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Impact of Contraception on HIV Acquisition, Disease Progression, and Viral Shedding. Elizabeth Stringer MD, MSc Center for Infectious Disease Research in Zambia, Lusaka, Zambia University of Alabama at Birmingham. The face of the HIV epidemic. Maternal Mortality sub-Saharan Africa.

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impact of contraception on hiv acquisition disease progression and viral shedding

Impact of Contraception on HIV Acquisition, Disease Progression, and Viral Shedding

Elizabeth Stringer MD, MSc

Center for Infectious Disease Research in Zambia, Lusaka, Zambia

University of Alabama at Birmingham

maternal mortality sub saharan africa
Maternal Mortality sub-Saharan Africa

Shah et al Reproductive Health Matters 2007

does hormonal contraception affect hiv disease acquisition hiv disease progression hiv shedding
Does hormonal contraception affect:

HIV disease acquisition?

HIV disease progression?

HIV shedding?

does hormonal contraception affect hiv disease acquisition hiv disease progression hiv shedding7
Does hormonal contraception affect:

HIV disease acquisition?

HIV disease progression?

HIV shedding?

hc hiv study

HIV acquisition

HC-HIV Study
  • Prospective study
  • 6,109 HIV-negative women
  • Thailand, Uganda, Zimbabwe
  • Women were on method at entry
  • 3 monthly follow-up for 15-24 months
  • Outcome: HIV acquisition
  • 213 seroconversions (2.8 / 100 woman years)

Morrison et al AIDS 2007

hc hiv study results

HIV acquisition

HC-HIV Study: Results

*Adjusting for site, living with partner, age, participant behavioral risk, primary partner risk, coital frequency, and condom use.

Morrison et alAIDS 2007

mombasa sex worker cohort

HIV acquisition

Mombasa Sex Worker Cohort
  • Open cohort study
  • HIV-1 negative sex workers
  • Outcome: incident HIV
  • Monthly follow-up
  • 1272 women

(> 4,700 woman-yrs follow-up)

  • 248 seroconversions

(8.5 per 100 woman-years)

Lavreys et al AIDS 2004

predictors of hiv acquisition in mombasa cohort n 1272
Predictors of HIV acquisition in Mombasa Cohort (n=1272)

HIV acquisition

Lavreys et al AIDS 2004

dmpa and hiv acquisition

HIV acquisition

DMPA and HIV Acquisition

**About two-thirds DMPA, one-quarter Net-EN users

*About two-thirds Net-EN, one-third DMPA users

Slide Courtesy of C.Morrison

ocps and hiv acquisition

HIV acquisition

OCPs and HIV Acquisition

Slide Courtesy of C.Morrison

does hormonal contraception affect hiv disease acquisition hiv disease progression hiv shedding14
Does hormonal contraception affect:

HIV disease acquisition?

HIV disease progression?

HIV shedding?

mombasa cohort and disease progression
248 seroconversions

161 women had accurate date of seroconversion

91 / 161 HIV seroconversions occurred within one year of a clinic visit when stored samples were HIV-1 RNA and Ab negative

70 / 161 had HIV-1 RNA detected at visit immediately prior to seroconversion

Disease Progression

Mombasa Cohort and Disease Progression

Baeten et al AIDS 2005

viral load set point

Disease Progression

Viral load set point
  • Viral load set point estimated to be established 16 weeks post acquisition
  • Median set point: 4.46 log10 copies/ml (95% CI 4.32-4.60)
  • DMPA users had higher set point (+0.33 log 10 copies/ml, p=0.03)

Baeten et al JAIDS 2005

multiple viral variants

Disease Progression

Multiple Viral Variants
  • 89/156 (57%) women had multiple viral variants
    • More common in women with hormonal contraceptive use (OR 2.7; p=0.003)
  • Women with multiple viral genotypes
    • Had higher viral loads 4-24 months after infection (4.84 vs. 4.64 log 10 copies/ml; p=0.04)
    • Had lower CD4 counts (median 416 vs 617 cells/uL, p=0.01) and a faster decline

Baeten et al JAIDS 2005

zambia iud study

Disease Progression

Zambia IUD Study
  • 599 recently-postpartum HIV+ women
  • Randomized trial
    • Copper IUD
    • User-choice hormonal contraception (oral contraceptive pills* or DMPA)
    • Between June 2002 and Oct 2003
  • Outcomes: pregnancy, safety, and switching
  • Primary outcome: pregnancy

* “Mini pill” during early BF; combined preparation thereafter

Stringer et al Am J Obstet Gynecol 2007

enrollment and follow up

Disease Progression

Enrollment and follow-up
  • Follow-up every 6 months
  • CD4+ every 12 mo, but once ART available, every 6 mo
  • Pregnancy testing and pelvic exam at each visit
  • PID diagnosed by Hagar’s Criteria
  • All women followed to pregnancy event, withdrawal, or until last enrolled participant had completed 24 months
slide21

Disease Progression

Baseline characteristics of cohort

slide22

Disease Progression

Analysis by Study Arm

*Fisher’s exact test

time varying analysis
Time-varying analysis

Disease Progression

* Cox model with exposure based at start of f/u

** extended Cox model treating contraception as a time-varying covariate.

Stringer unpublished data

Both models adjusted for initial CD4 count

does hormonal contraception affect hiv disease acquisition hiv disease progression hiv shedding28
Does hormonal contraception affect:

HIV disease acquisition?

HIV disease progression?

HIV shedding?

contraception and hiv infectiousness
Contraception and HIV infectiousness

HIV shedding

  • Genital HIV-1 shedding used as marker for infectiousness

(Pedraza, JAIDS 1999; Baeten, Curr HIV Res 2003)

  • No association between use of contraception and female-to-male HIV-1 transmission (European Study Group on Heterosexual Transmission of HIV, BMJ 1992)

Slide courtesy of Ludo Lavreys

detection of cervical hiv 1 dna depending on type of hormonal contraception used

HIV shedding

Detection of Cervical HIV-1 DNA Depending on Type of Hormonal Contraception Used

OR 12.3

(1.5-101)

OR 3.8

(1.4-9.9)

OR 2.9

(1.5-5.7)

OR 1.0

318 HIV-infected Kenyan women

Mostad,Lancet 1997

slide33

Risk of SIV Acquisition of Female Monkeys with Progesterone Implants

Slide courtesy of C. Morrison

Source: Marx (1996); Duerr (1997)

immune responses in macaques treated with siv and dmpa
No diff in α-SIV Ab response

No IFN-γ secreting cells detectable in Depo-treated arm at 1-2 weeks

Response of IFN-γ production delayed in Depo treatment arm

Immune responses in macaques treated with SIV and DMPA

Trunova Virology 2006

review
Review
  • Data on HC and HIV acquisition is varied
  • HC affected VL set point in new acquisitions
  • In our RCT women on HC had faster disease progression
    • Suggestion that DMPA worse than OCPs
    • Warrants more investigation
  • HC shown to increase cervical DNA viral shedding
changes in vaginal environment
Changes in vaginal environment
  • Related to vaginal thinning
    • Vaginal thinning in macaques treated with Progesterone
      • Marx, Nature 1996
    • Slight thinning of vaginal epithelial layer
      • Miller, AJOG 2000
  • Changes in vaginal microenvironment
    • Progesterone associated with decreased H202+ Lactobacillus
      • Miller, AJOG 2000
other possible mechanisms
Other possible mechanisms
  • Increasing HIV co-receptor expression
    • OCPs upregulates CCR5 receptors in women
      • Prakash, J of Reproductive Immunology 2002
    • Progesterone increases expression of CCR5 and CXCR4 expression
      • Patterson et al, Int AIDS Conf, 1998
  • Infection with multiple viral types
  • T cell activation
summary
Summary
  • Ensuring safe and effective contraception to HIV infected women is a priority
  • Understanding mechanisms of potential interactions between HC and immune system is critical
  • Evidence to date not compelling to change policy
slide40
END
  • Special thanks to:
    • Lusaka District Health Board, Lusaka, Zambia
    • Charles Morrison, FHI
    • Ludo Lavreys, Tibotech
    • CIDRZ team
    • Mike Saag
    • Sten Vermund
    • EGPAF
contraception on immune system function
Contraception on immune system function
  • Estrogen and progesterone decreases immune response (Th1>Th2)
  • Estrogen increases LTR induced viral replication
  • Estrogen and progesterone induce upregulation of CCR5 receptor on CD4 T cells in cervical epithelium of non-HIV women- Prakash J of Reproductive Immunology 2002

Enomoto et al JAIDS 2007

effect of progesterone on chemokine expression in vivo
Effect of progesterone on chemokine expression in vivo
  • PBMCs incubated with 50 ng/ml progesterone for 6 days
  • At 0, 3, and 6 days, RNA was extracted for CCR5, CXCR4, and CCR2b mRNA
  • Flow cytometry performed to localize increases in CCR5 and CXCR4

Patterson, et al, AJP, 1998