Hormonal contraceptive use and HIV progression: A systematic

review

Sharon Phillips, MD MPHDepartment of Reproductive Health and

ResearchWorld Health Organization

Kate Curtis, PhDDivision of Reproductive Health, CDC

Chelsea Polis, PhDOffice of Population and Reproductive Health

United States Agency for International Development

Need for comprehensive reproductive health services among women living with HIV

Women living with HIV who desire children should have support to safely conceive and deliver

Substantial unmet need for contraception and unintended pregnancy among women living with HIV

All women who wish to prevent pregnancy deserve access to voluntary family planning services

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Key Questions

Are women living with HIV who use hormonal contraception at increased risk of:

1. Death or progression to AIDSa. Measured by CD4 <200, initiation of

ART, or clinical AIDS

2. Change in CD4 or viral load

Methods

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Methods: Study selection

Primary reports of studies examining hormonal contraceptive use among women living with HIV

PUBMED and EMBASE searched for published articles in any language through December 15, 2011

634 unique references identified, 16 full-text articles assessed, 12 reports included

Excluded: studies with no comparison group; case control studies

Study information independently abstracted by 2 authors (SP & KC)

Methods: Quality criteria

Methodology used to minimize confounding Accurate measurement and analysis of

exposure Composition of comparison group Loss to follow-up Length of follow-up Additional considerations for RCTs

– Adequate randomization– Allocation concealment– Distribution of potential confounders between groups– Maintenance of comparability of groups

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7

Results

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Results

12 reports (of 11 studies) met inclusion criteria– 1 RCT (2 reports)– 10 observational

Outcomes considered1.Mortality or progression to AIDS2.Change in CD4 or viral load

Outcome 1: Mortality or progression to AIDS

9 reports of 8 studies

1 RCT (2 reports), 7 observational studies

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1. Mortality or progression to AIDS RCT: Stringer et al., 2007/2009 reanalysis

Designed to assess safety of IUD in women living with HIV

599 postpartum women living with HIV, Zambia

Randomized to either copper IUD or hormonal contraception (choice of OCs or DMPA)

2 year follow-up, 6 month visits

High loss to follow-up rates– 31% of hormonal group, 23% of IUD group

High method discontinuation/switching rates– 49% of IUD users discontinued, 76% of these switched to HC

– 13% of hormonal users discontinued, 16% switched to IUD

– Within hormonal group, 34% switched between OC and DMPA

1. Mortality (all cause) or progression to AIDSStringer 2007/2009 RCT (continued): HR (95%

CI)ITT Actual use

Mortality

OC vs IUD 1.06 (0.38-2.97) 1.24 (0.42-3.63)

DMPA vs IUD 1.39 (0.63-3.06) 1.83 (0.82-4.06)

CD4<200 or initiate ART

OC vs IUD 1.54 (0.98-2.42) 1.67 (1.1-2.51)

DMPA vs IUD 1.81 (1.26-2.6) 1.62 (1.16-2.28)

Composite outcome (mortality, CD4 <200, or initiate ART)

OC vs IUD 1.52 (1.0-2.32) 1.67 (1.1-2.51)

DMPA vs IUD 1.81 (1.3-2.53) 1.62 (1.16-2.28)

1. Mortality or progression to AIDS (Cohort) Author, year Design Population Progression Mortality

(all-cause*)AIDS/ mortality

Quality

MRC Collaborative1999

Prospective up to 4 yrs

505 HIV/GU clinic patientsBritain/Ireland

AIDSOCs ↔

OCs ↔ Poor

Kilmarx 2000

Prospective, median 81 mos

194 sex workers, Thailand

CD4< 200OCs ↔DMPA ↔

OCs ↔DMPA ↔

Poor

Allen2007

Prospective, 6 yrs

460 women, Rwanda

OCs ↔DMPA ↔

Fair

Stringer multi-country 2009

Prospective, median 1 yr

7846 women, 12 African countries

ART eligibleOCs ↔DMPA/ETG↔

OCs 0 (0-)DMPA ↔

ART, deathOCs ↔DMPA ↔

Fair

Polis 2010

Retrospective mean 4 years

625 newly seroconverted Uganda

OCs ↔DMPA ↔

AIDS, deathOCs ↔DMPA ↔

Good

Morrison 2011

Prospective median 58 months

306 newly seroconvertedUganda & Zimbabwe

AIDSOCs ↔DMPA ↔

AIDS, death, ART initiationOCs ↔DMPA ↔

Good

Heikinheimo 2011

Retrospective 5 years

40 womenFinland

ART initiationLNG-IUD ↔

Poor

*Except Allen 2007 (HIV-related mortality only)

Studies assessing injectables and progression to AIDS OR mortality

(composite outcome) (adjusted hazard ratio)

13

Stringer RCT (2009)*

(DMPA vs IUD)

Stringer Multi-Country (2009)

(Inj/imp† vs no HC)

Morrison (2011)

(DMPA vs no HC)

Polis (2010)

(DMPA vs no HC)

*Actual use analysis

Injectables decrease risk of progression

Injectables increase risk of progression

† DMPA, NET-EN, implants

Studies assessing OCs and progression to AIDS OR mortality (composite

outcome) (Adj hazard ratio)

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*Actual use analysis

Stringer RCT (2009)*

(OCs vs IUD)

Morrison (2011)

(OCs vs no HC)

Stringer Multi-Country (2009)

(OCs vs no HC)

Polis (2010)

(OCs vs no HC)

OCs decrease risk of progression

OCs increase risk of progression

1

Results: Outcomes considered

1.Mortality or progression to AIDS

2.Change in CD4 or viral load

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2. Change in viral load, CD4 (5 observational studies)

Author, year,study design

Population Changes in CD4

Changes in HIV RNA

Quality

Kilmarx, 2000Prospective cohort, median 81 months

194 sex workersThailand

Rapid declineOCs ↔DMPA ↔

Poor

Cejtin, 2003Prospective cohort, 1-2 years

1721 womenUS

HormonalContracept ↑(no adverse effect)

Hormonal Contracept ↔

Fair

Lavreys, 2004Prospective cohort, median 34 months

161 newly seroconverted sex workers Kenya

Hormonal Contracept ↔

Poor

Richardson, 2007Prospective cohort, 24 mos

283 postpartum womenKenya

OCs ↔DMPA ↔

OCs ↔DMPA ↔

Fair

Heikinheimo 2011

Retrospective cohort, 5 years

40 womenFinland

LNG-IUD ↔ LNG-IUD ↔ Poor

Discussion: Outcome 1Mortality or progression to AIDS

7 observational studies find no association between HC and HIV disease progression

1 RCT found increased rates of – time to CD4 count < 200 and – time to CD4 count < 200 and mortality – among HC users compared with IUD users (both

OC and DMPA users)

Discussion: Outcome 1Mortality or progression to AIDS

Strengths– Many observational studies with similar

findings, 2 with very strong methodology

– One very large study (n=7846) Limitations

– Some small sample sizes– Follow-up time– RCT:

• loss to follow-up• method switching• comparison with IUD

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Discussion: Outcome 2Change in viral load, CD4

5 observational studies find no adverse association between HC and change in viral load or CD4

Limitations– Small sample sizes– Failure to separate HC methods in some

studies– Lack of control for potential confounders

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Discussion:Study Quality – Observational studies Quality ranged from poor to good "Good" studies

– Incident HIV cases– Multivariate analysis– Time-varying analysis of use of hormonal contraception– Findings similar to those rated as "fair" and "poor"

"Fair" studies– Prevalent HIV cases– Control for baseline health characteristics in multivariate

model "Poor" studies

– No separate analysis of different contraceptive methods– Inclusion of other HC users in comparison group– No multivariate analysis

Discussion:Limitations in body of research

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Minimal or no information on newer methods (LNG-IUD, patch, ring, implants)

Limited data for women with clinical AIDS

All studies observational, with the exception of 1 RCT

Conclusion

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The preponderance of evidence thus indicates that use of OCs or of DMPA does not affect HIV disease progression among women with HIV

Acknowledgements

Members of the WHO Hormonal Contraception & HIV Advisory Group (manuscript review)Andy Gray, Olav Meirik, & Catherine Hankins

Assistance with project developmentMary Lyn Gaffield, Nathalie Kapp, & Roger Chou

Assistance with EROS software Agustin Ciapponi & Demián Glujovsky

Assistance with literature searchNellie Kamau & LaToya Armstrong

23Contact: phillipss@who.int

Studies assessing injectables and mortality (Adjusted hazard ratio)

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Stringer RCT (2009)*

(DMPA vs IUD)

Kilmarx (2000)

(DMPA vs non-DMPA†)

Polis (2010)

(DMPA vs no HC method)

Stringer Multi-Country

(2009)

(Imp/inj vs no HC method†)

Allen (2007)

(unspec inj. vs

never used injectables)Injectables decrease risk of mortality

Injectables increase risk of mortality

*Actual use analysis †Mostly OCs †DMPA, NET-EN, implants

Studies assessing OCs and mortality (Adjusted hazard ratio)

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Stringer RCT (2009)*

(OCs vs IUD)

Kilmarx (2000)

(OCs vs non-OCs†)

MRC (1999)

(OCs vs other/no contraception)

Polis (2010)

(OCs vs no hormonal method)

Allen (2007)

(OCs vs never used OCs)

OCs decrease risk of mortality

OCs increase risk of mortality

*Actual use analysis †Mostly DMPA

Studies assessing injectables and progression to AIDS (adjusted hazard

ratio)

26

Stringer RCT (2009)*

(DMPA vs IUD)

Stringer Multi-Country (2009)

(Inj/imp vs no HC†)

Morrison (2011)

(DMPA vs no HC)

Kilmarx (2000)

(DMPA vs non-DMPA†)

Injectables decrease risk of progression

Injectables increase risk of progression

*Actual use analysis †DMPA, NET-EN or implant

†Mostly OCs

1

Studies assessing OCs and progression to AIDS (Adjusted hazard

ratio)

27

Stringer RCT (2009)*

(OCs vs IUD)Kilmarx (2000) (OCs vs non-OCs†)Morrison (2011) (Low dose OCs vs no HC)Stringer Multi-Country (2009) (OCs vs no HC)MRC (1999) (OCs vs other or no HC)

OCs decrease risk of progression

OCs increase risk of progression

*Actual use analysis †Mostly DMPA

Study Flow

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Unique references identified (n=634)

References screened

(n=634) References excluded based on title/abstract

review (n = 618)

Full text articles assessed

for eligibility (n=16)

Full-text articles excluded, with reasons (n = 4)

Inadequate comparison group (either no comparison group (10;12) or used before/after data (11)

Case control study methodology (7)

Studies included (n = 12)