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
2
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: 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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8
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)
14
*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
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: [email protected]
Studies assessing injectables and mortality (Adjusted hazard ratio)
24
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)
25
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)