Professor Helen ReesExecutive Director, WRHI, Wits Reproductive Health and HIV Institute &

Ad Hominem Professor, Department of Obstetrics and Gynaecology,University of Witwatersrand

Honorary Professor, London School of Hygiene & Tropical Medicine

Contraception and HIV

“Love is the answer, but while you are waiting for the answer, sex raises some pretty good

questions.” Woody Allen

Women have a right to decide whether they want to become pregnant and bear children irrespective of their HIV status.Women must be enabled to make informed, voluntary decisions about contraception and then receive a safe, effective method of her choice.

Trends in Maternal Mortality Ratios

WHO 2010

Avoidance of unintended pregnancy is most effective way of reducing number of deaths: 40% of global deaths averted in 2008 by contraception (Darroch & Singh 2011: Ahmed et al 2011)

Over 150 million women use hormonal contraception worldwide, primarily oral

contraceptives (OCs) and injectable depot-medroxyprogesterone acetate (DMPA).

The overall demand for contraception is increasing

17 12 14 1018

11

59 6954 60 41 59

14 20

26 24

0

20

40

60

80

100

1990-1995

2000-2005

1990-1995

2000-2005

1990-1995

2000-2005

1990-1995

2000-2005

Unmet need Met need

% of married women aged 15–49

Latin America & Caribbean

North Africa & West Asia

South & Southeast Asia

Sub-Saharan Africa

Method mix: among currently married (CM) & sexually active not married (NM) women ,

% using specific method

CM

NM

CM

NM

CM

NM

CM

NM

CM

NM

CM

NM

Kenya 2008-09

Lesotho 2001 Malawi 2010 Swaziland 2006

Tanzania 2010

Zambia 2007

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Other

Condom

Pill

Injectable

Country and Survey Year

Pre

vale

nce

(%)

Lesotho 2009

Source: Demographic and Health Surveys 2006-1010

6 7 1324 25

38 43 44

5 7 10 12

2811

23

18 16

96 11

2621 19

36 2534 21 24

1329

12

2013

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20

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20

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80

100

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Lack of knowledge Health/side effects Opposition

The importance of some reasons for non-use has changed over time

% of married women aged 15–49 with unmet need

1986–1989 2002–2005

Adherence in contraceptive use

Status 1 year 2 years(%) n (%) n

Continued 42 79 21 39Lost to follow up

30 57 35 67

Discontinued 28 48 41 78Withdrew 2 5 2 5

189 progestin injectable users followed up for 2 years in family planning clinic in Soweto

Of those who discontinued: • 40% ‘taking a break’• >50% complained of side effects

Beksinska, Rees et al. Contraception 64(2001)

Adult female HIV prevalence

The importance of contraception as part of PMTCT

Prevention of HIV in women, especially young women

Prevention of unintended pregnancies in HIV-infected women

Prevention of transmission from an HIV-infected woman to her infant

Support for mother and family

Element 1 Element 2 Element 3 Element 4

.Significant contribution coming from the provision of contraceptive information, services and counselling.

Pregnancy Intentions & Incidence Study: Prospective Cohort Study of HIV Positive Women on ART in South Africa, Swartz S, Black V et al

• 851 non-pregnant women on different ARV regimens recruited from 4 WRHI-supported sites between August 2009 – January 2010

Contraceptive Use n (%)Consistent condom use 540 (63.5%)

Injectables 175 (20.6%)

Oral contraceptives 45 (5.3%)

Implants 4 (0.5%)IUDs 1 (0.1%)Dual (Condoms+HC) 131 (15.4%)

Overall 631 (74.1%)

How far can we push Dual Method use? Condom use at last sexual intercourse, amongst injectable

contraception users

Lesotho 2009 Malawi 2004 Namibia 2006-07

Swaziland 2006-07

Zambia 2007 Zimbabwe 2005-06

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(%)

Source: Demographic and Health Surveys 2004-1010

Glass ceiling?

Contraception and HIV: What to consider

Women at riskfor HIV

Acquisition

Women infected with HIV

Infectiousness Disease progression

Drug interactions

Prevention

Contraception and HIV: How WHO guidance has worked…

Acquisition Infectiousness Disease progression

WHO’s Medical Eligibility Criteria for Contraceptive Use

Research

WHO consultants & committee:

Systematic review, Grading of scientific evidence

The evidence is used to develop international recommendations and includes expert opinion where evidence is not available

International recommendations are adapted for national guidelines

Job aids (tools) are developed

Eligibility Criteria for Contraceptive use: WHO Classifications

Definition

Classification of Conditions Definition

1 No restriction on use

2 Benefits generally outweigh risks

3 Risks generally outweigh benefits

4 Unacceptable health risk

WHO Conclusions - 2008

• “Intermediate” level of evidence

• COC – Category 1 - “No Restriction”

• DMPA – Category 1 for women at risk of HIV – Category 2 for youth (bone concerns) “Advantages Outweigh Risks”

Source: WHO Medical Eligibility Criteria (2008)

Hormonal contraceptive use for women at high risk of HIV

DMPA – Category 1 - No Restriction

Balance of evidence suggests no association between progestin contraceptives and HIV acquisition, although studies of DMPA use conducted among higher risk populations have repeated inconsistent findings

“Intermediate” level of evidence

Source: WHO Medical Eligibility Criteria fourth edition 2009

ProgesteroneNature Med., 1996

DMPAJ. Infect. Dis., 2004

DMPAVirology, 2006

- Genescà et al., J. Med. Primatol. , 2007- Mascola et al., Nature Med. 2000- Veazey et al., Proc. Natl. Acad. Sci. USA 2008- Pal et al., Virology 2009- Turville et al., PLoS One 2008

Reported effect of progesterone or its derivatives References

Inhibition of IgG and IgA production and trans-epithelial transport (78;87-96;129-134)

Decreased frequency of antibody-secreting cells in women and female macaques (90;96)

Decreased specific IgG and IgA responses following mucosal immunization with attenuated HSV-2; induction of permissive conditions for intravaginal infection of mice with HSV-2 and Chlamydia trachomatis

(132-134)

Inhibition of T cell responses and cytotoxic activity (139-143;147)

Inhibition of perforin expression in T cells (140-142;144-146)

Decreased proliferation and Th1-type cytokine production by VZV-specific CD4+ T cells in HIV-1 patients (148)

Altered migration and decreased activity of NK cells (105;106;106;135;159;251;252)

PIBF-mediated shift towards Th2 cytokine expression profile (133;149-154)Altered migration and infiltration of lymphocytes, macrophages, and NK cells into the female genital tract tissues (117;118;157;158;183;191;253)

Increased expression of CCR5 on cervical CD4+ lymphocytes (81;82)

Thinning of cervico-vaginal epithelium in rhesus macaques (42;66)

Increased frequency of Langerhans cells in vaginal epithelium (76;77)

Regulation of HIV replication and LTR activity (254)

Suppression of IL-1, IL-2, and IL-6 release by human lymphocytes (148;177)

Inhibition of TLR-9-induced IFN-α production by human and mouse pDCs (162)

Increased shedding of HIV-1 in the genital tract (35-37)

Decreased FcγR expression on monocytes (159;160)Decreased vaginal colonization with H2O2-producing Lactobacillus (70)

Reported effects of progesterone and its derivatives on immune system & HIV-1 infection.

Hel Z. et al., Endocrine Rev., 2010, 79-97.

Hormones and HIV Possible Mechanisms

• Vaginal and cervical epithelium (ectopy, etc.)• Cervical mucus• Menstrual patterns • Vaginal and cervical immunology • Viral (HIV) replication• Acquisition of other STI

0.1 1 10Protective Harmful

Studies of Injectables & HIV Acquisition

Source: Adapted from Polis (2011)

Kumwenda 2008

Ungchusak 1996

Feldblum 2010

Heffron 2011

Bulterys 1994

Baeten 2007

Watson-Jones 2009

Kilmarx 1998

Morrison 2010

Myer 2007

Reid 2010

Kiddugavu 2003

Kleinschmidt 2007

Kapiga 1998

Prospective cohort study of 3790 HIV- 1 discordant couples from East and southern

Africa

Renee Heffron, Deborah Donnell, Helen Rees, Connie Celum, Edwin Were, Nelly Mugo, Guy de Bruyn, Edith

Nakku- Joloba, Kenneth Ngure, James Kiarie and Jared ‐Baeten

July 2011 – Partners in Prevention Study on HIV acquisition and HC presented at IAS

Conference, Rome

Contraception and HIV acquisition from men to women

Adjusted Cox PH Regression analysis

HIV incidence per 100 person years

HR (95% CI) P-value

No hormonal contraception

3.78 1.00

Any hormonal contraception

6.61 1.98(1.06 – 3.68)

0.03

Injectables 6.85 2.05(1.04 – 4.04)

0.04

Oral contraceptives 5.94 1.80(0.55 – 5.82)

0.33

21.2% of women used HC at least once during study

Contraception and HIV acquisition from women to men

Adjusted Cox PH Regression analysis

HIV incidence per 100 person years

HR (95% CI) P-value

No hormonal contraception

1.51 1.00

Any hormonal contraception

2.61 1.97 (1.12 – 3.45) 0.02

Injectables 2.64 1.95 (1.06 – 3.55) 0.03

Oral contraceptives 2.50 2.09 (0.75 – 5.84) 0.16

Conclusion

• Mounting evidence that hormonal contraceptives – particularly injectable methods - increase a woman’s risk of acquiring HIV-1

• First study to demonstrate that hormonal contraceptives increase an HIV 1 infected ‐woman’s risk of transmitting HIV 1 to her ‐partner

The Dilemma for an Uninfected Woman

• If she uses DMPA, • Less risk of pregnancy• More risk of HIV acquisition

• If she stops DMPA• Does she have other contraceptive options?• If not, she may become pregnant • More risk of HIV acquisition• More risk of pregnancy morbidity & mortality• Unwanted pregnancy may have worse infant outcomes

The Dilemma for the Infected woman

• If she uses hormonal contraception• Less risk of pregnancy• More risk of HIV transmission to partner

• If she stops hormonal methods• Does she have other contraceptive options?• If not she may become pregnant • More risk of HIV transmission to partner• More risk of pregnancy Morbidity & Mortality• Potential for transmission to infant• Unwanted HIV infected babies have higher morbidity and

mortality than wanted infants

0.1 1 10Protective Harmful

Studies of Injectables & HIV Acquisition

Source: Adapted from Polis (2011)

Kumwenda 2008

Ungchusak 1996

Feldblum 2010

Heffron 2011

Bulterys 1994

Baeten 2007

Watson-Jones 2009

Kilmarx 1998

Morrison 2010

Myer 2007

Reid 2010

Kiddugavu 2003

Kleinschmidt 2007

Kapiga 1998

WHO Expert Consultation on HC and HIV

• January 2012, Geneva, 75 participants from 18 countries

– HIV Acquisition– HIV Transmission– HIV Progression

• GRADE rating of the evidence• Discussion of MEC criteria• Programmatic implications• Research agenda

WHO Consultation – GRADE Rating

• HC/HIV progression evidence• 1 RCT, 6 cohort studies• Rated “low overall quality”• No change from Category 1

WHO Consultation – GRADE Rating

• HC/HIV transmission evidence• Rated “low overall quality”• No change from Category 1

WHO Consultation – GRADE Rating

• HC/HIV acquisition evidence• 8 cohort studies met minimum quality

criteria• Rated “low overall quality” but better

studies tended towards harm • Major focus of meeting

Contraception and HIV acquisition from men to women

Adjusted Cox PH Regression analysis

HIV incidence per 100 person years

HR (95% CI) P-value

No hormonal contraception

3.78 1.00

Any hormonal contraception

6.61 1.98(1.06 – 3.68)

0.03

Injectables 6.85 2.05(1.04 – 4.04)

0.04

Oral contraceptives 5.94 1.80(0.55 – 5.82)

0.33

21.2% of women used HC at least once during study

The Great Debate

Observational dataPossible selection biasPotential for Confounding Not always primary study endpointHC use not always well documentedSelf reported condom use unreliableCondom use differed between non-HC arms and HC arms

Progestin injectables and HIV acquisition: The Great debate

1. If left an MEC 1 – no change implies that the data are not convincing enough to support even theoretical concerns about injectable progestins and HIV acquisition

2. If moved to MEC 2 – a change implies that there are theoretical concerns which still allows use but if misunderstood might scare women and jeopardize global use without many alternatives being available

3. The meeting was divided between 1 & 2

The WHO Statement – February 2012

The WHO statement on Progestin-only injectables and HIV acquisition, 2012

………the group concluded that the World Health Organization should continue to recommend that there are no restrictions (MEC Category 1) on the use of any hormonal contraceptive method for women living with HIV or at high risk of HIV. However…..

……..because of the inconclusive nature of the body of evidence on possible increased risk of HIV acquisition, women using progestogen-only injectable contraception should be strongly advised to also use condoms and other preventive measures.

The group further wished to draw the attention of policy-makers and programme managers to the potential seriousness of the issue and the complex balance of risks and benefits.

The WHO statement on Progestin-only injectables and HIV acquisition, 2012

What then happened……

• Some activists, women's organisations and journalists said they did not understand the Category ‘1’ and the clarification

• Requested clarity on the messaging that should be given to women users

• Some researchers and donors considering an RCT as a definitive study

• Widespread calls for increasing the method mix in developing countries

• And the modellers are involved……

Where does high HIV prevalence coincide with high use of injectable hormonal contraceptives?

HIV prevalence among 15-49 year-old women*

The overlap between use of injectables and HIV prevalence

HIV: ‘high’ = > 1%; IHC: ‘high’ = upper quartile.

Injectable hormonal contraceptive use among 15-49 year-old women

*Adult HIV prevalence given for China.

From: AR Butler, JA Smith, D Stanton, TB Hallett. The global impact of an interaction between injectable hormonal contraception and HIV risk (subm.).

Number of HIV infections attributable to hypothesised IHC-HIV interaction per year

Regions with high HIV incidence and high IHC use have the most HIV infections attributable to use of injectable hormonal contraceptives

From: AR Butler, JA Smith, D Stanton, TB Hallett. The global impact of an interaction between injectable hormonal contraception and HIV risk (subm.)

Net effect: balance of reduced AIDS deaths & increased maternal deaths

Absolute change in the number of maternal and AIDS deaths on cessation of IHC use

Maximum benefits of stopping or reducing HC in regions of high HIV incidence and low maternal mortalityIncrease in total number of deaths in areas of high HC use and high maternal mortality

From: AR Butler, JA Smith, D Stanton, TB Hallett. The global impact of an interaction between injectable hormonal contraception and HIV risk (subm.)

And WHO went further to clarify its guidance

Based on current evidence, family planningprogrammes delivering services to women atrisk of, or living with, HIV infection can continueto offer all methods of hormonal contraception.However, as none of these methods protectsagainst HIV, the use of condoms or other HIVpreventive measures should always be stronglyrecommended.

WHO’s programmatic and research recommendations

Provide easy-to-understand and comprehensiveinformation to women and their partners aboutthe benefits of contraceptive options available tothem as well as any associated risks, includinginformation regarding the inconclusive nature ofthe evidence on possible increased risk of HIVacquisition among women using progestogen onlyinjectables.

WHO’s programmatic and research recommendations

WHO Recommendations: Research • Produce definitive epidemiological evidence about

HC and HIV acquisition, transmission & disease progression, evaluating longer-acting methods (e.g. implants, IUDs, injectables) & newer methods not previously included

• An RCT?

A Randomised Controlled Trial?

If millions of men were on a high dose of a first generation statin when newer statins with the same efficacy and fewer side effects was available, and the higher dose made men……

• Put on weight• Made their hair temporarily stop growing• And it took 9 months to return to normal• AND may possibly increase HIV risk

How long would the marketplace tolerate this?

From a Women’s health perspective……

Thank You• Ward Cates• Jenny Smith• Tim Hallett• John Cleland • Ellen Crabtree• Chelsea Polis• Vivian Black• Sharon Phillips• Mary Lyn Gaffield• Mitchell Warren• Charlie Morrison• Maggie Kilbourne-Brook• Zdenek Hel• Melanie Pleanar