+HIV and hormonal contraception: New data, ongoing controversySharon Phillips MD MPH

Medical Officer

Department of Reproductive Health and Research

World Health Organization

Geneva, Switzerland

+ HIV and unintended pregnancy: two important public health concerns

17 million women globally are living with HIV

>150 million women worldwide use a hormonal contraceptive method Injectables particularly common in sub-Saharan

Africa

Highly effective contraceptive methods prevent unintended pregnancy, maternal/infant morbidity and mortality, and vertical transmission of HIV

2

+ Key questions addressed by WHO: Do specific methods of hormonal contraception increase risk of:

1. HIV acquisition in uninfected women?

2. HIV transmission to uninfected male

partners?

3. HIV disease progression in women living with

HIV?

3

+ Do specific methods of hormonal contraception increase risk of:

1. HIV acquisition in HIV-negative women?

2. HIV transmission to HIV-negative male

partners?

3. HIV disease progression in women living with

HIV?

4

+2012 systematic review: Polis & Curtis

Systematic search of published literature Any language, any date through Dec 15, 2011 Included RCT, prospective cohort, or case-

control studies Excluded cross-sectional studies

Studies compared HIV-uninfected women using HC vs. HIV-uninfected women not using HC

5

Observational studies of OCs & HIV acquisitionAdjusted OR, IRR, or HR (log scale) and 95% CI

6Slide courtesy of C Polis

Observational studies of injectables & HIV acquisitionAdjusted OR, IRR, or HR (log scale) and 95% CI

7

Slide courtesy of C Polis

+Observed association: Causal or confounding?

Causal: DMPA use Increased risk of HIV acquisition

Confounding: DMPA use Less consistent use of condoms Increased risk of HIV acquisition Other potential factors: Provider bias in prescribing;

women more at risk more likely to use DMPA

With only observational data available impossible to determine what is truly being measured

Some biological data bolster argument for an association, but also inconsistent

Does it matter?

+New MEC Recommendation for New MEC Recommendation for women at high risk of HIVwomen at high risk of HIV

COC/CIC/POP 1

Patch/Ring 1

DMPA/NET-EN 11 See clarification

Implant 1

+ WHO HC-HIV consultation technical statement, Feb 2012

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…the group agreed that the data were not sufficiently conclusive to change current guidance…

…However, because of the inconclusive nature of the evidence, women using progestogen-only injectable contraception should be strongly advised to also always wear condoms and other HIV preventive measures…

Expansion of contraceptive method mix and further research on the relationship between hormonal contraception and HIV infection is essential. These recommendations will be continually reviewed in light of new evidence.

+ New data since WHO meetingMcCoy et al. analysis of MIRA data

Secondary data analysis of 4913 women in SA and Zimbabwe participating in HIV prevention study

11

Site-adjusted Cox PH

Baseline-adjusted Cox PH

IPTW Cox PH MSM

Injectables

1.32 (1.00-1.74)

1.27 (0.94-1.72)

1.34(0.75-2.37)

OCs 0.82(0.58-1.15)

0.84(0.57-1.22)

0.86(0.32-1.78)

* AIDS 2013 (in press)

+ Competing risks: Hormonal contraception for women living with HIV Restrictions on highly effective methods could

increase unintended pregnancies, if not replaced by other highly effective methods

Unintended pregnancy has implications on maternal and infant morbidity/mortality, perinatal HIV, possibly on response to ART, and on overall wellbeing

Pregnancy itself may impact risk of HIV transmission, additional evidence needed

12

+ Do specific methods of hormonal contraception increase risk of:

1. HIV acquisition in uninfected women?

2. HIV transmission to HIV-negative male

partners?

3. HIV disease progression in women living with

HIV?

13

+2012 systematic review: Polis, Phillips, & Curtis*Study selection

Systematic literature search Any language, any date through Dec 15, 2011 Studies compared HIV-infected women using HC to

HIV-infected women not using HC

Direct evidence: outcome = incident seroconversion in male partner of woman with known HC use status

Indirect evidence: outcome = genital HIV shedding or plasma viral load

14* AIDS 2013; 27:(493-505)

+Direct evidence: 1 study identified(Heffron 2012*)

2476 couples with HIV-infected women

59 genetically-linked seroconversions in men 40 to men with partners not using HC (1.51/100 py) 15 to men with partners using injectables (2.64/100

py) 4 to men with partners using OCs (2.50/100 py)

Partners of HC users twice as likely to seroconvert adjHR OCs: 2.1 (0.8-5.8) adjHR injectables: 2.0 (1.1-3.6)

15* Lancet Infectious Diseases 2012;12(1):19-26

+Indirect evidence from 17 studies

Genital HIV shedding: assessment techniques, outcomes, & findings from 11 reports inconsistent

Plasma viral load: generally consistent evidence of no association from nine reports

16

+Summary of transmission results

One well-conducted study raises potential concerns related to the use of injectable contraception and transmission

Given the paucity of direct evidence, mixed indirect evidence from 16 studies, and the potential for confounding, additional evidence is needed

17

+ Do specific methods of hormonal contraception increase risk of:

1. HIV acquisition in HIV-negative women?

2. HIV transmission to HIV-negative male

partners?

3. HIV disease progression in women living with

HIV?

18

+Voluntary contraception: Crucial care for women living with HIV Women living with HIV who wish to have

children should be supported

Women living with HIV who wish to defer or stop childbearing must similarly be supported Critical to their health and to preventing vertical HIV

transmission

Hormonal contraception highly effective and acceptable to women

+ 2012 systematic review: Phillips, Curtis, & Polis*

Systematic literature search; any language, any date through Dec 15, 2011

12 reports included (1 RCT, reported twice; 11 observational)

Excluded: studies with no comparison group; case control studies

HIV disease progression measured by mortality, time to CD4 count below 200, time to ART initiation, increase in HIV RNA viral load, or decrease in CD4 cell count

20* AIDS 2013 27(5): 787–794

+ Studies assessing OCs and mortality (Adj HR)

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Stringer RCT (2009)*

Kilmarx (2000)

MRC (1999)

Polis (2010)

Allen (2007)

OCs decrease risk of mortality

OCs increase risk of mortality *Actual use analysis

+ Studies assessing injectables and mortality (Adj HR)

22

Stringer RCT (2009)*

Kilmarx (2000)

Polis (2010)

Stringer Multi-Country (2009)

Allen (2007)

Injectables decrease risk of mortality

Injectables increase risk of mortality

*Actual use analysis

+Summary of HIV disease progression results

One randomized trial raised some concerns; had important limitations related to crossover and dropout

Ten observational studies reported no increased risk for HIV disease progression

+New MEC Recommendation for New MEC Recommendation for women living with HIV (unchanged women living with HIV (unchanged from prior recommendations)from prior recommendations)

COC/CIC/POP 1

Patch/Ring 1

DMPA/NET-EN 1

Implant 1

Women on ART may require special consideration regarding the use of hormonal contraceptives

+

2269 women living with HIV

HC does not accelerate disease progression and may be associated with slower progression

25

New since 2012 WHO meeting: Heffron 2013*

* AIDS 2013; 27(2): 261-267

Contraception

Adjusted HR (95% CI)

p-value

No HC Reference

Any HC 0.74 (0.56-0.98)

0.04

Injectables

0.72 (0.53-0.98)

0.04

OCPs 0.83 (0.48-1.44)

0.50

+Conclusions: Safety of hormonal contraception for women living with HIV

HIV disease progression: neither OCPs nor DMPA appear to accelerate HIV disease progression

Transmission to HIV-negative male partners: evidence base limited, inconsistent One direct study suggests increase risk with HC Indirect evidence on HC and shedding is inconsistent, on HC

and plasma viral load suggests no increase in risk Consider findings in context of increasing use of ART Importance of counseling on HC plus HIV prevention

interventions

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+Conclusions: Safety of hormonal contraception for HIV-negative women at risk for HIV acquisition OCPs: data do not suggest an increased risk of HIV

acquisition

Implants, rings, patches, hormonal IUDs: limited data

NET-EN: data are limited, do not suggest increased risk

DMPA: substantial uncertainty Potential risk must be balanced against risks of unintended

pregnancy (maternal morbidity & mortality, unsafe abortion, infant morbidity &mortality), and potential risk of HIV acquisition associated with pregnancy

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+Thank you!

Acknowledgments: Chelsea Polis, PhD Kathryn Curtis, PhD Mary Lyn Gaffield, PhD

Further information at: http://www.who.int/reproductivehealth/topics/family_planning/hc_hiv/en/

Contact: phillipss@who.int

+ HC for women using ARVs

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Type of ARV Hormonal methods of contraception

Intrauterine contraception (either Cu-IUD or LNG-IUD)

  COC, CIC, P/R, POP

DMPA, NET-EN, LNG/ETG

Initiation Continuation

Nucleoside reverse transcriptase inhibitors (NRTIs)

Category 1 Category 1 Category 2/3* Category 2

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Category 2 DMPA: Category 1NET-EN, LNG/ETG: Category 2

Category 2/3* Category 2

Ritonavir-boosted protease inhibitors

Category 3 DMPA: Category 1NET-EN, LNG/ETG: Category 2

Category 2/3* Category 2

* There is no known interaction between ART & IUD use. However, AIDS as a condition is classified as Category 3 for insertion and Category 2 for continuation unless the woman is clinically well on antiretroviral therapy, in which case both insertion and continuation are classified as Category 2

Method mix: among all married users, percent using specific method

Source: UNPD 2011