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
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
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

3. Figure 1: HIV Resistance Testing and Antiretroviral Therapy
No Treatment
Treatment A
Treatment B
Treatment C
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
Study 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
Margot, IAS, 2019, Presentation # MOPEB249

5. Figure 2: Study 292-1824 Switch 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/I Part 1: M184V/I only Part 2: M184V/I ±0-2 TAMs
No exclusionary mutation in HIV DNA analysis
E/C/F/TAF QD
N = 63*
12 weeks
Primary
Endpointa
24 weeks
Secondary
Endpointb
48 weeks
(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), tenofovir alafenamide (TAF)
Margot, IAS, 2019, Presentation # MOPEB249

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

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

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

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

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

11. Conclusions
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
Margot, IAS, 2019, Presentation # MOPEB249

12. Acknowledgements 1824 Study Investigators and Staff
V Abril López de Medrano, M Andreoni, JR Arribas Lopez, L Bernard, M Bickel, M Castaño Carracedo, 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 Miralles Álvarez, 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
Margot, IAS, 2019, Presentation # MOPEB249