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Differential Detection of M184V/I in HIV Plasma Genotypes and Proviral DNA

Explore the differential detection of M184V/I between historical HIV plasma genotypes and proviral DNA from PBMCs. Learn about resistance testing, treatment selection, and the Study 292-1824 switch study. Discover results comparing mutations from historical records and HIV DNA analysis.

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Differential Detection of M184V/I in HIV Plasma Genotypes and Proviral DNA

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  1. Differential Detection of M184V/I Between Plasma Historical HIV Genotypes and Proviral DNA from PBMCs N Margot, R Ram, IR McNicholl, R Haubrich, C Callebaut Gilead Sciences, Inc., Foster City, CA, USA 10th IAS Conference on HIV Science (IAS 2019) 21-24 July 2019 Mexico City, Mexico Poster MOPEB249

  2. Background Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services, 2018. Miller et al, Antiviral Therapy, 2012. Margot et al, the Journal of Infectious Diseases, 2017. Margot, IAS, 2019, Presentation # MOPEB249 • HIV resistance testing/monitoring is an integral part of HIV treatment¹ • Plasma resistance testing is used to generate the sequence and drug susceptibility phenotype of the circulating virus • Plasma resistance testing prior to antiretroviral (ARV) therapy initiation or in situation of virologic failure is conducted to help physicians select the appropriate regimen for the patient (Figure 1) • Plasma resistance testing requires detectable virus (HIV-1 RNA >50 copies/mL) • HIV-1 RNA >500 copies/mL required for most commercial assays • Cannot be conducted for patients with undetectable viral load (<50 copies/mL) seeking to switch treatment for tolerability or simplification reasons • Resistance to switch regimen could exist due to past virologic failure or transmitted drug resistance2, 3 • HIV DNA resistance testing that evaluates resistance mutations in PBMC-integrated HIV DNA may be used instead

  3. Figure 1: HIV Resistance Testing and Antiretroviral Therapy TreatmentA TreatmentB Treatment C No Treatment Treatment Switch Plasma Resistance Testing - RAM? Plasma Resistance Testing not Possible (VL<50 c/mL) HIV-1 RNA (copies/mL) 8 RAM: resistance-associated mutation; VL: HIV-1 RNA viral load Margot, IAS, 2019, Presentation # MOPEB249

  4. Methods Margot, IAS, 2019, Presentation # MOPEB249 • Study 292-1824 is an ongoing switch study in patients with historical M184V/I resistance mutation (Figure 2) • HIV-1 RNA <50 copies/mL for at least 3 months prior to screening • All screened patients (n=84) had historical plasma resistance record showing the presence of M184V/I • Records from commercial sources and local laboratories • HIV DNA resistance analysis assay was conducted for all patients to confirm the absence of exclusionary mutations (PI-R, INSTI-R, NRTI-R) (GenoSure Archive, Monogram Biosciences) • Detection of mutations from historical records and HIV DNA analysis were compared

  5. Figure 2: Study 292-1824Switch Study in Patients with Historical Detection of M184V/I • HIV-1-infected Adults • Switch from 2 NRTIs + 3rd agent  E/C/F/TAF • HIV-1 RNA < 50 c/mL • Historical Genotype showing M184V/IPart 1: M184V/I onlyPart 2: M184V/I ±0-2 TAMs • No exclusionary mutation in HIV DNA analysis E/C/F/TAF QD N = 63* 48 weeks 24 weeks Secondary Endpointb 12 weeks Primary Endpointa (a) Perez-Valero IDRW, 2017 (b) Perez-Valero WorldAIDS, 2018 (*) Enrolled patients 100% Suppression using Pure Virologic Failure E/C/F/TAF: single-tablet regimen containing elvitegravir (E), cobicistat (C), emtricitabine (FTC, F), tenofoviralafenamide (TAF) Margot, IAS, 2019, Presentation # MOPEB249

  6. Table 1: Detection of M184V or I (N=84)Historical HIV RNA report vs. HIV DNA report • HIV DNA: M184V/I mutation detected in only 48% patients Margot, IAS, 2019, Presentation # MOPEB249 Paired historical & archival data available for 84 screened patients

  7. Figure 3: Presence of M184V and M184IHistorical HIV RNA report vs. HIV DNA report Margot, IAS, 2019, Presentation # MOPEB249 M184V: detected with HIV DNA in 48% patients M184I: detected with HIV DNA in 33% patients

  8. Figure 4: Impact of Sample Timing in M184V/I Detection Time: Historical  Archive Time: ART Start  Archive ART H A ART H A 30 10 1 0.3 30 10 1 0.3 Time (years) Time (years) M184V/I Detected M184V/I Detected M184V/I Not Detected M184V/I Not Detected Median: 17.5 15.1 p=0.62* Median: 7.1 7.6 p=0.43* ART: antiretroviral therapy; H: historical HIV RNA genotypic report (plasma); A: Archival HIV DNA genotypic report (PBMCs); (*) Mann Whitney test Margot, IAS, 2019, Presentation # MOPEB249 Differential detection not due to time between HIV DNA analysis and historical HIV RNA analysis or time on ART

  9. Figure 5: Impact of Baseline ART Regimen in M184V/I Detection ART: antiretroviral therapy; INSTI: integrase strand transfer inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor Margot, IAS, 2019, Presentation # MOPEB249 Differential detection not associated with baseline regimen

  10. Figure 6: Impact of Baseline CD4/HIV-1 RNA in M184V/I Detection TND: target not detected; VL: Viral load; (*) Mann Whitney test Margot, IAS, 2019, Presentation # MOPEB249 Differential detection not associated with Baseline CD4 count or viral load

  11. Conclusions Margot, IAS, 2019, Presentation # MOPEB249 • In subjects with documented M184V/I on historical genotype (HIV RNA assay): • M184V not detected in 52% with HIV DNA assay • M184I not detected in 67% with HIV DNA assay (possibly due to A3G filtering) • Difference in detection of M184V/I between the 2 assays not associated with: • Time between historical HIV RNA testing and HIV DNA testing • Time on ART • Prior treatment regimen • Baseline CD4 count • HIV-1 RNA detection (TND, <20, <50) • Not detecting M184V/I with the HIV DNA assay may have potential clinical consequences when switching patients to 2-drug treatment containing FTC or 3TC, as the presence of M184V/I confers high-level resistance to FTC and 3TC

  12. Acknowledgements Margot, IAS, 2019, Presentation # MOPEB249 1824 Study Investigators and Staff V Abril López de Medrano, M Andreoni, JR Arribas Lopez, L Bernard, M Bickel, M CastañoCarracedo, D Coulston, E DeJesus, A Di Biagio, G Di Perri, C Duvivier, S Esser, J Gallant, M Galli, D Hagins, E Lazaro, A Lazzarin JM Llibre, J Mallolas, A Mills, C MirallesÁlvarez, JM Molina, O Osiyemi, I Perez-Valero, I Poizot-Martin, T Prazuck, D Prelutsky, P Pugliese, F Pulido, F Raffi, M Ramgopal, G Richmond, D Salmon-Ceron, J Schattenberg, P Sellier, P Shalit, HJ Stellbrink 1824 Study Participants and their Family E/C/F/TAF Project Team

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