1 / 24

Impact of Depot Medroxyprogesterone (DMPA) on Human Vaginal Leukocytes and HIV-1 Target Cells

Impact of Depot Medroxyprogesterone (DMPA) on Human Vaginal Leukocytes and HIV-1 Target Cells. Andrea Ries Thurman MD Neelima Chandra PhD (PI) Gustavo F Doncel MD PhD 23 JULY 2012. Background. Depot Medroxyprogesterone Acetate (DMPA):

akio
Download Presentation

Impact of Depot Medroxyprogesterone (DMPA) on Human Vaginal Leukocytes and HIV-1 Target Cells

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Impact of Depot Medroxyprogesterone (DMPA) on Human Vaginal Leukocytes and HIV-1 Target Cells Andrea Ries Thurman MDNeelima Chandra PhD (PI) Gustavo F Doncel MD PhD 23 JULY 2012

  2. Background • Depot Medroxyprogesterone Acetate (DMPA): • Highly effective long acting reversible contraceptive • Prevents Unintended/Mistimed Pregnancies • Only one absolute contraindication • High usage in developing world • World Contraceptive Use 2009, UN Population Division • Sole P-only injectable in the US

  3. Relevance: DMPA and HIV Acquisition • Observational studies AOR 1.73 – 3.90 for increased HIV acquisition with DMPA use • Ungchusak K et al. J AIDS Hum Retrovirol1996 • Martin HL et al. J Infect Dis1998 • Baeten JM et al. AIDS 2007 • Morrison CS et al. AIDS 2010 • Sero-discordant couples: Injectable use ↑↑ HIV-1 acquisition and transmission (AHR 2 – 3) • Heffron et al. Lancet Infect Dis2012 • 2012 WHO meeting re-consider medical eligibility criteria for DMPA in women at high risk of HIV-1 • Category 1*

  4. Epithelial Thinning • Cell layers, height in µm • Dramatic Atrophy with P/DMPA in NHP models • Marx PA et al. Nat Med 1996 • Smith SM et al. J InfectDis2000 • Jiang Y et al. J Med Primatol2009 • Pal R et al. Virology 2009 • Salle B et al. J Infect Dis2010 • Veazey RS et al. Nat Med 2003 • Humans • BahamondesL et al. Contraception 2000 • Mauck CK et al. Contraception 1999 • Miller L et al. ObstetGynecol 2000 • Ildgruben AK et al. ObstetGynecol 2003

  5. Epithelial Integrity • Other markers of epithelial integrity • E Cadherin and ZonaOccludin 1 (ZO-1) • Epithelial Cell Proliferation (Ki67) • E Cadherin density altered by vaginal estrogen therapy • Gorodeski GI. Endocrinology 2007

  6. Alteration of MucosalImmune Cells • Small cohorts support exogenous progesterone alters mucosal environment • WieserF et al. FertilSteril2001 • Ildgruben AK et al. ObstetGynecol2003 • Most data on endogenous and exogenous hormones and alteration of mucosal inflammatory/immune cell populations in humans from endometrium • Pudney et al. BiolReprod 2005 • Wira et al Am J ReprodImmunol 2011

  7. Objective • Determine if exogenous and endogenous progesterone alters epithelial integrity and the cellular inflammatory status of the vaginal mucosa • Secondary analysis • Mauck CK et al. Contraception 1999 Jul;60(1):15-24.

  8. 15 women (BTL, no hormonal contraception) Methods Luteal Phase Days 22 - 26 (Confirmed Serum P) 12 weeks ± 1 week post DMPA Follicular Phase Days 8 - 12 (Serum E2 and P)

  9. Endpoints • Epithelial integrity • Epithelial height in µm (reticles) and # cell layers • Epithelial proliferation (Ki67 cells) • Intracellular adhesion proteins E Cadherin and ZO-1 (Integrated Optical Density - IOD) • Immune cell populations by IHC • CD45, CD3, CD4, CD8, CD1a, CD68 bearing leukocytes • HLA-DR, CCR5 (markers of activation and proliferation )

  10. Results • Demographic data (N = 15) • Mean age 35.9 (± 3.1) years-old • Mean weight 158.5 (± 25.0) pounds • Mean menstrual cycle length 29.0 (± 1.4) days • All with previous pregnancy • Mean gravidity 2.7 (± 1.1) • Follicular versus luteal phase • All endpoints NS

  11. Epithelial Thickness& Proliferation

  12. Intracellular Adhesion Proteins (NS)

  13. E Cadherin ZO-1 Follicular DMPA Luteal

  14. Immune Cells(Significant Increase with DMPA)

  15. Activated Immune Cells (Significant Increase with DMPA)

  16. Follicular Luteal DMPA CD3 CD8 H I CCR5 HLA-DR

  17. CONCLUSIONS • Epithelial Thinning (thickness, #cell layers) NS • Epithelial Integrity (E Cadherin, ZO-1, Ki67) NS • DMPA use resulted in significant increase in: • CD45, CD3, CD8, CD68 leukocytes • CCR5 (LP), HLA-DR, markers

  18. Acknowledgments CONRAD Microbicide Development Laboratory Gustavo F Doncel MD PhD (Principal Investigator) Neelima Chandra PhD Sharon Anderson PhD Nazita Yousefieh PhD Nancy Gonyea Dept of Biostatistics Eastern Virginia Medical School Tina D Cunningham PhD CONRAD Clinical Team Christine Mauck MD MPH

  19. Epithelial Thickness& Proliferation

  20. Intracellular Adhesion Proteins (NS)

  21. E Cadherin ZO-1 Follicular DMPA Luteal

  22. Immune Cells(Significant Increase with DMPA)

  23. Activated Immune Cells (Significant Increase with DMPA)

  24. Follicular Luteal DMPA CD3 CD8 H I CCR5 HLA-DR

More Related