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

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