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1 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 2 FHI 360 Durham, NC

Harvard Medical School. Association between STI/RTI infections and the risk of altered innate immunity protein levels among hormonal contraception users.

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1 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 2 FHI 360 Durham, NC

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  1. Harvard Medical School Association between STI/RTI infections and the risk of altered innate immunity protein levels among hormonal contraception users Raina Fichorova1, Charles Morrison2, Gustavo Doncel3, Pai-Lien Chen2, Cynthia Kwok2, Tsungai Chipato4, Robert Salata5, and Christine Mauck6 1Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 2FHI 360 Durham, NC 3CONRAD, Eastern Virginia School, Norfolk, VA 4University of Zimbabwe, Harare, Zimbabwe 5Case Western Reserve University, Cleveland, OH 6CONRAD, Arlington, VA

  2. What are the biologic grounds for controversial effects of hormonal contraceptives on HIV risk?

  3. Biologic Variation Synthetic progestins & estrogens Multiple steroid receptors “ligand promiscuity” Cervico-vaginal biome STI/RTI pathogens Gene transactivation and repression Multiple transcription factors & Co-factors Diverse outcomes Inflammation Immune activation Viral entry/replication/cycle

  4. Normal microflora Bacterial vaginosis Cherpes et al. Sex Transm Infect 2008;84:57-61

  5. Study Objectives • Cross sectional analysis of cervical immunity biomarkers associated with STI/RTI in a large cohort of HIV negative women in Uganda and Zimbabwe, who used DMPA, COC or no hormonal contraceptives and to compare those who did and did not become HIV infected • Focus of well-measurable pro-inflammatory, anti-inflammatory and anti-viral proteins with established importance for the genital tract mucosal barrier

  6. Null Hypotheses • Subclinical, silent or clinically significant STIs/RTIs cannot be distinguished at the level of cervical inflammation-associated proteins • bivariate analysis • Hormonal contraceptives do not alter inflammatory responses to STI/RTI. • multivariate analysis of differences between groups • top quartile odd ratios for biological gradient of immune responses Resolving these hypotheses may identify whether or not there are hormone-dependent inflammatory risk biomarkers in the context of each specific STI/RTI

  7. N=633Matched , remained HIV negative N=199Became HIV positive within 3 months No hormonal contraceptives Combined oral contraceptives DMPA

  8. N=621Zimbabwe N=211Uganda P=0.0033 No hormonal contraceptives Combined oral contraceptives DMPA

  9. N=133Breastfeeding N=41Pregnant P<0.0001 P<0.0001 No hormonal contraceptives Combined oral contraceptives DMPA

  10. Unprotected sexual acts >15 >8-14 NH COC DMPA N=177 N=208 1-7 0 or no sex act P=0.0001

  11. N=225NH N=303DMPA N=293COC STI/RTI positive STI/RTI-free Non-pregnant & Non-breastfeeding Non-pregnant & Non-breastfeeding Non-pregnant & Breastfeeding Non-pregnant & Breastfeeding Pregnant Pregnant

  12. Cervical immune markers associated with clinical STI/RTI and risk of HIVBox-Cox transformation *p<0.05 Bivariate analysis; No associations in this analysis: IL-1b, IL-1RA and IL-1RA:IL-1 ratio

  13. STI/RTI alter cervical immunity biomarkers No hormonal contraception; Box-Cox transformed means Control: STI/RTI-free by both laboratory and clinical criteria RANTES ↑ and BD2 ↑and SLPI ↓ Associated with becoming HIV positive within 3 months

  14. DMPA and COC alter immune response to STI/RTIDMPA and COC different from NH *p<0.05; ** p<0.01 DMPA coc significantly different from NH marked with color, Box-Cox transformed, bivariate

  15. Analsyis of biomarker gradient additionally discriminated DMPA and COC users from each other and from NH Odds ratios of top quartile protein levels yes/noEach STI/RTI vs. No any STI/RTI IL-1RA b-Defensin-2

  16. Conclusions • These observations raise the possibility that the disturbed vaginal microbiome and sexually transmitted infections differentially sensitize the cervical mucosa to some of the adverse immune activation effects associated with injected or combined oral contraceptives (overall enhanced proinflammatory cytokine in COC users and reduced protective mediators in DMPA users) • Elevated RANTES, which was positively associated with becoming HIV positive in 3 months and observed in DMPA users regardless of STI/RTI while limited to HSV-positive COC users, offers a plausible explanation for the increased HIV risk previously observed in this cohort of women • More research should elucidate molecular mechanisms underlying HC/STI-RTI interactions as a possible basis for altering HIV acquisition and progression and improved contraceptive interventions

  17. Thanks! Fichorova Lab greets you  Sponsors HidemiYamamoto, Hassan Dawood, Yujin Lee, OlimpiaSuciu, BisiayoFashemi, TitilayoFashemi, Ryan Murray, Vanessa Tang-Fernandez, Bi Yu Li, Yoshika Yamamoto, Noah Beaty, Olivia Buck

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