Hormonal contraception and HIV acquisition in women: a systematic review of the

epidemiological evidence

International AIDS ConferenceJuly 25, 2012

Chelsea B. Polis, PhD - USAIDKathryn M. Curtis, PhD - CDC

HIV and unintended pregnancy: two important public health concerns

• Factors that increase risk of HIV contribute to the spread and consequences of the epidemic

• Unintended pregnancies can increase:– maternal and infant morbidity and mortality– vertical HIV transmission– sexual HIV acquisition/transmission?

2

Four key issues - hormonal contraception and:

HIV-negative women1. HIV acquisition?

Women living with HIV2. HIV disease progression to AIDS or death?

3. HIV transmission to men?

4. Drug interactions with antiretroviral therapy?

3

•Unclear which biological mechanisms might be relevant

•Unclear how existing animal data extrapolates to humans

•Findings are inconsistent with other studies in women

•Several potential biological mechanisms postulated

•Some possible mechanisms supported by animal data

•Some studies in women suggest increased risk

4

Does hormonal contraception biologically alter risk of HIV acquisition?

Study selection and abstraction

• Systematic search of published or in press literature– Any language, published through Dec 15, 2011– Included RCT or cohort studies, excluded cross-sectional

studies

• Studies compared HIV-negative women using HC against HIV-negative women not using HC

• Both authors systematically abstracted study information to assess various aspects of quality

5

Prospective, observational studies of OC pills & HIV acquisition(including studies that did not meet minimum quality criteria)

Adjusted OR, IRR, or HR (log scale) and 95% CI

6* includes MSM and Cox estimates0tan28a566028 0tan29a566029 0tan9a56609

Plummer 1991Sinei 1996Kilmarx 1998Heffron 2012*Feldblum 2010Baeten 2007Morrison 2007/2010*Kiddugavu 2003Kapiga 1998Saracco 1993Wand 2012Reid 2010Laga 1993Morrison 2012*Myer 2007Ungchusak 1996

OCs DECREASE HIV risk OCs INCREASE HIV risk

No relative risk calculated

Prospective, observational studies of injectables & HIV acquisition (including studies that did not meet minimum quality criteria)

Adjusted OR, IRR, or HR (log scale) and 95% CI

7

0tan28a566028 0tan29a566029 0tan9a56609Injectables DECREASE HIV risk Injectables INCREASE HIV risk

Ungchusak 1996 Kumwenda 2008Wand 2012 Feldblum 2010Heffron 2011*Bulterys 1994Kleinschmidt 2007 Baeten 2007Watson-Jones 2009Kilmarx 1998Morrison 2007/2010*Morrison 2012*Myer 2007

Reid 2010Kiddugavu 2003Kapiga 1998

= DMPA alone= NET-EN alone= Any in-jectable

LEGEND

= Mostly in-jectable, some OC

* includes MSM and Cox estimates

Studies failed to meet minimum quality criteria if:

Study contained two or more of these three flaws:1. Unclear definition of exposure to HC use2. High loss to follow up (>20% at 12 months)3. Lack of consideration of potential confounding

- or -Study authors noted that data were unlikely to

provide information on the biological effect of HC on HIV acquisition

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Among studies that met minimum quality criteria, we considered factors including:

• Frequency and accuracy in measurement of exposure, outcome, and key variables

• Study size and number of endpoints

• Population studied

• Purpose of data collection

• Statistical approach

• Potential for uncontrolled or residual confounding9

Causal associations vs. confounded associations: condom use example

Hormonal contraceptive use

(exposure)

Higher risk of HIV acquisition

(outcome)

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Less consistent

condom use(confounder)

OBSERVED ASSOCIATION IS CAUSALDUE TO CONFOUNDING

Oral contraceptive pills and HIV acquisitionSTUDIES MEETING MINIMUM QUALITY CRITERIA

110tan28a566028 0tan29a566029 0tan9a56609

Heffron 2012*

Baeten 2007

Morrison 2007/2010*

Kiddugavu 2003

Reid 2010

Morrison 2012*

Myer 2007

OCs DECREASE HIV risk OCs INCREASE HIV risk* includes MSM and Cox estimates

0tan28a566028 0tan29a566029 0tan9a56609Injectables DECREASE HIV risk Injectables INCREASE HIV risk

Heffron 2012*

Baeten 2007

Morrison 2007/2010*

Morrison 2012*

Kleinschmidt 2007 (crude IRR)

Myer 2007

Reid 2010

Kiddugavu 2003

= DMPA alone= NET-EN alone

= DMPA and NET-EN combined

LEGEND

12* includes MSM and Cox estimates

Injectables and HIV acquisitionSTUDIES MEETING MINIMUM QUALITY CRITERIA

Depicting estimates that combine DMPA and Net-En, if available

0tan28a566028 0tan29a566029 0tan9a56609Injectables DECREASE HIV risk Injectables INCREASE HIV risk

Kleinschmidt 2007

Morrison 2012

Myer 2007

= DMPA alone= Net-En

LEGEND

0tan28a566028 0tan29a566029 0tan9a5660913

NET-EN and HIV acquisitionSTUDIES MEETING MINIMUM QUALITY CRITERIA

Sensitivity analyses• Multiple factors could contribute to variation in

estimates on progestin-only injectables and HIV acquisition, particularly:– Analysis of serodiscordant couples– Length of inter-survey interval– Manner of handling condom use

• Additional data could help to elucidate reasons for variation

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Limitations• Body of evidence

– Potential for confounding in observational data– Many studies had limited power– Limited data for methods other than OCPs or injectables

• Systematic review– Assessing study quality is complex and multifactorial;

other reviewers may have used different criteria• WHO expert group vigorously discussed interpretation of

various study strengths and weaknesses, body of evidence

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Conclusions

• For OCPs and NET-EN, data available at the time of this review do not appear to suggest an association with HIV acquisition– Data for NET-EN limited to three studies

• For DMPA, data available at the time of this review neither establish a clear causal association nor definitively rule out the possibility of an effect on risk of HIV acquisition

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Acknowledgements

• Jared Baeten, Tim Farley, Ron Gray, Phil Hannaford, Renee Heffron, Charlie Morrison, Bert Petersen, and BMGF colleagues for comments on the review

• Participants of WHO HC-HIV consultation for discussion

• WHO colleagues, including Sharon Phillips, Mary Lyn Gaffield, Nathalie Kapp, and Michael Mbizvo

• Study investigators who generously responded to requests for information

• And many others for constructive input 17