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Objective ( Part 1)

Similar prevalence of baseline HIV-1 minority variants among responders and virologic failures, as well as increased detection of HIV-1 minority variants at treatment failure, in rilpivirine patients from the ECHO and THRIVE Phase III studies.

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Objective ( Part 1)

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  1. Similar prevalence of baseline HIV-1 minority variants among responders and virologic failures, as well as increased detection of HIV-1 minority variants at treatment failure, in rilpivirine patients from the ECHO and THRIVE Phase III studies L. Rimsky,1 V. Van Eygen,1 J. Vingerhoets,1K. Thys,1J. Aerssens,1 M. Stevens1and G. Picchio2 1Janssen InfectiousDiseases BVBA, Beerse, Belgium; 2Janssen Research & Development, LLC, Titusville, NJ, USA

  2. Objective (Part 1) • Assess if baseline minority variants* with resistance-associated mutations (RAMs) in reverse transcriptase (RT) played a role in rilpivirine (RPV) virologic failure (VF)¥ • Describe the minority variants with RT RAMs in RPV patients with virologic failure (VF) at time of failure‡ *HIV-1 quasispecies undetectable by Sanger population sequencing (SPS) and seen only by ultra-deep sequencing (UDS)¥49 RPV responders and 47 RPV VFs from the analysis of the Week 48 pooled ECHO and THRIVE trials with comparable baseline characteristics‡48 RPV VFs including 12 without NNRTI RAMs and NRTI RAMsUDS (Illumina® platform) with a median coverage of 215,377 reads per position (1% represents ±2000 reads)

  3. Frequency of baseline NNRTI RAMs detected by SPS among responders and VFs to RPV was comparable [N = 49] [N = 47] NNRTI RAMs present at baseline NNRTI RAMs not associated with VF in green; RPV RAMs in red1 ≥1 V90I V106I V108I E138AV179D V179I V189I F227C 1Rimsky L, et al. JAIDS 2012;59:39–46 *49 responders and 47 VFs with comparable baseline characteristics SPS = Sanger population sequencing

  4. Frequency of baseline NNRTI RAMs detected by UDS was similar among responders and VFs to RPV [N = 49] [N = 47] NNRTI RAMs present at baseline NNRTI RAMs not associated with VF to RPV in green;RPV RAMsin red1 ≥1 V90I V106I V108I E138AV179D V179I V189I F227C • 2 VFs had minority variants with 1 NRTI RAM at baseline (M184V and L210W) *49 responders and 47 VFs with comparable baseline characteristics UDS = ultra-deep sequencing; SPS = Sanger population sequencing MVs = minority variants 1Rimsky L, et al. JAIDS 2012;59:39–46

  5. Additional NNRTIRAMs detected by UDS in RPV VFs at failure RPV RAMs in red1 • The most commonly found NNRTI RAMs observed in minority variants were the same as those seen by SPS UDS = ultra-deep sequencing; SPS = Sanger population sequencing; MVs = minority variants 1Rimsky L, et al. JAIDS 2012;59:39–46

  6. Additional NRTI RAMs detected by UDS in RPV VFs at failure VFs [N = 48] • The most commonly found NRTI RAMs observed in minority variants were the same as those seen by SPS UDS = ultra-deep sequencing; SPS = Sanger population sequencing; MVs = minority variants

  7. Conclusions (Part 1) • UDS analysis of 97 RPV patients (49 responders and 48 VFs) from ECHO and THRIVE showed: • Minority variants at baseline did not play a role in RPV VF • Minority variants with NNRTI RAMs were detected at failure in an additional 7 of the 48 RPV VFs. Few NRTI RAMs were detected. These RT RAMs were the same as those seen by SPS • UDS confirmed the RPV resistance findings observed in ECHO and THRIVE

  8. Objective (Part 2) • Determination of the relative frequencies of K101E, E138K and/or M184I/V in a subset of RPV VFs* • Analysis of the linkage between K101E and E138K¥ • *34/48 RPV VFs with ≥1 of K101E, E138K or M184I/V detected by UDS at failure • ¥Linkage analysis performed on a subset of 6/34 RPV VFs with mixtures of mutations at 2 positions (101 and 138)

  9. Frequencies of M184I/V Frequency of quasispecies (%) VFs at failure Only the 34/48 VFs with at least one of E138K, K101E, M184I and M184V are displayed

  10. Frequencies of M184I/V and E138K Frequency of quasispecies (%) VFs at failure Only the 34/48 VFs with at least one of E138K, K101E, M184I and M184V are displayed

  11. Frequencies of M184I/V, K101E and E138K Frequency of quasispecies (%) VFs at failure • M184I/V can occur without K101E or E138K • K101E orE138K are on the same genome with M184I/V Only the 34/48 VFs with at least one of E138K, K101E, M184I and M184V are displayed

  12. Frequencies of M184I/V, K101E and E138K Frequency of quasispecies (%) VFs at failure • M184I/V can occur without K101E or E138K • K101E orE138K are on the same genome with M184I/V

  13. Linkage analysis: E138K and K101E were usually found in different genomes Variants with: K101 E138 K E K K E E K E 146,395paired-end reads from 6 RPV VFs with K101E/K + E138E/K

  14. Conclusions (Part 2) • When present in RPV VFs, M184I/V was usually observed at high frequency regardless of the presence of E138K or K101E • In RPV VFs, E138K and K101E were usually found in different genomes in association with M184I or V, suggesting different pathways of RPV resistance

  15. Acknowledgements • The patients and their families for their participation and support during the studies • ECHO and THRIVE Janssen study teams and the principal investigators: THRIVE Australia: D Baker, R Finlayson, N Roth; Belgium: R Colebunders, N Clumeck, J-C Goffard, F Van Wanzeele, E Van Wijngaerden; Brazil: CR Gonsalez, MP Lima, F Rangel, A Timerman; Canada: M Boissonnault, J Brunetta, J De Wet, J Gill, K Kasper, J Macleod; Chile: J Ballesteros; R Northland, Carlos Perez; China: L Hongzhou, L Taisheng, W Cai, H Wu, L Xingwang; Costa Rica: G Herrera; France: F Boue, C Katlama, J Reynes; Germany: K Arastéh, S Esser, G Fätkenheuer, T Lutz, R Schmidt, D Schuster, H-J Stellbrink; Great Britain: M Johnson, E Wilkins, IG Williams, A Winston; India: N Kumarasamy, P Patil; Italy: A Antinori, G Carosi, F Mazzotta; Mexico: J Andrade-Villanueva, JG Sierra Madero; Panama: A Canton Martinez, A Rodriguez-French, N Sosa; Portugal: R Marques; Puerto Rico: C Zorrilla; Russia: N Dushkina, A Pronin, O Tsibakova, E Vinogradova; South Africa: M Botes, F Conradie, J Fourie, L Mohapi, D Petit, D Steyn; Spain: B Clotet, F Gutierrez, D Podzamczer, V Soriano; Thailand: K Ruxrungtham, W Techasathit; USA: L Amarilis Lugo, R Bolan, L Bush, R Corales, L Crane, J De Vente, M Fischl, J Gathe, R Greenberg, K Henry, D Jayaweera, P Kumar, J Lalezari, J Leider, R Lubelchek, C Martorell, K Mounzer, H Olivet, R Ortiz, F Rhame, A Roberts, P Ruane, A Scribner, S Segal-Maurer, W Short, L Sloan, T Wilkin, M Wohlfeiler, B Yangco ECHO Argentina: L Abusamra, P Cahn, HE Laplume, I Cassetti, M Ceriotto, M Daniel Martins, A Krolewiecki; Australia: M Bloch, J Gold, J Hoy, P Martinez; Austria: A Rieger, N Vetter, R Zangerle; Brazil: CA Da Cunha, B Grinsztejn,JV Madruga, JH Pilotto, D Sampaio; Canada: P Junod, D Kilby, A Rachlis, S Walmsley; Denmark: J Gerstoft, L Mathiesen, C Pedersen; France: L Cotte, P-M Girard, JM Molina, F Raffi, D Vittecoq, Y Yazdanpanah, P Yeni; Great Britain: M Fisher,M Nelson,C Orkin, S Taylor; Italy: A Lazzarin, P Narciso, A Orani, S Rusconi; Mexico: G Amaya,G Reyes-Teran; Netherlands: B Rijnders; Puerto Rico: J Santana; Portugal: F Antunes, T Branco, R Sarmento E Castro, T Eugenio, K Mansinho; Romania: D Duiculescu, L Negrutiu, L Prisacariu; Russia: V Kulagin, E Voronin, A Yakovlev; South Africa: E Baraldi,N David,O Ebrahim,E Krantz,GH Latiff, D Spencer, R Wood; Spain: JR Arribas, J Portilla Sogorb, E Ribera, I Santos Gil; Sweden: K Westling; Thailand: P Chetchotisakd, T Sirisanthana, S Sungkanuparph, A Vibhagool; Taiwan: C-C Hung, H-C Lee, H-H Lin, WW Wong; USA: H Albrecht,N Bellos,D Berger, C Brinson, B Casanas, R Elion, J Feinberg, T File, J Flamm, C Hicks, S Hodder, C-B Hsiao, P Kadlecik, H Khanlou, C Kinder, R Liporace, C Mayer, D Mildvan, A Mills, RA Myers, I Nadeem, O Osiyemi, M Para, G Pierone, B Rashbaum, J Rodriguez, M Saag, J Sampson, R Samuel, M Sension, P Shalit, P Tebas, W Towner, A Wilkin, D Wohl • The authors would also like to thank Janssen rilpivirine team members, in particular, D Anderson, and P Williams for their important contributions to the presentation, C Van Hove for sequencing analysis support. Editorial support was provided by I Woolveridge of Gardiner-Caldwell Communications, Macclesfield, UK; this support was funded by Janssen LR, VVE, JV, KT, JA, MS and GP are full-time employees of Janssen

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