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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, MA2FHI 360 Durham, NC3CONRAD, Eastern Virginia School, Norfolk, VA4University of Zimbabwe, Harare, Zimbabwe5Case Western Reserve University, Cleveland, OH6CONRAD, Arlington, VA
Harvard Medical School
What are the biologic grounds for controversial
effects of hormonal contraceptives on HIV risk?
Biologic Variation
Synthetic progestins & estrogens
Multiple steroid receptors “ligand promiscuity”
Gene transactivation and repressionMultiple transcription factors
& Co-factors
Diverse outcomesInflammation
Immune activation
Viral entry/replication/cycle
Cervico-vaginal biome
STI/RTI pathogens
Cherpes et al. Sex Transm Infect 2008;84:57-61
Normal microflora
Bacterial vaginosis
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
Null Hypotheses
1. Subclinical, silent or clinically significant STIs/RTIs cannot be distinguished at the level of cervical inflammation-associated proteins – bivariate analysis
2. 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
37%
31%
32%
N=199Became HIV positive
within 3 months
37%
38%
26%
N=633Matched , remained HIV
negative
DMPA Combined oral contraceptives
No hormonal contraceptives
34%
30%
36%
N=211Uganda
38%
38%
24%
N=621Zimbabwe
P=0.0033
DMPA Combined oral contraceptives
No hormonal contraceptives
5%
20%
76%
N=41Pregnant
60%
11%
29%
N=133Breastfeeding
P<0.0001
DMPA Combined oral contraceptives
No hormonal contraceptives
P<0.0001
Unprotected sexual acts
40%
48%
12%
P=0.0001
DMPA
COC
NH
36%
49%
15%
45%
32%
23%
N=213
27%
18%
55%
N=234
>15 >8-14
1-7 0 or no sex act
N=177 N=208
N=293COC
N=303DMPA
Non-pregnant & Non-breastfeeding
63%14%
12%
7%2% 2%
62%12%
19%
6% 000000
N=225NH
Non-pregnant & Breastfeeding
Pregnant
STI/RTI positive STI/RTI-freeNon-pregnant & Non-breastfeeding Non-pregnant & Breastfeeding
Pregnant
80%
13%
3% 1% 2% 1%
Cervical immune markers associated with clinical STI/RTI and risk of HIV
Box-Cox transformation *p<0.05
IL-1b IL-6 IL-8 MIP-3a VEGF RANTES BD2 SLPI
Any STI/RTI
Signs+ Symptoms – *↑ *↑ *↑ *↑ *↑ *↑
Signs+ Symptoms + *↑
*↓
HIV+ in 3 months *↑ *↑
*↓
Bivariate analysis; No associations in this analysis: IL-1b, IL-1RA and IL-1RA:IL-1 ratio
STI/RTI alter cervical immunity biomarkers
RANTES ↑ and BD2 ↑ and SLPI ↓Associated with becoming HIV positive within 3 months
No hormonal contraception; Box-Cox transformed meansControl: STI/RTI-free by both laboratory and clinical criteria
DMPA and COC alter immune response to STI/RTIDMPA and COC different from NH *p<0.05; ** p<0.01
STI/RTI freeNugent 0-3Nugent 4-6
Nugent 7-10Gonorrhoea
ChlamydiaHSV2
Candida
↑* ↓*
↑** ↓**
↑**
↑**
↓* ↓* ↓* ↑** ↓*
↓** ↓** ↑** ↓**
↑*
STI/RTI freeNugent 0-3Nugent 4-6
Nugent 7-10Gonorrhoea
ChlamydiaHSV2
Candida
↑ ↑* ↑* ↑** ↑** ↑* ↑** ↓* ↓** ↑**
↑** ↑** ↑** ↑** ↓* ↑**
↑* ↑* ↑** ↑* ↓** ↑**
↑** ↓* ↑**
coc
DMPA
significantly different from NH marked with color, Box-Cox transformed, bivariate
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
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
Hidemi Yamamoto, Hassan Dawood, Yujin Lee, Olimpia Suciu, Bisiayo Fashemi, Titilayo Fashemi, Ryan Murray, Vanessa Tang-Fernandez, Bi Yu Li, Yoshika Yamamoto, Noah Beaty, Olivia Buck
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