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

Shah et al Reproductive Health Matters 2007

Menstrual cycle

Contraceptives in common use worldwide

DMPA (Depo Provera) Depot MedroxyProgesterone Acetate

Injectable

Every 3 months

OCPs (Oral Contraceptive Pills)

Combined low dose estrogen and progesterone

IUD (Intrauterine Contraceptive Device)

Copper T

Progesterone releasing

Does hormonal contraception affect:

–HIV disease acquisition?

–HIV disease progression?

– HIV shedding?

Does hormonal contraception affect:

–HIV disease acquisition?

–HIV disease progression?

– HIV shedding?

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

HIV acquisition

HC-HIV Study: Results Crude HR

(95% CI) pAdjusted HR

(95% CI)* p

No HC 1.0 1.0

OCP 1.0 (0.7-1.4) 0.9 1.0 (0.7-1.4) 0.9

DMPA 1.2 (0.9-1.7) 0.2 0.9 (0.6-1.8) 0.2

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

Morrison et al AIDS 2007

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

HIV acquisition

Predictors of HIV acquisition in Mombasa Cohort (n=1272)

Method AHR 95% CI pNone 1.0DMPA 1.8 1.4 - 2.4 <0.001OCPs 1.5 1.0 - 2.1 0.04Norplant 1.6 0.5 - 5.7 0.5IUD 1.1 0.4 - 3.0 0.9

Lavreys et al AIDS 2004

HIV acquisition

DMPA and HIV Acquisition

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

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

RR (95% CI)

0.1 1.0 10

Bulterys 1994

Ungchusak 1996

Kapiga 1998

Kilmarx 1998

Kiddugavu 2003

Lavreys 2004

Kleinschmidt 2005**

Myer 2006*

HIV acquisition

Slide Courtesy of C.Morrison

OCPs and HIV Acquisition

RR (95% CI)

0.1 1.0 10

Plummer 1991

Laga 1993

Saracco 1993

Plourde 1994

De Vincenzi 1994

Ungchusak 1996

Sinei 1996

Kilmarx 1998

Kapiga 1998

Kiddugavu 2003

Lavreys 2004

Morrison 2007

HIV acquisition

Slide Courtesy of C.Morrison

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

Baeten et al AIDS 2005

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)

Disease Progression

Baeten et al JAIDS 2005

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

Disease Progression

Baeten et al JAIDS 2005

Viral diversity and disease progression

Sagar et al J Virol 2003

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

Stringer et al Am J Obstet Gynecol 2007

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

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

Disease Progression

Hormonal (n=303)

IUD (n=296)

Age, mean (sd*) 25.9 (4.9) 26.3 (4.9)

Married, # (%) 272 (90) 264 (89)

Any prior contraceptive use, n (%) 186 (61) 181 (61)

Prior oral contraceptive use, n (%) 142 (47) 144 (49)

Prior injectable use, n (%) 47 (16) 49 (17)

Prior IUD use, n (%) 6 (2.0) 1 (0.3)

Enrollment CD4+ count, mean (sd) 493 (251) 514 (266)

BMI at enrollment, mean, kg/m2 (sd) 24.1 (4.0) 24.2 (3.9)

Baseline characteristics of cohort

Disease Progression

Hormonal IUD

Outcome #

Rate / 100 pt-yrs

# Rate / 100 pt-yrs HR

Pregnancy 27 4.62 14 2.17 2.2 (1.2, 4.2)

Discontinuation 38 6.81 146 28.6 0.23 (0.16, 0.33)

PID 0 0.00 1 0.16 ∞ (0.23, ∞)*

Analysis by Study Arm

*Fisher’s exact test

Disease Progression

Time to death by randomization arm Disease Progression

Time to CD4 count falling to below 200

cells/uL by randomization arm

Disease Progression

Time to either CD4 cell count falling to below

200 cells/uL or death by randomization arm

Disease Progression

Time-varying analysis Outcome

Type of Contraceptive method Initial Method Analysis* Time-varying analysis**

Death IUD

OCPs

DMPA

1.0

1.1 (0.4-3.0)

1.4 (0.6-3.0)

1.0

1.2 (0.4-3.6)

1.8 (0.8-4.1)

CD4 count dropping <200 cells/mm

IUD

OCPs

DMPA

1.0

1.3 (0.7-2.2)

1.4 (0.9-2.3)

1.0

1.2 (0.7-2.0)

1.31 (0.8-2.1)

CD4 count dropping below 200 cells/m3, or death

IUD

OCPs

DMPA

1.0

1.2 (0.7 - 2.0)

1.5 (1.0 - 2.2)

1.0

1.5(0.9 - 2.5)

1.7(1.2 - 2.6)

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

Disease Progression

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

Both models adjusted for initial CD4 count

Stringer unpublished data

Other studies HIV disease progression and HC

Study name Country Type Result

Cejtin et al, AIDS 2003

US Cross-sectional

analysis & longitudinal

No diff in change of VL or CD4

Richardson et al, AIDS 2007

Kenya Prospective cohort

No diff in VL or CD4 over timeShort follow-upSmall numbers

Allen S et al,J Women’s Health 2007

Rwanda Prospective cohort study

DMPA/OCPs protective on mortality

No CD4 counts or VL

Disease Progression

Does hormonal contraception affect:

–HIV disease acquisition?

–HIV disease progression?

– HIV shedding?

Contraception and HIV infectiousness

• 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

HIV shedding

Hormonal contraception and cervical DNA viral shedding

ANY HC DMPA OCPsWang AIDS (2004)

1.6 (1.03-2.6)

1.5 (0.8-2.9) 2.3 (0.9-6.7)

Mostad Lancet (1997)

2.9 (1.5-5.7) 3.8 (1.4-9.9)

Clemetson JAMA(1993)

11.6 (1.7-77.6)

HIV shedding

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

0

2

4

6

8

10

12

14

None DMP A L ow-dose O C High-dose O C

OR 2.9(1.5-5.7)

OR 3.8(1.4-9.9)

OR 12.3(1.5-101)

OR 1.0

318 HIV-infected Kenyan women Mostad,Lancet 1997

HIV shedding

What do animal models tell us?

Risk of SIV Acquisition of Female Monkeys with Progesterone Implants

Exposure Status

Number Exposed

Number Infected

Rate

RR 95% (CI)

Progesterone Implants

18 14 77.8 2.1 (0.9-4.9)

Placebo - Cycle Phase

11 4 36.4 7.8 (2.8-16.1)

Placebo - Follicular Phase

10 1 10.0

Source: Marx (1996); Duerr (1997)Slide courtesy of C. Morrison

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

Trunova Virology 2006

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

What could be happening here?

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

• 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

• 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

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

• 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

• 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