Contraception & HIV Still searching for answers after >2 - - PowerPoint PPT Presentation

Contraception & HIV

Still searching for answers after >2 decades

R Scott McClelland, MD, MPH University of Washington

Inter –CFAR Symposium on HIV Research in Women September 20th 2012

Overview

• Global use of contraception & unmet need
• Hormonal contraception & HIV acquisition
• Hormonal contraception & HIV transmission
• Hormonal contraception & progression of

HIV disease

• Current guidelines
• Where do we go from here?

Global Use of Contraception

• An estimated 800 million

women use modern methods of contraception

– 150 million use hormonal contraceptives – Others use IUDs, barriers, tubal ligation

Population Reference Bureau, 2008

Reported Contraceptive Use and Unmet Need in Married Women Region 1990 2007 Unmet Need Asia 57% 67% 9% Latin America 62% 72% 11% Africa 17% 28% 22%

Unmet Contraceptive Needs

Ref: Network Vol 23, number 3, 2004. Family Health International

• Globally, 200 million couples not using contraception

despite wanting to space or limit child bearing (WHO)

Benefits of Contraception

• Avoid unplanned pregnancies

– Potential for obstetrical complications – Spacing pregnancies benefits the health of women, infants, and children

• Family planning empowers women,

reducing gender inequality

• HIV-positive women may wish to reduce

risk of vertical transmission by preventing further pregnancies

J Infect Dis 1991 OC Users Non-OC Users

AOR 4.5 (95% CI 1.4-13.8)

Does hormonal contraceptive use increase the risk of HIV acquisition in women?

Bradford Hill Criteria for Causation

• Strength of association
• Consistency
• Specificity
• Temporal relationship
• Biological gradient
• Plausibility
• Experiment
• Coherence
• Analogy

• 1314 HIV-serodiscordant couples in which

the female partner was HIV-negative

• Participants in Partners in Prevention trial

from seven countries in Africa

• Used marginal structural modeling and Cox

proportional hazards regression to assess effect of contraceptive use on HIV acquisition

Lancet Infect Dis 2012

HC Use and HIV Acquisition

Incidence per 100 p-y Cox Model AHR (95% CI) No HC 3.78 Reference Any HC 6.61 1.98 (1.06-3.68) Injectable 6.85 2.05 (1.04-4.04) Oral 5.94 1.80 (0.55-5.82)

Heffron et al. Lancet Infect Dis 2012

• 5567 HIV-negative women
• Participants in the Carraguard Phase 3

Efficacy Trial in South Africa

• Used marginal structural models and Cox

models to assess effect of contraceptive use on HIV acquisition

– Overall and in subset 16-24 years old

AIDS 2012

HC Use and HIV Acquisition

Incidence per 100 p-y All women AHR (95% CI) Women <24 y.o. AHR (95% CI)

No HC 3.4 Reference Reference DMPA 4.6 1.28 (0.92-1.78) 1.68 (0.96-2.94) Net-En 3.5 0.92 (0.64-1.32) 1.36 (0.78-2.35) COC 2.8 0.84 (0.51-1.39) 1.02 (0.46-2.28)

Morrison et al. AIDS 2012

Marginal Structural Models

• 2236 HIV-negative women
• Participants screened for the PRO 2000/5

trial in South Africa

• Used Cox proportional hazards regression

AIDS 2012

HC Use and HIV Acquisition

Cox Model AHR (95% CI) No HC Reference Injectable 2.02 (1.37-3.00) Oral 0.95 (0.62-1.46)

Wand and Ramjee. AIDS 2012

Unprotected Sex Hormonal Contraception HIV Acquisition

• Sub-cutaneous progesterone implants

enhanced SIV vaginal transmission in macaques 7-fold compared to placebo

– Thinning of vaginal epithelium – Increased number of SIV DNA-positive cells in vaginal lamina propria – Higher plasma SIV RNA in first 3 months

Nature Med 1996

SIV Vaginal Transmission

Marx et al. Nature Med 1996

• Blish. Am J Reprod

Immunol 2011

Bradford Hill Criteria for Causation

• Strength of association
• Consistency
• Specificity
• Temporal relationship
• Biological gradient
• Plausibility
• Coherence
• Experiment
• Analogy

Can we disentangle the relationships between HC and HIV Acquisition?

Experimental Design

• Is it possible to conduct a

randomized trial of hormonal contraception versus some control?

To trial or not to trial…

Pros

• Potential for providing a

clear answer

• Potential for clarifying the

biological mechanisms Cons

• Difficult to identify a

suitable control condition

• Frequent switching of

contraceptive method

• Added complexity of HIV

prevention trials in setting

• f proven interventions
• Cost: most effective use
• f resources?

• Decision analysis modeling risk of HIV

acquisition and maternal mortality

• Chad, Kenya, South Africa, Uganda
• Assumes injectable progesterone

associated with 2.19-fold increased HIV risk

• Contraceptive methods (UN), failure rates

(Trussel Contracept 2011), maternal mortality & pregnancy outcome (WHO)

BJOG 2012

Rodriguez et al. BJOG 2012

• If progesterone injectables removed without

70-100% of women switching to IUD or COC, there could be up to 9 additional maternal deaths per HIV infection averted

Contraception 2012

• Modeled risks of unwanted births, maternal

deaths, and HIV acquisition associated with different contraceptive methods

• Kenya, South Africa, Zimbabwe
• Method-specific HIV risk for family planning,

sex workers, and discordant couples1-4

• Contraceptive methods (UN), failure rates

(Trussel 2007), maternal mortality & pregnancy outcome (WHO)

• 1. Heffron Lancet ID 2011, 2. Baeten AIDS 2007, 3-4. Morrison AIDS 2007 & 2010

Additional unwanted births per 100 HIV infections averted

• Jain. Contraception 2012

Additional maternal deaths per 100 HIV infections averted

• Jain. Contraception 2012

Does hormonal contraceptive use increase the risk of HIV transmission from women to men?

• 156 female index patients with 159 HIV-

negative male partners

– 26/114 (23%) of women who reported on contraceptive use were using COCs

• 19 (12%) male partners infected
• Reported no association between

hormonal contraceptive use and transmission to male partner

BMJ 1992

• 2,476 HIV-serodiscordant couples in which

the male partner was HIV-negative

• Participants in Partners in Prevention trial

from seven countries in Africa

• Used marginal structural modeling and Cox

regression to assess effect of contraceptive use on HIV transmission

– Genetically linked HIV transmission events

Lancet Infect Dis 2012

HC Use and HIV Transmission

Incidence per 100 p-y Cox Model AHR (95% CI) No HC 1.51 Reference Any HC 2.61 1.97 (1.12-3.45) Injectable 2.64 1.95 (1.06-3.58) Oral 2.50 2.09 (0.75-5.84)

Heffron et al. Lancet Infect Dis 2012

HC Use and Genital HIV Shedding

Log10 copies/swab Median* (IQR) Adjusted coefficient† (95% CI) No HC 3.14 (2.08-3.85) Reference Any HC 3.29 (2.08-3.91) 0.14 (0.04 to 0.23) Injectable 3.38 (2.08-4.02) 0.19 (0.08 to 0.30) Oral 2.96 (2.08-3.65) -0.05 (-0.24 to 0.14)

Heffron et al. Lancet Infect Dis 2012 * Log10 HIV RNA copies/swab

† Average difference in HIV RNA concentration

Female to Male HIV Transmission in Rakai, Uganda

• 224 male HIV-/female HIV+ couples
• Excluded intervals with condom use

Incidence per 100 PY aIRR (95% CI) Non-HC 7.0 Reference Any HC 6.9 1.04 (0.43-2.48) OC 10.6 1.42 (0.30-6.57) Injectables 5.9 0.92 (0.34-2.50)

Lutalo et al. CROI 2012

Does hormonal contraceptive use increase the rate of disease progression in HIV+ women?

Hormonal Contraception and HIV Progression

Higher Risk

• 1. Lavreys JID 2004
• 2. Stringer AJOG 2007
• 3. Stringer AIDS 2009

Neutral Risk Lower Risk

• 1. Kilmarx JID 2000
• 2. Cejtin AIDS 2003
• 3. Wang AIDS 2004
• 4. Richardson AIDS

2007

• 5. Allen J Women’s

Health 2007

• 6. Stringer AIDS 2009
• 7. Morrison JAIDS

2011

• 1. Polis AIDS 2010
• 2. Heffron CROI 2012

• 599 postpartum women in Lusaka, Zambia
• RCT IUD vs. hormonal contraception
• Followed for at least 2 years
• Primary endpoint: Safety and efficacy of

intrauterine device vs. hormonal contraception

• Secondary endpoints:

– Time to CD4<200 – Time to death – Combined endpoint: time to CD4<200 or death

Am J Obstet Gynecol 2007

HC vs. IUD in HIV-positive Women

• Only one episode of PID in IUD arm
• Higher rate of discontinuation in IUD arm
• Pregnancy higher in HC vs. IUD

– HR 2.2 (95% CI 1.2-2.4)

• Mortality did not differ significantly

– HR 1.4 (95% CI 0.7-3.0)

• Faster progression to CD4<200 with

hormonal contraception compared to IUD

– HR 1.6 (95% CI 1.04-2.03)

HC vs. IUD in HIV-positive Women

CD4 decline Death

• Time to CD4<200 or

death faster in HC vs. IUD

• HR 1.6 (95% CI 1.1-2.3)

CD4 decline

• r death

HC vs. IUD in HIV-positive Women

• IUD appeared safe and was more

effective than HC at preventing pregnancy

• No difference in mortality
• Time to CD4<200 longer with IUD vs. HC
• Limitations

– ~30% withdrew or lost to follow-up – ~30% discontinued allocated method – Generalizability? (Post-natal population)

• 303 HIV infected women contributed 1408

person-years of observation

– Neither DMPA use nor COCs associated with HIV disease progression

• DMPA aHR 0.90, 95%CI 0.76-1.08
• COC aHR 1.07, 95%CI 0.89-1.29

– In this study, STI symptoms and older age associated with greater risk of progression

JAIDS 2011

• 625 women in Uganda
• Followed from time of HIV seroconversion
• Evaluated effect of hormonal contraceptive

use on time to AIDS and death

AIDS 2010

Effect of Hormonal Contraception on Time to AIDS or Death in Rakai, Uganda

• HC not associated

with increased hazard

• f death (aHR 0.76,

95%CI 0.41-1.39)

Polis et al. AIDS 2010

Effect of Hormonal Contraception on Time to AIDS or Death in Rakai, Uganda

• HC associated with

lower risk of AIDS or death (aHR 0.70, 95%CI 0.50-0.97)

Polis et al. AIDS 2010

Clinical Trials?

Women’s Values and Preferences?

http://www.guardian.co.uk/global-development/2012

Thank you!