CHANGES IN GENITAL TRACT HIV TARGET CELLS WITH THREE PROGESTIN- BASED CONTRACEPTIVES Lisa B. Haddad 1, Alison Swaims Kohlmeier 2, Richard E. Haaland 2, Nakita L. Brown 3, L. Davis Lupo 2, Christina B. Mehta 4, Anandi N. Sheth 3, Kehmia Titanji 5, Clyde E. Hart 2, Igho Ofotokun 3 1 Emory University School of Medicine, Department of Gynecology and Obstetrics, Atlanta, Georgia; 2 Centers for Disease Control and Prevention, Laboratory Branch, Division of HIV/AIDS Prevention, Atlanta, GA; 3 Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, Atlanta, Georgia, and Grady Healthcare System, Atlanta, Georgia; 4 Emory University Rollins School of Public Health, Department of Biostatistics and Bioinformatics, Atlanta, GA, United States 5 Emory University School of Medicine, Department of Medicine, Division of Endocrinology, Atlanta, Georgia, United States
none Disclosures
Contraception and HIV risk Epidemiologic studies suggest Depot Medroxyprogesterone acetate (DMPA) may increase the risk of HIV acquisition There are several potential mechanisms for increased acquisition CD4 + T cells are heterogeneous with regards to their HIV susceptibility Certain T cell phenotypes may be more likely to be infected during vaginal sex Ex. CD4+ T-cells expressing HIV binding protein (CCR5) and activated T cells (e.g. HLA-DR+, CD38+) Mucosal trafficking and migration to lymphoid tissue is CCR7 dependent Murphy, Irvin & Herold, AJRI 2014 There are limited data evaluating other progestin-based contraceptives Ralph LJ et al. Lancet Infect Dis. 2015 Feb; 15(2):181-9.; Morrison CS et al. PLoS Med. 2015 Jan 22; 12(1).; Murphy K, Irvin SC, Herold BC. Am J Reprod Immunol. 2014;72(2):228-235. Byrne, E.H. et al. Lancet Infect. Dis. 16, 441 448 (2016).
Different Contraceptives
AIM: To evaluate changes to HIV target cell phenotypes in the genital mucosa and peripheral blood among HIV-negative women initiating DMPA, Etonogestrel Implant and Levonorgestrel Intrauterine Device (IUD).
Study Design Visits: Visit 1 - Luteal phase (>18 days post LMP) Visit 2 - Follicular (<10 days after LMP) Visit 3 and 4 12 & 14 weeks after contraception initiation Participants: age 18-45, HIV negative, regular cycles (22-35 days) x 3 months, not post partum/breastfeeding, no hormonal contraception/iud in 6 months
Study Design Multicolor flow cytometry on LSRII platform: stained for HIV target cells (Live/Dead viability dye and florochrome labeled T-cell markers (CD3, CD4, CD8), HIV susceptibility (CCR5), activation (CD38, HLA-DR) and trafficking markers (CCR7) Statistics Repeated-measures analyses using linear mixed models CVL model adjusted for PSA, blood, including CD3 counts >=100 Swaims-Kohlmeier A, et al. J Immunol. 2016 May 27.
Description of Cohort
CCR5 expression on CD4-T-cells in FGT DMPA IMPLANT IUD Non-significant increase after DMPA use Post-pre E=11.75, p=0.054, V3 (trough) E=14.04, p=0.044; V4 (peak) 9.5 (8.1), p= 0.2 Significant increase after implant use Post-pre E=14.7, p=0.009 No increase after IUD use Post-pre E=-0.2, p=0.97
CCR5 expression on CD4-T-cells in PBMCs DMPA IMPLANT IUD Significant increase after DMPA use Post-pre E=1.6, p=0.005 V3 (trough): E=1.8 (0.7), p=0.009; V4 (peak): E=1.4 (0.7), p=0.047 No increase after Implant use Post-pre E=0.7, p=0.23 No increase after IUD use Post-pre E=-0.3, p=0.66
Pre mean CVL Post mean DMPA Model estimate (Post-Pre) P-value Pre mean Post mean PBMC Model estimate (Post-Pre) p-value CD4% 48.2 (16.2) 50.5 (13.62 2.9 0.54 66.6 (10.9) 65.0(11.8) -1.31 0.43 CD8% 28.7 (14.0) 25.0 (16.1) -2.4 0.52 26.2 (11.6) 25.6 (13.6) 1.04 0.52 Among CD4+ T-cells CCR5% 25.4 (17.1) 37.5 (27.1) 11.8 0.054 4.0 (2.1) 5.7 (3.5) 1.6 0.0045 CD38% 35.9 (17.7) 38.6 (17.8) 0.4 0.94 18.7(6.5) 17.8 (6.6) -1.6 0.33 HLADR% 23.3 (15.3) 20.9 (16.2) -6.2 0.22 4.8 (3.4) 4.1 (2.2) -0.1 0.14 Among CD4+CCR5+ T-cells CD38% 60.3 (20.4) 55.0 (18.6) -10.4 0.17 24.0 (7.2) 23.2(8.1) -0.2 0.93 HLADR% 33.6 (21.3) 29.8 (17.3) -4.3 0.54 25.4 (8.8) 23.5 (8.1) -1.6 0.48 CCR7% 48.2 (18.7) 47.7 (18.4) 0.9 0.91 33.3 (15.4) 29.6 (11.8) -5.0 0.16 No significant changes in other immune makers
Pre mean Etonogestrel Implant CVL Post mean Model estimate (Post-Pre) P-value Pre mean Post mean PBMC Model estimate (Post-Pre) p-value CD4% 49.9 (13.7) 45.2 (12.3) -6.9 0.09 68.3 (9.0) 69.8 (10.0) -0.1 0.96 CD8% 20.6 (7.4) 28.0(12.5) 7.1 0.036 24.0 (8.3) 23.8 (10.0) 1.5 0.36 Among CD4+ T-cells CCR5% 22.4(18.5) 36.1(18.3) 14.7 0.009 4.0 (2.3) 4.6 (2.6) 0.7 0.23 CD38% 35.1(11.8) 43.0 (7.7) 8.8 0.052 18.0 (9.0) 18.2 (6.7) -1.6 0.31 HLADR% 25.2 (16.4) 17.5 (11.0) -8.7 0.059 3.1 (1.4) 2.4 (0.8) -0.2 0.07 Among CD4+CCR5+ T-cells CD38% 64.6 (15.1) 63.5 (10.6) -1.5 0.82 26.8 (10.6) 29.4 (8.9) 2.4 0.37 HLADR% 40.2 (15.1) 25.5 (16.0) -16.4 0.009 22.9 (6.27) 20.6 (5.6) -1.7 0.42 CCR7% 35.8 (22.7) 49.6 (16.0) 11.0 0.11 27.5 (11.9) 37.5 (12.0) 9.9 0.005 Significant decrease in %HLA-DR+ on HIV target cells within the FGT Significant increases in %CD8+ T-cells within the FGT Significant increase in %CCR7+ on HIV targets cells from PMBCs No significant changes any other activation markers in FGT or PBMC
Pre mean Levonorgestrel IUD CVL Post mean Model estimate (Post-Pre) P-value Pre mean Post mean PBMC Model estimate (Post-Pre) p-value CD4% 55.8(13.2) 46.2 (23.3) -10.5 0.034 66.9 (10.7) 63.9 (11.3) -3.9 0.06 CD8% 22.8 (7.9) 33.4(15.0) 11.9 0.003 25.5 (10.5) 28.4 (10.5) 3.7 0.049 Among CD4+ T-cells CCR5% 20.2 (17.6) 21.9 (17.7) -0.2 0.97 3.0 (1.4) 3.0 (1.3) -0.3 0.66 CD38% 32.4 (9.2) 42.5 (14.9) 8.3 0.12 16.7 (8.7) 18.9 (8.3) 0.9 0.63 HLADR% 14.9 (9.5) 12.5 (6.4) -4.1 0.44 3.3 (2.0) 4.0 (5.1) -0.1 0.17 Among CD4+CCR5+ T-cells CD38% 64.0 (18.8) 67.2 (14.3) -2.9 0.69 28.1 (6.1) 31.4 (7.7) 3.5 0.23 HLADR% 26.8 (14.4) 19.9 (7.0) -8 0.25 28.3 (8.4) 23.4 (10.9) 4.9 0.05 CCR7% 33.1 (22.5) 38.8 (16.4) 6.7 0.37 33.4 (13.9) 31.8 (11.6) -1.8 0.65 Significant increases in %CD8+ T-cells in FGT and PBMCs No significant changes in other immune makers either in the FGT or PBMC
Implications Etonogestrel implant and DMPA are associated with increased HIV susceptibility markers in FGT Immune responses following different contraceptives are not uniform Larger evaluations of the comparative effects of contraceptives on various mechanisms associated with HIV transmission risk are needed
Study Participants Emory: Nakita L. Brown Christina B. Mehta Anandi N. Sheth Kehmia Titanji Igho Ofotokun Gina Herring Susan Robinson Rachael Farah-Abraham Rama Amara Grady WIHS Staff Thank you This research supported by 1K23HD078153-01A1 (Haddad), Emory Center for AIDS Research (P30AI050409, CFAR03 (Haddad) and Emory Medical Care Foundation (Haddad). CDC: Alison Swaims Kohlmeier Richard E. Haaland L. Davis Lupo Clyde E. Hart