIROC IN TREATMENT-NAÏVE HIV-INFECTED SUBJECTS Antivir Ther. 2006, 11:S23 (abstract no. 18) R Landovitz1, G Faetkenhauer2, C Hoffmann3, H Horst4, J Strizki1, J Whitcomb5, F Gheyas1, D Knepp1 and W Greaves1 Baseline susceptibility assessed by multiple parameters did not appear to be associated with long-term virological breakthrough, nor was change in these parameters during the period of monotherapy of this study. It is unlikely that resistance was generated during the initial 14 days of this trial by the administration of monotherapy. The breakthrough parameters suggest that either susceptibility to vicriviroc was unaltered or not detected by these assays in the majority of isolates. The significance of the reduced RPMS values seen in 15% of breakthrough subjects requires further investigation. |
| 19 | THE PATHWAY LEADING TO TMC114 RESISTANCE IS DIFFERENT FOR TMC114 COMPARED WITH OTHER PROTEASE INHIBITORS Antivir Ther. 2006, 11:S24 (abstract no. 19) S De Meyer, H Azijn, E Fransen, I De Baere, M Van Ginderen, B Maes and M-P de Béthune Selection of TMC114-resistant HIV1 from WT strains is slower and more difficult than for other PIs. Characterization of the selected viruses showed that resistance to TMC114 occurs through a different pathway compared with other PIs. |
| 20 | NEXT GENERATION HIV PEPTIDE FUSION INHIBITORS TRI999 AND TRI-1144 DISPLAY ENHANCED ACTIVITY AGAINST ENFUVIRTIDE SENSITIVE AND RESISTANT VIRUSES Antivir Ther. 2006, 11:S25 (abstract no. 20) SA Stanfield-Oakley1, SM Mosier1, DK Davison1, RJMedinas1, L Jin1, MK Delmedico1, JJ Dwyer1, G Heilek-Snyder2 and ML Greenberg1 TRI-999 and TRI-1144 retained their antiviral activity against ENF-resistant viruses. These newer FIs also exhibited more uniform coverage of ENF-sensitive isolates evidenced by a narrower range of observed IC50s and the effect of genetic context on FI activity seems to be minimized. These findings demonstrate some of the enhanced antiviral activities of TRI-999 and TRI-1144. |
| 21 | VIROLOGICAL CHARACTERIZATION OF TREATMENT NAÏVE SUBJECTS FAILING AN APLAVIROC-BASED REGIMEN WITH EITHER LAMIVUDINE/ZIDOVUDINE OR LOPINAVIR/RITONAVIR Antivir Ther. 2006, 11:S26 (abstract no. 21) KM Kitrinos, DM Irlbeck, CC LaBranche, HA Madsen and JF Demarest M184V was the only detected resistance mutation associated with VF in subjects receiving APL/3TC/ZDV. For VFs receiving APL/LPV/r, a minority of viruses in the quasispecies of 5/9 subjects showed reduced susceptibility to APL. Changes in population tropism readouts were relatively infrequent; additional data show that such changes may occur in the absence of treatment and/or during the initial viral load decline. Overall, very few subjects receiving an APL-containing regimen experienced VF. The pathway to resistance for APL remains to be determined. |
| 22 | NATURAL VARIATION IN SUSCEPTIBILITY OF PATIENT-DERIVED HIV-1 TO AN INTEGRASE STRAND TRANSFER INHIBITOR Antivir Ther. 2006, 11:S27 (abstract no. 22) S Fransen, S Gupta, E Paxinos, W Huang, C Chappey, C Petropoulos and Neil Parkin The variation in InSTI susceptibility among untreated patients is relatively narrow and similar to that of most nucleoside reverse transcriptase inhibitors. Naturally occurring polymorphisms such as T97A and K156N in integrase can modulate InSTI susceptibility and may impact the magnitude of resistance in viruses from treated patients. |
| 23 | NATURAL POLYMORPHISM OF THE HIV-1 INTEGRASE GENE AND MUTATIONS ASSOCIATED WITH INTEGRASE INHIBITOR RESISTANCE Antivir Ther. 2006, 11:S28 (abstract no. 23) M Lataillade, J Chiarella and MJ Kozal In this sample of HIV-1 clade B clinical strains, the IN gene displayed a high level of diversity with 62% of the aa positions being polymorphic. INI mutations associated with INI resistance occurred frequently as natural polymorphisms. Major INI mutations associated with high level resistance to the compounds in late stage development were infrequent and this may help explain the excellent virological responses demonstrated in clinical trials. |
| 24 | METALLACARBORANES AS SPECIFIC AND POTENT INHIBITORS OF HIV PROTEASE AND ITS RESISTANT MUTANTS Antivir Ther. 2006, 11:S29 (abstract no. 24) J Pokorná1, P Cígler1, M Kozísek1, P Rezácová2, J Brynda2, J Plesek3, B Grüner3, J Sedlácek2, J Bodem4, H-G Kraeusslich4, V Král5 and J Konvalinka1 The novel type of binding, chemical and biological stability, low toxicity and the possibility to introduce various modifications make boron clusters attractive novel pharmacophores for potent and specific inhibition of drug-resistant HIV species. |
| 25 | IN VITRO SELECTION STRATEGY AND CHARACTERIZATION OF RESISTANCE TO A NOVEL HIGHLY POTENT HIV PROTEASE INHIBITOR SPI-256 Antivir Ther. 2006, 11:S30 (abstract no. 25) E Afonina, S Gulnik, H Yokoe and J Erickson I50V appeared to be a common mutational escape pathway to SPI-256 for WT as well as highly divergent, MDR PI-resistant viruses. However, the selection of virus resistant to SPI-256 was a very slow process and required multiple passages with small incremental increases of concentration. These results support the potential use of SPI-256 in both first-line and salvage therapy regimens. |
| 26 | ANTIVIRAL ACTIVITY OF SPI-256 AGAINST WT AND MDR STRAINS Antivir Ther. 2006, 11:S31 (abstract no. 26) SV Gulnik1, E Afonina1, M Eissenstat1, H Yokoe1, B. Yu1, M Markowitz2, NT Parkin3 and JW Erickson1 SPI-256 is more potent than currently approved PIs against WT HIV-1 in different in vitro assays. It maintains nanomolar potency against worst-case scenario MDR HIV isolates and is equipotent against viruses of different clades and co-receptor tropism. SPI-256 has the potential to be used as part of first line as well as salvage therapy in treatment regimens world-wide. |
| 27 | RESISTANCE-ASSOCIATED AMINO ACID SUBSTITUTIONS AND DRUG SUSCEPTIBILITY ANALYSIS OF VIRUS FROM SUBJECTS ENTERING THE PHASE II DOSE-RANGING STUDY OF A NEW PROTEASE INHIBITOR (PI), BRECANAVIR, HPR20001 (STRIVE) Antivir Ther. 2006, 11:S32 (abstract no. 27) C Craig1, P Yates1, J Flemming2, J Horton3, H Zhao3 on behalf of the STRIVE Study Team Brecanavir shows greater intrinsic antiviral activity than the other PIs tested, and lower FC than all PIs tested except tipranavir/ritonavir, which displays relatively low intrinsic potency and low clinical cut-off. The number of major PI mutations appears to differentiate viruses above and below thresholds. Preliminary analysis of this relatively small dataset suggests that specific mutations associated with increased FC might reflect in part association with higher numbers of mutations. These hypotheses are undergoing clinical evaluation in ongoing trials. |
| 28 | ANALYSES OF SUSCEPTIBILITY AND CROSS-RESISTANCE BETWEEN TMC114 AND OTHER PROTEASE INHIBITORS AMONG >56,000 ROUTINE SAMPLES, USING LINEAR REGRESSION MODEL-BASED FOLD CHANGE PREDICTIONS Antivir Ther. 2006, 11:S33 (abstract no. 28) M Staes1, E Van Craenenbroeck1, H Vermeiren1, J Villacian1, L Bacheler2, M-P de Béthune3, S De Meyer3, G Picchio4 These results confirm and extend the suggestion that TMC114 has a high genetic barrier to the development of resistance, and that HIV-1 isolates with high levels of resistance to individual or multiple PIs remain susceptible to TMC114. |
| 29 | PHENOTYPIC SUSCEPTIBILITY TO TMC-114 AND TIPRANAVIR BEFORE AND AFTER LOPINAVIR/RITONAVIR-BASED TREATMENT IN SUBJECTS DEMONSTRATING EVOLUTION OF LOPINAVIR RESISTANCE Antivir Ther. 2006, 11:S34 (abstract no. 29) M King1, TP Young1, B Bernstein1, L Klein1, DK Tokimoto1, MJ Fath1, N Parkin2, GJ Hanna1 and DJ Kempf1 Evolution of high-level resistance to lopinavir/ritonavir generally resulted in lower RC with relatively little change in susceptibility to tipranavir and modest changes in susceptibility to TMC-114 in some subjects. Boosted tipranavir or TMC-114, guided by resistance testing, may be useful for salvage therapy following incremental evolution of resistance on a lopinavir/ritonavir-based regimen. |
| 30 | PATTERNS OF TIPRANAVIR SUSCEPTIBILITY AND CROSS-RESISTANCE AMONG PATIENT SAMPLES SUBMITTED FOR ROUTINE RESISTANCE TESTING Antivir Ther. 2006, 11:S35 (abstract no. 30) NT Parkin, C Chappey and E Coakley Cross resistance between tipranavir and other approved PIs is lowest with nelfinavir and saquinavir, highest with amprenavir and atazanavir, but modest in any case. Viruses with single primary mutations remain largely sensitive to tipranavir, with the exception of I84V and V82L. |
| 31 | IMPACT OF OPTIMISED BACKGROUND REGIMEN ON VIROLOGICAL RESPONSE TO TMC-114 WITH LOW-DOSE RITONAVIR IN POWER 1, 2 AND 3, AS MEASURED BY THE PHENOTYPIC SUSCEPTIBILITY SCORE Antivir Ther. 2006, 11:S36 (abstract no. 31) T Vangeneugden1, B Winters2, L Bacheler3, G Picchio3, M-P de Béthune1, P McKenna2 and D Miralles1 Baseline PSS of the OBR, as determined by the LM-based virco®TYPE, was a strong predictor of virological response. Response to TMC-114/ritonavir treatment in the group of patients with the lowest PSS was still higher than for control, regardless of subgroup. |
| 32 | GENOTYPIC ANALYSIS OF THE GAG CA/SP1 CLEAVAGE SITE IN PATIENTS RECEIVING THE MATURATION INHIBITOR PA-457 Antivir Ther. 2006, 11:S34 (abstract no. 32) A Castillo1, C Adamson2, J Doto1, D Martin1, C Wild1, G Allaway1, E Freed2 and K Salzwedel1 No known PA-457 resistance mutations were observed in any of the 56 patients studied by population genotyping up to 28 days after the final dose. This is despite the fact that, due to the long half-life of PA-457, patients were exposed to sub-optimal drug concentrations for up to three weeks after completion of dosing, thus increasing the potential for resistance development. This suggests that there may be a fitness cost associated with the resistance mutations identified in vitro. PA-457 differs from drugs such as nevirapine and enfuvirtide to which resistance can develop rapidly in vivo during monotherapy. Future studies will determine whether PA-457 resistance emerges after more prolonged treatment. |
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Session 3: HIV pathogenesis, fitness and resistance Abstracts 33 thru 68, Pages S41 to S76 |
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| 33 | SEQUENTIAL EMERGENCE AND CLINICAL IMPLICATIONS OF K70E AND K65R VIRAL MUTANTS DURING PROLONGED TENOFOVIR MONOTHERAPY IN RHESUS MACAQUES WITH CHRONIC RT-SHIV INFECTION Antivir Ther. 2006, 11:S41 (abstract no. 33) KKA Van Rompay1, JA Johnson2, EJ Blackwood1, J Lipscomb2, N Bischofberger3, W Heneine2 and TW North4,5 These observations suggest that K70E and K65R emerge sequentially, often prior to their detection by conventional sequencing. Immune-mediated and residual drug-dependent antiviral activities both play a role in diminishing viraemia in some animals despite the emergence of K65R mutants. This implies that for persons infected with K65R-mutant HIV-1, continued tenofovir treatment may offer some benefit. |
| 34 | SELECTION OF NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) RESISTANT HIV-1 AFTER DISCONTINUATION OF A VIROLOGICALLY SUPPRESSIVE REGIMEN Antivir Ther. 2006, 11:S42 (abstract no. 34) CB Hare1, J Mellors2, A Krambrink3, Z Su3, D Skiest4, D Margolis5, S Patel3, D Barnas3, L Frenkel6, R Coombs6, F Aweeka1, G Morse7, DW Haas8, R Kim8, V Boltz9, S Palmer9, J Coffin9 and DV Havlir1 Individuals who discontinue NNRTI-containing ART while virologically suppressed are at substantial risk (20%) of demonstrating NNRTI resistance at virological rebound that may persist in plasma for months. The highest risk of resistance is associated with low-level viral replication (HIV RNA 51–400 c/ml) at treatment discontinuation (45% resistance). The effect of this resistance on response to subsequent NNRTI-containing ART warrants further study. |
| 35 | IMPACT OF ENFUVIRTIDE RESISTANCE GENOTYPE ON CD4 INCREASES IN PATIENTS WITH ONGOING VIRAL REPLICATION WHILE RECEIVING ENFUVIRTIDE Antivir Ther. 2006, 11:S43 (abstract no. 35) T Melby1, M DeSpirito1, R DeMasi1, G HeilekSnyder2, J Thommes3, ML Greenberg1 and N Graham1 Substitutions at the V38 position were associated with continued CD4 increases in patients failing ongoing enfuvirtide-based therapy independent of residual virological activity. Other substitutions in gp41 were associated with varying degrees of sustained CD4 increases from baseline and deserve further study. These data are consistent not only with a viral fitness cost but also suggest a reduced pathogenicity in viruses developing resistance to enfuvirtide. |
| 36 | STRONG DECREASE IN VIRAL REPLICATION CAPACITY IN HIV-1 CONTAINING BOTH K65R AND Q151M MUTATIONS Antivir Ther. 2006, 11:S44 (abstract no. 36) J Garcia-Perez1, M Perez-Olmeda1, S Sanchez-Palomino2, L Menendez-Arias3, L Valer4, F Garcia5, T Pumarola2, V Soriano4 and J Alcami1 A strong decrease (60%) in viral RC was observed in RV containing the K65R in association with Q151Mc as compared with single K65R (30%) and Q151Mc (5–10%) mutations. |
| 37 | REPLICATIVE CAPACITY, SUSCEPTIBILITY TO CHEMOKINES AND TO ENTRY INHIBITORS IN SEQUENTIAL HIV VARIANTS FROM THE ACUTE AND CHRONIC PHASE OF INFECTION Antivir Ther. 2006, 11:S45 (abstract no. 37) V Perrin and F Mammano During the acute phase of infection, selection appears to favour viral variants with high replicative capacity, associated with efficient CCR5 use. Later in infection, protection from the immune response becomes a dominant selective parameter, which forces the virus into a different compromise between replicative capacity and escape. |
| 38 | LOW REPLICATION CAPACITY OF SUBTYPE C HIV IN THE
PHENOSENSE ASSAY IS NOT A RESULT OF HETEROLOGOUS
SUBTYPE B GAG OR POL SEQUENCES Antivir Ther. 2006, 11:S43 (abstract no. 38) SS Choe and NT Parkin The lower RC values observed for subtype C-derived patient sequences does not appear to be a result of mismatched gag and pol sequences. Therefore, additional sequences outside of the gag and pol regions significantly influence RC. The location of these sequences, effects on drug susceptibility and the clinical relevance of these findings are under investigation. |
| 39 | FITNESS COMPARISON OF THYMIDINE ANALOGUE RESISTANCE PATHWAY MUTANTS IN HIV-1 REVERSE TRANSCRIPTASE Antivir Ther. 2006, 11:S47 (abstract no. 39) ZX Hu, F Giguel, H Hatano, P Reid, J Lu and DR Kuritzkes These results, together with our earlier data, help explain the clustering of 210W with TAM-1 mutations and 215F with TAM-2 mutations. |
| 40 | REPLICATIVE FITNESS OF A PANEL OF PROTOTYPICAL HIV-1 CONTAINING MULTIPLE NRTI-RESISTANCE MUTATIONS Antivir Ther. 2006, 11:S48 (abstract no. 40) J Weber1, M Mirza1, O Jegede1, J Weberova1, RW Shafer2 and ME Quiñones-Mateu1 We demonstrated that pairwise competitions are necessary to study small differences in the replicative fitness of drug-resistant viruses, which otherwise would remain undetected by using other methodology. In addition, we established relative replicative fitness values for this panel of viruses. This information will prove to be valuable since these viruses are being broadly used as references in the study of novel antiretroviral compounds. |
| 41 | REPLICATION CAPACITY AND DRUG SUSCEPTIBILITY OF LOPINAVIR-RESISTANT HIV-2 Antivir Ther. 2006, 11:S49 (abstract no. 41) H Mo1, X Lu2, S Masse1, T Dekhtyar1, L Lu1, R Mondal1, G Koev1, T Ng, B Bernstein1, F Gao2 and A Molla1 LPV/r may provide antiviral activity in HIV-2 infected patients. However, the emergence of a single mutation at I47A may be associated with significantly reduced LPV activity against HIV-2. However, these isolates may maintain susceptibility to TMC-114 and be hyper-susceptible to SQV. |
| 42 | A NOVEL ASSAY TO DETERMINE THE HIV-1 IN VITRO REPLICATION RATE INDEPENDENT OF VIRUS INPUT CONCENTRATION, AND ITS APPLICATION TO ANALYSE THE EVOLUTION OF THE REPLICATION RATE OF VIRUSES EMERGING FROM IN VITRO SELECTION WITH TMC-114 Antivir Ther. 2006, 11:S50 (abstract no. 42) LT Rimsky1, H Van Marck1, B Maes1, Y Verlinden2, L Bacheler3, H Azijn1, I De Baere1, G Kraus1 and M–P de Béthune1 A novel assay has been designed, which accurately and reproducibly determines the RR of fully replicative viruses, independently of virus input concentration. Viruses selected under pressure of TMC-114 show a decrease in RR, which correlates with the number of mutations in the protease. |
| 43 | DIMINISHED REPRESENTATION OF HIV-1 VARIANTS HARBOURING M184V MUTATIONS IN PRIMARY HIV INFECTION (PHI) Antivir Ther. 2006, 11:S51 (abstract no. 43) F Frankel, BG Brenner, D Moisi, M Oliveira, JP Routy, MA Wainberg and Co-Investigators of the Quebec Primary HIV-1 Infection Study The reduced transmissibility of M184V in PHI is not simply explained by rapid deselect ion of M184V or by the presence of less fit M184V minority species. These studies support the concept that viruses containing M184V may be negatively impacted in regard to transmission fitness as well as replication competence. |
| 44 | BLUNTED VIRAEMIA AND SLOW DRUG RESISTANCE EMERGENCE IN RHESUS MACAQUES FAILING CHEMOPROPHYLAXIS WITH EMTRICITABINE Antivir Ther. 2006, 11:S52 (abstract no. 44) JG García-Lerma, S Qari, R Otten, J Johnson, C Kim, E Jackson, M Monsour, R Janssen, TM Folks and W Heneine Breakthrough infections with SHIV during chemoprophylaxis with emtricitabine is associated with wild type virus and a substantial reduction in viraemia. Selection of drug resistance is slower than previously seen in monotherapy of established infections. This provides opportunities for early discontinuation of prophylaxis before drug resistance emerges. |
| 45 | FADING OF K103N-CONTAINING HIV-1 VARIANTS AFTER INITIAL AND REPEATED EXPOSURE TO SINGLE DOSE NEVIRAPINE FOR PREVENTION OF HIV-1 MOTHER-TO-CHILD TRANSMISSION (HIVNET 012) Antivir Ther. 2006, 11:S53 (abstract no. 45) TS Flys1, A Mwatha2, D Donnell2, C Nakabiito3, P Musoke3, F Mmiro3, JB Jackson1, LA Guay1 and SH Eshleman K103N was undetectable in plasma from most women within 6–8 weeks of single dose nevirapine exposure, and in plasma from all evaluable women within 4 years. This included women who were re-exposed to single dose nevirapine in a subsequent pregnancy during the follow-up period. K103N-containing variants persisted longer in women with subtype D and in women with higher baseline viral loads. |
| 46 | HIGH PREVALENCE OF THE K65R MUTATION IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED BATSWANA PATIENTS TREATED WITH DDI/D4T-BASED REGIMENS Antivir Ther. 2006, 11:S54 (abstract no. 46) F Doualla-Bell1,2, A Avalos3, B Brenner2, T Gaolathe1,3, M Mine1,3, S Gaseitsiwe1, B Spira2, M Essex1,4 and MA Wainberg2 In summary, the K65R substitution may emerge at a higher frequency in individuals infected with subtype C viruses who experienced treatment with ddI/d4T. In view of widespread ARV access in sub-Saharan countries, these findings establish a degree of concern in regard to the possibility that certain mutations, such as K65R, may emerge more rapidly in viruses of subtype C. |
| 47 | THE IMPACT OF THE N43D RESISTANCE MUTATION ON ENFUVIRTIDE SENSITIVITY AND SIX-HELIX BUNDLE STRUCTURE IN COMBINATION WITH THE E137K POLYMORPHISM Antivir Ther. 2006, 11:S55 (abstract no. 47) X Bai, KL Wilson, JE Seedorff, D Ahrens, J Green, DK Davison, L Jin, SA Stanfield-Oakley, S Mosier, T Melby, ML Greenberg and JJ Dwyer The impact of N43D and E137K on the stability and structure of the six-helix bundle provide a mechanistic basis for the effect on ENF susceptibility and structural insights into potential compensatory mutations. These data also suggest a possible structural basis by which ENF resistance mutations may cause defects in viral fitness. |
| 48 | ROLE OF HOST FACTORS IN DEFINING R5 VERSUS X4 DOMINANCE DURING PARTIALLY SUPPRESSIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2006, 11:S56 (abstract no. 48) Z Grossman1, P Hunt2 and SG Deeks2 Several observations support the hypothesis that X4 dominance over R5 occurring during therapy reflects a diminished density of CCR5-expressing T-cells in lymphoid tissues. |
| 49 | THE IMPACT OF STRUCTURAL AND FUNCTIONAL CONSTRAINTS ACTING AT THE NUCLEIC ACID LEVEL ON THE EVOLUTION OF DRUG RESISTANCE IN HIV-1 Antivir Ther. 2006, 11:S57 (abstract no. 49) RJM Gifford1, P Kellam1, DT Dunn3 and D Pillay1,2 on behalf of the UK Collaborative Group on HIV Drug Resistance We provide evidence of widespread structural and functional constraint acting within HIV-1 pol nucleic acid sequences. These constraints appear to limit or influence the spectrum of amino acids arising as a result of drug selection pressure and should be considered when developing new antiviral strategies. |
| 50 | IN VIVO SELECTION BY ENF OF ENV QUASISPECIES WITH OPTIMAL POTENTIAL FOR PHENOTYPIC EXPRESSION OF HR1 MUTATIONS Antivir Ther. 2006, 11:S58 (abstract no. 50) A Goubard, F Clavel, F Mammano and B Labrosse During ENF treatment in vivo, HR1 mutations are selected in unique env quasi-species that favour the expression of ENF resistance, a property that could be explained by an intrinsic lower susceptibility to ENF and/or by an increased replicative capacity. |
| 51 | DIFFICULTIES IN USING GENOTYPE DATA TO PREDICT HIV-1 CO-RECEPTOR TROPISM Antivir Ther. 2006, 11:S59 (abstract no. 51) EW Stawiski1, Y Liu1, JW Toma1, W Huang1, T Wrin1, S Fransen1, JM Whitcomb1, E Coakley1, NT Parkin1, SH Eshleman2, CJ Petropoulos1 and C Chappey1 V3 sequence can be used in predicting tropism, however, there are technical and analytical limitations to this approach to make this technique a diagnostic test with clinical value. Clinical data will be needed to assess the predictive value of both phenotype and genotype approaches. |
| 52 | CELL TO CELL HIV-1 TRANSFER BY DENDRITIC CELLS DEPENDS ON VIRUS REPLICATION IN DCS AND IS BLOCKED BY INHIBITORS OF HIV REPLICATION Antivir Ther. 2006, 11:S57 (abstract no. 52) B Bosch, R Peña, M Bofill, B Clotet and JA Esté We conclude that DC-SIGN participates in cis HIV infection of DCs and that virus replication in DCs is required for virus transmission to primary CD4 T cells. |
| 53 | LONGITUDINAL EVALUATION OF VIRAL CO-RECEPTOR TROPISM SWITCHES AMONG HIV-INFECTED PATIENTS WITH DRUG-RESISTANT VIRAEMIA Antivir Ther. 2006, 11:S61 (abstract no. 53) PW Hunt1, W Huang2, E Coakley2, C Petropoulos2, M Bates2, R Hoh1, JN Martin1 and SG Deeks1 Among stably-treated patients with drug-resistant viraemia, the incidence of new tropism changes is relatively low, occurs in both directions, and is often associated with relatively modest changes in CXCR4 entry. Deferring treatment change may carry a small risk of losing CCR5 inhibitors as an effective future treatment option. Furthermore, some treated patients with apparently pure R5 may have harboured X4 in the recent past. |
| 54 | HIV-1 PERSISTS IN AGED MEMORY CD4+ T LYMPHOCYTES DURING 8 YEARS OF EFFECTIVE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) WITHOUT SIGNS OF VIRAL EVOLUTION Antivir Ther. 2006, 11:S62 (abstract no. 54) HSLM Nottet1, SJ van Dijk1, EB Fanoy1, I Goedegebuure1, N Vrisekoop2, JCC Borleffs3 and CAB Boucher1 The absence of a decline in viral DNA load in combination with a reduction in viral RNA load suggest persistence of proviral HIV-1 in a stable latent HIV-1 reservoir. Flow cytometric analysis did suggest that proviral DNA is becoming part of normal T cell homeostasis explaining the high level of HIV DNA in aged memory cells. The lack of drug resistance mutations under continued drug pressure indicates absence of viral replication for up to 8 years. Indeed, viral evolution could not be detected in all 9 patients. |
| 55 | LOW-LEVEL VIRAEMIA PERSISTS FOR AT LEAST 7 YEARS IN PATIENTS ON SUPPRESSIVE ANTIRETROVIRAL THERAPY Antivir Ther. 2006, 11:S63 (abstract no. 55) S Palmer1, M King2, A Wiegand1, F Maldarelli1, B Bernstein2, G Hanna2, S Brun2, D Kempf2, J Mellors3 and J Coffin1 These results are consistent with our prior finding that persistent viraemia on treatment may originate from virus produced by cells that are infected before initiation of therapy. The newly described biphasic decay in persistent viraemia implies that relatively short-lived cells contribute to viraemia through 96–144 weeks, and very long-lived cells contribute thereafter. |
| 56 | LUNG MACROPHAGES PROVIDE A SANCTUARY FOR HIV-1 REPLICATION DURING ART Antivir Ther. 2006, 11:S64 (abstract no. 56) TA Wagner1,2, NH Tobin1,2, JL McKernan2, GH Learn1, JI Mullins1 and LM Frenkel1,2 The greater viral divergence and frequency of drug-resistant variants in HIV-1 from sputa suggests that lung cells, possibly macrophages, may provide a relative sanctuary from antiretrovirals that allows viral replication during “effective” ART. |
| 57 | HIV P7/P1 AND P1/P6-GAG CLEAVAGE SITE MUTATIONS ARE ASSOCIATED WITH SPECIFIC PR MUTATIONS AND PI RESISTANCE PROFILES. Antivir Ther. 2006, 11:S65 (abstract no. 57) J Verheyen1, E Litau1, T Sing2, U Schuldenzucker3, M Däumer1, M Oette4, T Lengauer2, D Hoffmann3, H Pfister1 and R Kaiser1 Certain CS mutations are strongly associated with different PR mutations and resistance profiles, but seem to be barely first line mutations during the evolution of PI resistance. Nevertheless, CS mutations could influence the genetic barrier for the evolution of specific PI resistance and should therefore be considered in HIV genotypic resistance tests. |
| 58 | AMINO ACID CHANGES IN GAG THAT DEVELOP IN VIVO DURING PROTEASE INHIBITOR THERAPY HAVE A DOMINANT EFFECT ON VIRAL REPLICATION AND SENSITIVITY TO PROTEASE INHIBITORS EX VIVO Antivir Ther. 2006, 11:S66 (abstract no. 58) S Koch1, R Coman1, I. Munoz1, BM Dunn1, JW Sleasman2 and MM Goodenow1 Positions in gag exert a dominant effect on PR processing of gag polyproteins, virus replication, and susceptibility to drug. Replicative capacity of viruses can be independent of susceptibility to PIs, while genotypic and phenotypic drug-resistant PR can exhibit susceptibility to PIs by changes in NC. The functional linkage between gag and PR provides targets for novel therapeutics to inhibit drug-resistant viruses. |
| 59 | IDENTIFICATION OF RECOMBINATION HOTSPOTS AND RNA HAIRPINS AT 3'-END OF RT FINGERS REGION OF UNIQUE RECOMBINANT FORMS Antivir Ther. 2006, 11:S67 (abstract no. 59) A Galli1, A Lai1, L Romano2, C Riva1, M Violin1, F Saladini2, L Dehò1, M Franzetti1, M Zazzi2 and C Balotta1 HIV-1 recombination, coupled with high mutation rate, widens viral diversity and prompts a deeper knowledge of the underlying mechanisms. The almost invariable presence of a hairpin suggests that this structure could be required for recombination in RT fingers region and could be related to the localization of the hotspot. Nevertheless, these findings do not have an epidemiological support since some subtypes, cocirculating at high level, seem unable to recombine in this region even if they share a common hairpin structure. Our finding hints at the search of additional features that influence the interaction of different subtypes at molecular level. |
| 60 | RESISTANCE TO HIV INFECTION BY siRNA DIRECTED AGAINST A CELLULAR METALLOENDOPROTEINASE Antivir Ther. 2006, 11:S68 (abstract no. 60) J Murray1, D Rubin2, J Sheng2, W O’Brien3 and T Hodge1 This is the first report of a host metalloendoproteinase that is required for HIV replication. Identification of host genes required for viral pathogenesis and which are non-essential for the cell provide unique targets for therapeutic intervention which may be insurmountable by the virus through mutation. |
| 61 | A COMPLEX ROLE FOR THE TETRASPANIN CD63 IN HIV REPLICATION Antivir Ther. 2006, 11:S69 (abstract no. 61) H Chen, B Friedrich, D Rojo, Z Chen and WA O’Brien In addition to its role in HIV entry of macrophages, CD63 also appears to affect late replication events, early after translation. Since CD63 is a major component of late endosomes, it is possible that CD63 is also involved in HIV maturation and budding, in various cells in addition to macrophages. Further delineation of the role of CD63 in HIV replication may lead to development of novel therapeutic compounds. |
| 62 | RESISTANCE TO HIV INFECTION OF PRIMARY MACROPHAGES FOLLOWING siRNA-MEDIATED DOWNREGULATION OF A CELLULAR METALLOENDOPROTEINASE Antivir Ther. 2006, 11:S70 (abstract no. 62) W O’Brien1, B Friedrich1, J Murray2, D Rubin3 and T Hodge2 Confirmation of the requirement for specific host genes for viral replication in primary macrophages is a critical step in the development of specific therapies that target actions of cellular proteins identified by gene trap. The absence of cytotoxic effects associated with downregulation in primary macrophages suggests that these gene products may not be essential for the cell, and may provide unique targets for therapeutic intervention. |
| 63 | CRYSTAL STRUCTURES OF RELATED HIV-1 PROTEINASE VARIANTS: RELATING THREE-DIMENSIONAL STRUCTURE AND VIRAL FITNESS Antivir Ther. 2006, 11:S71 (abstract no. 63) A Baharuddin1, M Fischer1, N van Maarseveen2, M Nijhuis2, CABBoucher2, R Hilfenfeld1 and JR Mesters1 1) The early mutations (day 28), V82T or both M36I and I54V, increase ritonavir drug resistance; 2) The combination of all 3 mutations (day 56, V82T, M36I and I54V), increases drug resistance further, has a marked effect on the proteinase structure which in turn reduces the viral replication capacity; 3) The late mutation A71V markedly compensates for the loss of fitness, to better than wild-type values; 4) The late mutation K20R compensates for the loss of the D35-R57 salt bridge by creating a new salt bridge to D35; 5) Ritonavir drug resistance seems to evolve in two stages: in an early stage, a combination of mutations is acquired that increase drug resistance (at the cost of structural integrity resulting in a reduced viral replication capacity), followed by a late stage in which mutations are acquired that restore viral fitness to even better than wild type values. |
| 64 | GENETIC CONSEQUENCES OF AN IMPERFECT HIV-1 Vif INHIBITOR: EFFECTS OF INCREASED APOBEC ACTIVITY ON EVOLUTION OF DRUG RESISTANCE Antivir Ther. 2006, 11:S72 (abstract no. 64) SK Pillai1,2, JK Wong1,2 and JD Barbour1 These results indicate that a partial Vif antagonist may accelerate the evolution of viral resistance to protease and RT inhibitors, while a highly potent inhibitor may lead to immediate error catastrophe in viral populations. These data warrant further theoretical and experimental studies of a Vif inhibitor prior to use in conjunction with other antiretrovirals in a clinical setting. |
| 65 | LONGITUDINAL ANALYSIS OF HIV ENVELOPE V3 SEQUENCE EVOLUTION AND CO-RECEPTOR USE IN ANTIRETROVIRAL NAÏVE INDIVIDUALS DURING THE FIRST 30 MONTHS OF HAART Antivir Ther. 2006, 11:S72 (abstract no. 65) AJ Low1,2, CJ Brumme1, W Dong1, ZL Brumme1, PK Cheung1, T Mo1, RS Hogg1,2, JSG Montaner1,2 and PR Harrigan1,2 V3 sequence evolution and co-receptor switch were observed after initiating HAART. Poor adherence and detection of baseline X4 were predictors of development of the “11/25” genotype, and were associated with a poorer CD4 cell response to HAART. Phenotypic switches to R5 virus were more common than to R5/X4 virus after starting HAART. |
| 66 | DETECTION AND QUANTIFICATION OF MINORITY HIV-1 ENV V3 LOOP SEQUENCES BY ULTRA-DEEP SEQUENCING: PRELIMINARY RESULTS Antivir Ther. 2006, 11:S74 (abstract no. 66) AMN Tsibris1, C Russ2, W Lee2, R Paredes3,5, RArnaout2,4,5, T Honan2, P Cahill2, C Nusbaum2 and DR Kuritzkes5 In our pilot experiment, ultra-deep sequencing accurately and reproducibly detected a minority V3 loop sequence from a mixture of amplicons. Use of ultra-deep sequencing of the V3 loop-coding segment of HIV-1 env holds promise for detecting minor species of the viral population and may be useful in investigating changes in population structure and viral tropism over time. |
| 67 | POSITIVE SELECTION OF THE HIV-1 ENVELOPE V3 REGION IN VIVO TARGETS SOLVENT ACCESSIBLE AMINO ACID RESIDUES Antivir Ther. 2006, 11:S75 (abstract no. 67) B Joos1, M Fischer1, A Schweizer1, H Kuster1, JBöni2, JK Wong3, R Weber1, A Trkola1 and HF Günthard1 Positively selected amino acid changes in the region encompassing the envelope C2V3-C3 domain occurred preferentially at exposed sites of the env surface. This suggests that these sites evolved in response to selective forces that were exerted by neutralizing antibodies. Thus, the structural model of gp120 converges remarkably well with our evolutionary analysis which suggests ongoing competition between host and pathogen in HIV-1 infected patients. Moreover, the results confirm the utility of these genetic algorithms in accurately detecting and monitoring selection pressure. |
| 68 | CONTRIBUTION OF GAG IN THE REPLICATIVE CAPACITY OF DRUG-NAÏVE VIRUSES (B AND NON-B) AND MULTIDRUGRESISTANT VIRUSES Antivir Ther. 2006, 11:S76 (abstract no. 68) E Dam1,2, JL Faudon2 , D Descamps1,3, O Launay4, X Duval5, C Dalban6, D Costagliola6 and F Clavel1 In subtype B viruses, the inclusion of entire HIV-1 gag sequences in the recombination cassette used in our RC assay did not reveal an increase in RC, whether in drug-naïve or in multidrug-resistant viruses. In non-B subtype viruses, however, the inclusion of whole gag resulted in improved RC, suggesting that genetic compatibility between gag-pol domains may play an important part in RC as measured in recombinant assays. |
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Session 4: Clinical implications of resistance Abstracts 69 thru 93, Pages S79 to S103 |
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| 69 | BASELINE DETECTION OF LOW-FREQUENCY DRUG RESISTANCE-ASSOCIATED MUTATIONS IS STRONGLY ASSOCIATED WITH VIROLOGICAL FAILURE IN PREVIOUSLY ANTIRETROVIRAL-NAÏVE HIV-1-INFECTED PERSONS Antivir Ther. 2006, 11:S79 (abstract no. 69) JA Johnson1, J-F Li1, X Wei1, C Craig2, C Stone2, JH Horton2, ER Lanier2 and W Heneine1 Sensitive testing for drug resistance-associated mutations found that the number of persons with detectable K103N, Y181C and/or M184V at baseline was more than triple the number identified by conventional sequencing. The clinical significance of drug-resistant viruses at frequencies <20% was demonstrated by their strong association with virological failure independent of viral load. These data imply that sensitive baseline testing can improve ART management of HIV-1-infected persons. |
| 70 | ALLELE-SPECIFIC PCR SHOWS LOW-LEVEL K65R IN TREATMENT-EXPERIENCED PATIENTS WITH L74V IN THE ABSENCE OF TAMs Antivir Ther. 2006, 11:S80 (abstract no. 70) ES Svarovoskaia1, NA Margot2, AS Bae1, JM Waters1, K Borroto-Esoda1 and MD Miller2 No K65R was detected among treatment-naïve patients by an AS-PCR technique with a quantitation cut-off of 0.5%. Prior therapy with abacavir or didanosine can result in a population genotype that shows K65R or L74V/I but does not detect low-level K65R present in a minority of L74V/I patients. Subsequent treatment intensification with TDF resulted in poor virological response and may result in expansion of a pre-existing K65R mutant. |
| 71 | DEFINING LOWER (L) AND UPPER (U) PHENOTYPIC CLINICAL CUTOFFS (CCO’S) FOR TIPRANAVIR (TPV), LOPINAVIR (LPV), SAQUINAVIR (SQV) AND AMPRENAVIR (APV) CO-ADMINISTERED WITH RITONAVIR (R) WITHIN THE RESIST DATASET USING THE PHENOSENSE ASSAY (MONOGRAM (MGRM) BIOSCIENCES) Antivir Ther. 2006, 11:S78 (abstract no. 71) EP Coakley1, C Chappey1, P Flandre2, R Pesano1, N Parkin1, V Kohlbrenner3, DB Hall3 and DL Mayers3 These analyses define the LCCO and UCCO for TPV/r, LPV/r, SQV/r, and APV/r by the PhenoSense assay and highlight the unique susceptibility profile of TPV among highly drug-resistant isolates. |
| 72 | VIROLOGICAL FAILURE AND EMERGENCE OF TREATMENT-SPECIFIC HIV-1 DRUG RESISTANCE PATTERNS ON FIRST-LINE HAART IN PREVIOUSLY UNTREATED PATIENTS FROM THE SWISS HIV COHORT STUDY (SHCS) Antivir Ther. 2006, 11:S82 (abstract no. 72) H Günthard1, V von Wyl1, S Yerly2, J Böni3, J Schüpbach3, P Burgisser4, T Klimkait5, M Battegay5, H Furrer6, A Telenti4, B Hirschel7, P Vernazza8, E Bernasconi9, M Rickenbach10, L Perrin2, B Ledergerber1 and the SHCS While having an equally low virological failure rate compared to NNRTI containing regimens, PI/r induced resistance affects fewer drug classes. Thus, PI/r regimens seem to leave more treatment options open should the initial regimen fail. |
| 73 | PHENOTYPIC AND GENOTYPIC DETERMINANTS OF RESISTANCE TO TMC-114: POOLED ANALYSIS OF POWER 1, 2 AND 3 Antivir Ther. 2006, 11:S83 (abstract no. 73) S De Meyer1, T Vangeneugden1, E Lefebvre2, H Azijn1, I De Baere1, B Van Baelen1 and M-P de Béthune1 Baseline TMC-114 FC was the strongest predictor of virological response. Reduced response at TMC-114 FC >10 correlated with ≥10 PI resistance-associated mutations. No mutation associated with a diminished response, alone or in combination with 1–2 others, resulted in TMC-114 FC >10. |
| 74 | DRUG RESISTANCE OUTCOMES IN A TRIAL COMPARING LOPINAVIR/RITONAVIR (LPV/r) MONOTHERAPY TO LPV/r + ZIDOVUDINE/LAMIVUDINE (MONARK TRIAL) Antivir Ther. 2006, 11:S84 (abstract no. 74) M Norton1, C Delaugere2, G Batot3, JF Delfraissy4 and C Rouzioux2 To date, two of 83 subjects starting LPV/r monotherapy and none of 53 subjects starting a LPV/r-based 3-drug regimen developed PI resistance mutations. The barrier for the selection of PI resistance with LPV/r monotherapy may be lower than with LPV/r-based 3-drug regimens. |
| 75 | SELECTION OF PROTEASE INHIBITOR (PI) RESISTANCE MUTATIONS DURING VIROLOGICAL FAILURE OF LOPINAVIR/RITONAVIR (LPV/R) MONOTHERAPY IN AN INDUCTION-MAINTENANCE STUDY Antivir Ther. 2006, 11:S85 (abstract no. 75) JR Hackett Jr1, V Holzmayer1, N Marlowe2, MP DeHaan3, KY Robinson3, KJ Wikstrom3, KR Niemi3, MS King3, BA da Silva3 and GJ Hanna3 Both cases demonstrated drug-selected (though not PI-specific) resistance mutations at baseline, and may have harboured PI resistance at levels undetectable by population sequencing. Virological suppression was maintained with a 3-drug LPV/r-containing regimen, but breakthrough viraemia occurred after deintensification to monotherapy, followed by progressive evolution of PI resistance. Risk of PI resistance with failure of PI monotherapy may be higher than with a 3-drug regimen, stressing the need for appropriate selection of patients for this strategy. |
| 76 | ABSENCE OF HIV-1 SHEDDING IN THE MALE GENITAL TRACT AFTER 1-YEAR OF LOPINAVIR/RITONAVIR ALONE OR IN COMBINATION WITH COMBIVIR®: A SUBSTUDY OF MONARK TRIAL Antivir Ther. 2006, 11:S86 (abstract no. 76) J Ghosn1, G Peytavin2, J Galimand1, PM Girard3, F Raffi4, JF Delfraissy5, I Cohen-Codar6, C Rouzioux1 and ML Chaix1 In this small study, Kaletra® monotherapy yielded potent reduction in BPVL at W48, leading to the absence of passive diffusion of HIV-RNA from blood plasma to semen. No local viral production was evidenced in semen despite the local absence of therapeutic antiretroviral-drug concentrations in the 5 patients receiving Kaletra® alone. |
| 77 | DEVELOPMENT OF DRUG RESISTANCE IN A SUB-SAHARAN COHORT OF HIV-1-INFECTED ADULT PATIENTS RECEIVING FIXED-DOSE COMBINATION OF STAVUDINE 30 MG/LAMIVUDINE/NEVIRAPINE AS STANDARD FIRST-LINE REGIMEN Antivir Ther. 2006, 11:S87 (abstract no. 77) AG Marcelin1, B Jarrousse2, A Derache1, M Ba3, ML Dakouo4, A Doumbia5, I Haidara5, T Traoré5, L Tégna2, B Diarra Sonou6, Z Traore5, I Katilé3, D Traore4, B Dembélé5, A Maïga2,5, B Diarra5, G Carcelain1, E Klement2, C Katlama1,2 and V Calvez1 Early failures to d4T+3TC+NVP were associated in 50% of cases with no resistance mutation. The fact that more than 50% of the viruses harbouring NNRTI mutations contained Y181C mutation in this study could be related to the use of d4T. Actually, d4T would not prevent the selection of Y181C mutation, inversely to that was observed in subtype B when zidovudine was associated to NVP. This phenomenon can also be related to the CRF_02 subtype. It has been recently shown that HIV-1 subtype can influences the type of NVP mutation (higher frequency of Y181C for subtype A and K103N for subtype D). The absence of TAMs suggests that zidovudine or d4T could be used in second line regimen after early failure to d4T+3TC+NVP. |
| 78 | PREVALENCE AND PREDICTORS OF TRIPLE-CLASS ANTIRETROVIRAL DRUG RESISTANCE IN ROUTINE HIV PRIMARY CARE Antivir Ther. 2006, 11:S85 (abstract no. 78) S Napravnik, J Keys, EB Quinlivan, DA Wohl, AM Myers and JJ Eron Jr The majority of patients with TC-DR have extensive ARV exposure particularly to non-HAART regimens, while HAART initiators are at low risk of acquiring TC-DR over a median of 4 years of follow-up. |
| 79 | INITIAL VIROLOGICAL FAILURE WITH HIV DRUG RESISTANCE AND IMPACT OF RESISTANCE ON DISEASE PROGRESSION AND DEATH FOR PATIENTS BEGINNING PI, NNRTI OR PI+NNRTI BASED STRATEGIES: THE FIRST STUDY Antivir Ther. 2006, 11:S89 (abstract no. 79) MJ Kozal1, K Huppler Hullsiek2, RD MacArthur3, G Peng2, Y Xiang2, JD Baxter4 M Van den Berg-Wolf5, J Uy6, EE Telzak7 and RM Novak6 for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) For treatment-naïve patients on three ART strategies, the risk of having an AIDS event or death varied with the ability to achieve virological suppression prior to virological failure and with the class(es) of drug resistance that developed. Considering the impact of resistance by class, NNRTI resistance was the strongest predictor of disease progression. |
| 80 | SELECTION OF DRUG-RESISTANCE MUTATIONS DURING GUIDED TREATMENT INTERRUPTIONS IS ASSOCIATED WITH SUBOPTIMAL ANTIRETROVIRAL TREATMENTS PRIOR TO HAART Antivir Ther. 2006, 11:S90 (abstract no. 80) L Darwich, J Martinez-Picado, R Bellido, A Blanco, M Bofill, B Clotet and L Ruiz Suboptimal therapy prior to HAART is associated with a higher risk of selecting drug-resistance mutations (mainly TAMs) during GTI, shorter treatment interruption periods and higher accumulation of proviral DNA mutations. In patients who had always received HAART the selection of mutations is rare and it involves mutations of low genetic barrier, being suitable candidates for GTI. Treatment history and HIV-1 DNA genotyping are useful markers to predict time-off therapy in patients with undetectable RNA viraemia. |
| 81 | EVOLUTION OF RESISTANCE TO SALVAGE THERAPY WITH OR WITHOUT A PRECEDING STRUCTURED TREATMENT INTERRUPTION: IMPACT ON VIROLOGICAL RESPONSE Antivir Ther. 2006, 11:S91 (abstract no. 81) A Thorne1, PR Harrigan2, N LaPierre2 and S Walmsley3 for the CTN 164 Investigators Reversion to wild type virus after a 12 week STI did not impact the likelihood of virological suppression to a salvage regimen. At the time of virological failure, only 30% had new key mutations, which were most commonly observed to the NNRTI component of the salvage regimen. |
| 82 | VIROLOGICAL RESPONSE TO ANTIRETROVIRAL THERAPY IN THE SETTING OF THE K65R MUTATION Antivir Ther. 2006, 11:S92 (abstract no. 82) AB Nevins1, M Wirden2, SY Rhee1, J Taylor1, WJ Fessel3, M Horberg3, A Scarsella4, SY Lee4, W Towner5, V Calvez2, RW Shafer1 and AR Zolopa1 Among this international cohort of treatment-experienced patients with the K65R mutation, over half achieved a viral load of <400 copies/ml. The use of a thymidine analogue did not appear to improve the response although the use of TDF was associated with an improved response. |
| 83 | THE ROLE OF THYMIDINE ANALOGUES IN RESCUE THERAPY IN PATIENTS CARRYING K65R MUTATION Antivir Ther. 2006, 11:S93 (abstract no. 83) A Antinori1, MP Trotta1, P Lorenzini1, G Carosi2, N Gianotti3, F Maggiolo4, C Torti2, A Castagna3, M Andreoni5 and CF Perno5 for Genotypic Networking Organization Multicentric Observation (GNOMO) Study Group Inclusion of TA in the salvage regimen (D4T rather than AZT) predicts better response to rescue therapy in presence of K65R. Concomitant presence of M184V may have a favourable effect on virological outcome. |
| 84 | INITIATIVES FOR DEVELOPING AND COMPARING GENOTYPE INTERPRETATION SYSTEMS: AN UPDATED ANALYSIS OF VALIDATION OF EXISTING RULES-BASED ALGORITHM FOR ABACAVIR AND ddI EVALUATED ON VIROLOGICAL RESPONSE Antivir Ther. 2006, 11:S94 (abstract no. 84) D Costagliola1, A Cozzi-Lepri2, KL Assoumou1 and 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 show that with a large enough dataset and adequate distribution of resistance levels, the performance of interpretation systems for identifying abacavir and ddI resistance can be evaluated and that several of these systems performed well. |
| 85 | RISK FACTORS FOR SELECTION OF THE L74I REVERSE TRANSCRIPTASE MUTATION IN HIV-1 INFECTED PATIENTS Antivir Ther. 2006, 11:S95 (abstract no. 85) AG Marcelin1, M Wirden1, B Roquebert1, A Derache1, A Simon2, J Ghosn3, S Dominguez3, C Katlama3 and V Calvez1 L74I mutation accounted for about a third of amino acid changes at position 74. But, this mutation is rarely considered in clinical trial analyses and in studies conducted to determine genotypic algorithms. These findings show that this mutation should be systematically taken into account in such analyses to determine its impact on antiretroviral treatment. Further studies are required to determine the biochemical mechanisms underlying the selection of L74I rather than L74V in patients with a TAM profile 2 or a large number of TAMs. |
| 86 | RELATION BETWEEN ANTIRETROVIRAL ACTIVITY OF STAVUDINE (d4T) AND THE NUMBER OF REVERSE TRANSCRIPTASE (RT) MUTATIONS: ZENAM STUDY Antivir Ther. 2006, 11:S96 (abstract no. 86) JL Blanco1, E Teniente1, J Mallolas1, E Martinez1, M Lonca1, M Laguno1, M Larrousse1, A Leon1, A Milinkovic1, T Pumarola2 and JM Gatell1 d4T retains significant antiretroviral activity when the number of TAMs is lesser than 4 and despite the presence of K65R. |
| 87 | EVALUATION OF RESISTANCE PATTERNS IN TREATMENT-NAÏVE SUBJECTS WITH VIROLOGICAL FAILURE ON ATAZANAVIR- OR ATAZANAVIR/RITONAVIR-CONTAINING REGIMENS Antivir Ther. 2006, 11:S97 (abstract no. 87) D McGrath, J Hammond, D Frederick, M Mathew, K Kastango, and C McLaren Phenotypic PI resistance or primary PI substitutions, including I50L, were not seen in the small number of subjects with virological failure on initial ATV300/RTV100 therapy. The ATV-signature I50L – or I50I/L – substitution was detected only in ATV400-subjects. The NRTI M184V substitution was found in the majority of on-study isolates from virological failures. |
| 88 | CHARACTERIZATION OF PROTEASE INHIBITOR (PI) RESISTANCE MUTATION I50L IN ROUTINE CLINICAL SAMPLES (RCS) BETWEEN 1998 AND 2005 Antivir Ther. 2006, 11:S98 (abstract no. 88) P Sista1, L Bacheler1, B Wasikowski2, T Pattery3 and S McCallister4 Following the regulatory approval of atazanavir in 2003, the incidence of I50L has risen significantly with a related higher incidence of N88S. The I50L mutation alone conferred resistance to atazanavir, but not other PIs. However, increasing numbers of other primary PI mutations led to a proportional increase of clinically relevant phenotypic resistance to some PIs. |
| 89 | DIFFERENT PATTERNS OF MUTATIONS INVOLVED IN THE GENOTYPIC RESISTANCE SCORE FOR ATAZANAVIR BOOSTED VERSUS ATAZANAVIR UNBOOSTED IN MULTIPLY FAILING PATIENTS Antivir Ther. 2006, 11:S99 (abstract no. 89) A Bertoli1, MM Santoro1, P Lorenzini2, F Ceccherini-Silberstein1, A Lazzarin3, G Di Perri4, R Esposito5, P Caramello4, A Cargnel6, P Narciso2, G Rizzardini6, G Filice7, L Minoli7, G Carosi8, A Antinori2 and CF Perno1 The set of mutations contained in the genotypic resistance score was different in patients taking ATV300/r versus ATV400. This may be due to different drug levels of atazanavir (boosted versus unboosted) that may favour different pathways of escape from antiviral pressure. |
| 90 | ATAZANAVIR SUSCEPTIBILITY SPECTRUM EXTENDS TO HIV-1 NON-B SUBTYPES AND HIV-2 VIRAL ISOLATES Antivir Ther. 2006, 11:S100 (abstract no. 90) Y-F Gong1, B. Eggers1, H Yang1, V Gali1, P-F Lin1, N Parkin2, S McCallister3 and RJ Colonno3 These in vitro results demonstrate that the atazanavir antiviral spectrum may extend beyond subtype B, to other HIV-1 subtypes and to HIV-2. These data suggest that atazanavir may be clinically useful for HIV-infected patients from diverse geographical regions. |
| 91 | GENOTYPIC DETERMINANTS OF THE VIROLOGICAL RESPONSE TO FOSAMPRENAVIR/RITONAVIR IN PROTEASE INHIBITORS-EXPERIENCED PATIENTS Antivir Ther. 2006, 11:S101 (abstract no. 91) B Masquelier1, KL Assoumou2, D Descamps3, L Bocket4, J Cottalorda5, A Ruffault6, AG Marcelin7, L Morand-Joubert8, C Tamalet9, C Charpentier10, G Peytavin11, Z Antoun12, F Brun-Vézinet3, D Costagliola2 and the ANRS Resistance Study Group A genotypic mutation score, predictive of viral load response at 3 months, could be constructed based on clinical virological data from a multi-PI experienced patient cohort. This tool, along with pharmacokinetic monitoring, should be of interest for the management of PIs-experienced patients. |
| 92 | DE-SELECTION OF THE I50V MUTATION OCCURS IN CLINICAL ISOLATES DURING APTIVUS/r (TIPRANAVIR/RITONAVIR) BASED THERAPY Antivir Ther. 2006, 11:S102 (abstract no. 92) R Elston1, J Scherer2, D Hall2, J Schapiro3, R Bethell1, V Kohlbrenner2 and D Mayers2 The I50V mutation is associated with increased susceptibility to tipranavir. If the I50V mutation is present at baseline during Aptivus/r-based therapy, it is de-selected upon virological rebound. The presence of the I50V mutation may increase susceptibility to tipranavir even in the presence of tipranavir-associated mutations and this should be taken into consideration when correlating individual mutations with phenotypic susceptibility. |
| 93 | IN VITRO PHENOTYPIC SUSCEPTIBILITY OF HIV-2 CLINICAL ISOLATES TO PROTEASE INHIBITORS: AMPRENAVIR, ATAZANAVIR, LOPINAVIR, AND TIPRANAVIR Antivir Ther. 2006, 11:S103 (abstract no. 93) D Descamps1, D Desbois1, F Damond1, G Collin1, S Matheron1, A Taieb2, G Peytavin1, A Bénard2, P Campa3, G Chêne2, F Brun-Vézinet1, and the French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2) In HIV-2 wild type isolates, IC50 to APV, ATV and TPV are higher compared to HIV-1, raising the hypothesis of a lower activity of these PIs in HIV-2 infected patients. Substitutions at position 82, 84 and 90 impact the phenotypic susceptibility to ATV, APV, LPV and TPV. These phenotypic susceptibility results ask the question of which PIs could not be recommended in HIV-2 patients initiating HAART. |
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Session 5: Epidemiology Abstracts 94 thru 124, Pages S107 to S137 |
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| 94 | PREVENTION OF RECTAL SHIV TRANSMISSION IN MACAQUES BY TENOFOVIR/FTC COMBINATION Antivir Ther. 2006, 11:S107 (abstract no. 94) J Gerardo García-Lerma1, R Otten1, S Qari1 , E Jackson1, W Luo1, C Kim1, D Adams1, S Bashirian1, M Monsour1, D Delinsky2, R Schinazi2 , R Janssen1, T Folks1 and W Heneine1 Tenofovir/FTC combination provides a high level of protection against repeated virus challenges, demonstrating that chemoprophylaxis with potent antiretrovirals can provide an effective strategy for preventing sexual HIV transmission. Despite high antiviral activity, FTC alone did not provide full protection in this model suggesting that chemoprophylaxis with drug combinations will be more effective than single drugs in preventing sexual HIV transmission. |
| 95 | PRIMARY RESISTANCE TO ENFUVIRTIDE IN RECENTLY INFECTED, ANTIRETROVIRAL-NAÏVE PATIENTS, ANRS CO3 AQUITAINE COHORT Antivir Ther. 2006, 11:S108 (abstract no. 95) O Peuchant1, S Capdepont1, JM Ragnaud2, V Aurillac-Lavignolle3, R Thiébaut3, H Fleury1, B Masquelier1 and the ANRS CO3 Aquitaine Cohort We have shown the first cases of primary resistance to enfuvirtide in recently infected patients in south-western France. This finding suggests that the epidemiological surveillance of the transmission of drug-resistant HIV-1 should include the resistance to enfuvirtide, and that genotyping the gp41 could be of use before beginning enfuvirtide-containing therapy. |
| 96 | ANALYSIS OF LEVELS OF K103N-CONTAINING HIV-1 VARIANTS IN ANTIRETROVIRAL DRUG NAÏVE AFRICAN WOMEN WITH HIV-1 SUBTYPES A, C AND D WHO SUBSEQUENTLY RECEIVED SINGLE DOSE NEVIRAPINE FOR PREVENTION OF HIV-1 MOTHER-INFANT TRANSMISSION Antivir Ther. 2006, 11:S109 (abstract no. 96) JD Church1, LA Guay1, TE Taha2, SE Hudelson1, S Chen2, DR Hoover3, SA Fiscus4, F Mmiro5, P Musoke5, N Kumwenda2, JB Jackson1 and SH Eshleman1 In baseline samples from women with subtypes A, C and D, NVP resistance mutations were not detected by the ViroSeq system, and K103N was rarely detected above 0.5% by the LigAmp assay. Using this approach, we did not find subtype-based differences in baseline levels of K103N-containing variants that could explain the dramatic differences in the frequencies of nevirapine resistance in women with these subtypes after nevirapine exposure. |
| 97 | INCREASE IN TRANSMITTED NNRTI DRUG RESISTANCE AMONG RECENTLY HIV INFECTED PATIENTS FROM NORTH AMERICA AND AUSTRALIA Antivir Ther. 2006, 11:S110 (abstract no. 97) SJ Little1, S May1, F Hecht2, M Markowitz3, ES Daar4, J Kaldor5, RM Grant6, Michael Bates7, C Woelk1, SL Kosakovsky Pond1, L Liu1, V DeGruttola8, SDW Frost1 and DD Richman1,9 An increase in the rate of transmitted high-level NNRTI resistance was observed in this cohort. Given that NNRTI resistance does not appear to significantly affect viral fitness, both acquired and transmitted NNRTI resistance will likely be associated with long-term persistence of NNRTI resistance and potential risk of further resistance transmission. |
| 98 | TRANSMISSION OF DRUG-RESISTANCE IN EUROPE IS CHARACTERIZED BY SINGLE MUTATIONS AND REVERTANTS Antivir Ther. 2006, 11:S111 (abstract no. 98) AMJ Wensing1 J Vercauteren2, DA van de Vijver 1, J Albert 3, G Poggensee4, JC Schmit5, D Struck5, AM Vandamme 2, B Asjo6, C Balotta7, R Camacho8, S Coughlan9, Z Grossman10, A Horban11 , K Korn12, C Nielsen13 , D Paraskevis14, E Puchhammer-Stockl15, C Riva7, L Ruiz16, R Schuurman1, M Salminen17, A Sonnerborg18, M Stanojevic19, 20 and CAB Boucher 1 on behalf of the SPREAD-program The SPREAD-program provides the first representative data on transmission of HIV drug- resistance across Europe. 9.1% of newly diagnosed patients was infected with HIV carrying drug-resistant mutations. Interestingly, the magnitude of resistance is frequently limited to single mutations. This might be due to reversion of resistance patterns as indicated by the high prevalence of mixtures and revertants. |
| 99 | TRANSMITTED HIV DRUG RESISTANCE IS ASSOCIATED WITH METHAMPHETAMINE USE AMONG RECENTLY HIV INFECTED MSM IN SOUTHERN CALIFORNIA, USA Antivir Ther. 2006, 11:S112 (abstract no. 99) LN Drumright1, PM Gorbach2, SDW Frost1, SA Strathdee1, C Woelk1, SL Kosakovsky Pond1, ES Daar3, DD Richman1, 4 and SJ Little4 This preliminary study suggests that methamphetamine use may be associated with increased risk of acquiring a drug-resistant strain of HIV, as all participants were recently HIV infected and treatment-naïve. Further examination of social/sexual networks of MSM who use methamphetamine and the reasons for development of and transmission of HIV drug resistance in these networks compared to other networks should be conducted in order to prioritize prevention strategies. |
| 100 | COMPENSATORY FIXATION EXPLAINS LONG TERM PERSISTENCE OF THE M41L IN HIV-1 REVERSE TRANSCRIPTASE IN A LARGE TRANSMISSION CLUSTER Antivir Ther. 2006, 11:S113 (abstract no. 100) MCDG Huigen1, J Albert2,3, A Lindström2,3, A Ohlis4, G Bratt 4, L de Graaf 1, M Nijhuis1 and CAB Boucher1 In this study we have demonstrated that the negative impact of the M41L substitution on replication capacity can be (partly) compensated by additional mutations in RT. The presence of these compensatory mutations explains the fixation of the M41L change in RT in untreated patients for a prolonged period of time. |
| 101 | WHAT IS THE DRUG RESISTANCE MUTATIONAL INFECTIOUS BURDEN IN AN HIV-1 PREVALENT COHORT AND THE RELATIONSHIP TO INCIDENCE OF TRANSMITTED RESISTANCE? Antivir Ther. 2006, 11:S114 (abstract no. 101) D Pillay1,2, C Sabin1, D Pao3, D Dunn4 and M Fisher3 The viral burden of infectious drug- resistant virus has fallen in recent years in this cohort. We predict that transmission of resistance will consequently fall. Surprisingly, the viral load burden of M184V was less than half of than for T215 variants in prevalent infections. This may explain the reduced prevalence of this mutation in transmitted resistant viruses, in addition to post-transmission reversion events. |
| 102 | REDUCED LEVELS OF PRIMARY RESISTANCE TO NRTIs IN SAN FRANCISCO IS DISCERNABLE USING TWO INDEPENDENT SENTINEL POPULATIONS Antivir Ther. 2006, 11:S115 (abstract no. 102) HM Truong1,2, JD Klausner2,3, FM Hecht2 and RM Grant1,2 Primary drug resistance did not differ substantially in the two studies, despite important differences in referral patterns and screening criteria. The overall prevalence of primary resistance in San Francisco was markedly lower in 2004 (8% or 12% depending on the site) compared with 1996-2001 (18% to 27% depending on the year). The decline was entirely attributable to decreasing primary nRTI resistance. Screening STD clinic populations for acute infection is increasing and creates an opportunity for cost-effective surveillance for primary drug resistance. |
| 103 | CATEGORIZATION OF TRANSMITTED HIV DRUG RESISTANCE USING THE WHO/CDC HIV DRUG RESISTANCE THRESHOLD SURVEY METHOD Antivir Ther. 2006, 11:S116 (abstract no. 103) DE Bennett1,5, AJ Smith1, L McCormic 2, N Prachan3, E Sey4, T Bingha4, C Ciesielsk1,3, D Sutherland5, S Bertagnolio5, D Mackellar1 and M Myatt6 The WHO/CDC HIVDR-TS method based on the first 47 specimens correctly categorized the HIVDR prevalence estimates based on all specimens genotyped in each of the two areas. The TS method may make HIVDR surveillance feasible in resource-limited countries where relatively few HIV diagnoses are made during the period of recent infection. |
| 104 | PREVALENCE OF HIV-1 DRUG RESISTANCE IN SWITZERLAND BETWEEN 1999 AND 2004: NO TREND FOR AN INCREASE Antivir Ther. 2006, 11:S117 (abstract no. 104) V von Wyl1, S Yerly2, J Böni3, J Schüpbach3, P Bürgisser4, T Klimkait5, M Rickenbach6, L Perrin2, S Bonhoeffer7, B Ledergerber1, H Günthard1 and the SHCS Overall, the prevalence of HIV-1 drug resistance remained stable over time. Most encouraging, no increase in prevalence of triple drug resistance was observed over a 5 year period since 1999. Analyses should adjust for patients’ treatment histories since prevalence estimates can vary significantly by different treatment exposure. |
| 105 | TRANSMISSION OF HIV-1 DRUG RESISTANCE IN SWITZERLAND: A 10-YEAR MOLECULAR EPIDEMIOLOGY SURVEY Antivir Ther. 2006, 11:S118 (abstract no. 105) S Yerly1, V von Wyl2, J Böni2, J Schüpbach2, P Bürgisser3, T Klimkait4, M Rickenbach5, B Ledergerber2, H Günthard2, L Perrin1 and the SHCS The overall transmission rate of drug-resistant HIV-1 was remarkably stable from 1996 to 2005 in Switzerland. Transmission events of dual and triple class resistant viruses were rare and did not increase over time. However, in 2005 a significant increase in transmission of NNRTI resistance was observed. |
| 106 | REGIONAL VARIATION IN HIV STRAIN AND DRUG RESISTANCE: THE CANADIAN EXPERIENCE WITH A NATIONAL SURVEILLANCE PROGRAM Antivir Ther. 2006, 11:S119 (abstract no. 106) JI Brooks, RG Pilon, HW Merks, NJ Goedhuis, G Jayaraman, CP Archibald and PA Sandstrom Overall, subtype B predominates in new HIV infections with transmitted DR rates similar to those from other western countries. Closer analysis reveals that there are significant regional differences in the pattern of transmitted DR. Although phylogenetic analysis can link some transmitted DR clusters, regional prescribing practices for ART are likely have a greater effect. Aggregate DR reporting may prove inaccurate in areas with regional variation in prescribing practises and may adversely affect policy decisions. |
| 107 | PREVALENCE OF HIV-1 DRUG RESISTANCE-ASSOCIATED MUTATIONS IN A LARGE COHORT OF ANTIRETROVIRAL THERAPY (ART) NAÏVE HIV-INFECTED INDIVIDUALS IN THE UNITED STATES FROM 2000–2004 Antivir Ther. 2006, 11:S120 (abstract no. 107) LL Ross, A Florance, B Wine, C Craig, C Vavro, D McClernon, M Tisdale, R Balu, T Lancaster, M Shaefer and ER Lanier The estimated incidence of HIV resistance-associated mutations more than doubled from 2000 to 2004 in this large cohort of ART-naïve US subjects. Mutation detection in subjects with HIV-RNA ≤100,000 copies/ml increased substantially from 2000 to 2004, while multi-class resistance-associated mutations didn’t increase substantially over time. By drug class within the entire cohort, incidence of NNRTI resistance-associated mutations increased most, from 2% in 2000 to 7% by 2004. This observation agrees with work by others suggesting that the incidence of NNRTI mutations in ART naïve subjects is higher than the incidence of NRTI or PI mutations. |
| 108 | PREVALENCE OF HIV DRUG RESISTANCE AMONG ANTIRETROVIRAL NAÏVE INDIVIDUALS OF UNKNOWN INFECTION DURATION Antivir Ther. 2006, 11:S121 (abstract no. 108) D Smith1,2, R Pesano3, E Cachay1, H Aiem1, Y Lie3, D Richman1,2 and S Little1 Modelling by Weinstock et al. showed that HIV drug resistance testing was at least equivalent in cost to other HIV medical care practices when the prevalence of primary drug resistance in antiretroviral naïve populations was between 8–10%. However, most public health agencies do not routinely offer drug resistance testing for antiretroviral naïve individuals. Regardless if the duration of the HIV infection is known, our data suggest that routine drug resistance testing for individuals newly diagnosed with HIV would be a cost effective clinical practice. |
| 109 | ANALYSIS OF ANTIRETROVIRAL DRUG RESISTANCE AND HIV-1 SUBTYPE AMONG MEN WHO HAVE SEX WITH MEN RECENTLY INFECTED WITH HIV-1 IN THE UNITED STATES: THE EXPLORE STUDY Antivir Ther. 2006, 11:S122 (abstract no. 109) SH Eshleman1, M Husnik2, S Hudelson1, D Donnell2, Y Huang3, S Hart4, JB Jackson1, T Coates5, M Chesney6 and B Koblin7 Antiretroviral drug resistance is relatively common among recently infected men who have sex with men in the United States, but non-subtype B HIV-1 is not. |
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Session 5: Epidemiology Abstracts 110 thru 141, Pages S123 to S154 |
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| 110 | INCREASE OF NON-B HIV-1 RESISTANT VIRUS IN PRIMARY INFECTED PATIENTS: 9 YEARS OF FRENCH EXPERIENCE (1996–2004) Antivir Ther. 2006, 11:S123 (abstract no. 110) ML Chaix1, C Deveau2, V Calvez3, J Cottalorda4, C Delamarre5, C Delaugerre1, D Descamps6, C Goujard7, J Izopet8, E Kohli9, J Legoff10, AG Marcelin3, B Masquelier11, P Palmer12, I Pellegrin11, JC Plantier13, A Ruffault14, A Schmück15, V Schneider16, C Tamalet17, M Wirden3, C Rouzioux1, F Brun-Vezinet6, L Meyer2 D Costagliola18 and the ANRS AC11 Resistance Group, Cohort PRIMO, and INTERPRIM Study Groups The frequency of acquired resistant virus at the time of primary infection was stable over time, over 5% for NRTI and NNRTI. We clearly confirm the increasing of non-B strains in France with a significant increase of non-B resistant virus. |
| 111 | RESISTANCE MUTATIONS IN SUBTYPE C ISOLATES FROM INDIAN PATIENTS RECEIVING NRTIS PLUS NNRTIs AND EXPERIENCING A TREATMENT FAILURE Antivir Ther. 2006, 11:S124 (abstract no. 111) A Deshpande1 and HJ Fleury2 We present here the first data available on resistance to NRTIs and NNRTIs in India. In these subtype C isolates, we have observed most of the mutations noted for subtype B with some additional substitutions (at positions 98, 203, 208 and 221) which will warrant attention in the algorithms used. |
| 112 | TRENDS OF PRIMARY DRUG RESISTANCE IN CHRONICALLY HIV-INFECTED PATIENTS IN GERMANY, 2001–2005 Antivir Ther. 2006, 11:S125 (abstract no. 112) M Oette1, R Kaiser2, M Däumer2, G Fätkenheuer2, JK Rockstroh3, H Knechten4, A Sagir1, H Pfister2, D Häussinger1 and the RESINA Study team Resistant virus strains can be found in 9% of treatment-naïve chronically HIV-infected patients at initiation of HAART in Germany. From 2001 to 2005 an increase in prevalence of resistance was found that almost reached statistical significance. A subgroup demonstrating a clear change in prevalence was not identified. In conclusion, further surveillance of primary HIV drug resistance is essential. Genotypic resistance testing before administration of first-line HAART should be regarded as standard of care and should not be restricted to certain subgroups. |
| 113 | TRANSMITTED DRUG RESISTANCE CLUSTERS WITH THE INFECTING HIV-1 SUBTYPE: A SINGLE CENTRE ANALYSIS OF ALL NEW HIV-1 DIAGNOSES IN LONDON Antivir Ther. 2006, 11:S126 (abstract no. 113) A Garcia-Diaz1, C Booth1, G Nebbia2, A Chawla1, M Johnson1,2 and AM Geretti The prevalence of primary resistance was significant, but lower than recently suggested, and nearly entirely restricted to white MSM with subtype B. The genetic diversity of HIV-1 infections continues to increase in London. Non-B subtypes are no longer restricted to heterosexual transmission and immigration. Although subtype B remains the predominant clade among MSM in London, there is evidence for onward transmission of non-B subtypes in this population. |
| 114 | RESISTANCE ASSOCIATED MUTATIONS AND GENETIC DIVERSITY IN HIV-INFECTED PATIENTS FROM MEXICO Antivir Ther. 2006, 11:S127 (abstract no. 114) M Flores-Hermandez, L Zurita, RA Rodríguez-Díaz, LL Fuentes-Romero, E Cabrera-Muñoz, E Vidal, N Rivera-Martinez and LE Soto-Ramírez The most prevalent RAMs were those related to NRTIs, followed by PIs and NNRTIs, corresponding to the length of use of each group of drugs in Mexico. TAMs are the most prevalent RAMs found with a predominance of pattern 1. Interestingly, the frequency of RAMs is lower to that found in other Latin-American countries with a significant lesser time of ARV use as Cuba and Chile. Subtype B continues to be the predominant subtype in Mexico while B/F recombinants similar to those found in South America are now present. |
| 115 | HIV-1 REVERSE TRANSCRIPTASE (RT) MUTATIONS FOR HIV DRUG RESISTANCE SURVEILLANCE AND EPIDEMIOLOGY: APPLICATION TO PUBLISHED STUDIES OF PRIMARY INFECTION Antivir Ther. 2006, 11:S128 (abstract no. 115) RW Shafer1, SY Rhee1, D Pillay2, A Dalwani1, V Miller3, P Sandstrom4, JM Schapiro5, DR Kuritzkes6 and D Bennett7 Although additional studies with larger numbers of sequences are needed, our comparisons between svDRMs and atypical mutations do not suggest that the atypical mutations in these studies represent revertants resulting from loss of drug selection. The combined analysis of the sequences from these studies demonstrates the wide spectrum of mutations that can be observed in primarily infected persons and the need for a standard approach to measuring primary HIV-1 genotypic resistance. |
| 116 | LIMITATIONS IN USING ONLINE TOOLS TO DETERMINE HIV-1 SUBTYPE IN CLINICAL PATIENTS: A COMPARISON OF 5 TOOLS Antivir Ther. 2006, 11:S129 (abstract no. 116) C Loveday, E MacRae and on behalf of the ICVC Clinical Collaborative Research Group There was 58.4% concordance across all 5 tools. Use of one tool alone, compared with any of the other tools will result in misclassification of 20% or more of patients’ subtype. Unassignment of sequences by REGA and STAR probably reflects the stringency of the tools. Discordance across the tools reflects the difficulty in keeping these tools up-to-date to determine new and recombinant viruses. The evolution of new, complex recombinant viruses at a community level will result in subtyping becoming increasingly difficult to interpret. |
| 117 | THE PREVALENCE OF ANTIRETROVIRAL DRUG RESISTANCE IN PATIENTS WITH LOW-LEVEL DETECTABLE VIRAEMIA WHILE ON HAART Antivir Ther. 2006, 11:S130 (abstract no. 117) CL Booth1, A Garcia-Diaz1, G Nebbia2, M Youle1, M Johnson1,2 and AM Geretti1,2 Although virological failure was uncommon in the overall clinical cohort, the prevalence of resistance was high in treated patients with VL>50 and <5.000 cp/ml and blips were in some cases associated with the detection of resistant virus. NRTI resistance remains common and NRTI mutation patterns reflect the previously extensive use of thymidine analogues. |
| 118 | DRUG RESISTANCE MUTATIONS IN A COHORT OF PATIENTS UNDER HAART IN SENEGAL ENROLLED BETWEEN 1998 AND 2001: DISCORDANCE BETWEEN SELECTED MUTATIONS AND DRUG REGIMENS USED Antivir Ther. 2006, 11:S131 (abstract no. 118) C Toure-Kane1, H Diop-Ndiaye1, J-F Etard2, I Ndiaye3, NF Ngom-Gueye3, PS Sow3, C Butel2, EDelaporte, S Mboup1, M Peeters2 and the ANRS1290 Study Group Overall, the same major mutations were selected by non-B strains but not always under similar drug combinations, especially for NRTIs. More clinical and biological studies are necessary to analyse mutations selected by non-B strains and to improve the interpretation algorithms. |
| 119 | STUDY OF ANTIRETROVIRAL RESISTANCE IN TREATED PATIENTS WITH VIROLOGICAL FAILURE (START STUDY): AN ITALIAN SURVEY OVER THE PERIOD 2003–2005 Antivir Ther. 2006, 11:S132 (abstract no. 119) M Violin1, A Galli1, S Corvasce1, R Velleca1, I Caramma1, M Franzetti1, M Andreoni2, A Antinori3, B Bruzzone4, V. Micheli5, L. Monno6, A De Luca7, F Ceccherini-Silberstein2, L Palmisano8, M Zazzi9 and C Balotta1 for the START Study High levels of resistance to antiretroviral classes were found using either the IAS-USA definition or ARS interpretation. Nevertheless, the prevalence of NRTI and PI-associated mutations seems to decrease overtime, while resistance to NNRTIs remains stable. This trend may be due to the increasing number of PI sparing regimens or, alternatively, to the availability of boosted PIs. Several mutations have a significant impact on viral load; this seems to occur irrespective of their effect on viral replicative capacity. |
| 120 | NEWER ANTIRETROVIRAL TREATMENT REGIMENS DRIVE HIV-1 RT AND PR MUTATIONAL PATTERNS IN A NATIONAL REFERENCE LABORATORY DATABASE Antivir Ther. 2006, 11:S133 (abstract no. 120) R Kagan1, T Merigan2, M Winters2, T Huard3 and M Lewinski1 Antiretroviral treatment regimens and utilization continue to drive PR and RT mutation patterns. Reasons for decreased NRTI associated resistance may include decreased usage of thymidine analogs and didanosine and fewer suboptimal triple-NRTI regimens. Increases of some, but not all, NNRTI mutations may have resulted from increased utilization of efavirenz-based regimens. Mutations associated with resistance to newer PI regimens are increasingly seen in clinical samples. |
| 121 | RISE AND FALL OF THE RT K65R INCIDENCE IN THE PORTUGUESE RESISTANCE DATABASE Antivir Ther. 2006, 11:S134 (abstract no. 121) R Camacho1, K Theys2, A Abecasis1,2, K Deforche2, AP Carvalho1, J Cabanas1, P Gomes1 and A-M Vandamme2 The rising prevalence of K65R from 2001 to 2004 was mainly driven by the use of TDF in combinations that are not recommended by today’s standard of care. Its unexpected decline in 2005 reflects the decreasing use of such combinations. |
| 122 | CUMULATIVE PREVALENCE OF HIV DRUG RESISTANCE IN HIV+ PATIENTS IN CLINICAL CARE Antivir Ther. 2006, 11:S135 (abstract no. 122) AD Shah1, T Kyriakides1, KR Amico2, J Chiarella1, G Friedland1 and MJ Kozal1 During the period of study for this HIV+ patient population, the cumulative prevalence of genotypic resistance rose at ~5% rate per 6-months but appeared to plateau around 50%. The point prevalence of resistance grossly underestimated the burden of resistance in the population. Testing all available plasma samples helped identify resistance that may have been undetected if generated only by clinician request. |
| 123 | OCCULT HEPATITIS B VIRUS INFECTION IN HIV INFECTED PATIENTS FROM SOUTH AFRICA Antivir Ther. 2006, 11:S136 (abstract no. 123) A Lukhwareni, SG Selabe, LM Moropeng, JM Ngobeni, RJ Burnett and MJ Mphahlele The results strongly indicate that HIV infection is a risk factor for HBsAg-negative HBV infection (i.e. occult HBV) and lamivudine natural resistance strains due occurs |
| 124 | EVOLUTION OF THE PREVALENCE OF HIV DRUG RESISTANCE PATTERNS OVER 9 YEARS OF HAART AND ITS RELATION WITH CHANGES IN THE FAILING TREATMENT REGIMENS: AN ANALYSIS OF A LARGE ITALIAN DATABASE Antivir Ther. 2006, 11:S137 (abstract no. 124) M Zazzi1, P Corsi2, A Gonnelli3, M Di Pietro4, A Giacometti5, P Almi6, M Trezzi7, E Boeri8, N Gianotti8, S Menzo9, R del Gobbo5, D Francisci10, A Nerli11, L Galli12 and A De Luca13 for the ARCA Collaborative Group Cross-resistance has increased over time and specific resistance patterns have changed, as a result of specific drug pressures introduced in clinical practice. |
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Session 6: Mechanisms of HIV drug resistance Abstracts 125 thru 109, Pages S141 to S119 |
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| 125 | AZT SELECTS MUTATIONS IN THE CONNECTION (A371V) AND RNASE H (Q509L) DOMAINS OF RT THAT INCREASE AZT RESISTANCE IN COMBINATION WITH TAMS AND REDUCE SUSCEPTIBILITY TO OTHER NRTIS Antivir Ther. 2006, 11:S141 (abstract no. 125) J Brehm1, D Koontz1, V Pathak2, N Sluis-Cremer1 and J Mellors1 The A371V and Q509L mutations are co-selected on the same genome as TAMs and increase AZT resistance when combined with TAMs. They also increase cross-resistance to 3TC, abacavir and tenofovir, but this effect is minor, indicating that the mutations are largely specific for AZT. Biochemical studies are in progress to identify the molecular mechanism(s) involved. |
| 126 | THE HIV-1 REVERSE TRANSCRIPTASE CONNECTION DOMAIN FROM TREATMENT-EXPERIENCED PATIENTS CONTRIBUTES TO AZT RESISTANCE Antivir Ther. 2006, 11:S142 (abstract no. 126) GN Nikolenko1*, KA Frankenberry1*, S Palmer1, F Maldarelli1, JW Mellors2, JM Coffin1 and VK Pathak1 These results indicate for the first time that mutations in the connection domain can contribute to clinical AZT resistance and provide new insights into the mechanisms of drug resistance. These studies indicate the need to include the C-terminal domains of RT in future genotypic and phenotypic analyses of NRTI resistance. |
| 127 | INFREQUENT OCCURRENCE OF MUTATIONS IN THE C-TERMINAL REGION OF REVERSE TRANSCRIPTASE MODULATES SUSCEPTIBILITY TO RT INHIBITORS Antivir Ther. 2006, 11:S143 (abstract no. 127) S Gupta, S Fransen, EE Paxinos, W Huang, E Stawiski, CJ Petropoulos and NT Parkin These results indicate for the first time that mutations in the connection domain can contribute to clinical AZT resistance and provide new insights into the mechanisms of drug resistance. These studies indicate the need to include the C-terminal domains of RT in future genotypic and phenotypic analyses of NRTI resistance. |
| 128 | DISTINCT MECHANISMS OF HIV-1 NNRTI HYPERSUSCEPTIBILITY: INCREASED ENZYME SUSCEPTIBILITY TO NNRTI AND DECREASED REVERSE TRANSCRIPTASE IN THE VIRION Antivir Ther. 2006, 11:S144 (abstract no. 128) SA Clark, N Sluis-Cremer and JW Mellors NNRTI HS can be conferred by two distinct phenotypes: increased enzyme susceptibility to NNRTI (e.g. 118I/215Y) or decreased virion associated levels of RT (208Y/215Y and 118I/208Y/215Y). The viruses that contained less RT replicated less efficiently than those with wild-type levels of RT. These distinct mechanisms highlight the complexity of the NNRTI HS phenotype. |
| 129 | COMPOUND SPECIFIC DIFFERENCES IN THE LEVELS OF RESISTANCE OF HIV-RT CATALYSED STRAND TRANSFER, DNA POLYMERASE AND RNASE H ACTIVITIES TO INHIBITION BY NNRTIS Antivir Ther. 2006, 11:S145 (abstract no. 129) JQ Hang, Y Li, Y Yang, H Zommer, R Mackenzie, T Mizadegan, P Reynen, N Cammack and K Klumpp NNRTIs from different structural classes can inhibit polymerase, strand transfer and RNase H activities of HIV-RT. The effects of NNRTI resistance mutations on inhibition of the three different HIV-RT activities are compound and HIV-RT acitivity dependent. The resistance fold shift in the strand transfer assay was generally higher than that determined in the polymerase or RNase H assays, suggesting contributions from mutation effects on polymerase and RNase H activities on overall susceptibility shifts in the strand transfer assay. |
| 130 | THE IMPACT OF HIV-1 GP41 AMINO ACID SUBSTITUTIONS ON CO-RECEPTOR TROPISM AND SUSCEPTIBILITY TO CO-RECEPTOR INHIBITORS Antivir Ther. 2006, 11:S146 (abstract no. 130) W Huang, J Toma, S Fransen, N Parkin. J Whitcomb and C Petropoulos Envelope variants with different tropism and sensitivity to CXCR4 or CCR5 inhibitors but having identical V3 sequences contain alternative genetic determinants important for HIV-1 entry. These results reinforce the complexity of genetic determinants of CXCR4 tropism and drug resistance. We will present a model to explain how R5 tropic HIV-1 may acquire the ability to efficiently utilize CXCR4 for entry. |
| 131 | SELECTION OF DRUG RESISTANCE MUTATIONS IN SHIV SF162 FOLLOWING A SINGLE DOSE TREATMENT OF THE MICROBICIDE PSC-RANTES IN A RHESUS MACAQUE MODEL Antivir Ther. 2006, 11:S147 (abstract no. 131) DM Moore1, JL McGhee1, RS Veazey3 and EJ Arts1,2 We have identified the first known selection of an entry inhibitor resistant virus resulting from a single dose microbicide treatment (PSC). These findings suggest that even the limited diversity found in this SHIVSF162 population still permits the rapid emergence of entry inhibitor resistance and forecasts possible difficulties in anti-HIV-1 microbicide treatment. |
| 132 | ABSENCE OF PROTEASE MUTATIONS UPON VIROLOGICAL FAILURE OF FIRST-LINE FOSAMPRENAVIR/RITONAVIR IS NOT EXPLAINED BY THE ALTERNATIVE SELECTION OF P7/P1 OR P1/P6 GAG CLEAVAGE SITE MUTATIONS Antivir Ther. 2006, 11:S145 (abstract no. 132) M Ait-Khaled1, F Xu2, M Tisdale2, S MacManus2, PJ Yates2, RC Elston3 and W Snowden1 Absence of PRO mutations in first-line FPV/r VFs is not explained by the alternative selection of p7/p1 and p1/p6 CS mutations, even after prolonged replication in the presence of FPV/r. The balance between patients’ adherence and the potency and pharmacokinetic characteristics of boosted PIs remains a plausible explanation for the absence of PRO mutations in VFs of PI/r-regimen. |
| 133 | SUBSTITUTIONS WITHIN GAG BUT OUTSIDE THE CLEAVAGE SITES CAN CAUSE PROTEASE INHIBITOR RESISTANCE Antivir Ther. 2006, 11:S149 (abstract no. 133) M Nijhuis, NM van Maarseveen, D de Jong, P Schipper, IW Goedegebuure and CAB Boucher In this study we have demonstrated that substitutions within gag but outside of the cleavage site contribute directly to PI resistance by enhancing the overall gag processing by wild type protease. |
| 134 | IDENTIFICATION OF NOVEL SITES OF SUBSTRATE CO-EVOLUTION WITH RESISTANT VARIANTS OF HIV-1 PROTEASE Antivir Ther. 2006, 11:S150 (abstract no. 134) M Kolli1, C Chappey2 N Parkin2 and CA Schiffer1 Co-evolution of cleavage site substrates in the Gag and Gag-Pol polyproteins with resistance mutations in HIV-1 protease appears to be more widespread than previously reported. These observations suggest further avenues of experimentation to more fully understand the potential impact of Gag and Gag-Pol cleavage sites mutations on drug susceptibility and protease inhibitor resistant virus fitness. |
| 135 | ENSEMBLE MOLECULAR DYNAMICS SIMULATIONS OF HIV-1 PROTEASE WITH THE INHIBITOR SAQUINAVIR: INSIGHTS INTO THE MOLECULAR BASIS OF DRUG RESISTANCE CAUSED BY THE G48V AND L90M MUTATIONS Antivir Ther. 2006, 11:S151 (abstract no. 135) S Kashif Sadiq, S Wan and PV Coveney The primary mutation associated with saquinavir therapy, L90M, increases the flexibility of HIV-1 protease, leading to both increased drug resistance and decreased enzymatic stability. G48V compensates L90M through restoration of enzymatic stability explaining the clinical pathway of development of the prior after the latter. Furthermore, HIV takes advantage of both these mutations to increase the likelihood of adoption of a kinetic mechanism of drug expulsion that involves increased coupling toAntiviral Therapy 2006; 11:S151 the highly mobile flaps of the protease. |
| 136 | THE HIV-1 PROTEASE INHIBITOR PL-100 HAS A HIGH GENETIC BARRIER AND SELECTS A NOVEL PATTERN OF MUTATIONS Antivir Ther. 2006, 11:S152 (abstract no. 136) JJ Wu1, S Dandache1, B Stranix1, C Panchal1 and MA Wainberg2 The novel mutational pathway and favorable pharmacokinetic profile justify further clinical development of the drug to treat PI-naïve and experienced patients. |
| 137 | CHARACTERIZATION OF HIV-1 RESISTANT ISOLATES GENERATED DURING IN VITRO PASSAGE WITH BOTH ATAZANAVIR AND AMPRENAVIR IN COMBINATION Antivir Ther. 2006, 11:S153 (abstract no. 137) C Cabrera, S Marfil, E García, M Bofill, B Clotet and L. Ruiz Selection of resistance to ATZ, APV or ATZ plus APV revealed three independent patterns of resistance mutations. The mutation pattern selected by the combination of ATZ plus APV conferred reduced susceptibility to both PI in spite of no changes occurred at position 50. |
| 138 | PHENOTYPIC NNRTI RESISTANCE AND GENETIC DIVERSITY IN DRUG-NAÏVE INDIVIDUALS Antivir Ther. 2006, 11:S154 (abstract no. 138) DV Nissley1,2, JD Church3, LA Guay3 JB Jackson3, JN Strathern2, SH Eshleman3 NNRTI-resistant viruses are present at low levels in most ARV drug naïve Ugandan women, which could potentially compromise the efficacy of NNRTI-containing regimens for HIV-1 prevention or treatment. In 36% of these samples, phenotypic NNRTI resistance was not explained by IAS-defined NNRTI resistance mutations. The frequency of drug resistance varies among individuals suggesting that discrete viral populations have different levels of genetic diversity and may be replicating with different levels of fidelity. |
| 139 | DETECTION OF DINUCLEOSIDE POLYPHOSPHATES FORMED IN AZT-TREATED, HIV-INFECTED CELLS Antivir Ther. 2006, 11:S155 (abstract no. 139) AJ Smith, PR Meyer and WA Scott These results show that compounds are formed in AZT-treated, HIV-1 infected Jurkat cells that have properties expected of NpxAZT. The ability of these compounds to serve as substrates for chain elongation provides a very sensitive, enzymatic assay for their presence in a cell extract. Their formation is enhanced when the infection is carried out with HIV-1 mutants with elevated excision activity. This assay can serve as a link between the in vitro data characterizing HIV-1 drug resistance and the in vivo environment. |
| 140 | AZT-MP AND MAGNESIUM DEPENDENCY FOR AZT RESISTANCE STUDIED WITH REVERSE TRANSCRIPTASE BEARING TAMS Antivir Ther. 2006, 11:S156 (abstract no. 140) J Lennerstrand, M Bennett, GR Bluemling, M Ruckstuhl and RF Schinazi High AZT resistance in cell culture systems expressing TAMs-containing HIV-1-RT has previously been attributed to AZT’s bulky azido group preventing dead-end complex formation. Perhaps high intracellular levels of AZT-MP also are responsible for resistance. Differences between physiological and enzymatic assay Mg2+ levels should also be considered when measuring NRTI resistance in vitro. We show moderate increases in AZT resistance with AZT-MP and Mg2+ at the chosen concentrations. However further studies are needed to determine these RNase-H effectors roles in NRTI resistance. |
| 141 | POLYMORPHISMS IN THE VIRAL REVERSE TRANSCRIPTASE PREDICT THE EVOLUTION TOWARDS DISTINCT THYMIDINE ANALOGUE MUTATIONAL PATTERNS: A LONGITUDINAL ANALYSIS Antivir Ther. 2006, 11:S157 (abstract no. 141) A De Luca1, CF Perno2, F Ceccherini-Silberstein2, L Romano3, P Corsi4, A Gonnelli3, C Martinelli5, A Chiodera6, M De Gennaro7, A Vivarelli8, M Trezzi9, P Almi10, G Punzi11, L Monno11, M Zazzi12 for the ARCA Collaborative Group Several reverse transcriptase polymorphisms seem to predict subsequent evolution toward specific TAM patterns. The strongest association was found between 200A/E/I/K and subsequent TAM-1 and 211G/S and subsequent TAM-2. The mechanistic role of these polymorphisms deserves further exploration. |
| 142 | THE H208Y MUTATIONS IN REVERSE TRANSCRIPTASE IS SIGNIFICANTLY ASSOCIATED WITH NRTI-EXPOSURE, M184V AND TAM MUTATION PATHWAYS Antivir Ther. 2006, 11:S158 (abstract no. 142) AM Geretti1, C Sabin1, D Dunn2, on behalf of the UK Collaborative Group on HIV Drug Resistance, and the UK Collaborative HIV Cohort (CHIC) Study Group There is a strong positive association between H208Y and NRTI-experience, particularly in the context of highly NRTI-resistant virus with M184V and type 1 TAMs. These findings suggest a role in augmenting resistance or a possible compensatory function for H208Y. |
| 143 | RESIDUE K70 IN HIV-1 REVERSE TRANSCRIPTASE: A CROSSROAD BETWEEN EXCISION AND DISCRIMINATION MECHANISMS OF NRTI RESISTANCE Antivir Ther. 2006, 11:S159 (abstract no. 143) S Zelina, C-W Sheen, J Mellors and N Sluis-Cremer Mutations at residue 70 in HIV-1 RT can confer resistance to NRTI by either a nucleotide analogue discrimination of excision phenotype. For efficient excision the enzyme requires a basic amino acid (R or K; R more efficient) at residue 70. Neutral (N) or acidic (E) substitutions at residue 70 allow discrimination between the natural dNTP and nucleotide analogue, but nearly eliminate excision activity of RT even when combined with TAMs. These results highlight a key split between discrimination and excision mechanisms of NRTI resistance that occurs at residue 70. |
| 144 | NRTI RESISTANCE ASSOCIATED WITH THE RT MUTATION K70E IN HIV-1 Antivir Ther. 2006, 11:S160 (abstract no. 144) M Van Houtte1, M Staes1, AM Geretti2, T Pattery1 and L Bacheler3 In clinical isolates, K70E conferred resistance to 3TC and ddI, low-level resistance to ABC and ddC and modest decreases in susceptibility to TDF and d4T. K70E increased susceptibility to AZT. The K70E mutation may counteract the effect of M184V on ABC, ddI and ddC susceptibility. |
| 145 | INTERACTIONS OF DIOXOLANE THYMINE TRIPHOSPHATE (DOT-TP) WITH WILD-TYPE AND DRUG-RESISTANT MUTANT HIV-1 REVERSE TRANSCRIPTASES Antivir Ther. 2006, 11:S161 (abstract no. 145) E Murakami1, A Basavapathruni2, CM Bailey2, KS Anderson2, MJ Otto1 and PA Furman1 NRTI resistance consists of decreased binding/incorporation and/or excision of the chain-terminating NRTI. RTs containing the D67N/T70R/T215Y/K219Q and T69S-SS/T215Y mutations show enhanced removal of DOT-MP from terminated primer. On the other hand, the Q151M and K65R mutations appear to cause decreased binding/incorporation of DOT-TP. Both K65R and Q151M mutations show decreased excision which would confer greater stability to the terminated primer. These opposing mechanisms could offset somewhat the overall resistance profile and susceptibility. Little or no resistance was observed with the enzymes harboring mutations resistant to 3TC (M184V) and non-nucleoside RT inhibitors (K103N). |
| 146 | CHANGES IN LEVELS OF DNTPS, CARBOVIR-TP AND TENOFOVIR-DP IN PURIFIED HUMAN CD4+ AND CD8+ PERIPHERAL BLOOD T CELLS FOLLOWING TREATMENT WITH TENOFOVIR +/- ABACAVIR +/- LAMIVUDINE Antivir Ther. 2006, 11:S162 (abstract no. 146) S Singer1, D Irlbeck1, A Pruvost2, G Freeman1, G Yuen1, S Sparks1, S Novick1, R Harvey1 and R Lanier1 Analysis of total PBMCs for NRTI active drug levels may not accurately reflect the cell populations targeted by HIV as significant differences were seen between CD4 and CD8 subsets. In contrast to prior work with transformed cell lines, we observed significant increases for endogenous dNTPs in these purified PBMC subsets with NRTI treatment; although similar fold increases in the analogous active drug anabolite (dGTP and carbovir-TP) suggest this mechanism is not a major factor in failure of tenofovir/abacavir/lamivudine. We believe these results merit confirmation and further study by independent groups. |
| 147 | DRUG UPTAKE TRANSPORTERS EXPRESSION ON T-LYMPHOCYTES AND THEIR REGULATION DURING HIV-1 INFECTION IN VITRO Antivir Ther. 2006, 11:S163 (abstract no. 147) G Minuesa1, S Purcet2, I Erkizia1, M Molina-Arcas2, L Ruiz1, FJ Casado, B Clotet1, M Pastor-Anglada2 and J Martinez-Picado1 These results strongly support the idea that AZT uptake into T-cells involves a carrier-mediated transport mechanism which might contribute to regulate intracellular drug concentrations. Furthermore, the identification of specific NRTIs transporters could be a novel target to optimize pharmacological therapeutic responses. |
| 148 | THE IN VIVO SELECTION OF MUTATIONS L74I/V IS LINKED TO COMBINED NUCLEOSIDE REVERSE TRANSCRIPTASE AND NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR EXPOSURE Antivir Ther. 2006, 11:S164 (abstract no. 148) R Camacho1, K Theys2, A Abecasis1,2, K Deforche2, AP Carvalho1, J Cabanas1, P Gomes1 and A-M Vandamme2 L74V and L74I are preferentially selected in patients under NRTIs also exposed to NNRTIs. In a small percentage of cases, no prior history of ABC or ddI was reported suggesting these mutations might be directly selected by NNRTIs. Further studies are needed to clarify these resistance pathways. |
| 149 | INVOLVEMENT OF NOVEL HIV-1 REVERSE TRANSCRIPTASE MUTATIONS IN THE REGULATION OF NNRTI RESISTANCE Antivir Ther. 2006, 11:S165 (abstract no. 149) V Svicher1, T Sing2, MM Santoro1, A Bertoli1, C Gori3, A Artese4, S Alcaro4, A d’Arminio Monforte5, A Antinori3, T Lengauer2, CF Perno1,3 and F Ceccherini-Silberstein1 Our study gives evidence that NNRTI-resistance is more complex than the classical one step full-resistance given by a single mutation. Mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response to antiretroviral drugs and for the assessment of potential efficacy of new-generation NNRTI. |
| 150 | FACILITATED SELECTION OF K65R RESISTANCE WITH TENOFOVIR PRESSURE IN SUBTYPE C HIV-1 ISOLATES Antivir Ther. 2006, 11:S166 (abstract no. 150) BG Brenner, M Oliveira, D Moisi, F Doualla-Bell and MA Wainberg TFV-based regimens will need to be carefully monitored in subtype C infections for possible facilitated selection of K65R. In addition, these data establish concern in regard to the use of TFV in HIV prevention studies in areas of the world in which subtype C viruses are predominant. |
| 151 | IDENTIFICATION OF NRTI-BOOSTING NNRTIs BY A CELL-BASED HIV SCREEN Antivir Ther. 2006, 11:S167 (abstract no. 151) P Gerondelis1, M Underwood1, S Foster1, G Roberts1, E Garvey1, G Freeman2, R Harvey1, A Spaltenstein2, S Daluge2, R Lanier Using a cell-based approach in a search for PUB inhibitors, we did not identify any compound that boosted ZDV activity without having intrinsic antiviral activity. We did, however, identify compounds that boosted ZDV activity to a degree similar to that observed with efavirenz and nevirapine. Cellular and biochemical data suggest that these compounds are in fact NNRTIs themselves, albeit with much weaker antiviral activity than efavirenz and nevirapine. |
| 152 | INDEPENDENT PATTERNS OF SEQUENCE VARIATION IN HIV-1 PRO AND RT ARE FACILITATED BY FREQUENT RECOMBINATION Antivir Ther. 2006, 11:S168 (abstract no. 152) F Maldarelli1, M Kearney1, S Palmer1, S Thawani, J Mican2, D Rock-Kress2, C Rehm2, J Mellors3, J Coffin1 Among chronically infected individuals, gene-specific sequence diversity in pro and pol is comparable and stable over time. Despite this stability, these genes vary independently, even in the absence of drug selection pressure, and exhibit frequent recombination. |
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Session 6: Resistance of test interpretation and prediction of clinical response Abstracts 153 thru 156, Pages S171 to S181 |
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| 153 | PHENOTYPES AND PHENOTYPE ESTIMATES: INTERPRETATION AND PREDICTION OF CLINICAL RESPONSE Antivir Ther. 2006, 11:S171 (abstract no. 153) PR Harrigan The advantages of phenotypic measures or estimates of HIV drug resistance over genotypic methods include the fact that the result is a direct measure of resistance, providing a single, objective, and quantitative parameter per drug which can be associated with clinical response. |
| 154 | RULES AND ALGORITHMS, DERIVATION, DEVIATION AND VALIDATION Antivir Ther. 2006, 11:S172 (abstract no. 154) JM Schapiro HIV drug resistance testing has demonstrated moderate short-term virological benefit in clinical trails. Cost benefit estimates are comparable with other acceptable interventions and these assays are now widely incorporated in clinical practice in many countries. Despite this, interpretation of resistance assay results remains an imperfect science at best. |
| 155 | PREDICTING HIV THERAPY RESPONSE BY COMPUTATIONAL MODELLING OF LARGE CLINICAL DATASETS Antivir Ther. 2006, 11:S173 (abstract no. 155) B Larder The utility of HIV genotyping to assess clinical drug resistance is limited by difficulties in interpretation. Interpretation systems relate HIV genotype with drug susceptibility using ‘rules’ or algorithms. |
| 156 | RESISTANCE TESTING AND NEW ANTIRETROVIRAL USE IN THE CLINIC: WHAT ARE WE GETTING? Antivir Ther. 2006, 11:S174 (abstract no. 156) A Zolopa Resistance testing has been widely employed in the management of ARV regimens for most of the past decade of HAART therapy. Multiple studies have demonstrated that resistance tests provide prognostic information about response to new regimens after failure of a prior regimen and clinical trials have demonstrated positive impacts on viral load responses. |
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Session 7: New resistance technologies and interpretations Abstracts 157 thru 172, Pages S177 to S192 |
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| 157 | ACCURATE PREDICTION OF VIROLOGICAL RESPONSE TO HAART USING THREE COMPUTATIONAL MODELLING TECHNIQUES Antivir Ther. 2006, 11:S177 (abstract no. 157) BA Larder1, D Wang1, F De Wolf2, J Lange3, A Revell1, S Wegner4, J Montaner5, R Harrigan5, JA Metcalf6 and HC Lane6 These results suggest that all three methods can yield fairly accurate predictions of response and their combination may provide a modest improvement in accuracy over any one method. As with previous studies, the predictions for clinics with data in the training data set were somewhat more accurate than for ‘unfamiliar’ clinics. The accuracy of these models, trained using relatively small datasets, was encouraging. |
| 158 | PREDICTION OF ANTIRETROVIRAL (ARV) TREATMENT OUTCOME USING CLINICAL VARIABLES PLUS GENOTYPE (GSS) VERSUS A GENOTYPE MODELED ON PAST ARV TREATMENT Antivir Ther. 2006, 11:S178 (abstract no. 158) SY Rhee1, T Liu1, WJ Fessel2, AR Zolopa1, JM Schapiro1 and RW Shafer1 In multivariate analysis, eCARE susceptibility scores (ECS) as well as GSS were each significant independent predictors of virological suppression at week 24. In areas where genotypic resistance testing is not available, a treatment ≥ genotype model provides useful information that may help care providers select active ARV treatment combinations. |
| 159 | BAYESIAN GRAPHICAL MODELS IN THE ANALYSIS OF HIV DRUG RESISTANCE DATA FROM THE UK HIV DRUG RESISTANCE DATABASE Antivir Ther. 2006, 11:S179 (abstract no. 159) F Lewis1, E Fearnhill2, R Murray1, D Pillay3, D Dunn2, A Leigh Brown1, UK Drug Resistance Collaboration When modelling clinical cohort data even a simple case (3TC) becomes complex: dominant effect of 184 is lost, drug background and interactions between mutations are important. |
| 160 | DEVELOPMENT OF VIRCO®TYPE RESISTANCE ANALYSIS, INCLUDING CLINICAL CUT-OFFS, FOR TMC-114 Antivir Ther. 2006, 11:S180 (abstract no. 160) B Winters1, H Vermeiren1, E Van Craenenbroeck1, P Lecocq1, T Vangeneugden2, M-P de Béthune2 and L Bacheler3 Virco®TYPE resistance analysis integrates complex interactions among multiple protease gene mutations to provide a quantitative prediction of TMC-114 drug susceptibility, which can be interpreted using CCOs. Since these CCOs were defined using data from power 1, 2 and 3, their relevance for patients with different baseline characteristics is unclear. In the power studies, baseline TMC-114 FC predicted by Virco®TYPE was negatively correlated with week 8 virological response. |
| 161 | CORRELATION OF HIGHLY-SENSITIVITY GENOTYPIC HIV DRUG RESISTANCE TO PHENOTYPIC DRUG RESISTANCE SCREENING Antivir Ther. 2006, 11:S181 (abstract no. 161) MS Lalonde1, KR Henry1, R Troyer1, F Kyeyune2, K Demers2, M Kamya3, C Whalen1, P Mugyenyi2, F Bajunirwe4, HA Baird5 and EJ Arts1 This study serves as a proof of concept for the suitability of OLA to monitor specific genetic changes in HIV-1 infections which may confer drug resistance. In combination with phenotypic analysis, it can serve as means to tailor drugs for individual patient and earlier diagnostic detection of the drug resistance in the future. |
| 162 | CLINICALLY RELEVANT PHENOTYPIC RESISTANCE CUT-OFF LEVEL FOR RITONAVIR-BOOSTED FOSAMPRENAVIR Antivir Ther. 2006, 11:S182 (abstract no. 162) I Pellegrin1, P Merel1, G Coureau2, D Breilh3, H Fleury1, E Lazaro4, D Neau4, P Morlat4, F Demuylder5, T Pattery5 and R Thiébaut2 The very good agreement between the previously defined ZEPHIR score and the Virtual-Phenotype based interpretation is an argument for the validity of both algorithms. Nevertheless, these genotypic and phenotypic algorithms need to be validated in larger prospective studies. |
| 163 | INVESTIGATION OF DIFFERENTIAL IMPACT OF MUTATIONS ASSOCIATED WITH COMPLEX HIV-1 PROTEASE MULTI-DRUG RESISTANCE PATTERNS USING BIO-INFORMATICS RESISTANCE DETERMINATION (BIRD) Antivir Ther. 2006, 11:S183 (abstract no. 163) H Van Marck1, I Dierynck1, G Muyldermans2, L Borozdina3, R Keen3, G Kraus1, M-P de Béthune1, S Hallenberger1 and K Hertogs1 The BIRD approach allows for the generation and characterisation of large panels of viruses with multiple combinations of mutations, in terms of both viability and susceptibility to inhibitors. This new tool will help clarify complex resistance patterns. |
| 164 | EVOLUTION OF GENOTYPIC RESISTANCE ALGORITHMS AND THEIR IMPACT ON THE INTERPRETATION OF CLINICAL TRIALS: AN OPTIMA TRIAL SUBSTUDY Antivir Ther. 2006, 11:S184 (abstract no. 164) SS Desai1, TC Kyriakides1, M Holodniy2, J AlSalmans1, BP Griffith1 and MJ Kozal1 Underestimation of drug resistance by older genotypic algorithms resulted in use of ARVs incorrectly thought to be sensitive. Patients assumed to be on ≥3 sensitive agents had high rates of HIV disease progression. Use of older genotypes in the interpretation of ongoing long-term clinical trials should take into account this underestimation since results may be different if viral sequences are interpreted with newer algorithms. |
| 165 | CHANGES IN HIV-1 GENOTYPE ASSOCIATED WITH GOING OFF-TRACK IN ACTG 398 Antivir Ther. 2006, 11:S185 (abstract no. 165) G DiRienzo1, S Hammer2 and J Mellors3 Using valid statistical approaches for multiple testing, we identify the emergence of known resistance mutations to drugs in ACTG 398 regimens at the time of HIV-1 RNA rebound. This indicates the selection of resistant variants as the cause of going “off track” rather than medication non-adherence. |
| 166 | AN ALTERNATIVE TIMING STRATEGY FOR RESISTANCE GENOTYPING Antivir Ther. 2006, 11:S186 (abstract no. 166) W Shealey1, B Shepherd1, L Sutton1, G Barkanic1, A Kheshti1,2, T Sterling1, S Kalams1, S Raffanti1,2 and R D’Aquila1 The alternative timing of genotyping soon after starting initial therapy detected more resistance mutations than did testing prior to starting therapy, using a commercially available method. Estimate of resistance prevalence among drug-naïve subjects doubled with post-therapy testing, and better approximated prevalence estimated in untreated acute/early infections. Confirmation of pre-therapy minority subpopulations is underway. A larger study is warranted to confirm this finding, improve precision of estimates, and to study whether specific mutations are better detected post-therapy than pre-therapy. |
| 167 | A METHOD TO ESTIMATE THE WEIGHTS FOR MUTATIONS WITHIN GENOTYPIC RESISTANCE SCORES: APPLICATION TO ATAZANIR AND SAQUINAVIR Antivir Ther. 2006, 11:S187 (abstract no. 167) P Flandre1, AG Marcelin2, V Soriano3, S Yerly4, Katlama C2 and V Calvez2 This boostrap approach allows to weight the impact of different mutations in genotypic resistance scores and improves their prediction of virological response. |
| 168 | PREDICTING ORDERED ACCUMULATION OF MUTATIONS OF HIV UNDER TREATMENT USING AN ESTIMATE OF THE HIV IN VIVO FITNESS FUNCTION DURING TREATMENT Antivir Ther. 2006, 11:S188 (abstract no. 168) K Deforche1, R Camacho2, K Van Laethem1, P Lemey1,4, Y Moreau3, A-M Vandamme1 We estimated a complex fitness function of virus under in vivo protease selective pressure solely from cross-sectional sequence data, and successfully used it to predict resistance evolution under drug selective pressure. This technique may be useful to build a detailed predictive model for treatment response, which takes into account drug resistance, replication capacity and evolutionary aspects. |
| 169 | MULTI-GENOME SEQUENCING (MGS): A NEW, SENSITIVE METHOD OF DETECTING LOW FREQUENCY DRUG–RESISTANT MUTANTS Antivir Ther. 2006, 11:S189 (abstract no. 169) D Barnas1, M Kearney2, V Boltz2, S Patel1, F Maldarelli2, CB Hare3, D Havlir3, Z Su4, A Krambrink4, D Margolis5, S Palmer2, J Coffin2 and J Mellors1 Using MGS, we detected low-frequency K101E, Y188C, and G190E mutants in patients who had discontinued an NNRTI-containing regimen but not in treatment naïve individuals. These mutations were missed by standard sequencing and were at codons not analysed by ASP. Low frequency polymorphisms at NNRTI resistance sites were detected in most samples. Although MGS cannot assess linkage of resistance mutations, it is a promising new method for the detection of rare drug-resistant variants with sensitivity comparable to ASP and the advantage of analyzing all codons of interest. |
| 170 | DIRECTIONAL MOLECULAR CLONING SYSTEM USING INVERTED NUCLEOTIDES FOR CLONING SPECIFIC CLINICALLY IMPORTANT GENE TARGETS FROM VIRUSES Antivir Ther. 2006, 11:S190 (abstract no. 170) S Zhang, ES Smith, EH Fiss, DH Gelfand, and TW Myers This method allows for rapid directional cloning of viral sequences without the need for restriction enzymes which may cut within the unknown target sequence. The use of Mg2+-activated DNA polymerases with proofreading activity for the RT/PCR minimizes mutations introduced during cDNA synthesis and/or PCR amplification. |
| 171 | CLONAL PHENOTYPIC CONFIRMATION OF GENOTYPIC V3-LOOP TROPISM PREDICTION ON A TREATMENT-NAÏVE HIV-1 INFECTED SUBJECT SAMPLE Antivir Ther. 2006, 11:S191 (abstract no. 171) K Van Baelen, I Vandenbroucke, E Rondelez, V Van Eygen, A Deloof, H Vermeiren and LJ Stuyver Clonal genotypic and phenotypic tropism analysis on a treatment-naïve HIV-1-infected patient revealed the presence of both R5-, dual- and X4-tropic virus strains. In this study, tropism algorithm predictions were accurate for isolates with clear affinity for their co-receptor (RR and XX group, possibly also RU), but might need refinement for isolates showing discordant predictions (RX (and possibly RU) group). |
| 172 | RECONSTRUCTION OF HIV-1 FULL GENOME CLONES WITH BACILLUS SUBTILIS Antivir Ther. 2006, 11:S192 (abstract no. 172) T Ueda1, M Itaya2, K Tsuge2, K Fujita2, M Matsuda1, M Nishizawa1 and W Sugiura1 We successfully established a B.subtilis HIV-1 reconstruction system. In addition, the system allows shuffling of each DNA fragment, and recovery of HIV-1 virus through the random combination of five fragments. |
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