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18th International HIV Drug Resistance Workshop:
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Cite as: Antiviral Therapy 2009; 14 Suppl 1:xx (abstract no. ??)
where "xx" is the page number and "??" is the abstract number.
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Oral Presentations Abstracts 1 thru 44, Pages A3 to A44 |
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| 1 | ERADICATION OF HIV INFECTION: ANY PROBLEM, HOWEVER COMPLICATED, IF LOOKED IN THE RIGHT WAY, BECOMES MORE COMPLICATED Antiviral Therapy 2009; 14 Suppl 1:A3 (abstract no. 1) D Margolis The causes of persistence of HIV infection in the face of current therapy appear to be multifactorial: latent but replication-competent provirus in resting CD4+ T-lymphocytes, cryptic viral expression below the limits of detection of clinical assays and viral sanctuary sites might all contribute to persistence. |
| 2 | ROLES OF NFAT, CELL DIVISION AND IL-7 STIMULATION ON HIV-1 REACTIVATION FROM LATENCY IN PRIMARY MEMORY T-CELLS Antiviral Therapy 2009; 14 Suppl 1:A4 (abstract no. 2) A Bosque and V Planelles Although CD3/CD28 stimulation provides a potent signal to study viral reactivation ex vivo, it would be unlikely to have therapeutic use. In an effort to find alternative pathways, we screened a number cytokines and chemokines. We found that a combination of IL-2 and IL-7 is a potent inducer of latent HIV-1 independently of NFAT and NFκB. Therefore, reactivation via IL-2 and IL-7 represents an alternative pathway to T-cell receptor engagement and represents a novel therapeutic avenue for purging latent reservoirs. |
| 3 | SJ23B, A JATROPHANE DITERPENE, INDUCES HIV RECEPTORS DOWNREGULATION AND HIV TRANSCRIPTION THROUGH ACTIVATION OF RAS-MEK PATHWAY AND CLASSICAL PKCS Antiviral Therapy 2009; 14 Suppl 1:A5 (abstract no. 3) LM Bedoya1, N Márquez2, N Martínez3, S Gutiérrez-Eisman3, A Álvarez1, MA Calzado2, JM Rojas3, G Appendino4, E Muñoz2 and J Alcami1 SJ23B is a potent anti-HIV agent, sharing some mechanisms of action with prostratin, but structurally different from phorbol-esters. This compound induces two responses: HIV reactivation through transactivation of HIV-LTR and downregulation of HIV receptors, preventing de novo infection of susceptible CD4+ T-cells. |
| 4 | LONGITUDINAL DYNAMICS OF PERSISTENT VIREMIA IN ELITE CONTROLLER PATIENTS VERSUS PATIENTS ON SUPPRESSIVE THERAPY Antiviral Therapy 2009; 14 Suppl 1:A6 (abstract no. 4) S Palmer1,2, M King3, A Wiegand2, T Miura4, B Block4, F Pereyra4, F Maldarelli2, V Dahl1, J Mellors5, B Walker4 and JM Coffin6 The majority of patients classified as elite controllers had detectable low-level viremia. While the overall mean level of viremia was similar to that of patients on suppressive therapy, longitudinal analysis revealed larger intra- and interpatient variability for elite controllers compared with patients on suppressive therapy. These substantial viral RNA fluctuations implicate a different source for the low-level viremia in the two groups, despite the similarity in levels. These findings suggest that elite controllers experience ongoing rounds of viral replication followed by immune response and viremic control. |
| 5 | HIV-SPECIFIC CD4+ T-CELLS MAY CONTRIBUTE TO VIRAL PERSISTENCE IN HIV-INFECTED ELITE CONTROLLERS Antiviral Therapy 2009; 14 Suppl 1:A7 (abstract no. 5) PW Hunt1, H Hatano1, E Sinclair1, EL Delwart1,2, TH Lee2, MP Busch1,2, R Hoh1, Z Grossman3, JN Martin1 and SG Deeks1 The cell-associated viral burden (DNA and RNA) in HIV-infected elite controllers is strongly associated with level of potential target cells (activated CD4+ T-cells and HIV-specific CD4+ T-cells), but not with other host responses. Plasma HIV RNA levels were only associated with the %activated CD8+ T-cells. Collectively, these data suggest that activated and/or HIV-specific CD4+ T-cells are major contributors to viral persistence in this setting. |
| 6 | HIV-1 PLASMA VIRUS DIVERSITY PERSISTS DESPITE SUPPRESSION WITH ANTIRETROVIRAL THERAPY Antiviral Therapy 2009; 14 Suppl 1:A8 (abstract no. 6) M Kearney1, S Yu1, W Shao1, JW Mellors2, JM Coffin1 and F Maldarelli1 HIV-1 gag-pro-pol genetic diversity did not change significantly despite 10,000-fold reduction in viremia with suppressive ART. These data suggest that both short-and long-lived cells are infected with similar virus populations before therapy is initiated and that active cycles of HIV-1 replication are completely blocked by ART. |
| 7 | THE ROLE OF CHITINASE-3-LIKE-1 IN BACTERIAL TRANSLOCATION DURING HIV-1 INFECTION Antiviral Therapy 2009; 14 Suppl 1:A9 (abstract no. 7) AJ Smith, TW Schacker, MB Sivertson, MM Shepherd, MJ Henry-Stanley, CL Wells and AT Haase Collectively, this data provides mechanistic insight surrounding microbial translocation during HIV-1 infection. CHI3L1’s expression in the gut may facilitate bacterial translocation across an intact intestinal epithelial barrier as a means driving systemic immune activation. This data advocates continued research in this area to develop novel therapeutic targets to attenuate chronic immune activation in HIV-1 infection. |
| 8 | MARKERS OF CELLULAR IMMUNE ACTIVATION DO NOT CORRELATE WITH LEVELS OF RESIDUAL VIREMIA IN PATIENTS ON LONG-TERM SUPPRESSIVE ANTIRETROVIRAL THERAPY Antiviral Therapy 2009; 14 Suppl 1:A10 (abstract no. 8) F Cossarini1,2, A Wiegand1, J Mican3, M Polis4, C Rehm4, A O’Shea3, C Poethke1, J Spindler1, R Dewar5, J Higgins5, M Kearney1, J Coffin1,6, J Mellors7 and F Maldarelli1 CD8+ T-cell activation decreases significantly after prolonged antiretroviral therapy reaching levels undistinguishable from those in uninfected persons. Despite a potential trend in CD8+CD38+ HLA-DR+ T-cells, the level of residual viremia on therapy did not correlate with CD8+HLA-DR+ or CD8+CD38+ T-cells, suggesting that low-level viremia may not be sufficient to stimulate CD8+ T-cell activation. |
| 9 | NO EVOLUTION OF HIV-1 TOTAL DNA AND 2-LTR CIRCLES AFTER 24 WEEKS OF RALTEGRAVIR-CONTAINING REGIMEN: A SUBSTUDY OF RANDOMIZED EASIERANRS 138 TRIAL Antiviral Therapy 2009; 14 Suppl 1:A11 (abstract no. 9) C Delaugerre1, I Charreau2, J Braun2, ML Néré1, N de Castro3, P Yeni4, JM Chennebault5, A Lafeuillade6, J Ghosn7, F Simon1, JP Aboulker2, JM Molina3 and the ANRS 138 study group In this randomized trial, no modification in total and 2-LTR DNA was observed after 24 weeks in either raltegravir or enfuvirtide arms, suggesting that the majority of viral DNA is non-dynamic in patients with plasma controlled <400 copies/ml. |
| 10 | ANTIRETROVIRAL INTENSIFICATION DOES NOT REDUCE PERSISTENT HIV-1 VIREMIA ON THERAPY Antiviral Therapy 2009; 14 Suppl 1:A12 (abstract no. 10) J Dinoso1, J Jones2, D McMahon2, A Wiegand3, M Kearney3, J Spindler3, S Palmer3,4, S McNulty2, J Metcalf5, E Acosta6 , R Siliciano1, J Coffin3,7, J Mellors2 and F Maldarelli3 Intensification with antiretrovirals targeting RT, protease or integrase does not decrease the level of residual viremia. These results are inconsistent with the hypothesis that persistent viremia results from ongoing complete cycles of viral replication. New therapeutic approaches will be required to eliminate HIV-1 reservoirs. The speaker will review the state of the field and introduce the concepts to be covered by the other speakers in this session before addressing the topic that is summarized by the title below. |
| 11 | STATE OF THE ART PRESENTATION: V3-DEPENDENT AND -INDEPENDENT PATHWAYS TO SMALL MOLECULE CCR5 INHIBITOR RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A13 (abstract 11) JP Moore Several unusual aspects of CCR5 inhibitor resistance merit further understanding to guide clinical use of these new drugs. |
| 12 | DIFFERENT MECHANISMS OF HIV-1 INHIBITION BY CCR5 AGONISTS/ANTAGONISTS (MARAVIROC, TAK-779 AND PSC-RANTES) ARE LINKED TO DIFFERENT DRUG RESISTANCE MECHANISMS Antiviral Therapy 2009; 14 Suppl 1:A14 (abstract no. 12) M Lobritz, A Ratcliff, A Marozsan, D Dudley and E Arts CCR5 receptor downregulation by PSC-RANTES or RANTES provides minimal contribution to overall HIV-1 inhibition under physiological conditions. However, the other CCR5 antagonists are non-competitive, allosteric inhibitors incapable of receptor downregulation. The effect of CCR5 downregulation by PSC-RANTES appears to be short-lived as an inhibitory mechanism and as compared with subsequent competitive inhibition. Competitive inhibition, and not receptor downregulation, is the likely factor that contributed to the immediate selection of PSC-RANTES-resistant SHIV clone in vaginal microbicide model. |
| 13 | TRANSITIONS FROM CCR5 TO CXCR4 USE IN THE ABSENCE OF ANTIRETROVIRAL DRUG PRESSURE PROCEED INCREMENTALLY AND MAY OCCUR THROUGH A MULTITUDE OF GENETIC PATHWAYS Antiviral Therapy 2009; 14 Suppl 1:A15 (abstract 13) W Huang1, E Coakley1, J Toma1, E Stawiski1, A Frantzell1, H Schuitemaker2, CJ Petropoulos1 and AB van ‘t Wout2 Detailed characterization of emerging CXCR4-using variants in the virus populations of eight individuals indicates that HIV uses a multitude of mutational pathways to change from CCR5 to CXCR4 use. Furthermore, our observations indicate that CCR5 to CXCR4 transitions are incremental, not quantum, and are consistent with the ‘R5, dual-R, dual-X’ model that we have proposed to describe the evolution of CXCR4 use from R5-tropic virus populations. |
| 14 | ESTIMATING EVOLUTIONARY PATHWAYS TO CXCR4 USAGE FROM CROSS-SECTIONAL DATA Antiviral Therapy 2009; 14 Suppl 1:A16 (abstract no. 14) A Thielen1, A Altmann1, J Bogojeska1, R Kaiser2 and T Lengauer1 Since 11/25 mutations predominantly appeared as one of the first mutations in our trees, it can be assumed that most other mutations associated with X4 viruses are compensatory mutations following after the coreceptor switch and that there is no ongoing evolution towards X4 viruses over time. |
| 15 | SCREENING FOR HIV TROPISM USING POPULATION-BASED V3 GENOTYPIC ANALYSIS: A RETROSPECTIVE VIROLOGICAL OUTCOME ANALYSIS USING STORED PLASMA SCREENING SAMPLES FROM MOTIVATE-1 Antiviral Therapy 2009; 14 Suppl 1:A17 (abstract no. 15) PR Harrigan1, R McGovern1, W Dong1, A Thielen2, M Jensen3, T Mo1, D Chapman4, M Lewis5, I James5 and H Valdez4 Despite apparently poor sensitivity of standard genotyping for predicting non-R5 HIV relative to standard Trofile, early virological reductions in this treatment-experienced population were similar regardless of the assay used. |
| 16 | MODIFICATION OF THE CCR5 BINDING SITE BY MUTATIONS IN gp120 INFLUENCE DRUG SUSCEPTIBILITY AND VIRAL INFECTIVITY IN ONE SUBJECT WITH CLINICAL RESISTANCE TO VICRIVIROC Antiviral Therapy 2009; 14 Suppl 1:A18 (abstract 16) RA Ogert1, Y Hou1, L Ba1, C Buontempo1, N Murgolo2, P Qiu2, J Duca3, J Strizki1, R Ralston1 and JA Howe1 The amino acid changes we characterized primarily conferred VCV resistance or influenced envelope infectivity. A specific combination of four of the seven mutations was required for the complete VCV resistance phenotype, suggesting that CCR5 antagonists have a high barrier to resistance. Functionally, the combination of mutations resulted in increased dependence on the envelope interaction with the N terminus of CCR5 for viral entry. |
| 17 | HIGH-RESOLUTION STRUCTURES OF HIV-1 RT/RNA:DNA TERNARY COMPLEXES WITH TENOFOVIR DIPHOSPHATE AND dATP Antiviral Therapy 2009; 14 Suppl 1:A19 (abstract no. 17) K Das1,2, R Bandwar1,2, J Bauman1,2, S Tuske1,2, SH Hughes3 and E Arnold1,2 The canonical base pairing of the RNA:DNA duplex is disrupted in a region between the two active sites. The 2´-OH group of the RNA-template overhang forms a hydrogen bond with the main chain carbonyl of G152. The binding of TFV-DP and dATP at the polymerase active site in the RT/RNA:DNA is similar to their binding to RT/ DNA:DNA complexes. |
| 18 | THE HIV-1 RT MUTANT Q151L SHOWS DECREASED REPLICATION CAPACITY, SELECTIVE HIGH-LEVEL RESISTANCE TO GS-9148 AND HYPERSUSCEPTIBILITY TO TENOFOVIR AND ZIDOVUDINE Antiviral Therapy 2009; 14 Suppl 1:A20 (abstract no. 18) R Kulkarni1, NA Margot1, F. Myrick2, J Svarovskaia2, J Chen1, E Lansdon1, AS Ray1, T Cihlar1, S Swaminathan1, MD Miller1 and KL White1 Resistance selection revealed Q151L as a novel resistance pathway for GS-9148 in vitro. The Q151M complex shows lower resistance to GS-9148, potentially explaining the lack of its appearance during in vitro selection. The hypersusceptibility of Q151L to TFV and ZDV suggest potential utility of combination therapy of GS-9131 with these agents. |
| 19 | MECHANISMS ASSOCIATED WITH HIV-1 RESISTANCE TO ACYCLOVIR BY THE V75I MUTATION IN REVERSE TRANSCRIPTASE Antiviral Therapy 2009; 14 Suppl 1:A21 (abstract no. 19) EP Tchesnokov1, A Obikhod2, I Massud2, A Lisco3, C Vanpouille3, B Brichacek3, J Balzarini4, C McGuigan5, M Derudas5, L Margolis3, RF Schinazi2 and M Götte1 The results of this study suggest that ACV is vulnerable to two different resistance pathways. Discrimination against the inhibitor at the level of incorporation appears to be the dominant mechanism. Changes at position V75 can affect the precise positioning of amino acids Q151 and/or R71 that are directly involved in the catalytic step. Together, these findings warrant further investigation with respect to the detailed resistance profile of ACV to better assess its potential clinical utility in combination with established antiretrovirals. |
| 20 | MECHANISMS OF INHIBITION AND RESISTANCE TO TRANSLOCATION DEFICIENT REVERSE TRANSCRIPTASE INHIBITORS Antiviral Therapy 2009; 14 Suppl 1:A22 (abstract no. 20) B Marchand1, L Michailidis1, EI Kodama2, E Ryan1, R Do1, M Matsuoka2, N Ashida3, E Nagy4, H Mitsuya5,6, MA Parniak4 and SG Sarafianos1 We found that EFdA inhibits RT by preventing translocation of the polymerase, introducing a novel mechanism of inhibition for a nucleoside analog. We named this type of inhibitors ‘translocation-deficient RT inhibitors’ (TDRTI). Mutations M184V, T165R and I142V confer resistance to TDRTIs by both discrimination and excision mechanisms. To our knowledge, this is the first example of a mutant RT (M184V/T165R/I142V) using these previously thought mutually exclusive mechanisms to evade inhibition by an NRTI. |
| 21 | RECOMBINANT VIRUSES EXPRESSING SUBTYPE B OR SUBTYPE C REVERSE TRANSCRIPTASE REVEAL NO DIFFERENCE IN THE RATE OF K65R RESISTANCE TO TENOFOVIR IN CELL CULTURE Antiviral Therapy 2009; 14 Suppl 1:A23 (abstract no. 21) C Dobard, J Lipscomb, JA Johnson, JG Garcia-Lerma and W Heneine In our in vitro system, the kinetics of K65R selection was similar for recombinant viruses expressing either subtype B or subtype C RT. These findings do not exclude the possibility of different selection conditions or viral regions other than the RT influencing the selection of K65R in subtype C isolates. |
| 22 | HIV-1 REVERSE TRANSCRIPTASE FIDELITY VARIANTS ALTER LEVELS OF MUTATION DURING REPLICATION Antiviral Therapy 2009; 14 Suppl 1:A24 (abstract no. 22) DV Nissley1,2, O Alptürk3, Z Ambrose3, K Eaton2, JN Strathern2 and N Sluis-Cremer3 We characterized HIV-1 RT variants that increase mutation frequency, alter the mutational spectrum and affect viral replication. These fidelity variants map to multiple regions in RT and expand the repertoire of enzyme:nucleic acid interactions that determine the quality of replication. These variants may be useful to compare the evolution of drug resistance in low fidelity RT viruses with that of wild-type and to determine whether fidelity variants play a role in generating drug resistance. |
| 23 | DIFFERENT EVOLUTION AND PATTERNS OF GENOTYPIC RESISTANCE PROFILES IN EMTRICITABINE PLUS TENOFOVIR AND LAMIVUDINE PLUS TENOFOVIR CONTAINING REGIMEN Antiviral Therapy 2009; 14 Suppl 1:A25 (abstract no. 23) V Svicher1, C Alteri1, F Forbici2, MM Santoro1, D Schols3, K Van Laethem3, E Boumis2, P De Longis2, P Narciso2, A Antinori2, F Ceccherini-Silberstein1, J Balzarini3 and CF Perno1,2 In vivo analysis, confirmed by in vitro experiments, showed lower rates of M184V development in FTC+TDF regimens versus 3TC+TDF and highlighted TDF as having a protective role in M184V emergence. RT mutational patterns, more complex than currently known, may contribute to resistance to NRTI, including FTC/3TC. |
| 24 | LAMIVUDINE RESISTANCE MUTATIONS IN HBV REVERSE TRANSCRIPTASE CAN BE SELECTED EVEN AT EXTREMELY LOW LEVELS OF VIRAL REPLICATION Antiviral Therapy 2009; 14 Suppl 1:A26 (abstract no. 24) V Svicher1, C Alteri1, C Gori2, R Salpini1, F Marcuccilli1, R Longo3, M Bernassola3, V Gallinaro4, S Romano3, M Visca3, A Ursitti3, M Feasi5, V Micheli6, M Angelico1, G Cassola5, G Parruti7, G Gubertini6, GM De Sanctis4, F Ceccherini-Silberstein1, G Cappiello3, A Spanò3 and CF Perno1 HBV resistance mutations occur and can be detected even at very low/undetectable viremia, thus supporting their active search also at low level of viremia. The persistence of low levels of HBV replication, the consequent appearance of drug resistance mutations and their predictive value of subsequent virological failure should be considered in setting rational therapeutic strategies, including pro-active switches of successful antiviral therapies. |
| 25 | HIV INTEGRASE INHIBITOR DISSOCIATION RATES CORRELATE WITH EFFICACY IN VITRO Antiviral Therapy 2009; 14 Suppl 1:A27 (abstract no. 25) JA Grobler, PM Mckenna, S Ly, KA Stillmock, CM Bahnck, RM Danovich, G Dornadula, DJ Hazuda and MD Miller Residence times of InSTIs on integrase/DNA complexes comparable to or exceeding the half-life of the pre-integration complex in the cell results in functionally irreversible ‘one-shot kill’ of integration. Resistance conferring mutations increase the rate of inhibitor dissociation from integrase providing an opportunity for integration to occur. Improved efficacy of second- generation InSTIs will likely be driven by increases in inhibitor residence time on integrase. |
| 26 | DRUG CONCENTRATION, SELECTIVE ADVANTAGE AND SELECTION DYNAMICS OF RALTEGRAVIR-RESISTANT MUTANTS Antiviral Therapy 2009; 14 Suppl 1:A28 (abstract no. 26) E Dam, R Quercia and F Clavel Selective advantage curves explain why N155H can be selected early in the course RAL resistance evolution in vivo, but is later replaced by genotypes that include Q148HKR. Intracellular half-life of RAL, as measured by its antiviral activity, is short and comparable to that of NNRTIs. |
| 27 | NEW INTEGRASE BINDING INHIBITORS ACTING IN SYNERGY WITH RALTEGRAVIR Antiviral Therapy 2009; 14 Suppl 1:A29 (abstract no. 27) L Thibaut1, S Rochas1, J Dourlat1, C Monneret1, K Carayon2, E Deprez2, JF Mouscadet3, E Soma1 and S Lebel-Binay1 QNL111 displayed a potent activity against integrase enzyme and HIV-1 virus replication. QNL111 prevented the binding of HIV-1 to its substrate, confirming the new mechanism of action of this new INBIs’ family. Furthermore, these results highlighted the huge potential interests of this new class of integrase inhibitors: firstly, QNL111 and RAL act in synergy on wild-type viruses and secondly, QNL111 remained active on highly RAL-resistant viruses. |
| 28 | THE STRUCTURE OF AN ENTIRE HIV-1 RNA GENOME Antiviral Therapy 2009; 14 Suppl 1:A30 (abstract no. 28) JM Watts, KA Wilkinson, RJ Gorelick and KM Weeks The HIV-1 genome, and potentially most large coding RNAs, is punctuated by numerous previously unrecognized, but conserved, RNA regulatory motifs. High-throughput SHAPE reveals a comprehensive view of HIV-1 RNA genome structure and further application of this technology will make possible newly informative analysis of any RNA in a cellular transcriptome. |
| 29 | SUBTYPE-SPECIFIC AMINO ACID POLYMORPHISMS IN THE HIV-1 REVERSE TRANSCRIPTASE CONNECTION SUBDOMAIN OF CRF01_AE ARE ASSOCIATED WITH HIGHER 3´-AZIDO-3´-DEOXYTHYMIDINE RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A31 (abstract no. 29) KA Delviks-Frankenberry1, GN Nikolenko1, F Maldarelli2, S Hase3, Y Takebe3 and VK Pathak1 These results demonstrate that the amino acid composition of CRF01_AE in the background of TAMs exhibits higher AZT resistance than subtype B containing TAMs, and this resistance is associated with the T400 amino acid in the CRF01_AE CN. Our results show that mixing the RT pol, CN and RH domains from different subtypes, specifically the CRF01_AE pol and the subtype B CN and RH, can underestimate AZT resistance levels. These observations indicate the need to develop subtype-specific genotypic/phenotypic assays to provide more accurate estimates of drug resistance. |
| 30 | MUTATIONAL ANALYSIS OF RESIDUE ASN348 IN HIV-1 REVERSE TRANSCRIPTASE Antiviral Therapy 2009; 14 Suppl 1:A32 (abstract no. 30) J Radzio1, G Tachedjian2 and N Sluis-Cremer1 These analyses further support previous findings that N348I confers AZT resistance via an RNase-H-dependent mechanism. However, nevirapine resistance appears to be independent of the RNase H activity of the enzyme. Additional mechanistic studies, including subunit selective mutational analyses, are currently in progress. |
| 31 | A NOVEL MOLECULAR MECHANISM OF DUAL RESISTANCE TO NUCLEOSIDE AND NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Antiviral Therapy 2009; 14 Suppl 1:A33 (abstract no. 31) GN Nikolenko, KA Delviks-Frankenberry and VK Pathak These experiments demonstrate that specific mutations in the cn and RNase H domain exhibit dual resistance to NRTIs and NNRTIs, provide insights into NNRTI resistance and suggest a novel mechanism by which mutations from treatment-experienced patients’ RT CN and RNase H domain can exhibit dual NRTI and NNRTI resistance. |
| 32 | VIROLOGIC FAILURE OF REGIMENS CONTAINING TWO NRTIS PLUS EFAVIRENZ IS NOT ASSOCIATED WITH THE SELECTION OF MUTATIONS IN THE CONNECTION OR RNASE H DOMAINS OF REVERSE TRANSCRIPTASE Antiviral Therapy 2009; 14 Suppl 1:A34 (abstract no. 32) J Brehm1, CW Sheen1, M Hughes2, C Lalama2, R Haubrich3, S Riddler1, N Sluis-Cremer1 and J Mellors1 Virologic failure of two NRTIs plus efavirenz was associated with the frequent selection of mutations in the polymerase domain, but not in the connection or RNase H domains of RT. Previously reported mutations in the connection and RNase H domains of RT were probably not detected because failure was identified early using a sensitive protocol-specified definition and the treatment regimen contained efavirenz and not nevirapine, which can select N348I. |
| 33 | EFFECT OF MUTATIONS IN THE RT CONNECTION DOMAIN ON PHENOTYPIC SUSCEPTIBILITY AND VIROLOGIC RESPONSE TO ETRAVIRINE Antiviral Therapy 2009; 14 Suppl 1:A35 (abstract no. 33) J Vingerhoets1, L Tambuyzer1, R Paredes2, S Nijs1, B Clotet2, JM Schapiro3 and G Picchio4 This analysis showed no clear effect of the CDMs on phenotypic susceptibility and virologic response to ETR. |
| 34 | ANALYSING DRUG RESISTANCE IN TERMS OF SUBSTRATE RECOGNITION IN HCV NS3/4A PROTEASE Antiviral Therapy 2009; 14 Suppl 1:A36 (abstract no. 34) K Romano and C Schiffer These results imply that drug resistance is occurring in a manner that selectively weakens inhibitor binding, but maintains substrate recognition and cleavage. Therefore, future NS3/4A protease inhibitors that fit better within the substrate binding region should be less susceptible to drug resistant mutations. As we have observed previously in the system of HIV-1 protease, drug design strategies that incorporate this constraint can lead to the development novel protease inhibitors less susceptible to resistance and more robust in HCV treatment. |
| 35 | IDENTIFICATION OF HIV-1 MATRIX DETERMINANTS OF FITNESS COMPENSATION IN A PROTEASE INHIBITOR RESISTANT VIRUS Antiviral Therapy 2009; 14 Suppl 1:A37 (abstract no. 35) CM Parry1,2, P Cane1 and D Pillay1,2 We determined that the matrix and part of capsid can confer more PI resistance than regions including the p7-p1 and p1-p6 CSM. We also identified that three amino acid changes in matrix can restore the RC of a multidrug-resistant protease from 5% of WT to over 70%. The mechanism for both findings was unclear but it was independent of CSM, emphasizing that studies using full-length Gag are warranted. |
| 36 | COMPUTATIONAL MODELS DEVELOPED WITHOUT A GENOTYPE FOR RESOURCE-POOR COUNTRIES PREDICT RESPONSE TO HIV TREATMENT WITH 82% ACCURACY Antiviral Therapy 2009; 14 Suppl 1:A38 (abstract no. 36) AD Revell1, D Wang1, R Harrigan2, J Gatell3, L Ruiz4, S Emery5, MJ Pérez-Elías6, C Torti7, J Baxter8, F DeWolf9, Brian Gazzard10, AM Geretti11, S Staszewski12, R Hamers13, AMJ Wensing14, J Lange15, JM Montaner2 and BA Larder1 Models trained with sufficiently large, representative datasets can predict virological response accurately without a genotype. The results highlight the value of viral load information. This approach has potential for optimizing antiretroviral therapy in resource-poor countries. |
| 37 | DRUG RESISTANCE PATTERNS AMONG HIV-INFECTED CHILDREN AND ADULTS FAILING KALETRA-BASED REGIMENS IN SOUTH AFRICA Antiviral Therapy 2009; 14 Suppl 1:A39 (abstract no. 37) G Hunt1, J Ledwaba1, Z El-Khatib1,2, A Coovadia3, L Kuhn4, D Katzenstein5 and L Morris1 Children failing Kaletra-based regimens had more frequently detectable PI and M184I/V mutations, whereas adults had high levels of NNRTI-associated mutations and no detectable PI mutations. The NNRTI mutations were likely selected and archived during first-line therapy, but their persistence on a PI-based therapy and the absence of PI resistance mutations is unexpected. |
| 38 | IMPACT OF NEWLY HIV DIAGNOSED INDIVIDUALS ON THE TRANSMISSION OF DRUG RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A40 (abstract no. 38) S Yerly1, T Junier2, A Gayet-Ageron3, E Boffi E Amari3, V von Wyl4, HF Günthard4, B Hirschel3, T Klimkait5, E Zdobnov2, L Kaiser1 and the Swiss HIV Cohort Study Reconstruction of the HIV transmission networks shows that newly diagnosed HIV infections are a significant source of onward transmission, particularly of resistant strains, thus suggesting an important self-fuelling mechanism for TDR. This has to be taken into account in the context of universal HIV testing and immediate antiretroviral therapy strategy to reduce transmission. |
| 39 | SUCCESSFUL IDENTIFICATION OF SOURCES OF TRANSMITTED DRUG-RESISTANT HIV-1 VIA A CROSS-SECTIONAL PHYLOGENETIC ANALYSIS Antiviral Therapy 2009; 14 Suppl 1:A41 (abstract no. 39) V von Wyl1, S Yerly2, J Böni3, C Shah3, P Bürgisser4, T Klimkait5, P Taffé4, R Kouyos6, B Ledergerber1, HF Günthard1 and the Swiss HIV Cohort Study (SHCS) This cross-sectional analysis suggests that at least 11% of all sequences with TDR mutations or one-fifth of all TDR clusters have originated from an ART-exposed chronically infected patient. Moreover, 36% of observed TDR and 43% of TDR clusters may be attributed to onward transmission of recently infected patients. |
| 40 | ADDITION OF EXTENDED ZIDOVUDINE TO EXTENDED NEVIRAPINE PROPHYLAXIS REDUCES RESISTANCE IN INFANTS WHO WERE HIV-INFECTED IN UTERO: THE PEPI-MALAWI STUDY Antiviral Therapy 2009; 14 Suppl 1:A42 (abstract no. 40) J Lidstrom1, N Kumwenda2, DR Hoover3, G Kafulafula4, Q Li2, LM Mofenson5, MG Fowler1,6, MC Thigpen6, TE Taha2 and SH Eshleman1 Addition of extended ZDV to extended NVP prophylaxis significantly reduced the risk of NVP resistance at 14 weeks in infants with in utero HIV infection, provided that HIV infection was diagnosed and the prophylaxis was stopped by 6 weeks of age. |
| 41 | PRE-EXISTING LOW-LEVELS OF THE K103N HIV-1 RT MUTATION ABOVE A THRESHOLD IS ASSOCIATED WITH VIROLOGICAL FAILURE IN TREATMENT-NAÏVE PATIENTS UNDERGOING EFV-CONTAINING ANTIRETROVIRAL TREATMENT Antiviral Therapy 2009; 14 Suppl 1:A43 (abstract no. 41) DD Goodman1, NA Margo2, DJ McColl2, MD Miller2, K Borroto-Esoda1 and ES Svarovskaia1 Utilization of AS-PCR resulted in an overall increase in detection of K103N in treatment-naïve patients as compared with detection by population sequencing only. The presence of low-levels of K103N was associated with risk of VF within the 3TC+ZDV group. The results suggest a threshold quantity of K103N at baseline that is predictive of VF. |
| 42 | PREVALENCE AND CLINICAL SIGNIFICANCE OF TRANSMITTED DRUG-RESISTANT (TDR) HIV MUTATIONS BY ULTRA-DEEP SEQUENCING (UDS) IN HIV-INFECTED ARV-NAÏVE SUBJECTS IN CASTLE STUDY Antiviral Therapy 2009; 14 Suppl 1:A44 (abstract no. 42) M Lataillade1,2, J Chiarella2, R Yang1, S Schnittman1, V Wirtz1, M Mancini1, J Uy1, D Seekins1, M Krystal1, D McGrath1, B Simen3, M Egholm3 and M Kozal2 Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virological response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virological failure. |
| 43 | BULK SEQUENCE-DETECTABLE RESISTANCE MUTATIONS IN PERIPHERAL RNA FOLLOWING SINGLE-DOSE NEVIRAPINE ARE ASSOCIATED WITH POORER TREATMENT RESPONSES BUT DO NOT ADEQUATELY EXPLAIN TREATMENT FAILURE Antiviral Therapy 2009; 14 Suppl 1:A45 (abstract no. S50) JA Johnson1, JF Li1, C Yang2, I Zulu3, L Njobvu4, J Stringer4, V Shanmugam2, A McNulty2, E Lehotzky2,5, O Bolu2, P Peters1, S Pathak1, W Heneine1 and P Weidle1 Although minority mutations when present with sequence-detectable mutations strengthened the association with failure, they alone did not predict failure. Even in the absence of detectable resistance, sdNVP-exposed women, when compared with unexposed, experienced significant virological failure close to the time of sdNVP exposure possibly suggesting transient resistance sanctuaries not readily detectable in peripheral viruses. |
| 44 | RESISTANCE MUTATIONS DETECTED BY OLIGONUCLEOTIDE LIGATION ASSAY OF HIV-1 DNA AT TIME OF INITIATION OF NEVIRAPINE-CONTAINING ANTIRETROVIRAL THERAPY ARE ASSOCIATED WITH VIROLOGIC FAILURE Antiviral Therapy 2009; 14 Suppl 1:A49 (abstract no. 44) T Wagner1, G Jourdain2,3, N Ngo-Giang-Huong2,3, W Sirungsi4, V Klinbuayaem5, F Fregonese6, I Nantasen2, G Halue7, M Techpornroong8, A Nilmanat9, P Wittayapraparat10, V Chalermpolprapa11, P Pathipvanich12, P Yuthavisuthi7, L Frenkel1 and M Lallemant2,3 NVP resistance detected in HIV-1 DNA by a sensitive method (OLA) immediately prior to the initiation of ART was strongly associated with virological failure in women previously exposed to sdNVP to prevent MTCT. Access to simple and inexpensive assays to detect low concentrations of NVP-resistant HIV-1 prior to the initiation of ART may improve ART selection and the associated outcomes of antiretroviral therapy. |
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CLINICAL IMPLICATIONS OF RESISTANCE Abstracts 45 thru 58, Pages A49 to A62 |
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| 45 | EFFICACY OF RALTEGRAVIR AND FACTORS ASSOCIATED WITH TREATMENT FAILURE IN A ROUTINE CLINICAL CARE SETTING: THE SWISS HIV COHORT STUDY Antiviral Therapy 2009; 14 Suppl 1:A49 (abstract no. 45) AU Scherrer1, V von Wyl1, CA Fux2, M Opravil1, HC Bucher3, A Fayet4, LA Decosterd4, B Hirschel5, HJ Furrer2, D Mertz4, S Yerly5, T Klimkait3, B Ledergerber1 and HF Günthard1 Multiple factors were associated with RAL failures, such as low GSS of the OBT, low drug levels and poor adherence. Efficacy data from this routine clinical setting were comparable to previous published randomized controlled trials. Response rate in switch patients was very high. However, contrary to the SWITCHMRK-trials, 62% of our patients were kept on a boosted PI. |
| 46 | WEEK 48 RESULTS FROM THE PHASE III STUDY A4001026 (MERIT) – ‘TIME TO LOSS OF VIROLOGIC RESPONSE’ (TLOVR) VIROLOGY ANALYSIS OF FAILURES IN THE ENHANCED TROFILE™-CENSORED SUBPOPULATION Antiviral Therapy 2009; 14 Suppl 1:A50 (abstract no. 46) C Craig1, M Lewis1, P Simpson1, C Delogne1, E van der Ryst1, J Heera2, J Goodrich2, M Perros1 and M Westby1 The presence of an M184V mutation was most commonly associated with virologic failure in MVC-treated subjects (50%), whereas EFV failure was most commonly associated with NNRTI RAMs (53%). As with treatment-experienced MVC-treated subjects, emergence of CXCR4-using virus (27%) or reduced susceptibility of R5 virus (13%) was observed. Resistance was not observed in approximately half of MVC-treated (50%) and EFV-treated subjects analysed (41%). |
| 47 | GENOTYPIC AND PHENOTYPIC HIV TROPISM TESTING PREDICTS THE OUTCOME OF MARAVIROC REGIMENS Antiviral Therapy 2009; 14 Suppl 1:A51 (abstract no. 47) P Braun1, E Wolf2, M Hower3, S Scholten4, W Köthemann5, A Neuwith5, F Wiesmann1, C Höhn1, A Balogh2, R Ehret1, A Trein6, S Christensen7, H Jäger2 and H Knechten1 Combining MVC with further active drugs is an effective option in clinical practice for heavily pretreated patients. Good treatment response was observed in 68% of patients, which is also due to combinations of new drugs. A major issue before starting MVC-containing regimens remains the correct interpretation of discordant virus tropism results. Although both methods show similar positive predictive values, an important advantage of genotype-based tropism prediction remains the capability to analyse even samples with low or no detectable viral loads. |
| 48 | GENOTYPIC- AND PHENOTYPIC-WEIGHTED OBT SUSCEPTIBILITY SCORES ARE SIMILARLY STRONG PREDICTORS OF VIROLOGIC RESPONSE <50 COPIES/ML AT WEEK 48 IN MOTIVATE 1 AND 2 Antiviral Therapy 2009; 14 Suppl 1:A52 (abstract no. 48) C Boucher1, JM Schapiro2, D Kuritzkes3, JM Llibre4, M Lewis5, P Simpson5, C Delogne5, V Sharma6, A Parliyan6, D Chapman6, M Perros5, H Valdez6 and M Westby5 Weighted phenotypic and genotypic estimates of OBT activity are similarly predictive of undetectable viremia in MOTIVATE when applied to a defined population without on-treatment OBT changes. Approximately 80% of such patients with baseline CD4 ≥50 cells/mm3 initiating maraviroc with the equivalent of two fully active agents by either p-wOBTSS or g-wOBTSS had <50 RNA copies/ml at week 48. |
| 49 | EMERGENCE OF MUTATIONS AND PHENOTYPIC RESISTANCE WITH TIPRANAVIR TREATMENT IN PROTEASE INHIBITOR-EXPERIENCED PATIENTS Antiviral Therapy 2009; 14 Suppl 1:A53 (abstract no. 49) D Hall1, J Schapiro2, J Baxter3, C Boucher4, J Scherer5, M Witvrouw6, C Tilke5 and R Bethell6 Virologic failure while on a tipranavirbased regimen does not lead to a change in phenotypic susceptibility to DRV, FPV, LPV or SQV, even in patients who continued on the failing regimen. The most commonly selected mutations in patients who failed on a TPV-based regimen were A82T, I84V and I24L/M. L24M has not been reported previously as selected by PI-based therapy. |
| 50 | PHENOTYPIC PROTEASE INHIBITOR RESISTANCE IN THE CLINIC FROM 2006 TO 2008: AVAILABLE TREATMENT OPTIONS Antiviral Therapy 2009; 14 Suppl 1:A54 (abstract no. 50) D Hall1, J Scherer2, M Witvrouw3, A Paquet4, E Coakley4 and R Bethell3 Based on phenotypic testing 95% of patients had at least one PI option available. The second generation profile for TPV is supported by susceptibility observed in 32.5% of those resistant to all four first- generation PIs and DRV. When multiple PIs are available, differences in position in the PS range will be important. |
| 51 | EMERGING RESISTANCE MUTATIONS IN ANTIRETROVIRAL-EXPERIENCED HIV PATIENTS FAILING TIPRANAVIR OR DARUNAVIR IN THE SPANISH DRUG RESISTANCE DATABASE Antiviral Therapy 2009; 14 Suppl 1:A55 (abstract no. 51) E Poveda1, L Anta1, JL Blanco2, MJ Pérez-Elías3, F García4, JL Gómez-Sirvent5, JA Iribarren6, V Soriano1 and C de Mendoza1 on behalf of the Spanish Resistance Platform (ResRIS) Resistance mutations emerging in patients failing TPV and DRV differ significantly, but half of patients may display cross-resistance. Thus, resistance testing is mandatory to ensure the benefit of sequential use of these drugs. Of note, mutation 54L is selected in half of DRV failures, which may enhance TPV response. |
| 52 | NRTI-SPARING REGIMEN (NNRTI+PI) WAS MORE LIKELY TO BE ASSOCIATED WITH DRUG RESISTANCE COMPARED WITH NNRTI+NRTI OR PI+NRTI IN THE RANDOMIZED ANRS 121 TRIAL Antiviral Therapy 2009; 14 Suppl 1:A56 (abstract no. 52) AG Marcelin1 , C Soulié1, L Assoumou1, J Ghosn2, C Duvivier3, G Peytavin4, JM Molina5, D Costagliola1, C Katlama1 and V Calvez1 In this trial, the use of NRTI+PI regimen for the treatment of antiretroviral-naïve patients was less successful than classical NRTI-based regimen and was associated with more resistance for PIs and NNRTIs. The selection of NNRTI resistance was particularly observed in patients with high viral load and low EFV through levels. The NNRTI+PI strategy should not be recommended as antiretroviral first-line regimen, particularly in patients with high viral load and susceptible to have adherence problems. Contrary to the results observed in most of the trials evaluating mono or double PIs strategies, gag gene mutations were not involved in the low efficacy of this strategy. |
| 53 | EFFECT OF RT CONNECTION DOMAIN MUTATIONS ON EFAVIRENZ AND NEVIRAPINE PHENOTYPIC SUSCEPTIBILITY IN NNRTI-RESISTANT CLINICAL HIV-1 ISOLATES Antiviral Therapy 2009; 14 Suppl 1:A57 (abstract no. 53) R Paredes1,2, L Tambuyzer3, C Pou1, MC Puertas1, J Martinez-Picado1,4, J Vingerhoets3, G Picchio5 and B Clotet1,2 None of the CDMs tested seemed to have a major impact on phenotypic susceptibility to EFV or NVP in already NNRTI-resistant clinical isolates. |
| 54 | POSITIVE AND NEGATIVE DRUG SELECTION PRESSURES ON THE N348I CONNECTION DOMAIN MUTATION: NEW INSIGHTS FROM IN VIVO DATA Antiviral Therapy 2009; 14 Suppl 1:A58 (abstract no. 54) H Price1, D Dunn2, D Asboe1, A Pozniak1, B Gazzard1, D Pillay3 on behalf of the UK HIV Drug Resistance Database and the UK Collaborative HIV Cohort (CHIC) Study This is the first clinical evidence to suggest (a) that efavirenz may select for N348I, in addition to nevirapine; (b) that stavudine may select for N348I, in addition to zidovudine; and (c) that tenofovir may protect against the mutation. The latter could either be due to a direct effect whereby N348I hypersensitizes HIV-1 to tenofovir or an indirect effect whereby other mutations selected by tenofovir (most likely K65R) inhibit the emergence of N348I. |
| 55 | PHENOTYPIC RESISTANCE AND RESPONSE TO TIPRANAVIR, EVIDENCE FOR HYPERSUSCEPTIBILITY Antiviral Therapy 2009; 14 Suppl 1:A59 (abstract no. 55) JD Baxter1, J Schapiro2, CAB Boucher3, J Scherer4, R Bethell5, M Witvrouw5, C Tilke4 and DB Hall6 Phenotypic testing identifies patients who respond well to TPV, adding to genotypic screening results. These findings suggest that phenotypic hypersusceptibility to TPV is associated with improved virologic response and is worthy of further investigation. |
| 56 | DETECTION OF CLINICALLY RELEVANT ANTIRETROVIRAL DRUG RESISTANCE MUTATIONS AMONG TREATED PATIENTS UNDERGOING TESTING AT LOW LEVELS OF VIREMIA Antiviral Therapy 2009; 14 Suppl 1:A60 (abstract no. 56) AM Geretti1, AN Phillips1, S Kaye2, C Booth1 and NE Mackie2 on behalf of the UK HIV Drug Resistance Database and the UK Collaborative HIV Cohort Study Several clinically relevant mutations can be detected at high frequency at low levels of viremia. Genotypic resistance testing at low VL is informative and can guide a timely and optimized therapeutic change in patients failing antiretroviral therapy. |
| 57 | IMPACT OF GAG GENETIC DETERMINANTS AND GAG–POL FRAMESHIFT STABILITY ON VIROLOGICAL RESPONSE TO DUAL-BOOSTED PROTEASE INHIBITOR COMBINATIONS IN ANTIRETROVIRAL-NAÏVE PATIENTS (ANRS 127 TRIAL) Antiviral Therapy 2009; 14 Suppl 1:A61 (abstract no. 57) L Larrouy1, C Chazallon2, R Landman1, C Capitant2, G Collin1, A Storto1, G Peytavin1, G Pialoux3, C Katlama4, PM Girard5, P Yeni1, JP Aboulker2, F Brun-Vezinet1 and D Descamps1 on behalf of the ANRS 127 study group Polymorphisms in the p17/p24 in the p1/p6gag gag CS were associated with a lower VR rate at week 16 in naïve patients initiating therapy with dual-boosted PI combinations. Impact of frameshift RNA folding and stability on VR might be explored in larger databases. |
| 58 | VIROLOGIC OUTCOME ASSOCIATED WITH GENOTYPE-GUIDED THERAPY IN PATIENTS WITH TRANSMITTED HIV-1 DRUG RESISTANCE (TDR) BETWEEN 2003 AND 2006 Antiviral Therapy 2009; 14 Suppl 1:A62 (abstract no. 58) SY Rhee1, WJ Fessel2, TF Liu1, L Hurley2, D Klein2, S Follansbee2, J Flamm2, M Horberg2 and RW Shafer1 First-line therapy for TDR had a success rate >80%. Patients with NNRTI TDR responded to two NRTIs plus a boosted PI. Patients with other forms of one-class resistance generally responded to standard first-line therapies. Multiclass resistance was treated successfully in all but one case. |
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HBV DRUG RESISTANCE Abstracts 59 thru 64, Pages A65 to A70 |
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| 59 | LAMIVUDINE-RESISTANT HEPATITIS B VIRUS IN NEWLY DIAGNOSED HIV PATIENTS WITH CHRONIC HEPATITIS B IN SPAIN Antiviral Therapy 2009; 14 Suppl 1:A65 (abstract no. 59) A Treviño1, V Soriano1, C Rodríguez2, A Madejon1, C Barros3, P Parra1, P Tuma1, J del Romero2 and C de Mendoza1 The recognition of primary LAM- resistant HBV in antiretroviral-naïve HIV–HBV-coinfected individuals might have important implications in the selection of first-line antiretroviral therapy. HIV–HBV dually infected patients might benefit from both HIV and HBV drug resistance testing to optimize selection of anti-HBV active antiretroviral therapy. |
| 60 | HEPATITIS B VIRUS GENOTYPES AND RESISTANCE IN HIV–HBV COINFECTION Antiviral Therapy 2008; 13 Suppl 3:A66 (abstract no. 60) A Garcia-Diaz1, J Ainsworth2, J Anderson3, Y Gillece4, S Johnston5, N Mackie6, M Wansbrough-Jones7 and AM Geretti1 on behalf of the SURF study group We found evidence of HBV resistance to 3TC in 3TC-experienced and naïve patients, but no recognised TDF resistance mutations. Diverse HBV genotypes circulate in UK. |
| 61 | MOLECULAR EPIDEMIOLOGY OF HBV–HIV-1 COINFECTION IN JAPAN: VIRAL GENOTYPES AND DRUG RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A66 (abstract no. 61) S Fujisaki1, Y Yokomaku1, J Hattori1, S Ibe1, M Utsumi1, M Hamaguchi1, Y Iwatani1 and W Sugiura1,2 Our finding that genotype A was predominant in HBV–HIV-coinfected cases has a striking effect on the HBV epidemic in Japan as the majority of HBV cases transmitted by blood transfusion or MTCT has been genotype C. We are concerned about an alternative outbreak of genotype A HBV in the HIV-1-infected MSM population and shifting of HBV genotype from C to A in Japan. The narrow genetic diversity in genotype A cases suggests that A was recently introduced into the MSM population and sexual contacts within MSM were more active than speculated from HIV-1 tree analyses. |
| 62 | NOVEL PATTERNS OF MUTATIONS IN HBV REVERSE TRANSCRIPTASE ASSOCIATED WITH LAMIVUDINE RESISTANCE IN HBV–HIV-COINFECTED PATIENTS Antiviral Therapy 2009; 14 Suppl 1:A67 (abstract no. 62) V Svicher1, C Alteri1, V Cento1, C Gori2, R Salpini1, F Marcuccilli1, A Bertoli1, M Arlotti3, M Puoti4, N Ladisa5, G Rizzardini6, F Ceccherini-Silberstein1, A D’Arminio Monforte7, CF Perno1 and the ICONA study group Our study shows that HBV resistance profiles to lamivudine can be more complex than those observed in HIV and highlights the existence of HBV RT polymorphisms able to modulate lamivudine virological response. Their knowledge is crucial for a correct set up of antiviral therapy in both HBV-monoinfected and HBV–HIV-coinfected patients. |
| 63 | FREQUENCIES OF HBsAg MUTATIONS IN DRUG-RESISTANT HBV ISOLATES Antivir Ther 2008; 13 Suppl 3:A68 (abstract no. 63) J Verheyen1, M Fraune1, N Sichtig1, FC Wilhelm1, M Obermeier2, T Berg2, T Lengauer3, D Glebe4 and R Kaiser1 In HBV-failing antiviral therapy, treatment-associated polymerase and HBsAg mutations were often found together. HBsAg mutations can confer immune-escape and detection-escape in commercial tests or even result in truncated proteins, which might enhance the pathogenicity. More functional analyses of HBsAg mutations in treatment failures are needed to understand the mechanism of selection. |
| 64 | IMPACT OF GENOTYPIC MUTATIONS OF THE HEPATITIS B VIRUS CAPSID ON VIRAL LOAD AND LIVER ENZYMES IN HEPATITIS B VIRUS-INFECTED PATIENTS Antiviral Therapy 2009; 14 Suppl 1:A69 (abstract no. 64) L Wittkop1, A Cassany2, M Delaleau2, P Trimoulet3, J Foucher4, R Thiébaut1, H Fleury3 and M Kann2 V27I and T91V significantly increased HBV VL. Further studies with larger datasets and confirmation by mutant expression in hepatoma cells have to be performed to evaluate the molecular mechanisms. |
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HCV DRUG RESISTANCE Abstracts 65, Page A73 |
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| 65 | A NEAR FULL-LENGTH GENOTYPING STRATEGY FOR HEPATITIS C VIRUS GENOTYPES 1a AND 1b Antiviral Therapy 2009; 14 Suppl 1:A70 (abstract no. 65) J Snoeck1,2, L Kerremans1, G Vuagniaux3, JS Liz3, R Crabbé3, J Verbeeck1, M Van Ranst1, R Camacho4, S Vandooren5 and A-M Vandamme1 We developed a sensitive near full-length genotyping assay for HCV genotypes 1a and 1b. This assay can be used to study resistance in several viral target proteins, to study the effect in other viral proteins that interact with the target protein and to help to unravel mechanisms of action of orphan antiviral drugs. |
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EPIDEMIOLOGY Abstracts 66 thru 73, Pages A77 to A84 |
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| 66 | INTER-RELATIONSHIPS BETWEEN RISK BEHAVIOURS, CLUSTERED HIV TRANSMISSION EVENTS AND THE SPREAD OF DRUG RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A77 (abstract no. 66) BG Brenner1, J-P Routy2, M Roger3, D Stephens, D Moisi, F Ohnona, MA Wainberg1 and the Montreal PHI Cohort A novel prevention strategy (Project sPOT) promoting HIV testing and motivational counselling has been initiated to address high rates of onward HIV spread in non-diagnosed and newly infected populations in Montreal. |
| 67 | INCREASING PREVALENCE OF DRUG-RESISTANCE MUTATIONS AMONG TREATMENT-NAÏVE HIV-INFECTED PATIENTS IN JAPAN FROM 2003 TO 2008 Antiviral Therapy 2009; 14 Suppl 1:A78 (abstract no. 67) J Hattori1, S Yoshida2, T Ito3 , H Gatanaga4, M Kondo5, K Sadamasu6, S Kato7, Y Tanabe8, M Ueda9, T Shirasaka10, H Mori11, R Minami12, W Sugiura1,13 and the Japanese Drug Resistance HIV-1 Surveillance Network The prevalence of transmitted drug-resistant HIV cases in Japan increased until 2007, but began to decrease in 2008. This finding emphasizes the importance of continuous surveillance to understand the epidemiological status and to consider strategies to prevent transmission of drug-resistant HIV. |
| 68 | INTEGRATION OF ROUTINE HIV-1 DRUG RESISTANCE TESTING INTO THE SAN FRANCISCO HIV/STD SURVEILLANCE PROGRAM Antiviral Therapy 2009; 14 Suppl 1:A79 (abstract no. 68) HM Truong1,2, T Kellogg3, W McFarland1,3, J Klausner1,3, B Louie3 and RM Grant1,2 Monitoring primary HIV-1 drug resistance at STD clinics may assist clinicians in selecting treatment and post-exposure prophylaxis regimens that are active against viruses being transmitted in the community, as well as provide health departments with surveillance data in a sentinel population. |
| 69 | COMPARISON OF THE PREVALENCE OF HIV RESISTANCE
MUTATIONS BETWEEN US AND FOREIGN-BORN NAÏVE
CHRONICALLY INFECTED PATIENTS NEW YORK CITY (NYC) Antiviral Therapy 2009; 14 Suppl 1:A80 (abstract no. 69) C Salama and A Ashraf We saw a lower rate of resistance mutations among naïve chronically infected patients, relative to other studies performed in NYC. However, this was not clearly related to the large numbers of immigrants in our population, as US-born and foreign-born patients had a similarly low relative rate of resistance. |
| 70 | PREVALENCES OF MUTATIONS IN PATIENTS WITH DISCORDANT PHENOTYPIC PREDICTIONS FROM MONOGRAM BIOSCIENCES DATABASE OF ROUTINE CLINICAL SAMPLES FROM 2006–2008 Antiviral Therapy 2009; 14 Suppl 1:A81 (abstract no. 70) R Bethell1, J Scherer2, M Witvrouw1, A Paquet3, E Coakley3 and D Hall4 Common DRV-associated resistance mutations 50V, 54l and 76V that are associated with an improved clinical response to TPV/r were more prevalent in patients with phenotypic resistance to DRV and susceptibility to TPV. In contrast, 82l/T and 83D, mutations associated with resistance to TPV but not to DRV, were more prevalent in patients with resistance to TPV and susceptibility to DRV. |
| 71 | GENETIC DIVERSITY AND COMPLEXITY OF DRUG RESISTANCE CONTINUE TO INCREASE IN THE REVERSE TRANSCRIPTASE AND PROTEASE REGIONS OF HIV-1 Antiviral Therapy 2009; 14 Suppl 1:A82 (abstract no. 71) H van Vlijmen1, M Van Houtte2, K Van der Borght2, P Lecocq2, L Bacheler3 and P Sista3 Although patients have been treated with drugs from the three main antiretroviral classes for over 10 years now, the genetic diversity in HIV-1 continues to increase. The large genetic diversity of HIV-1 sequences has led to 20 distinct resistance profiles revealing alternative options for choosing treatment regimens. |
| 72 | WHAT IMPACT WILL PrEP INTERVENTIONS HAVE ON INCIDENCE AND TRANSMITTED DRUG RESISTANCE IN RESOURCE-RICH COUNTRIES? Antiviral Therapy 2009; 14 Suppl 1:A83 (abstract no. 72) V Supervie1, JG García-Lerma2, W Heneine2 and S Blower1 PrEP interventions could substantially reduce transmission in San Francisco. They are more likely to decrease, than increase, number of resistant infections. However interventions will appear to increase TDR because it is monitored as a proportion of new infections. Our results imply it is essential to develop better interpretation strategies for tracking TDR. |
| 73 | INCREASING PREVALENCE OF TRIPLE-CLASS ANTIRETROVIRAL EXPERIENCED PATIENTS IS NOT ASSOCIATED WITH VIROLOGIC FAILURE: DATA FROM THE CFAR NETWORK OF INTEGRATED CLINICAL SYSTEMS (CNICS) COHORT Antiviral Therapy 2009; 14 Suppl 1:A84 (abstract no. 73) JL Aldous1, S Jain1, S Sun1, C Mathews1, M Kitahata2, J Kahn3, M Saag4, B Rodriguez5, S Boswell6, SD Frost1, RH Haubrich1 and the CNICS 002 Study Team Among patients on ARVs, the prevalence of triple-class exposure has steadily increased from 23% in 2000 to 35% in 2008. However, virologic failure has decreased over the same period, dropping from 30% in 2000 to 11% in 2008. Moreover, failure associated with triple-class exposure has decreased, such that by 2008 those with triple-class exposure were no longer at significantly increased risk of treatment failure. |
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HIV PATHOGENESIS, FITNESS AND RESISTANCE Abstracts 74 thru 81, Pages A87 to A94 |
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| 74 | THE EFFECT OF ANTIRETROVIRAL THERAPY WITHOUT CCR5 ANTAGONISTS ON HIV-1 TROPISM IN THE MOTIVATE STUDIES OF MARAVIROC IN TREATMENT-EXPERIENCED PATIENTS WITH R5 HIV-1 Antiviral Therapy 2009; 14 Suppl 1:A87 (abstract no. 74) CF Perno1, M Nelson2, L Waters2, B Clotet3, R Paredes3, J Heera4, H Mayer4, N Dang5, H Valdez6 and E Van Der Ryst7 Antiretroviral treatment regimens that do not include CCR5 antagonists appear to have a minimal effect on HIV-1 tropism in patients who initiate treatment with R5 virus. Almost all patients with R5 virus at baseline and who received optimized background therapy plus placebo in the MOTIVATE 1 and 2 studies still gave an R5 tropism result at time of failure. |
| 75 | DETECTION OF CXCR4-USING HIV-1 VARIANTS IN LONGITUDINALLY OBTAINED PAIRED PLASMA AND PBMC SAMPLES USING 454-SEQUENCING Antiviral Therapy 2009; 14 Suppl 1:A88 (abstract no. 75) AB van ‘t Wout1, L Swenson2, MRA Welkers1, W Dong2, H Schuitemaker1 and PR Harrigan2 In the majority of patients, CXCR4-using variants were detected above the 5% level by 454-sequencing in samples that were obtained prior to the first detection of CXCR4-using variants in the phenotypic MT-2 assay. Further in-depth analysis will provide insight into the evolutionary pathways that lead to CXCR4 use. |
| 76 | CONSERVED HIV-1 ENVELOPE GLYCOPROTEIN CYTOPATHICITY IN PATIENTS RECEIVING ENFUVIRTIDE TREATMENT WITH VIROLOGICAL FAILURE BUT IMMUNOLOGICAL SUCCESS Antivir Ther 2008; 13 Suppl 3:A89 (abstract no. 76 C Cabrera, S Marfil, M Curriu, F Cunyat, B Clotet and J Blanco The presence of a V38A mutation in different gp41 backgrounds did not result in a loss of fusion or apoptogenic potential of HIV-1 Env, which were highly related and variable among patients. The immunological success associated with the cluster of mutations V38A+N140I appears to be unrelated to an impairment of Env cytopathicity; therefore, alternative mechanisms should be explored to explain this phenomenon. |
| 77 | EFFECT OF RALTEGRAVIR RESISTANCE MUTANTS IN HIV-1 INTEGRASE ON VIRAL FITNESS AND DRUG SUSCEPTIBILITY Antiviral Therapy 2009; 14 Suppl 1:A90 (abstract no. 77) Z Hu and DR Kuritzkes Although single primary RAL resistance mutations Q148H/K/R and N155H reduced viral replication capacity in the absence of drug, relative fitness in the presence of RAL was greater than WT. The greater fitness of 155H versus 148H and of 140S/148H versus 92Q/155H corresponds well with the clinical trials data and helps explain the temporal pattern of RAL resistance evolution. |
| 78 | CHARACTERIZATION OF MUTATIONS CONFERRING RESISTANCE TO INTEGRASE INHIBITORS AND THEIR IMPACT ON HIV-1 REPLICATIVE FITNESS Antivir Ther. 2008, 13(Suppl 3:A91 (abstract no. 78) AM Rhea1, J Weber1, AC Vazquez1, JD Rose1, D Winner1, N Margot2, PD Olivo1, D McColl2, M Miller2 and ME Quiñones-Mateu1 The clinical impact of reduced viral fitness associated with INI mutations is not completely understood. Here we have shown that most amino acid substitutions, although associated with resistance to INIs, have a major effect in HIV-1 replicative fitness. This is particularly relevant to mutations associated with the Q148 pathway. As in the case of recently developed antiretroviral drugs, further studies will lead to a better understanding of the effects of integrase inhibitor resistance on HIV-1 replicative fitness. |
| 79 | MUTATION T74S IN HIV-1 SUBTYPE B AND C PROTEASES RE-SENSITIZES THEM TO PROTEASE INHIBITORS AND CONFERS FITNESS ADVANTAGE Antiviral Therapy 2009; 14 Suppl 1:A92 (abstract no. 79) EA Soares1,3, AF Santos1, LM Gonzalez1, MS Lalonde2, DM Tebit2, A Tanuri1, EJ Arts2 and MA Soares1,3 T74S is not a major drug-resistant mutation, but it re-sensitizes multiresistant viruses to certain PIs. T74S is a bonafide accessory mutation, restoring fitness of multidrug-resistant viruses in both subtypes B and C. T74S should be further studied in clinical settings and considered in drug resistance interpretation algorithms. |
| 80 | NATURAL PRESENCE OF RESISTANCE MUTATION Y181C IN HIV-1 GROUP O VARIANTS IS CLADE-DEPENDENT Antiviral Therapy 2009; 14 Suppl 1:A93 (abstract no. 80) A Depatureaux1, M Leoz1, A Vessière2, D Rousset2, F Damond3, F Simon4 and JC Plantier1 Y181C is a resistance-associated mutation naturally present in 55.7% of HIV-O isolates and can be considered as a signature mutation of clade A. Natural presence of the wild-type residue 181Y in 43% of the strains highlights the need of phenotypic analyses to conclude to a possible sensitivity to NNRTI and its use in therapeutic management. |
| 81 | EFFECT OF THE HIV-1 REVERSE TRANSCRIPTASE POLYMORPHISM LEU-214 ON REPLICATION CAPACITY AND DRUG SUSCEPTIBILITY Antiviral Therapy 2009; 14 Suppl 1:A94 (abstract no. 81) MC Puertas1, MJ Buzón1, A Artese2, S Alcaro2, L Menéndez-Arias3, CF Perno4, B Clotet1, F Ceccherini-Silberstein4 and J Martinez-Picado1,5 The impact of the Leu-214 polymorphism on viral replication when associated with Tyr-215 may explain the strong negative association observed in NRTI-failing patients between that TAMs1 and Leu-214. Leu-214 also plays a direct role in drug susceptibility; the molecular-modeling studies and in vitro assays suggest that viruses containing Tyr-215 were more susceptible to ZDV in the presence of Leu-214 than in the presence of Phe-214. |
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PERSISTENCE, RESERVOIRS AND ELIMINATION STRATEGIES Abstracts 82 thru 87, Pages A97 to A102 |
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| 82 | EVOLUTION OF 2-LTR EPISOMAL HIV-1 DNA IN RALTEGRAVIR-TREATED PATIENTS AND IN VITRO-INFECTED CELLS Antiviral Therapy 2009; 14 Suppl 1:A97 (abstract no. 82) S Reigadas1, ML Andreola2, L Wittkop3, O Cosnefroy2, G Anies1, P Recordon-Pinson1, R Thiébaut3, B Masquelier1 and H Fleury1 Both in vitro and ex vivo data suggest an increase of 2-LTR HIV-1 DNA in the presence of RAL, whereas the evolution of total HIV-1 DNA showed a decrease over time in RAL-treated patients. The high frequency of deletions on RAL could be related to an increased accessibility of host’s cell nuclease to the LTR junctions. |
| 83 | HIV-1 NUCLEOSIDE ANALOGUE TRIPHOSPHATE LEVELS ARE SIGNIFICANTLY LOWER IN PRIMARY HUMAN MACROPHAGES THAN IN HUMAN LYMPHOCYTES Antiviral Therapy 2009; 14 Suppl 1:A98 (abstract no. 83) C Gavegnano, E Fromentin and RF Schinazi Emtricitabine-TP, carbovir-TP, tenofovir- DP, (-)-β-d-dioxolane-guanine-TP and zidovudine-MP were significantly lower in macrophages than human PBMCs (P<0.05; t-test), suggesting that these nucleosides may undergo decreased conversion to their active triphosphate forms in macrophages. Coincubation of zidovudine, (-)-β-d-dioxolane-guanine did not markedly alter (-)-β-ddioxolane- guanine-TP levels in macrophages. These data provide the foundation for better understanding the dynamics between HAART and viral reservoirs, with a goal of eradication HIV from these sanctuaries. |
| 84 | ANALYSIS OF HIV DNA MOLECULES IN SINGLE INFECTED CELLS FROM RECENTLY AND CHRONICALLY INFECTED PATIENTS Antiviral Therapy 2009; 14 Suppl 1:A99 (abstract no. 84) S Palmer1,2, L Josefsson1, J Brännström1, F Maldarelli2, M Kearney2, W Shao2, D Rock3, J Mellors4, J Albert1 and J Coffin5 These results suggest that most infected CD4+ T-cells in blood contain only one copy of HIV DNA, implying a limited potential for recombination in virus produced by these cells. The infection rate of CD4+ T-cells is much greater than monocytes. The genetic similarity between HIV populations in CD4+ T-cells and plasma implies ongoing exchange between these compartments. |
| 85 | A NEW IN VITRO SYSTEM TO MODEL HIV-1 LATENCY Antiviral Therapy 2009; 14 Suppl 1:A100 (abstract no. 85) A Marini1 and F Romerio2 This system is suitable to study the biology of HIV-1 latency, including whole-genome transcriptional analyses at different stages of HIV-1 latency. Moreover, our in vitro model is amenable to investigate the mechanisms of CD4+ T-cell death following HIV-1 reactivation. |
| 86 | LONG-TERM PERSISTENCE OF RESISTANCE MUTATIONAL PATTERN AND EVOLUTION OF HIV-TROPISM IN BLOOD PLASMA AND IN INFECTED CELLS OF PATIENTS WHO ACQUIRED A MULTIDRUG-RESISTANT HIV-1 STRAIN AT THE TIME OF PRIMARY INFECTION Antiviral Therapy 2009; 14 Suppl 1:A101 (abstract no. 86) J Ghosn1,2, J Galimand1, L Meyer3, C Goujard2, C Deveau3, C Rouzioux1 and ML Chaix1 for the PRIMO Cohort Study Group (ANRS CO 06) MDR HIV strains acquired at PHI persisted throughout a median 78-month follow-up. Tropism (three X4-tropic) was unchanged during follow-up in both HIV RNA and HIV DNA, supporting the early expansion of a monoclonal population. |
| 87 | RECTAL CELL-ASSOCIATED HIV-1 RNA AS A MARKER FOR TRIALS TARGETING THE RESERVOIR Antiviral Therapy 2009; 14 Suppl 1:A102 (abstract no. 87) A Lafeuillade, A Cheret, G Hittinger, D Bernardini, C Cuquemelle, E Jullian and C Poggi Evaluating gut-associated viral load can be standardized using commercially available tests. These preliminary results show that rectal cell-associated HIV-1 RNA could be a new marker of ‘deep’ viral activity in future trials. |
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MECHANISMS OF HIV DRUG RESISTANCE Abstracts 88 thru 101, Pages A105 to A118 |
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| 88 | THERAPY-SELECTED MUTATIONS AT RT POSITION 215 COUNTERACT SELECTION OF K65R IN HIV-2-INFECTED PATIENTS Antiviral Therapy 2009; 14 Suppl 1:A105 (abstract no. 88) JC Silva1, AC Miranda1, MF Gonçalves1, E Valadas4, K Mansinho1, K Van Laethem5, A-M Vandamme5, P Gomes1,2,3 and RJ Camacho1,2 on behalf of the Portuguese HIV-2 Study Group As observed in HIV-1, mutations selected by therapy at HIV-2 RT position 215 apparently counteract the selection of K65R. The mutation K70R does not seem to have the same effect. The factors driving resistance to thymidine analogues in HIV-2 along the Q151M+K65R or S215 (A/C/F/L/P/Y) pathways remain unknown. Further studies are needed to investigate this mechanism. |
| 89 | TISSUE CULTURE SELECTION EXPERIMENTS CONFIRM THAT THE PREFERENCE OF SUBTYPE C VIRUSES FOR THE K65R MUTATION IS TEMPLATE DRIVEN Antiviral Therapy 2009; 14 Suppl 1:A106 (abstract no. 89) MA Wainberg, CF Invernizzi, M Oliveira, D Coutsinos, D Moisi and BG Brenner Nucleotide sequences at and around position 65 in the HIV subtype C template play a key role in the enhanced selection of K65R, which is independent of the subtype origin of the RT enzyme. These findings demonstrate the significance of polymorphisms at positions 64/65 in the RT template in the development of drug resistance. |
| 90 | DECREASED NUCLEOTIDE EXCISION MEDIATED BY AN ACCESSORY MUTATION OF THE Q151M COMPLEX OF HIV-1 REVERSE TRANSCRIPTASE Antiviral Therapy 2009; 14 Suppl 1:A107 (abstract no. 90) T Matamoros and L Menéndez-Arias In vitro, V75I decreases excision of AZT and d4T in the presence of a PPi donor. Our results suggest that V75I could delay the acquisition of resistance to thymidine analogues by interfering with the nucleotide-excision mechanism. |
| 91 | THE RALTEGRAVIR RESISTANCE MUTATIONS Y143C/R IMPACT THE STRAND-TRANSFER ACTIVITY AND TO A LESSER EXTENT THE 3´-PROCESSING ACTIVITY OF THE HIV-1 INTEGRASE Antiviral Therapy 2009; 14 Suppl 1:A108 (abstract no. 91) B Masquelier1, G Anies1, V Parissi2, C Calmels2, S Reigadas1, H Fleury1 and ML Andréola2 The mutations Y143C and Y143R strongly affected the strand-transfer activity of integrase in vitro and, to a lesser extent, the 3´-end processing was also impaired. A slight increase in FC was only observed with the 3´-end processing assay in the presence of RAL, suggesting that the in vivo or ex vivo resistance to RAL conferred by these two mutations could be driven by the 3´-processing step rather than the strand-transfer activity. Further experiments including secondary mutations will be needed to explain compensatory changes and/or increased in vitro resistance. |
| 92 | IMPAIRED REPLICATION CAPACITY SEGREGATES GENETIC PATHWAYS TO RALTEGRAVIR RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A109 (abstract no. 92) S Fransen, S Gupta, A Frantznell, C Petropoulos and W Huang Our observations indicate that, with the exception of Y143R+N155H, combinations of primary raltegravir resistance mutations within the same viral genome are restricted by severely diminished RC. This provides a likely explanation for the non-overlapping nature of the multiple genetic pathways to raltegravir resistance. |
| 93 | MUTATIONS IN gp41 OF HIV-1 ENVELOPE GENE IMPACT ON RESISTANCE OF CCR5 INHIBITORS Antiviral Therapy 2009; 14 Suppl 1:A110 (abstract no. 93) Y Wei, A Chamberland, F Vaisheva, G Bélange-Jasmin, O Asin Milan, M Sylla and CL Tremblay Although gp120, especially V3 loop, plays an important role in the resistance of CCR5 inhibitors, our data suggest that changes in gp41 may have impact on the resistance to CCR5 inhibitors. Combined mutations show paradoxical results according to the drug concentration used suggesting that these mutants could use a drug-bound receptor at low concentrations of the drug. |
| 94 | STRUCTURAL AND BIOCHEMICAL INSIGHTS INTO ALTERED DRUG RESISTANCE PATHWAYS IN NON-CLADE B HIV-1 PROTEASES Antiviral Therapy 2009; 14 Suppl 1:A111 (abstract no. 94) RM Bandaranayake1, E Nalivaika1, M Kolli1, J Kakizawa2, A Heroux3, NM King1, W Sugiura2 and CA Schiffer1 Sequence polymorphisms in HIV-1 CRF01_AE cause significant structural changes within the protease when compared with clade B protease. The inherent baseline resistance within CRF01_AE enables the protease to gain a high level of NFV resistance via the single non-active site mutation N88S, whereas the clade B protease requires a combination of an active site (D30N) and non-active site (N88D) mutation in order to gain NFV resistance, the mechanism of which can be understood structurally. |
| 95 | DETERMINATION OF THE SUBSTRATE ENVELOPE FOR THE MULTIDRUG-RESISTANT HIV-1 PROTEASE Antiviral Therapy 2009; 14 Suppl 1:A112 (abstract no. 95) LC Kovari1, Z Liu1, RS Yedidi1, JS Brunzelle2 and IA Kovari1 Ligand binding energy calculations are consistent with our crystallographic studies, showing reduced binding energy caused by diminished protease–substrate interactions in MDR HIV-1 protease–substrate complexes. Knowledge of the MDR HIV-1 protease substrate envelope contributes to the design of inhibitors targeting specifically the MDR form of the virus. |
| 96 | MECHANISM OF DARUNAVIR RESISTANCE ACQUISITION IN MULTI-PROTEASE INHIBITOR RESISTANT HIV-1 Antiviral Therapy 2009; 14 Suppl 1:A113 (abstract no. 96) M Fujino2, H Miura2, J Hattori1, S Ibe1, S Fujisaki1, M Matsuda2, M Nishizawa2, Y Iwatani1 and W Sugiura1,2 The high antiretroviral potential of darunavir against multi-PI-resistant viruses was confirmed. However, genetic barriers in the acquisition of darunavir resistance appeared to be lower in multi-PI-resistant viruses than in wild-type virus. |
| 97 | FACTORS ASSOCIATED WITH THE L76V PROTEASE MUTATION IN HIV-1-INFECTED PATIENTS WITH VIROLOGICAL FAILURE OF LOPINAVIR/RITONAVIR Antiviral Therapy 2009; 14 Suppl 1:A114 (abstract no. 97) A Baras1, K Champenois2, P Choisy3, Y Yazdanpanah2,3,4 and L Bocket1 In this study, L76V mutation presence was not related to viral subtype. However, the number of LPV/RTV resistance mutations was the only variable independently associated with L76V mutation occurrence. |
| 98 | INSIGHTS INTO THE MECHANISM OF RESISTANCE – COEVOLUTION OF THE NELFINAVIR-RESISTANT HIV-1 PROTEASE AND THE P1–P6 CLEAVAGE SITE Antiviral Therapy 2009; 14 Suppl 1:A115 (abstract no. 98) M Kolli and CA Schiffer Mutations within the p1–p6 cleavage site frequently co-occur with the NFV-resistant D30N/ N88D protease and have been shown to reduce phenotypic susceptibility to a number of PIs. Increased resistance due to this co-evolution is the result of structural changes within the protease and/or alterations in Gag processing, thus maintaining the balance between loss of inhibitor binding and efficient proteolytic activity. |
| 99 | DIFFERENCES IN THE FRAMESHIFT-REGULATING P1-SITE IN TREATMENT-NAÏVE AND PI-RESISTANT HIV ISOLATES Antiviral Therapy 2009; 14 Suppl 1:A116 (abstract no. 99) E Knops1, G Théberge-Julien2, R Kaiser1, D Hoffman3, L Brakier-Gingras2 and J Verheyen1 An increase in frameshift efficiency is not a general mechanism of HIV drug resistance, and the predicted free energy of hairpin does not correlate with measured frameshift efficiencies. In PI-resistant HIV treatment- associated mutations occur at both C-terminal gag cleavage sites, and there is evidence that also specific selection occurs at pol CS TFP/p6-pol. |
| 100 | EFFECT OF PARTIAL INHIBITION OF HIV-1 POLYPROTEIN PROCESSING AND MATURATION ON VIRAL INFECTIVITY Antiviral Therapy 2009; 14 Suppl 1:A117 (abstract no. 100) B Müller, M Anders, H-M Tervo, OT Keppler and H-G Kräusslich The results indicate that very low amounts (~5%) of Gag processing intermediates display a trans-dominant effect on HIV particle maturation with the maturation cleavage between CA and SP1 being of particular importance. This leads to a subsequent inhibition of early post-entry steps in viral replication. Further analyses aim at the role of resistance-associated cleavage site mutations on viral replication. |
| 101 | HIV-1 GAG MODULATES PROTEASE ACTIVITY BY A CLEAVAGE SITE-INDEPENDENT PATHWAY Antiviral Therapy 2009; 14 Suppl 1:A118 (abstract no. 101) SK Ho1, RM Coman1, BM Dunn1, JW Sleasman2 and MM Goodenow1 Dominant determinants in Gag, independent of the cleavage sites, modulate protease activity in wild-type and PI-resistant viruses. |
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NEW RESISTANCE TECHNOLOGIES AND INTERPRETATIONS Abstracts 102 thru 115, Pages A121 to A134 |
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| 102 | THE POTENTIAL ROLE OF MINORITY MUTATION ASSAYS IN SURVEILLANCE OF TRANSMITTED DRUG RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A121 (abstract no. 102) AJ Buckton1, D Prabhu1, G Murphy1, JV Parry1, JA Johnson2, D Pillay1,3 and PA Cane1 Detection of transmitted drug resistance can be improved using minority species assays compared with standard genotyping methods. However, the applicability of these new technologies to national surveillance structures remains unclear. Our data suggest that, at least of the M184V mutation assay, application to large scale surveillance will better estimate rates of TDR. This is also compatible with the hypothesis that the M184V mutation has a high rate of reversion following transmission, requiring more sensitive assays to detect it. |
| 103 | REAPPEARANCE AND PERSISTENCE OF MINORITY QUASISPECIES OF K103N-HARBORING HIV-1 PRESENT PRIOR TO ART IN PATIENTS WITH PRIMARY HIV-1 INFECTION AFTER TREATMENT INTERRUPTION Antiviral Therapy 2009; 14 Suppl 1:A122 (abstract no. 103) KJ Metzner1, V von Wyl1, C Leemann1, B Preiswerk1, C Grube1, H Kuster1, J Böni2, R Weber1 and HF Günthard1 Minority quasispecies of K103N-harboring viruses, present in acutely HIV-1 infected patients prior to ART, can reappear and persist after interruption of suppressive antiretroviral therapy. |
| 104 | CHARACTERIZATION OF HIV-1 SEQUENCE ARTIFACTS INTRODUCED BY BULK PCR AND DETECTED BY 454 SEQUENCING Antiviral Therapy 2009; 14 Suppl 1:A123 (abstract no. 104) W Shao1, VF Boltz2, M Kearney2, F Maldarelli2, JW Mellors3, C Stewart4, A Levitsky1, N Volfovsky1, RM Stephens1 and JM Coffin5 Our results imply that 454 sequencing can reliably detect HIV-1 resistance mutations at frequencies down to about 1%, about 10-fold less sensitive than allele-specific PCR. However, much greater levels of sensitivity can be achieved for specific mutations at certain sites, and, potentially, by modification of the PCR step. The high rate of recombination introduced by standard PCR amplification needs to be overcome for accurate linkage analysis of drug resistance mutations and haplotype determination. |
| 105 | NEXT GENERATION SEQUENCING AS AN EFFICIENT AND COST-EFFECTIVE METHOD OF HIV DRUG RESISTANCE SURVEILLANCE Antiviral Therapy 2009; 14 Suppl 1:A124 (abstract no. 105) H Ji1, N Massé1, S Tyler2, B Liang3, Y Li1, H Merks1, M Graham3, P Sandstrom1 and J Brooks1 Pooled specimen pyrosequencing is a promising approach to rapidly and inexpensively determine TDR prevalence. This approach accurately identified the TDR mutations present as components of mixtures. The enhanced ability to detect minor frequency variants on a population scale may prove to be important in heralding the emergence of TDR. |
| 106 | SELECTION AND COEVOLUTION OF MUTATIONAL PATTERNS IN THE HIV-1 INTEGRASE CHARACTERIZED BY PYROSEQUENCING ANALYSIS Antiviral Therapy 2009; 14 Suppl 1:A125 (abstract no. 106) F Ceccherini-Silberstein1, D Armenia1, R D’Arrigo2, I Vandenbroucke3, H Van Marck3, L Fabeni1, V Cento1, K Van Baelen3, G Rizzardini4, S Lo Caputo5, V Tozzi2, P Narciso2, A Antinori2, L Stuyver3 and CF Perno1,2 Ultradeep sequencing allows detection and quantification of pre-existing raltegravir-resistant viruses that are not detected by standard genotype/phenotype analysis. The impact of resistance mutations was confirmed by phenotyping. Mechanisms of selection and coevolution of integrase minor variants and their clinical relevance warrants further investigation. |
| 107 | A HIGH MOI INFECTION METHOD USING WILD-TYPE AND InSTI-RESISTANT VIRUSES QUANTITATIVELY DIFFERENTIATES AMONG CANDIDATE SECOND GENERATION InSTIs Antiviral Therapy 2009; 14 Suppl 1:A126 (abstract no. 107) PM McKenna, JA Grobler, DJ Hazuda and MD Miller These studies show that second generation InSTIs better control replication of both wild-type virus and a virus (Q148H/G140S) that is highly resistant to current InSTIs, such as raltegravir and elvitegravir. The combination of high-MOI selection methods with viruses containing clinically relevant resistant mutants provides a quantitative method to differentiate among potent second generation InSTIs. |
| 108 | RESISTANCE ANALYSIS TO MATURATION, PROTEASE, REVERSE TRANSCRIPTASE AND INTEGRASE INHIBITORS BASED ON 3&ACUTE;GAG(P2/P7/P1/P6)/PR/RT/INT-RECOMBINANT VIRUSES: A USEFUL TOOL IN THE MULTITARGET ERA OF ANTIRETROVIRAL DRUGS Antiviral Therapy 2009; 14 Suppl 1:A127 (abstract no. 108) J Weber1, JD Rose1, AM Rhea1, AC Vazquez1, D Winner1, K Henry2, R Gibson2, PD Olivo1, EJ Arts2 and ME Quiñones-Mateu1 Despite the success of HAART, HIV-1 has demonstrated a remarkable ability to mutate and develop resistance to all ARV drugs. Our novel technology permits the use of a single phenotypic assay (VIRALARTS™ HIV) to monitor drug resistance based on recombinant viruses carrying a linked HIV-1 genomic segment, which contains the target enzymes for PIs, RTIs and INIs as well as the CA-p2, p2-p7, p7-p1 and p1-p6 cleavage sites in Gag (MIs). |
| 109 | GENOTYPIC, PHENOTYPIC AND VIRTUAL PHENOTYPIC RESISTANCE PATTERNS FOR DARUNAVIR AND TIPRANAVIR: AN INDEPENDENT ANALYSIS OF A QUEBEC HIV-1 COHORT HIGHLY RESISTANT TO ALL OTHER PROTEASE INHIBITORS Antiviral Therapy 2009; 14 Suppl 1:A128 (abstract no. 109) A Talbot1,2, P Grant2, J Taylor2, JG Baril1, H Charest3, TF Liu2, B Brenner4, M Roger1, R Shafer2, R Cantin3 and A Zolopa2 In this independent clinical cohort with highly PI-resistant HIV, phenotypic resistance to darunavir and tipranavir was rare. GIS, other than the virtual phenotype, do not perform well in predicting tipranavir susceptibility, while all GIS perform reasonably well in predicting darunavir phenotypic susceptibility. The mutations 54L, 32I and/or 47V in protease predict isolates that may be more susceptible to tipranavir than darunavir. |
| 110 | DEVELOPMENT OF A NOVEL UNIVERSAL PROTOCOL FOR SCREENING AND SEQUENCING OF HIV-1 POL ACROSS CLADES FOR SUBTYPE IDENTIFICATION AND ANALYSIS OF DRUG RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A129 (abstract no. 110) T Nie, M Detorio and RF Schinazi A universal protocol was developed using specific and novel primers by one-step RT-PCR and sequencing. This protocol represents an effective tool for evaluation and identification of HIV-1 genotypes. Its capacity for rapid profiling of HIV-1 sequences may be useful for analysis of drug resistance across HIV-1 populations. This protocol provides a foundation for understanding and prediction of the effects of experimental or approved drugs on various HIV-1 clades/subtypes. |
| 111 | EVALUATION OF THE GENOTYPIC PREDICTION OF HIV-1 TROPISM VERSUS A PHENOTYPIC ASSAY AND CORRELATION WITH THE VIROLOGICAL RESPONSE TO MARAVIROC: THE GENOTROPISM STUDY Antiviral Therapy 2009; 14 Suppl 1:A130 (abstract no. 111) P Recordon-Pinson1, C Soulié2, D Descamps3, M Lazrek4, C Charpentier5, B Montes6, MA Trabaud7, J Cottalorda8, C Amiel9, L Morand-Joubert10, C Tamalet11, D Desbois12, M Macé13, V Ferré14, A Vabret15, A Ruffault16, J Izopet17, H Fleury1, F Brun-Vézinet3, AG Marcelin2, J Reynes6, P Flandre18, V Calvez2 and B Masquelier1 and the ANRS AC11 Resistance Study Group Genotypic prediction of tropism could be associated with VR even in patients screened by a phenotypic assay. The ongoing replication on MVC with or without genotypic evolution of the V3 loop deserves further investigation. |
| 112 | COMPARISON OF POPULATION AND 454 GENOTYPING AND TROFILE PHENOTYPING FOR TROPISM DETERMINATION IN PATIENTS SELECTED FOR MARAVIROC INITIATION Antiviral Therapy 2009; 14 Suppl 1:A131 (abstract no. 112) L Vandekerckhove1, C Verhofstede1, I Vandenbroucke2, C Booth3, H Van Marck2, AM Geretti3 and L Stuyver2 on behalf of the Tropism Study Group In comparison with 454 sequencing, Sanger sequencing showed 100% specificity and approximately 10% sensitivity for X4 detection. As the clinically relevant sensitivity threshold for tropism prediction has not been established, population sequencing may provide a rapid assessment tool on its own or be integrated with more sensitive methodologies. In one possible testing algorithm, population V3 sequencing could be applied to first-line screening, allowing the rapid identification of samples with a high content of X4 sequences, thereby reducing the number of samples for more extensive analyses as 454. This approach needs further clinical validation and will demand a thorough standardization of the Sanger sequencing and interpretation methodology. Additionally, determination of relevant clinical cutoffs for X4 minorities remains challenging. |
| 113 | PERFORMANCE OF AN HIV-1 CORECEPTOR TROPISM ASSAY UTILIZING REPLICATE V3 LOOP SEQUENCING AND HETERODUPLEX ANALYSIS WITH CAPILLARY ELECTROPHORESIS Antiviral Therapy 2009; 14 Suppl 1:A132 (abstract no. 113) R Baumann1, H Hamdan1, D Schwab1, T Robins2, J Vichayanonda1 and RM Kagan1 In samples from treatment-experienced patients, concordance between two independently developed genotypic tropism assays was comparable to the concordance of each assay with a phenotypic method. The proportion of X4 viruses detected did not vary significantly by assay type. Further comparisons of CE-HDA to the Trofile-enhanced sensitivity (ES) phenotypic assay are warranted. Clinical outcome studies are needed to assess the predictive values of different tropism assays for patients treated with CCR5 antagonists. |
| 114 | AMINO ACID CHANGES IN gp41 OF HIV-1 ASSOCIATED WITH CORECEPTOR TROPISM Antiviral Therapy 2009; 14 Suppl 1:A133 (abstract no. 114) E Stawiski, W Huang, J Whitcomb, L Napolitano, C Petropoulos and E Coakley These findings support previous observations that that determinants of tropism may lie outside of V3. Further studies will be needed to confirm the degree to which these GP41 mutations contribute directly to CRT determination. |
| 115 | POPULATION AND CLONAL TROPISM PHENOTYPING OF CLINICAL ISOLATES AND COMPARISON WITH NEXT GENERATION SEQUENCING AND PREDICTION TOOLS Antiviral Therapy 2009; 14 Suppl 1:A134 (abstract no. 115) K Van Baelen1, E Rondelez1, L Van Wesenbeeck1, W Mostmans1, H Van Marck1, V Van Eygen1, C Verhofstede2, L Vandekerckhove2, I Vandenbroucke1, L Stuyver1 and the Tropism Work Group D/M virus could not be detected using the most sensitive methods in 18 plasma samples from patients failing HAART. Phenotypic approaches detected X4 virus present at 10% or more of the virus population. A total of 692 cases of mainly concordant and some discordant datasets (clonal phenotype versus V3 prediction tool) became available, which in turn can be used to improve the prediction algorithms. Most of the samples failing phenotyping approaches could be characterized by deep sequencing and V3-loop prediction. Our data indicate that 454 sequencing combined with improved prediction tools could provide a sensitive alternative to phenotyping. |
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RESISTANCE TO NEW ANTIRETROVIRAL AGENTS Abstracts 116 thru 129, Pages A137 to A150 |
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| 116 | EVOLUTION OF RESISTANCE TO THE HIV INTEGRASE INHIBITOR (INI) ELVITEGRAVIR CAN INVOLVE GENOTYPIC SWITCHING AMONG PRIMARY INI RESISTANCE PATTERNS Antiviral Therapy 2009; 14 Suppl 1:A137 (abstract no. 116) J Waters1, N Margot2, R Hluhanich2, J Svarovskaia1, J Harris1, K Borroto-Esoda1, MD Miller2 and DJ McColl2 The initial appearance of EVG resistance involved simple INI-R mutation patterns followed by further evolution via a variety of pathways including genotypic switching, as was also described among VFs on RAL. Genotypic switching, such as from E92Q to Q148 mutations, was associated with the emergence of higher levels of phenotypic resistance to both EVG and RAL. |
| 117 | ASSESSMENT OF PREVALENCE OF MINORITY Q148R VARIANTS IN ANTIRETROVIRAL (ARV)-EXPERIENCED PATIENTS AND IN ARV-NAÏVE PATIENTS Antiviral Therapy 2009; 14 Suppl 1:A138 (abstract no. 117) C Charpentier1,2, C Piketty3, P Tisserand1, D Laureillard3, M Karmochkine3, A Si-Mohamed1 and L Weiss2,3 Our findings showed that the high prevalence of minority Q148R variants found in ARV-experienced patients is not the consequence from a history of long-term reverse transcriptase inhibitors-containing therapies, since similar data were found in ARV-naïve patients. Overall, although the presence of these minority variants was frequent, it was not consistently associated with viral rebound; their impact on long-term viral suppression needs to be further investigated. |
| 118 | EFFECT OF MUTATIONS AT CODON 69 OF HIV-1 REVERSE TRANSCRIPTASE ON SUSCEPTIBILITY TO APRICITABINE AND OTHER NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Antiviral Therapy 2009; 14 Suppl 1:A139 (abstract no. 118) J Southby1, K Limoli2, J Goss2 and S Cox1 Mutations at position 69 of the HIV RT affected susceptibility to ATC to varying degrees, with single substitutions, doublets and deletions at position 69 generally resulting in low fold changes in susceptibility to ATC, while isolates with triplets at position 69 generally showed greater reductions in ATC susceptibility. With the exception of tenofovir and didanosine, the fold changes in susceptibility to ATC of the mutations at position 69 were generally lower than for the other NRTIs tested. |
| 119 | C-TERMINAL REVERSE TRANSCRIPTASE MUTATIONS N348I AND T369I REDUCE ETRAVIRINE SUSCEPTIBILITY, BUT ONLY IN THE PRESENCE OF ADDITIONAL NNRTI MUTATIONS Antiviral Therapy 2009; 14 Suppl 1:A140 (abstract no. 119) Gupta, S Fransen, A Frantzell, E Coakley, E Stawiski, CJ Petropoulos, W HuangGupta, S Fransen, A Frantzell, E Coakley, E Stawiski, CJ Petropoulos, W Huang C-terminal RT mutations N348I and T369I reduced ETR susceptibility only in combination with well-characterized NNRTI mutations, such as K103N, L100I and Y181C. Thus, C-terminal RT mutations likely act as enhancing mutations for ETR, but have minimal impact when present in isolation. |
| 120 | IN VITRO RESISTANCE PROFILE OF TMC278, A NEXT-GENERATION NNRTI; EVIDENCE OF A HIGHER GENETIC BARRIER AND A MORE ROBUST RESISTANCE PROFILE THAN FIRST GENERATION NNRTIS Antiviral Therapy 2009; 14 Suppl 1:A141 (abstract no. 120) LT Rimsky1, H Azijn1, I Tirry1, J Vingerhoets1, R Mersch1, G Kraus1, M-P de Béthune1 and G Picchio2 These in vitro results suggest that TMC278 is a potent next-generation NNRTI, with a higher in vitro genetic barrier and a more robust resistance profile than first-generation NNRTIs. |
| 121 | NOVEL NNRTIs MORE ACTIVE ON K103N+Y181C MUTANTS THAN ON WILD-TYPE HIV-1 Antiviral Therapy 2009; 14 Suppl 1:A142 (abstract no. 121) D Jochmans1, E Arnoult2, C Mordant2, R Lépine2, M Van Ginderen1, B Van Schoubroeck1, C Masungi1, S Hallenberger1, K Hertogs1 and J Guillemont2 Our continued effort to find new NNRTIs revealed two unique molecules. Although their activity on wild-type HIV-1 is limited and precludes clinical usefulness, both show a significantly increased activity on viruses containing K103N and/or Y181C. This changes the paradigm that K103N and Y181C are always associated with NNRTI resistance. Further structural studies may reveal novel insights to improve the NNRTI class of HIV inhibitors. |
| 122 | MINORITY DRUG RESISTANCE MUTATIONS ASSOCIATED WITH THE NNRTI MUTATION K103N IN ARV-NAÏVE AND NNRTI-TREATED HIV-1-INFECTED PATIENTS Antiviral Therapy 2009; 14 Suppl 1:A143 (abstract no. 122) V Varghese1, R Shahriar1, S-Y Rhee1, BB Simen2, M Egholm2, B Gharizadeh3, F Babrzadeh3, WJ Fessel4 and RW Shafer1 Among patients failing an NNRTI in whom K103N alone is detectable by SGRT, UDPS is likely to detect multiple additional ETR resistance mutations suggesting that ETR is not likely to be highly active in this population. In contrast, among patients with transmitted NNRTI resistance in whom K103N alone is detectable by SGRT, ETR is likely to be effective. |
| 123 | STRUCTURE–ACTIVITY–RESISTANCE RELATIONSHIPS OF 6-MODIFIED 3´-AZIDO-2´,3´-DIDEOXYGUANOSINE NUCLEOTIDES AS INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE Antiviral Therapy 2009; 14 Suppl 1:A144 (abstract no. 123) BD Herman1, A Obikhod2, M Detorio2, H-W Zhang2, J Nettles2, SJ Coats3, RF Schinazi2, JW Mellors1 and N Sluis-Cremer1 6-Modified-AZG nucleotides are recognized and incorporated by HIV-1 RT as adenosine analogs. Some of these novel analogs, in particular the 6-amino derivative (RS-667-TP), exhibit potent activity against WT and NRTI-resistant RT. These findings further support the key role of base structure in activity-resistance profiles of nucleotide analogs. |
| 124 | TENOTHIOVIR AND ADETHIOVIR: ACYCLIC THIOPHOSPHONATES OVERCOMING HIV DRUG RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A145 (abstract no. 124) S Priet1, K Barral1, N Payrot1, C Weck1, A Frangeul1, J Neyts2, J Balzarini2, J-L Romette1, B Canard1, and K Alvarez1 The decreased rate of excision of our analog was not affected by the next correct nucleotide, suggesting that the dead end complex formation was not influenced by thiophosphonates. The effect of thiophosphonates on AZT-resistant viruses in infected cell cultures is currently under investigation. |
| 125 | THE RESISTANCE PATHWAY OF A NOVEL PROTEASE INHIBITOR IN SUBTYPE B AND CRF01_AE. AN IN VITRO STUDY Antiviral Therapy 2009; 14 Suppl 1:A146 (abstract no. 125) EL Asahchop1, B Brenner1, J Martinez-Cajas1, M Oliveira1, T Toni1, M Ntemgwa1, D Moisi1, B Spira1, C Tremblay2 and MA Wainberg1 PL-100 selects both minor and major PI resistance mutations in subtype B and CRF01_AE. The CRF01_AE isolate with the K55R and I85V mutations showed significant decrease susceptibility to PIs. PL-100 seems to have the potential for cross resistance with other PIs. Further studies are required to confirm these pathways. |
| 126 | CONFIRMATION OF THE NEGATIVE IMPACT OF PROTEASE MUTATIONS I47V, I54M, T74P AND I84V AND THE POSITIVE IMPACT OF PROTEASE MUTATION V82A ON VIROLOGICAL RESPONSE TO DARUNAVIR/RITONAVIR Antiviral Therapy 2009; 14 Suppl 1:A147 (abstract no. 126) S De Meyer1, D Descamps2, B Van Baelen1, E Lathouwers1, A Cheret3, A-G Marcelin4, V Calvez4 and G Picchio5 The negative impact of protease mutations I47V, I54M, T74P and I84V, and the positive impact of protease mutation V82A on virological response to DRV/r was confirmed in two independent datasets. |
| 127 | HIGH PREVALENCE OF BEVIRIMAT RESISTANCE MUTATIONS IN NON-B SUBTYPES AND IN PI-RESISTANT HIV ISOLATES Antiviral Therapy 2009; 14 Suppl 1:A148 (abstract no. 127) J Verheyen1, C Verhofstede2, E Knops1, L Vandekerckhove2, A Fun3, D Brunen3, K Dauwe2, A Wensing3, H Pfister1, R Kaiser1 and M Nijhuis3 Mutations conferring resistance to bevirimat were observed in approximately one third of treatment-naïve subtype-B HIV isolates and in 60% of treatment-naïve non-B isolates. Interestingly, an accumulation of bevirimat resistance mutations was observed in subtype B isolates with resistance mutations in the viral protease. |
| 128 | RESISTANCE MUTATIONS IN THE VIRAL PROTEASE ALTER BEVIRIMAT RESISTANCE PATTERNS IN VITRO Antiviral Therapy 2009; 14 Suppl 1:A149 (abstract no. 128) A Fun, NM van Maarseveen, REM Maas and M Nijhuis This study shows that the rate of selection of bevirimat resistance is unaffected by PI resistance mutations. However, PI mutations in the viral protease shift the bevirimat resistance pathway towards selection of mutations in the QVT-motif. These data suggest a strong interaction between HIV protease and the gag QVT-motif, affecting bevirimat susceptibility. |
| 129 | EVOLUTION OF CORECEPTOR TROPISM AND V3 LOOP RESISTANCE MUTATIONS IN THE BLOOD CELLULAR RESERVOIR AFTER INTRODUCTION OF MARAVIROC Antiviral Therapy 2009; 14 Suppl 1:A150 (abstract no. 129) L Morand-Joubert1, P Flandre2, C Soulié3, C Charpentier4, D Desbois5, A Ruffault6, AG Marcelin3, B Masquelier7, V Calvez3 and the ANRS AC11 Resistance Study Group In this limited dataset, the evolution of coreceptor nature and of V3 loop resistance mutations in the blood cellular compartment under treatment pressure of maraviroc was uncommon. The presence of X4 viruses in PBMC does not seem to influence the virological response to maraviroc. |
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DRUG RESISTANCE IN RESOURCE-POOR COUNTRIES Abstracts 130 thru 174, Pages A153 to A197 |
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| 130 | DYNAMICS OF ACCUMULATION OF DRUG RESISTANCE MUTATIONS IN THE ABSENCE OF VIROLOGICAL MONITORING IN HIV-1-INFECTED ZAMBIAN CHILDREN USING ADULT TRIOMUNE (FIXED-DOSE COMBINATION D4T, 3TC AND NVP) Antiviral Therapy 2009; 14 Suppl 1:A153 (abstract no. 130) RK Gupta1, D Ford2, D Kabamba3, V Mulenga3, M Kalumbi3, C Kalengo3, R Chileshe3, P Grant4, S Kirk4, J Mbasa5, M Thomason2, A Ferrier2, C Chintu3, DM Gibb2, D Pillay5 and AS Walker2 The 24 month virological suppression rates were encouraging. resistance to NNRTI/lamivudine was high in virological failures as compared with adult studies, with a higher rate of TAM accumulation than reported in Western cohorts. complete lack of drug activity in the failing regimen at 24 months was associated with failure to increase CD4% over baseline, suggesting no residual benefit of existing therapy. |
| 131 | VIROLOGICAL RESPONSE TO FIRST-LINE HAART IN HIV-1-INFECTED CHILDREN IN MALI: RATE OF FAILURE AND RESISTANCE AFTER 6 MONTHS OF ANTIRETROVIRAL TREATMENT Antiviral Therapy 2009; 14 Suppl 1:A154 (abstract no. 131) D Germanaud1, A Derache2, M Traore3, Y Madec4, S Toure3, F Dicko3, H Coulibaly3, M Sylla3, V Calvez2 and AG Marcelin2 These results suggest that, under NNRTI-based regimen, early detection of VF could allow to reinforce adherence in children with HIV-1 RNA<1,000 copies/ml or to change for a PI-based regimen if HIV-1 RNA>1,000 copies/ml. Moreover, the low frequency of TAM suggests that most NRTIs can be used in a second-line regimen after early failure to AZT or d4T/3TC/NVP. |
| 132 | MUTATIONS ASSOCIATED WITH ETRAVIRINE RESISTANCE AMONG PATIENTS INFECTED WITH HIV-1 SUBTYPE CRF01_AE AND FAILING FIRST-LINE NEVIRAPINE- AND EFAVIRENZ-BASED REGIMENS Antiviral Therapy 2009; 14 Suppl 1:A155 (abstract no. 132) W Manosuthi1,2, DM Butler3, W Chantratita2, C Sukasem2, DD Richman3,4 and DM Smith3,4 The prevalence of high-level etravirine resistance in clinical practice is substantial after virological failure of first-line NNRTI-based regimens, particularly nevirapine, among patients infected with CRF01_AE in Thailand. as etravirine RAM codons are conserved across subtypes, the prevalence of resistance is likely to be high in other resource-limited settings where failing nevirapine-based regimens are continued because of limited virologic monitoring. Thus, etravirine resistance rates will likely increase, even in populations not using etravirine. |
| 133 | DYNAMICS OF EMERGENCE AND LINKAGE OF HIV REVERSE TRANSCRIPTASE Q151M MDR COMPLEX IN CHILDREN WITHIN FIRST-LINE ANTIRETROVIRAL ROLLOUT UNCOVERED BY SINGLE-GENOME SEQUENCING Antiviral Therapy 2009; 14 Suppl 1:A156 (abstract no. 133) JL Mbisa1, RK Gupta2, PA Cane1, D Kabamba3, V Mulenga3, M Kalumbi3, C Chintu3, DM Gibb4, AS Walker4 and D Pillay1,2 The evolution and genetic linkage of drug resistance mutations in non-B subtypes is different from subtype B, and is associated with unique C-terminal mutations. The study suggests that the development of drug resistance in a resource-poor setting is extensive and likely to compromise second-line therapies to a greater extent than previously thought. Therefore, further experiments are needed to evaluate the emergence of drug resistance in non-B subtypes And its effects on long-term management of HIV-1 therapy. |
| 134 | PHENOTYPIC DATA TO GUIDE SELECTION OF REVERSE TRANSCRIPTASE INHIBITORS IN SECOND-LINE THERAPY FOLLOWING EXTENDED VIROLOGICAL FAILURE IN UGANDA Antiviral Therapy 2009; 14 Suppl 1:A157 (abstract no. 134) N Ndembi1, A McCormick2, P Kaleebu1, D Pillay2,3, L Bacheler4, T Pattery5, R Goodall6, D Dunn6, P Katundu7, M Chirara8, C Gilks9, D Yirrell10, P Munderi1 and C Kityo7 Isolates from the majority of patients with prolonged viraemia up to 96 weeks on either of these two first-line NORA regimens maintain susceptibility to didanosine and tenofovir. abacavir resistance was present in 55% of patients who failed on Combivir™/abacavir. etravirine is predicted to have significant activity in approximately one-half of the nora participants following prolonged failure on Combivir™/nevirapine. These findings should help inform selection of second-line regimens in resource-limited settings. |
| 135 | ANTIRETROVIRAL TREATMENT OF HIV-INFECTED WOMEN CAN INDUCE MULTICLASS DRUG RESISTANCE IN THEIR BREASTFEEDING INFANTS Antiviral Therapy 2009; 14 Suppl 1:A158 (abstract no. 135) J Lidstrom1, N Kumwenda2, G Kafulafula3, DR Hoover4, J Kumwenda3, LM Mofenson5, MG Fowler1,6, MC Thigpen6, TE Taha2 and SH Eshleman1 Breastfeeding infants with HIV infection can acquire resistance to ARV drugs in their mother’s treatment regimen. NRTI resistance could have been acquired in these infants by super-infection with NRTI-resistant HIV from the mother, or by exposure to non-suppressive levels of NRTIs in breast milk. Further studies are needed to assess the risks and benefits of initiating ARV treatment in breastfeeding women whose infants are HIV-infected. |
| 136 | ASSOCIATION BETWEEN MUTATIONS AFFECTS DRUG RESISTANCE SELECTION BY SINGLE-DOSE NEVIRAPINE IN HIV-1 SUBTYPE C Antivir Ther 2008, 13(Suppl 3):A159 (abstract no. 136) R Kantor1, A DeLong1, J Ledwaba2, A Kamau3, C Seebregts4, T de Oliveira5, J Hogan1, N Martinson6,7, J McIntyre6, L Morris2 and D Katzenstein8 for the South African Treatment and Resistance Network (SATURN) Diverse resistance patterns of common NRM and 16 associated mutations were selected by sdNVP in 67% women. NRM selection was associated with high VL and low CD4+ T-cell. associations between RT mutations affects drug resistance selection in HIV-1 subtype C and might increase drug resistance and/or fitness of HIV-1 subtype C. |
| 137 | MINORITY RESISTANCE DETECTION IN STORED DRIED BLOOD SPOTS INDICATES HIGH SPECIMEN INTEGRITY AND PROVIDES AN EXPANSIVE RECORD OF ARCHIVED RESISTANCE Antivir Ther 2008, 13(Suppl 3):A160 (abstract no. 137) X Wei1, AS Youngpairoj1, C Garrido2, N Zahonero2, A Corral2, C de Mendoza2, W Heneine1, JG Garcia-Lerma1 and JA Johnson1 Our ability to identify minority resistance demonstrates that, if stored properly, DBS is a high-integrity specimen type for drug resistance testing. We detected mutations from current and past treatment not detected by bulk genotyping, including K65R. Our data further support the global utility of DBS for drug resistance surveillance and clinical monitoring. |
| 138 | FEASIBILITY OF THE WORLD HEALTH ORGANIZATION’S HIV DRUG RESISTANCE ASSESSMENT STRATEGY FOR RESOURCE-LIMITED COUNTRIES SCALING UP ART Antiviral Therapy 2009; 14 Suppl 1:A161 (abstract no. 138) DE Bennett1, S Bertagnolio1, N Parkin1 and M Jordan2 The WHO strategy is generally feasible in resource-limited countries and is producing useful data to support public health action to limit HIVDR. New strategies are proposed to address sample size limitations in smaller countries. |
| 139 | HIV DRUG RESISTANCE GENOTYPING EXTERNAL QUALITY ASSURANCE (EQA) FOR LABORATORIES IN THE WORLD HEALTH ORGANIZATION (WHO) RESNET DURING 2007–2009 Antiviral Therapy 2009; 14 Suppl 1:A162 (abstract no. 139) NT Parkin1, J Fitzgibbon2, J Bremer3 and S Bertagnolio1 The use of a single and stringent criteria (such as 99%) for evaluation of sequence-based assays might be unrealistic when using clinical samples containing mixed bases at several positions. Acceptance criteria might need to be relaxed for such samples (for example, 98% identity) or be flexible and based on the number of mixed positions in each sample. |
| 140 | MONITORING OF HIV-1 DRUG RESISTANCE MUTATION DEVELOPMENT FROM PATIENTS UNDER ANTIRETROVIRAL THERAPY FROM SHANDONG PROVINCE, CHINA Antiviral Therapy 2009; 14 Suppl 1:A163 (abstract no. 140) J Zhang1, D Kang2, J Fu2, X Sun2, B Lins2, J Nkengasong1 and C Yang1 Our data indicates that among the patients with detectable VL, about half developed resistance mutations to the first-line regimens, and the mutation patterns became more complex as ART continued in these patients. Our very limited patient monitoring on first-line ART in resource-limited settings indicates that in order to maintain the effectiveness of the first-line regimens, strategic drug resistance monitoring in ARV-treated patients is critical in addition to educating the importance of adherence to patients. |
| 141 | HIV-1 PRIMARY DRUG RESISTANCE AND RECENT INFECTION IN A PROSPECTIVE COHORT OF MEN ATTENDING PUBLIC STI CLINICS IN MUMBAI Antiviral Therapy 2009; 14 Suppl 1:A164 (abstract no. 141) HM Truong1,2, C Lindan1, T Kellogg3, M Mathur4, S Mungekar4, H Jerajani4 and RM Grant1,2 HIV-1 seroincidence was high among men attending STI clinics. Primary HIV-1 drug resistance prevalence was low among recently-infected patients. High numbers of lifetime visits to FSW was associated with both recent infection and primary HIV-1 drug resistance. Patients with no prior tipranavir experience had ≥3 of the mutations that the manufacturer associates with decreased virological response. Current algorithms regard mutations at positions 20, 36 and 69 to be associated with resistance, although these polymorphisms are wild type for subtype C viruses.... |
| 142 | RESISTANCE PATTERNS IN SUBTYPE A/AE-INFECTED PATIENTS UNDER HAART IN ISRAEL Antiviral Therapy 2009; 14 Suppl 1:A165 (abstract no. 142) D Turner1, B Avidor1, I Levy2, K Riesenberg3, S Maayan4, D Averbuch4, Z Sthoeger5, D Elbirt5, M Chowers6, V Istomin7, E Kedem8, E Shahar8, D Ram9, F Mileguir9, E Mendelson9 and Z Grossman9,10 The frequency of certain mutations in naïve A/AE patients was found to be significantly different from subtype B virus. distinct polymorphisms between the subtypes might account for different pathways of resistance development that could impact the utility of treating with specific regimens. Further studies on larger cohorts are needed before clinically relevant conclusions can be drawn. |
| 143 | SILENT MUTATIONS AT HIV-1 REVERSE TRANSCRIPTASE IMPACT DIFFERENTIALLY THE LEVEL OF RESISTANCE TO TAM IN SUBTYPE B, C AND F STRAINS FOUND IN BRAZIL Antiviral Therapy 2009; 14 Suppl 1:A166 (abstract no. 143) AFNPC Pires, CM Abreu, AN Martins, MB Arruda, RM Brindeiro, AR Calazans and A Tanuri Synonymous substitutions at positions K65 and K66 in RT gene altered the HIV-1 subtypes B, C and F susceptibility to thymidine analogues even in the presence of TAM. We were able to observe that this impact on phenotypic resistance was subtype Dependent. |
| 144 | HIV DRUG RESISTANCE AFTER HAART DISCONTINUATION AMONG TREATMENT-NAÏVE WOMEN WHO INITIATE ANTIRETROVIRAL THERAPY FOR THE PREVENTION OF MOTHER-TO-CHILD TRANSMISSION IN RIO DE JANEIRO, BRAZIL Antiviral Therapy 2009; 14 Suppl 1:A167 (abstract no. 144) JH Pilotto1,2, B Grinsztejn1, V Veloso1, JC Couto-Fernandez1, A Rodrigues-Pedro1, CA Velasco-de-Castro1, J Eurico Ribeiro2, R Khalili1, S Muri1, R Ismerio1, R Hoffman3, J Currier3 and MG Morgado1 This cohort of ARV-naïve pregnant women who initiated HAART for the prevention of MTCT had a high prevalence of baseline resistance, as well as a high incidence of new mutations after postpartum HAART discontinuation. These findings support resistance testing prior to HAART initiation for MTCT in Brazil and highlight the need for studies to address the impact of post-partum HAART discontinuation on future treatment outcomes. |
| 145 | LOW PREVALENCE OF DRUG RESISTANCE MUTATIONS FOR SALVAGE THERAPY IN HIV-1 PATIENTS FAILING ANTIRETROVIRAL THERAPY IN RIO DE JANEIRO, BRAZIL Antiviral Therapy 2009; 14 Suppl 1:A168 (abstract no. 145) JC Couto-Fernandez1, AA Pereira2, ML Guimarães1, LA Inocêncio2, MC Rachid3, VG Veloso4 and MG Morgado1 Low prevalence of resistance mutations to the new generation of PI, NNRTI and EI were observed in our large database of the HIV-1 genotyping test. The impact of resistance mutations due to darunavir seems lower in comparison to tipranavir in patients failing other PI-based regimens. Although prior failure to other PI or NNRTI might produce cross-resistance, the results show that all of these antiretroviral drugs could be a good option for patients who have failed other ART regimens. |
| 146 | BRAZILIAN NETWORK FOR HIV DRUG RESISTANCE SURVEILLANCE (HIV-BResNet): A NEW SURVEY OF HIV RECENT DIAGNOSED INDIVIDUALS COLLECTED IN 2007/8 Antiviral Therapy 2009; 14 Suppl 1:A169 (abstract no. 146) LA Inocencio1, AA Pereira1, MCA Sucupira2, JCC Fernandez3, CP Jorge4, DFC Souza1, H Fink5, RS Diaz2, IM Becker6, TA Suffert7, MB Arruda8, O Macedo9, MBG Simão1, A Tanuri8 and the HIV-BResNet Working Group Despite the extensive antiretroviral exposure and high rates of virological antiretroviral failure in Brazil, the general prevalence of primary resistance is still low. However, intermediate level of primary resistance was found in the four major Brazilian cities as well as a substantial increase of NNRTI resistance, confirming the critical need to start larger sampling surveys to better define the risk factors associated with transmission of resistant HIV. |
| 147 | HIV-1 ANTIRETROVIRAL RESISTANCE MUTATIONS IN SUBTYPES B, C AND F: RESULTS OF THE BRAZILIAN GENOTYPE LABORATORY NETWORK (RENAGENO) Antiviral Therapy 2009; 14 Suppl 1:A170 (abstract no. 147) A Alvarenga1, LV Araújo2, JE Ferreria2, MC Sucupira3, JCC Fernandez4, D Sousa1, LA Inocencio1, M Simão1, EC Sabino2, RS Diaz3 and RENAGENO network Special attention should be given to resistance profiles in non-B subtype viruses. The accumulation of knowledge regarding such profiles in the developing world is desirable. |
| 148 | THE ASSOCIATION BETWEEN PRIMARY ANTIRETROVIRAL RESISTANCE AND HAART VIROLOGICAL FAILURE IN A DEVELOPING SET Antiviral Therapy 2009; 14 Suppl 1:A171 (abstract no. 148) LH Gagliani1,2, WT Alkmim Maia1, M Caseiro2, D Sá-Filho2, C Sucupira1 and RS Diaz1 Although some individuals with primary resistance achieved viral suppression under empiric HAART, the higher prevalence of primary resistance in the virological failure group might suggest that primary resistance greatly impairs antiretroviral activity. Although Brazilian guidelines do not recommend resistance tests before treatment initiation, a special individualization should be given to this geographic region. |
| 149 | PRIMARY ANTIRETROVIRAL RESISTANCE AMONG INDIVIDUALS WITH RECENT HIV INFECTION IN THE CITY OF SÃO PAULO, BRAZIL: USE OF FULL-LENGTH GENOME SEQUENCING TO EVALUATE SIX ANTIRETROVIRAL CLASSES Antiviral Therapy 2009; 14 Suppl 1:A172 (abstract no. 149) MCA Sucupira1, S Sanabani2, RM Côrtes1, LM Janini1, EC Sabino2, EG Kallas1,3 and RS Diaz1 We present a comprehensive analysis of resistance to antiretrovirals from individuals with recent HIV infection in São Paulo, Brazil using sampling schematics that are truly representative of this region in Brazil. Primary resistance to NNRTI was higher than resistance to NRTI or PI, which might reflect the higher replicative capacity and transmission fitness of NNRTI-resistant viruses, as suggested by the higher viral load median in this group of patients. |
| 150 | PREVALENCE OF HIV-1 TRANSMITTED RESISTANCE IN A SURVEILLANCE STUDY IN CENTRAL MEXICO, ACCORDING TO CALIBRATED POPULATION RESISTANCE Antiviral Therapy 2009; 14 Suppl 1:A173 (abstract no. 150) RA Rodriguez-Diaz, LL Fuentes-Romero, M Viveros-Rogel, M Hernandez-Flores and LE Soto-Ramirez There was a higher prevalence in transmitted resistance to all groups of drugs when we compared CPR-SDRM program with the criteria originally considered that used mutations for secondary resistance, supporting the use of specific surveillance criteria to determine more adequately transmitted resistance. Use of surveillance criteria allowed a better comparison between other studies. According to this data, Mexico should be doing resistance testing before treatment. |
| 151 | HIV DRUG RESISTANCE IN THE ANDEAN REGION: A LOOK AFTER THE UNIVERSAL ACCESS TO HAART IN THE ANDEAN REGION Antiviral Therapy 2009; 14 Suppl 1:A174 (abstract no. 151) J Guanira1,2, JR Lama1,2, O Montoya3, P Segura1,2, Eric Ramos1,2, Carmela Ganoza1,2, S Montano4, T Kochel4, R Grant5 and J Sanchez1,2 for the Peruvian HIV Sentinel Surveillance Working Group In the Andean region, the prevalence of primary antiretroviral drug resistance continues to be low in 2006, even after public-funding-based HAART programs were scaled up. The Andean region has made a transition from NRTI predominant primary resistance to NNRTI predominant primary resistance, an expected pattern as mono- and bi-therapy are no longer used in these countries and NNRTI-based regimens are the most commonly used for naïve patients. Sentinel surveillance systems monitoring primary antiretroviral drug resistance must continue in the region to guide the recommendations for HAART. |
| 152 | PRIMARY RESISTANCE IN NEWLY DIAGNOSED HIV-1INFECTED DRUG-NAÏVE INDIVIDUALS FROM BUENOS AIRES, ARGENTINA: A TWO-PERIOD COMPARISON Antiviral Therapy 2009; 14 Suppl 1:A175 (abstract no. 152) AE Rubio, MA Pando, DA Dilernia, J Trinchero, NI Rovner and H Salomon The increment in PRM prevalence observed in the overall NDDN population between 2003–2005 and 2006–2008 in Buenos Aires, Argentina leaves an open controversial debate of whether drug-naïve patients should be tested prior to starting antiretroviral treatment. However, the similar prevalence observed in the MSM population highlights the need to carry out careful analyses in order to accurately establish PRM in different at-risk NDDM populations. |
| 153 | HIGH FREQUENCY OF PRIMARY MUTATIONS ASSOCIATED WITH ANTIRETROVIRAL DRUG RESISTANCE IN RECENTLY DIAGNOSED HIV-INFECTED CHILDREN IN BUENOS AIRES, ARGENTINA Antiviral Therapy 2009; 14 Suppl 1:A176 (abstract no. 153) M Vignoles1, G Barboni2, MR Agosti3, M García3, S González Ayala3 and H Salomón1 Our results showed a high frequency of antiretroviral drug resistance mutations in recently diagnosed infants aged <5 years. Therefore, drug resistance testing before HAART initiation in paediatric populations should be implemented as a standard of care, even in developing countries such as Argentina, for a rational and cost-effective use of drugs. |
| 154 | EVALUATION OF MINORITY POPULATIONS OF HIV-1 WITH K103N AND M184V RESISTANCE MUTATIONS AMONG HIV-1-INFECTED CHILDREN IN BUENOS AIRES, ARGENTINA Antiviral Therapy 2009; 14 Suppl 1:A177 (abstract no. 154) M Vignoles1, G Barboni2, MR Agosti3, M García3, S González Ayala3 and H Salomón1 It was shown that having 2–10% of M184V at baseline enhanced its selection in high percentages in a short time after HAART initiation. Further research regarding the presence of minority quasispecies before initiation of HAART in large paediatric populations should be undertaken to evaluate their clinical impact during HAART. |
| 155 | PREVALENCE OF DRUG-RESISTANT HIV-1 VARIANTS AT INITIATION OF STANDARD FIRST-LINE HAART IN AFRICA Antiviral Therapy 2009; 14 Suppl 1:A178 (abstract no. 155) RL Hamers1, AM Wensing2, M Siwale3, M Botes4, F Conradie5, S Abdallah6, CL Wallis5, W Stevens5, M van Vugt1, DA van de Vijver7, R Schuurman2 and TF Rinke de Wit1 on behalf of the PharmAccess African Studies to Evaluate Resistance (PASER) program Among individuals in the cohort with earlier ARV exposure, 26% harbored resistance at initiation of standard first-line HAART. Among ARV-naïve individuals >5% carried resistance. NNRTI-resistance was most prevalent, by contrast to countries with a long treatment history where baseline resistance is dominated by NRTI-mutations. We cannot exclude that undisclosed PMTCT might have contributed to the high rates observed. Longitudinal monitoring studies are needed to determine the consequences for treatment outcome and to ensure adequate selection of first-line regimens. |
| 156 | HIV RESISTANCE TO ANTIRETROVIRAL DRUGS IN TREATED AND TREATMENT-NAÏVE PATIENTS IN CLINICS USING NATIONAL GUIDELINES FOR ART IN THE DEMOCRATIC REPUBLIC OF CONGO Antiviral Therapy 2009; 14 Suppl 1:A179 (abstract no. 156) J Muwonga1,2, S Edidi1, C Butel3, M Monleau3, A Okenge4, J Lambert Mandjo4, H Mukumbi5, JJ Muyembe2, F Mbayo2, DK Nzongola2, E Delaporte3, F Boillot6,7 and M Peeters3 Overall, rates of genotypic drug resistance were low but an important difference between the two cities was observed. The majority of patients with VL failure were resistant to ≥2 of the 3 drugs from their actual regimen. Importantly, two patients (non-subtype C) had the K65R mutation compromising the efficacy of second- line regimens for which TDF is recommended. |
| 157 | HIGH PREVALENCE OF GENOTYPIC RESISTANCE MUTATIONS IN DNA AND GENETIC VARIABILITY IN LONG-TERM ART-EXPERIENCED PATIENTS INFECTED WITH HIV-2 IN ABIDJAN, CÔTE D’IVOIRE Antiviral Therapy 2009; 14 Suppl 1:A180 (abstract no. 157) TA Toni1,2, M Mbamy2, E Asahchop1, M Ntemgwa1, H Chenal2 and MA Wainberg1 ART-experienced HIV-2 individuals in RCI showed high prevalence of genotypic resistance mutations associated with ART. Monitoring of HIV-2 viral load and drug resistance mutations will considerably improve effectiveness of long-term treatment. More data are required to update ART guidelines for HIV-2. |
| 158 | VARIED PATTERNS OF HIV-1 DRUG RESISTANCE AMONG PATIENTS ON FAILING FIRST-LINE ANTIRETROVIRAL THERAPY IN THE SOUTH AFRICAN NATIONAL ROLL-OUT PROGRAMME Antiviral Therapy 2009; 14 Suppl 1:A181 (abstract no. 158) CL Wallis1, JW Mellors2, WDF Venter1, I Sanne1 and W Stevens1,3 Overall, the varied drug resistance patterns observed after failure of first-line therapy indicates that resistance testing would be useful in identifying the most appropriate second-line therapy. Blind regimen ‘switches’ are not likely to provide optimal second-line treatment responses in all patients, although the overall cost-effectiveness of resistance testing is uncertain. Sentinel surveillance for drug resistance should be part of national treatment programs to identify effective and low-cost treatment regimens. |
| 159 | HIV-1 TRANSMITTED DRUG RESISTANCE SURVEILLANCE IN THREE PROVINCES IN SOUTH AFRICA DURING 2002–2007 Antiviral Therapy 2009; 14 Suppl 1:A182 (abstract no. 159) J Ledwaba1, G Hunt1, M Rakgotho1, Z El-Khatib1,2, B Singh1, L Makubalo3, A Puren1 and L Morris1 TDR rate was below the WHO threshold (<5%) in three provinces. The low amplification rates are most likely a result of the use of samples collected for serology. Low frequencies of K103N minority variants suggest that incorporating AS-PCR in TDR surveys might be useful, as minority variants have been shown to have clinical implications in treatment. |
| 160 | PROTEASE INHIBITOR RESISTANCE IS UNCOMMON IN PATIENTS ON FAILING SECOND-LINE LOPINAVIR/RCONTAINING REGIMEN IN SOUTH AFRICA Antiviral Therapy 2009; 14 Suppl 1:A183 (abstract no. 160) CL Wallis1, JW Mellors2, WDF Venter1, I Sanne1 and W Stevens1,3 Major lopinavir resistance mutations were rare (2%) among patients failing second-line therapy with AZT, ddI and lopinavir/r in the South African rollout programme. Many nucleoside options remain after failure. In addition, darunavir and etravirine appear to be good options for third-line therapy based on the resistance profiles observed. |
| 161 | HIV DRUG RESISTANT MUTATIONS IN HIV-1 SUBTYPE C CHILDREN FAILING ANTIRETROVIRAL THERAPY IN SOUTH AFRICA Antiviral Therapy 2009; 14 Suppl 1:A184 (abstract no. 161) CL Wallis1, S Varughese2, K Technau3 and W Stevens1,4 Similar mutation profiles are observed in children and adults failing ARVs on the national program in South Africa. As expected, the majority of patients failing the NNRTI-based first-line regimen harbour a combination of M184V and NNRTI mutations. The V82A mutation attributes to 33% of PI-regimen-based failures. Reasons for failure in the absence of major PR mutations requires further investigation. |
| 162 | ITEMSET MINING: AN APPROACH TO IDENTIFY CO-OCCURRENCE OF DRUG RESISTANCE MUTATIONS AMONG HIV-1-INFECTED PATIENTS FAILING THERAPY Antiviral Therapy 2009; 14 Suppl 1:A185 (abstract no. 162) A Kamau1, CJ Seebregts2, D Katzenstein3, R Kantor4, S Cassol5, J Ledwaba6, L Morris6, C Hoffman7 and T de Oliveira1,8 for the South African Treatment and Resistance Network (SATuRN) The datamining algorithm identified co-occurrence of DRM with a high level of accuracy (100%) and sequence data might be readily correlated with clinical information. Application to treatment of HIV-1 in South Africa suggested that P225/K103 co-occurrence increases with continued EFV among subtype C HIV-1. The P225 mutation did not occur in isolation and some combinations were more common in patients with lower viral loads and CD4+ T-cell counts. |
| 163 | RISK OF BROAD-SPECTRUM RESISTANT VIRUS IN HIV-1-INFECTED CHILDREN AFTER FIRST-LINE TREATMENT FAILURE IN A LARGE ACCESS PROGRAM IN MAPUTO, MOZAMBIQUE Antiviral Therapy 2009; 14 Suppl 1:A186 (abstract no. 163) ML Chaix1, I Jani2, E Macassa2, D Bila2, A Vubil2, S Andersson3, N Briand4, C Rouzioux1, P Vaz2 and S Blanche1 This exhaustive study in a large group of children treated according to WHO guidelines in Mozambique revealed a high rate of virological success (73%). Residual viral replication in children receiving d4T/ZDV+3TC+nevirapine treatment is associated with a time dependent risk of broad-spectrum resistance, including resistance to drugs currently used for second-line treatment. |
| 164 | ASSOCIATION BETWEEN MEDICATION POSSESSION RATIO AND VIROLOGICAL M6 AND M12 OUTCOMES IN HIV-1-INFECTED ADULTS ON ANTIRETROVIRAL TREATMENT IN ABIDJAN, CÔTE D’IVOIRE Antiviral Therapy 2009; 14 Suppl 1:A187 (abstract no. 164) ML Chaix1, E Messou2, D Gabillard3, A Minga2, E Losina4, T N’Dri-Yoman2, K Freedberg4, C Rouzioux1, C Danel2 and X Anglaret3 In this large observational study, 49% of patients with detectable VL at M12 had no resistance. In these patients, switching to second-line ART on the basis of a detectable VL would have been inappropriate. The strong association between MPR and M12 virological status highlights the critical importance of adherence and suggests MPR as a good marker. |
| 165 | RESISTANCE PATTERNS AMONG HIV-TREATED PATIENTS WITH VIROLOGICAL FAILURE, BUSIA DISTRICT, KENYA Antiviral Therapy 2009; 14 Suppl 1:A188 (abstract no. 165) E Alonso1, M Arnedo2, N Eisenberg1, A Jaén3, C Ferreyra1, L Ibáñez3, L Flevaud1, A Khamadi4, P Roddy1, J Mashala1, A Alvarez1, E Velilla1 and D Dalmau3 on behalf of Busia OR Study Group Virological failure rates in resource-limited settings are similar to those observed in developed countries. Moreover, genotypic results available were concordant with antiretroviral treatment received by failing patients, reinforcing the importance of treatment adherence in the context of lack of regular access to VL monitoring and genotype. Thus, our data contribute to the debate of whether genotyping is essential and feasible to do in resource-poor countries. |
| 166 | HIV DIVERSITY AND DRUG RESISTANCE IN WESTERN KENYA FROM PLASMA AND NON-PLASMA GENOTYPING Antiviral Therapy 2009; 14 Suppl 1:A189 (abstract no. 166) R Kantor1, L Diero2, A DeLong1, M Balamane3, RM Lloyd4, W Injera2, L Kamle2, F Mambo2, S Muyonga2, L Watetu2, EJ Carter1, D Katzenstein3, J Hogan1 and N Buziba2 Within diverse HIV subtypes and recombinants identified in western Kenya, low-cost, concordant non-plasma sequencing is feasible, even in difficult conditions. High rates of drug resistance and unique resistance patterns were identified and have potential detrimental effects on second-line therapy in resource-limited settings. |
| 167 | HIV-1 PRIMARY DRUG RESISTANCE IN PROTEASE AND REVERSE TRANSCRIPTASE POLYMERASE AND RNase H DOMAINS FROM VIRUSES INFECTING CAMEROONIAN SUBJECTS Antiviral Therapy 2009; 14 Suppl 1:A190 (abstract no. 167) EA Soares1, MF Makamche2, JD Siqueira1, E Lungwena2, J Mbuagbaw2, L Kaptue2, T Asonganyi2, HN Seuánez1,3, G Alemnji3 and MA Soares1,3 Primary drug resistance is still low in Cameroon, despite increasing access to ARV treatment. Mutations found appear to last without drug pressure for an extended time, as patients had been likely infected for years. RNH mutations with documented impact on virus resistance were found, but their impact on subsequent ARV therapy response, as well the role of HIV genetic diversity on their natural occurrence and persistence are yet to be fully understood. |
| 168 | PREVALENCE OF HIV-1 DRUG RESISTANCE IN HIV-1-INFECTED PATIENTS TREATED IN DOUALA, CAMEROON Antiviral Therapy 2009; 14 Suppl 1:A191 (abstract no. 168) C Charpentier1,2, F Talla3, A Joko4, A Si-Mohamed1 and L Bélec1,2 Our study highlighted the urgent need in improving viral load assessment in resource-limited settings to optimize ARV therapy management and preserve second-line regimen drugs and in increasing data on HIV non-B subtype resistance profiles. |
| 169 | ART SCALING UP IN CAMEROON: INCREASE OVER TIME OF ARV DRUG RESISTANCE MUTATIONS IN PATIENTS SEEKING ART CARE Antiviral Therapy 2009; 14 Suppl 1:A192 (abstract no. 169) A Aghokeng1,2, C Kouanfack3, C Montavon2, A Ayouba2, C Laurent2, A Kenfack3, A Bourgeois4, S Koulla-Shiro3, E Mpoudi-Ngole1, E Delaporte2,4 and M Peeters2 Overall, we found a significant increase in drug resistance mutations among treatment-naïve patients over time, especially for the widely used NRTIs. The proportion of resistant strains in this group does not reflect recently transmitted resistance, but is representative for new patients likely to be evaluated for treatment by a clinician. The results are also in line with the intermediate resistance prevalences observed for NNRTI and NRTIs in Yaoundé and Douala in 2007, using the WHO HIVDR threshold survey antenatal clinic attendees (<25 years and first pregnancy). The presence of Y115FY is intriguing and needs to be further elucidated. |
| 170 | EVALUATION OF PRIMARY RESISTANCE IN HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 (HIV-1) CIRCULATING IN ANGOLA AND MOZAMBIQUE BASED ON AN HIV DRUG RESISTANCE THRESHOLD SURVEY (HIVDR-TS) Antiviral Therapy 2009; 14 Suppl 1:A193 (abstract no. 170) RFC Ferreira da Silva1, CM Abreu2, EC Branco1, E Bule3, S Stakteas3, RS Aguiar2, PA Brindeiro2, AN Martins2, MB Arruda2, R de Moraes Brindeiro2, FG da Silva1, D Serrano4, LJ Costa5 and A Tanuri2 This work demonstrates a great genetic diversity in the HIV population circulating in Angola. More importantly, although the rates of primary resistance to both NNRTIs and PIs in Angola are considered low, there is already an intermediate level of transmitted resistance (5–15%) related to NRTIs. In Mozambique we found a high prevalence of HIV-1 subtype C. However, subtypes A and D were also detected together with mosaics in northern region. Contrasting with Angola, no primary resistance mutations to PI, NNRTI and NRTI were found. |
| 171 | IMPACT OF HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 PROTEASE POLYMORPHISMS ON RESISTANCE TO PROTEASE INHIBITORS IN A NIGERIAN POPULATION Antiviral Therapy 2009; 14 Suppl 1:A165 (abstract no. 161) B Chaplin1, G Eisen1, S Meloni1, J Idoko2, D Onwujekwe3, D Olaleye4, W Gashau5, R Nkado6, C Okany7, E Ekong8, R Murphy9 and P Kanki1 In a Nigerian population of treated patients failing first-line ART, an array of HIV-1 subtypes were present, and minor protease mutations were found to occur at levels higher than those in PI-naïve subtype B patients in a subtype-specific manner. |
| 172 | ANALYSIS OF HIV DIVERSITY AND DRUG-RESISTANCEASSOCIATED CHANGES AMONG DRUG-NAïVE AND -EXPOSED PATIENTS IN BURKINA FASO Antiviral Therapy 2009; 14 Suppl 1:A166 (abstract no. 172) K Sathiandee1, DM Tebit2, L Sangaré3, F Tiba1, T Ouedraogo4, Y Saydou2, A Makamtse2, H Somlare2, G Bado2, BG Kouldiaty2, B Coulibaly4, I Zabsonre3, Sl Yameogo3, S Traoré4, JY Drabo3 and H-G Kräusslich1 To determine a possible influence of the genetic background on resistance, a subset of sequences was analysed in a newly developed phenotypic assay based on a CRF02_AG HIV-1 proviral plasmid. Finally, genetic diversity and minority population resistance mutations were analysed in plasma and breast milk samples from women receiving perinatal prophylaxis with nevirapine at the time of delivery. |
| 173 | EMERGING HIV-1 REVERSE TRANSCRIPTASE MUTATION PATTERNS AMONGST ANTIRETROVIRAL THERAPY (ART)NAÏVE PATIENTS IN ABUJA, FEDERAL CAPITAL OF NIGERIA – POTENTIAL IMPACT ON TREATMENT EFFICACY Antiviral Therapy 2009; 14 Suppl 1:A167 (abstract no. 173) RE Ugbena1, I Wurie1, C Yang2, C Mattson2, K Diallo1, O Bassey1, J Aberle-Grasse2, V Shanmugam2, A Azeez3, T Jelpe1 and M Mukhtar1 With the high proportion of DRM detected in patients infected with CRF06_cpx and six patients harbouring primary RT mutations, the baseline genotyping results should alert us to pay close attention to the treatment outcomes of these patients. We might also need to consider the impact of viral diversity on the efficacy of ART programs. |
| 174 | EVALUATION OF SAMPLETANKER® FOR COLLECTION, STORAGE AND TRANSPORT OF DRIED PLASMA FROM A RESOURCE-LIMITED SETTING (R-LS) TO A RESOURCE-RICH SETTING (R-RS) FOR HIV-1 GENOTYPIC ANALYSIS Antiviral Therapy 2009; 14 Suppl 1:A197 (abstract no. 174) C Loveday1, E MaCrae1, M Holodniy2, R Mathis3, D Burns3, J Cooper3, Z Grossman4 and RM Lloyd, Jr3 ST provided a highly flexible means of storing and transporting samples from our site, with 91.5% rates of genotyping, and >98% similarity with paired frozen plasma. Further, we demonstrated its utility in a low-technology laboratory setting with an 80% reduction in transport costs. ST provides a tool to examine an ‘alternative pathway’ to deliver patient-specific virological care to those in R-LS. |
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