confounded by contraception · hormonal contraception and hiv . ... ppt template, light colors,...
TRANSCRIPT
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Confounded by Contraception
Ward Cates MTN Regional Meeting October 13, 2011
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Acknowledgments
Colleagues from: – FHI 360
– USAID
– University of Witwatersrand
– University of Washington
– And many more…
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• 1.75 billion women of reproductive age
• 16 million women HIV-infected; 80% in Sub-Saharan Africa
• Hormonal contraception used >150 million women (COCs: >100 million; DMPA: >50 million)
• Injectable progestin (DMPA and Net-En) use increasing rapidly, especially Southern Africa
Hormonal Contraception and HIV
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Hormones and HIV Possible Mechanisms
• Vaginal and cervical epithelium (ectopy, etc.)
• Cervical mucus
• Menstrual patterns
• Vaginal and cervical immunology
• Viral (HIV) replication
• Acquisition of other STI
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Serum Levels in Progestin Contraceptives
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HC/HIV Acquisition Research Timeline
• 1987 – Plummer IAS presentation • 1988-on – Multiple secondary analyses • 1996 – Marx monkey model/NIH review
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Different Views on Hormone/HIV Association - 1996
00.10.20.30.40.50.6
Less Convinced Same More Convinced
Contraception HIV Both
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HC/HIV Acquisition Research Timeline
• 1998 – HIVNET 021 → FHI’s HC/HIV study • 2007 – 1st WHO HC/HIV Consultation • 2009 – FHI’s External Consultation • 2012 – 2nd WHO HC/HIV Consultation
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Partners/HSV Study: HC/HIV Analysis
• 7 African countries, 14 sites • 3321 Discordant Couples
– Followed for 1-2 years – 2/3 couples – woman HIV-positive
• Overall Linked HIV Incidence – Male → Female – 4.1/100 p-y – Female → Male – 1.7/100 p-y
Source: Heffron (2011))
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Partners/HSV Study: HC/HIV Acquisition – HIV-negative Women
• 1314 HIV-neg women – 7% COCs, 16% DMPA
• HIV+ male: transmission to HIV- female – HIV Incidence: 4.1/100 p-y – Adjusted HR for COCs: 1.8 (0.6-5.8) – Adjusted HR for DMPA: 2.1 (1.0-4.0)
Source: Heffron (2011)
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Prospective Studies of COCs & HIV Acquisition
Plummer 1991 Sinei 1996* Kilmarx 1998 Plourde 1994 Heffron 2011 Feldblum 2010 Baeten 2007 Morrison 2010 Kiddugavu 2003 Kapiga 1998
Saracco 1993 Reid 2010 Laga 1993 Myer 2007 De Vincenzi 1994 Ungchusak 1996
Source: Adapted from Polis (2011)
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0.1 1 10Protective Harmful
Prospective Studies of Injectables & HIV Acquisition
Mostly injectable, some OC
Mostly injectable, some OC
Source: Adapted from Polis (2011)
Kumwenda 2008
Ungchusak 1996
Feldblum 2010
Heffron 2011
Bulterys 1994
Baeten 2007
Watson-Jones 2009
Kilmarx 1998
Morrison 2010
Myer 2007
Reid 2010
Kiddugavu 2003
Kleinschmidt 2007
Kapiga 1998
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• OCs - 2/16 prospective studies found a significantly increased HIV risk
• DMPA – 5/14 prospective studies found significantly increased HIV risk
• Only 2 were designed to test hypothesis, others were secondary analyses
HC/HIV Acquisition Summary – October, 2011
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Limitations of HC/HIV Observational Studies
• Potential for unmeasured selection bias and confounding
• Hormonal contraceptive use not adequately documented
• Limited power - low HC use, few HIV+
• Non-hormonal comparison group has greater proportion of condom users
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Potential Spurious Implications
• Self-selection into HC use affects risk of HIV exposure
• HC users compared to “non-users”; definition of “non-users” varies, often includes condom-contraceptors
DMPA users
“Non- users”
Study 1: No
condoms or DMPA
Study 2: largely
condom users
Exposure to HIV
Exposure to HIV
Exposure to HIV?
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Non-Hormonal Group – Greater condom use – Higher partner risk score
DMPA Group – Less condom use – Plausible biologic effect
PROTECTIVE HARMFUL
HC/HIV Results – What Do They Mean?
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Why an RCT Now?
• All previous studies observational – selection/confounding biases likely
• Macaque studies continue to find increased SIV transmission with DMPA
• HIV prevention trials have high HIV rates among young women; most using DMPA
• Recent HC/HIV findings have raised visibility
• We need to resolve this important global health issue once and for all
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Design Issues for an HC-HIV RCT
• How many arms should the study have, and what should those arms be?
• What should the target population be?
• Will women accept random assignment to dissimilar contraceptive methods?
• What age groups should we focus on?
• How do we maximize retention and adherence?
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The ECHO Trial – An Ongoing RCT for HC/HIV
• Location: East London, South Africa
• 2 Arms: DMPA cf IUD
• Participants: 9000 total, HIV-neg and HIV-pos women
• Outcomes: Contraceptive discontinuation, unintended pregnancy, HIV acquisition, HIV disease progression
• Status: Using local resources only, an estimated 10% have been enrolled
Source: Hofmeyr (2011)
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But Wait, There’s Even More
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Hormonal Contraception In Context
Pregnancy
Desires Pregnancy
Pre-Conception Counseling
Contraception
Does NOT Desire
Pregnancy
Pregnancy
HC Other
HIV-uninfected Woman
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Does Pregnancy Affect HIV Risks?
• Partners HSV/HIV Trial - same database • 7 African countries, 14 sites • 3321 Discordant Couples
– Followed for 1-2 years – 2/3 couples – woman HIV-positive
• Overall Linked HIV Incidence – Male → Female – 3.6/100 p-y – Female → Male – 1.7/100 p-y
Source: Mugo (2011)
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Pregnancy/HIV Acquisition – HIV-negative Women
• 320 pregnancies in HIV- women – 29% • HIV+ male: transmission to HIV-pregnant
female – HIV Incidence: 7.4/100 p-y – Crude HR: 2.3 (1.2 – 3.7), p = 0.003 – Adjusted HR: 1.5 (0.9 – 3.1), p = 0.08
Source: Mugo (2011)
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So…What’s An Uninfected Woman To Do?
• If she uses DMPA, – Less risk of pregnancy – More risk of HIV acquisition
• If she “falls” pregnant, – More risk of HIV acquisition – More risk of pregnancy M&M
• Tradeoffs
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HC/HIV: Today’s Conclusions
• Concerning DMPA findings from recent analyses – Point estimates higher than previous studies
• Intriguing pregnancy results – Reproductive choice tradeoffs
• Requires an RCT to answer more definitively • Awaiting WHO consultancy and funders
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Many Thanks