Hormonal Contraception and HIV

A ROUNDTABLE AT THE INTEREST WORKSHOP, LUSAKA, 2014 • Professor Helen Rees, Wits RHI, Johannesburg, SA • Dr Mike Mbizvo, Zimbabwe • Dr Chelsea Polis, USAID, Washington • Dr Nelly Mugo, Kenyatta National Referral Hospital and UW

1. Global rates of change in maternal mortality are slow, and only 16 countries will achieve the MDG 5

target by 2015.

Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic

analysis for the Global Burden of Disease Study 2013. The Lancet, May 2014.

MMR in Sub Saharan Africa 510/100,000 live births UN MDG 2013

2. Estimated number of adults and children newly infected with HIV, 2012

Relative risk of death during pregnancy for HIV +ve versus HIV –ve women

Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic

analysis for the Global Burden of Disease Study 2013. The Lancet, May 2014.

3. Contraception is an essential public health tool in the prevention of maternal mortality in HIV+ve and HIV–ve

women and in preventing MTCT. Over 150 million women use hormonal contraception, primarily oral contraceptives and injectable progestins.

Hormonal contraceptives constitute over 57% of methods used in Africa

Use of injectable progestin contraceptives has increased in Africa.

Hormonal Contraception and HIV: What to consider

Women at risk for HIV

Acquisition

Women infected with HIV

Infectiousness Disease progression

Drug interactions

Prevention

Biological Plausibility that hormones may influence HIV acquisition

• Vaginal and cervical epithelium (mucosal thickness, cervical ectopy, etc.)

• Changes in cervical mucus • Menstrual patterns • Vaginal and cervical immunology • Viral (HIV) replication • Acquisition of other STI that may serve as mediators • However, data are often sparse or potentially could point in different

directions, and, most importantly, without clinical data no laboratory study would be sufficient to answer this question….

Where did the debate begin?

Exposure Status

Number Exposed

Number Infected

Rate

RR 95% (CI)

Progesterone Implants

18 14 77.8 2.1 (0.9-4.9)

Placebo - Cycle Phase

11 4 36.4 7.8 (2.8-16.1)

Placebo - Follicular Phase

10 1 10.0

Preston Marx. Nature Med., 1996

DMPA J. Infect. Dis., 2004

DMPA Virology, 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

New animal data Physiologic doses of DMPA (unlike what have been used in previous studies, which have been much larger) in pigtail macaques did not increase plasma viral load or genital viral shedding; suggesting a possible non-biological explanation (e.g., potential confounding) for increased in female-to-male HIV transmissions with DMPA use by the female partner observed in one clinical study (if effects seen in macaques in this study are similar to effects in human women). Radzio 2014

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.

But new biological data continues to confuse…… “The results of this study confirm that DMPA use for up to 18 years exerts no effect on vaginal thickness or on Langerhans cell count……….we also believe that if DMPA users are at a greater risk of HIV acquisition, the mechanism is probably unrelated to the change in vaginal thickness or atrophy provoked by the hypoestrogenic status induced by this contraceptive method.” Bahamondes, 2014

What do the many clinical trials tell us….?

In subgroup analysis, injectable contraceptive users had increased risk for acquiring and transmitting HIV-1 to their partner and HIV-1 seropositive women using injectable contraception had higher genital HIV-1 RNA concentrations,

suggesting a mechanism for increased transmission risk.

There is no evidence of an association between HIV infection and injectable contraceptives.

Addressing the gap in information and action related to hormonal contraception and HIV to ensure that complex and confusing messages from international sources are clarified, and that women in communities with the greatest need for clear information are included in the design and implementation of new clinical trials aiming to provide more evidence and answers.

WHO’s Medical Eligibility Criteria for Contraceptive Use

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

M

*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 .

Maternal mortality ratio (Death per 100,000 live births) 2013

At the end of this Roundtable ask yourselves this……

1. What does the current data tell you about the relationship between hormonal contraceptives, especially DMPA, and HIV?

2. Is there enough data to allow policymakers to confidently make policy recommendations about either the ongoing use of DMPA or on its withdrawal in high HIV/high maternal mortality settings?

3. If not, what additional studies would you suggest to develop a more definitive answer to this question?

If there was a drug used by 100 million men worldwide, with a twenty year old serious yet unanswered question relating to HIV risk, wouldn’t the world have spent money on finding the answer by now? And wouldn’t the world be investing more in new generation drugs?

With thanks

• Ward Cates, FHI 360 • Charlie Morrison, FHI 360 • Chelsea Polis, USAID • Susie Cornell, Wits RHI • And to the many researchers who continue to

grapple with this problem and the women who try to make sense of the feedback