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Contraception and HIV Professor Helen Rees

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1 Contraception and HIV Professor Helen Rees
Executive 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

2 “Love is the answer, but while you are waiting for the answer, sex raises some pretty good questions.” Woody Allen

3 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.

4 Trends in Maternal Mortality Ratios
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) WHO 2010

5 Over 150 million women use hormonal contraception worldwide, primarily oral contraceptives (OCs) and injectable depot-medroxyprogesterone acetate (DMPA).

6 The overall demand for contraception is increasing
% of married women aged 15–49 The demand for contraception worldwide is increasing, while unmet need is decreasing in most regions. As demand increases family planning programs have to satisfy not just unmet need, but also the growing number of users of family planning methods. Latin America & Caribbean North Africa & West Asia South & Southeast Asia Sub-Saharan Africa 6

7 Method mix: among currently married (CM) & sexually active not married (NM) women , % using specific method Source: Demographic and Health Surveys

8 The importance of some reasons for non-use has changed over time
% of married women aged 15–49 with unmet need We compare estimates from the earliest round of the Demographic and Health Surveys (late 1980s) with those from the most recent round (early 2000s). Nonuse due to lack of knowledge about family planning declined between the late 1980s and early 2000s. This suggests that programs to raise awareness about family planning are working. However, health concerns and fear of side effects have increased. Note: Earlier surveys asked women to provide only their primary reason for nonuse, whereas recent studies solicited all of their reasons for nonuse. However, since most women gave only one reason for nonuse in recent surveys, an informal comparison of trends can be undertaken. We explore trends in women’s reasons in the eight countries for which information was available in both time periods. 1986–1989 2002–2005 8

9 Adherence in contraceptive use
189 progestin injectable users followed up for 2 years in family planning clinic in Soweto Status 1 year 2 years (%) n Continued 42 79 21 39 Lost to follow up 30 57 35 67 Discontinued 28 48 41 78 Withdrew 2 5 Of those who discontinued: 40% ‘taking a break’ >50% complained of side effects Beksinska, Rees et al. Contraception 64(2001)

10 Adult female HIV prevalence

11 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 Contraception Element 1 Element 2 Element 3 Element 4 . Significant contribution coming from the provision of contraceptive information, services and counselling.

12 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%) 519 initiation sites vs 332 down-referral sites Baseline pregnancies: 38 (4.3%) pregnant at baseline and excluded – 32% EFV conceptions Eligibility criteria: , on ART, not pregnant, no prior sterilization/hysterectomies

13 How far can we push Dual Method use
How far can we push Dual Method use? Condom use at last sexual intercourse, amongst injectable contraception users Glass ceiling? Source: Demographic and Health Surveys

14 Contraception and HIV: What to consider
Women at risk for HIV Women infected with HIV Disease progression Drug interactions Prevention Acquisition Infectiousness 14

15 Contraception and HIV: How WHO guidance has worked…
Disease progression Acquisition Infectiousness 15

16 WHO’s Medical Eligibility Criteria for Contraceptive Use

17 WHO consultants & committee:
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

18 Eligibility Criteria for Contraceptive use: WHO Classifications
Classification of Conditions Definition 1 No restriction on use 2 Benefits generally outweigh risks 3 Risks generally outweigh benefits 4 Unacceptable health risk Definition

19 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” Review the problems with each of the existing studies. Source: WHO Medical Eligibility Criteria (2008) HC/HIV Update, August '11

20 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 Review the problems with each of the existing studies. Source: WHO Medical Eligibility Criteria fourth edition 2009 HC/HIV Update, August '11

21 Progesterone Nature Med., 1996 DMPA Virology, 2006 DMPA J. Infect. Dis., 2004 - 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

22 Reported effects of progesterone and its derivatives on immune system & HIV-1 infection.
Reported effect of progesterone or its derivatives References Inhibition of IgG and IgA production and trans-epithelial transport (78;87-96; ) 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 ( ) Inhibition of T cell responses and cytotoxic activity ( ;147) Inhibition of perforin expression in T cells ( ; ) 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; ) 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) Hel Z. et al., Endocrine Rev., 2010,

23 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 Slide 3: Possible Mechanisms - Susceptibility: This slide shows some of the possible mechanisms by which the risk of HIV acquisition might be enhanced or in some cases reduced by hormonal contraception. Changes in the vaginal/cervical epithelium: For example cervical ectopy appears to be associated with oral contraceptive use and the glandular and vascular nature of columnar epithelium associated with cervical ectopy may enhance a woman’s susceptibility to the virus. Also, thinning of the vaginal epithelium associated with DMPA use could enhance risk of HIV transmission. Also DMPA use may lead to a reduction in hydrogen-peroxide producing lactobacilli in the vagina. The corresponding increase in vaginal pH may be enhance HIV acquisition. Cervical mucus: Thick cellular cervical mucus associated with OC use may increase the number of HIV target cells and thus increase women’s susceptibility to HIV. Increased numbers of lymphocytes may also increase a woman’s infectiousness to her sex partner. Menstrual Patterns: Irregular uterine bleeding may lead to an increased risk of HIV while reduced volume of menstrual flow and reduced retrograde menstruation among hormonal users may serve to reduce HIV susceptibility. . HC/HIV Update, August '11

24 Studies of Injectables & HIV Acquisition
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 Source: Adapted from Polis (2011)

25 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

26 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

27 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

28 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

29 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 pregnancy morbidity & mortality Unwanted pregnancy may have worse infant outcomes

30 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 pregnancy Morbidity & Mortality Potential for transmission to infant Unwanted HIV infected babies have higher morbidity and mortality than wanted infants

31

32 Studies of Injectables & HIV Acquisition
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 Source: Adapted from Polis (2011)

33 WHO Expert Consultation on HC and HIV
4/6/2017 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 HC/HIV Update, August '11

34 WHO Consultation – GRADE Rating
HC/HIV progression evidence 1 RCT, 6 cohort studies Rated “low overall quality” No change from Category 1

35 WHO Consultation – GRADE Rating
HC/HIV transmission evidence Rated “low overall quality” No change from Category 1

36 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

37 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

38 The Great Debate Observational data Possible selection bias Potential for Confounding Not always primary study endpoint HC use not always well documented Self reported condom use unreliable Condom use differed between non-HC arms and HC arms

39 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

40 The WHO Statement – February 2012

41 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…..

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

43

44 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……

45 Where does high HIV prevalence coincide with high use of injectable hormonal contraceptives?
HIV prevalence among year-old women* The overlap between use of injectables and HIV prevalence *Adult HIV prevalence given for China. Injectable hormonal contraceptive use among year-old women Overlap in southern and eastern Africa. Current use taken form world contraceptive use data table over last five years. Sources DHS onwards but took most recent available data. Older countries DMPA not sued mus=ch. HIV: ‘high’ = > 1%; IHC: ‘high’ = upper quartile. From: AR Butler, JA Smith, D Stanton, TB Hallett. The global impact of an interaction between injectable hormonal contraception and HIV risk (subm.).

46 Number of HIV infections attributable to hypothesised IHC-HIV interaction per year
Excess infections in past year attributed to HC - % of new infections Number countries with generalised epidemics this is stronger data. Be more cautiois eg with Thailand becvasue of cocnentrated epidcmics. annotated next to each bar is the rank out of all countries with available data (116 total). Looking at 205 onwards. Taken country numbers form tow maps above. 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.)

47 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 Absolute numbers. Overall, stopping all IHC use would reduce the total deaths per year globally by 45,000 with an odds ratio of 2.19, but would result in an increase of 5,700 deaths with the more modest estimate of 1.2. If there is no real effect of IHC on HIV acquisition then stopping IHC would cause at least 18,000 more maternal deaths per year worldwide, spread primarily through Africa and South and South-East Asia. Need to be more certain about recommending stopping. Maximum benefits of stopping or reducing HC in regions of high HIV incidence and low maternal mortality Increase 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.)

48 And WHO went further to clarify its guidance

49 WHO’s programmatic and research recommendations
Based on current evidence, family planning programmes delivering services to women at risk of, or living with, HIV infection can continue to offer all methods of hormonal contraception. However, as none of these methods protects against HIV, the use of condoms or other HIV preventive measures should always be strongly recommended.

50 WHO’s programmatic and research recommendations
Provide easy-to-understand and comprehensive information to women and their partners about the benefits of contraceptive options available to them as well as any associated risks, including information regarding the inconclusive nature of the evidence on possible increased risk of HIV acquisition among women using progestogen only injectables.

51 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?

52 A Randomised Controlled Trial?

53 From a Women’s health perspective……
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?

54 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


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