Should women with HIV, or at high risk of contracting HIV, use progestogen-containing contraception?BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f6695 (Published 14 November 2013) Cite this as: BMJ 2013;347:f6695
- Sarah Louise Giles, GP locum and overseas volunteer doctor at Kitovu Hospital, Masaka, Uganda1,
- Felicia Lester, assistant professor2
- 1c/o Uganda River of Life Ministries, PO Box 985, Masaka, Uganda
- 2University of California, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California, USA
- Correspondence to: S L Giles
Nearly 150 million women worldwide use hormonal methods of contraception, predominantly oral contraceptives taken daily (both combined hormonal pills and progestogen-only pills for the purpose of this article) and long acting injectables such as depot medroxyprogesterone acetate and norethisterone enantate.1 When used correctly, these are highly effective in preventing pregnancy and are reversible. Side effects of medroxyprogesterone are similar in those who are seropositive for HIV and those who are HIV negative,2 and antiretroviral therapy does not reduce its effectiveness.3 However, antiretroviral therapy can make oral contraceptives less effective at preventing pregnancy, and oral contraceptives can increase antiretroviral drugs’ toxicity.3
Concerns have been raised about possible harmful effects of hormonal contraception in patients infected with HIV and those at high risk of contracting HIV. These effects can be considered in three main categories: HIV acquisition, HIV infectivity, and rate of progression of HIV. Several biologically plausible mechanisms have been proposed for these effects, including effects on genital HIV viral shedding, vaginal epithelial thickness, degree of cervical ectopy, or local and systemic immune responses.4 However, there is little consistent evidence.
Any potential for harm is important given that in sub-Saharan Africa, women of childbearing age are disproportionately affected by HIV. It is essential to offer women the opportunity to prevent HIV acquisition, not only for their own health but to prevent mother to child transmission. The most upstream means of primary prevention for HIV is preventing unintended pregnancy in the first place. Disease progression puts the woman at risk of opportunistic infections and increases the risk of transmitting the disease to an uninfected partner.
However, it is equally important to avoid denying access to contraceptives without adequate evidence, since those areas where unintended pregnancy poses the greatest threat to women’s lives are often the same areas where the risks of HIV acquisition are the highest.
There are no firm recommendations to guide the contraceptive choices for HIV positive patients, and even recent advisory publications by the World Health Organization5 and Centers for Disease Control and Prevention6 have seemed reluctant to take a definitive stand.
What is the evidence of uncertainty?
We searched PubMed and the Cochrane Library for randomised controlled trials and systematic reviews published up to and including July 2013, using the search terms “contraception” AND “hormonal” AND “HIV” to answer the following questions.
Does use of progestogen-containing contraceptives increase acquisition of HIV by women?
Most observational studies found no statistically significant association between oral contraceptive use and HIV acquisition (with most studies analysing oral contraceptives as a group). A recent systematic review7 identified eight prospective observational studies meeting minimum quality criteria. Seven of the studies assessed the impact of oral contraceptives on HIV acquisition, only one of which found a borderline significant effect (adjusted hazard ratio 1.46 (95% confidence interval 1.00 to 2.13)).8 A secondary data analysis of 4913 women, too recent to be included in the systematic review, showed no significant association between HIV acquisition and use of progestogen-only pills or combined hormonal pills.9
In the systematic review,7 there was inconsistent evidence of a relation between use of injectable contraceptives and HIV acquisition: three studies noted an increased rate of HIV acquisition, whereas five showed no association. This heterogeneity could reflect differences in study design. The three studies showing positive associations had methodological strengths including short inter-survey intervals, adjustments for time-dependent confounding, and validation of reported contraception use with clinical records. However, the degree of effect seen was variable, with adjusted hazard ratios ranging from 1.48 (1.02 to 2.15)10 to 2.05 (1.04 to 4.04).11 Some of the effect, if present, could be mediated by differences in sexual behaviour in hormonal contraception users.
Only three studies in the systematic review7 and a more recent (unpublished) secondary analysis of a large multi-country microbicide trial specifically evaluated use of injectable norethisterone enantate,12 showing no significant association with HIV acquisition. If norethisterone is truly safer than medroxyprogesterone acetate regarding HIV acquisition, this might reflect differences in the degree of ovulation suppression (as evidenced by increased likelihood of amenorrhoea with medroxyprogesterone13), resulting in different degrees of vaginal atrophy. Additionally, molecular studies suggest that these progestogens may modulate local immune capacity in the vaginal epithelium in different ways.14
Does use of progestogen-containing contraceptives increase HIV infectivity (that is, HIV transmission to seronegative male partners)?
Only one, well conducted, observational study directly measured incident HIV infection rate in male sexual partners.11 Although it suggests that use of injectable contraception (but not oral contraception) significantly increased female-to-male HIV transmission, it was underpowered to do so.
Two systematic reviews were identified,15 16 and the 2013 review identified only observational studies.16 Apart from the one study directly measuring incident HIV infection in male partners,11 the other 11 studies considered genital viral shedding or plasma viral load as an imperfect proxy for infectivity.
The direct study included 2476 serodiscordant couples in which the seronegative partner was male. It showed a doubling of HIV transmission to male partners of HIV positive women using medroxyprogesterone with an adjusted hazard ratio of 1.95 (1.06 to 3.58). There was also an increased risk with use of oral contraception (mostly combined oral contraceptives), but this was not statistically significant.11 This study had many methodological strengths, including frequent follow-up, low loss to follow-up, and statistical adjustment for multiple confounders, as well as genetic linkage of HIV transmission, but the total number of transmissions was small, and statistical power and precision limited.
Most of the indirect studies were cross-sectional, with associated difficulty in assigning temporal association, and most showed no effect of hormonal methods on genital RNA or DNA shedding. There was also no convincing association between use of hormonal contraception and viral load.
Does use of progestogen-containing contraceptives affect disease progression in HIV positive women?
In a 2013 systematic review of 11 studies,17 only one flawed randomised trial showed increased disease progression in HIV positive women using hormonal contraception,18 19 while the other 10 cohort studies (only two of which were considered methodologically strong20 21) did not suggest any increase in disease progression.
The randomised trial was carried out in 599 HIV infected postpartum women who were not receiving antiretroviral therapy at the time of randomisation.18 19 However, it was not designed or powered to detect an impact on HIV progression by method of contraception, lacked a control group receiving no contraception, and had a high loss to follow-up and disproportionate discontinuation of contraceptive method in the group using an intrauterine device. Thus actual use analysis was performed in addition to intention to treat, although this negates the advantages of randomisation. This showed a significant increase in composite disease progression in users of hormonal contraception compared with users of a copper intrauterine device (the T380A): with intention to treat analysis, medroxyprogesterone had a hazard ratio of 1.81 (1.30 to 2.53) and oral contraceptive had a hazard ratio of 1.52 (1.00-2.32); with time varying analysis, adjusted hazard ratios for medroxyprogesterone and oral contraceptive were 1.62 (1.16 to 2.28) and 1.67 (1.10 to 2.51) respectively (results for the two types of hormonal contraception were not significantly different).19 Importantly, the rate of pregnancy was also higher in users of hormonal contraception (hazard ratio 2.4 (1.3 to 4.7)).
The systematic review included seven prospective cohort studies (including a large multicountry analysis22), none of which reported an increase in HIV disease progression with hormonal contraception. Some studies had few contraceptive users, and the relatively long follow-up periods (usually at least 2 years) may still be insufficient.
Is ongoing research likely to provide relevant evidence?
We searched the Clinical Trials database, using the search terms “hormonal” AND “HIV” AND “contraception” and were unable to find any upcoming trials relevant to this article. However, a meta-analysis pooling the individual patient data for about 37 000 women from 18 studies is reportedly being undertaken by Morrison and colleagues at Family Health International, and this may shed more light on the impact of hormonal contraception on HIV acquisition.
What should we do in light of the uncertainty?
In 2012 the WHO recommended that there should be no restriction on the use of any hormonal contraceptive method for women living with HIV or at high risk of acquiring it.5 However, it also recommended that women using progestogen-only injectable contraception be strongly advised to use condoms (male or female) and other preventive measures against HIV transmission (such as encouraging voluntary counselling and testing and avoiding high risk sexual behaviours). Subsequent recommendations by the Centers for Disease Control and Prevention concurred with this guidance.6
Current evidence suggests that medroxyprogesterone (but not oral contraceptives) may increase HIV acquisition, albeit to an uncertain degree and without high quality evidence. Norethisterone may be a safer injectable option, but further work is needed to clarify this. Oral contraceptive use does not seem to increase HIV acquisition (and limited observational evidence for progestogen-only pills is reassuring9).
Medroxyprogesterone may be associated with an increased female-to-male transmission of HIV, but the evidence is weak. The data regarding HIV progression are conflicting. There is a lack of good quality work considering newer hormonal methods. Options to discuss in counselling women should include:
Simultaneous use of condoms, particularly (but not exclusively) if medroxyprogesterone is the chosen method of contraception. This would offer additional protection against other sexually transmitted infections, which would be beneficial since Herpes simplex virus 2, in particular, increases heterosexual transmission of HIV. However, dual use is not commonly practised by couples, even in research settings, and its promotion may stigmatise barrier methods. In addition, many women choose injectable contraception because they are unable to use condoms.
Alternative methods of contraception—Oral contraceptives (though with potential interactions with antiretroviral therapy3), the copper intrauterine device (with careful exclusion of sexually transmitted infections and monitoring for pelvic infection), and possibly injectable norethisterone (if superior safety is confirmed) seem safer than injectable medroxyprogesterone. We await further information on other methods of female contraception such as the cap (which may offer cervical protection against HIV) and intrauterine devices containing levonorgestrel and implants containing progestogen (as these contain far lower levels of progestogen than medroxyprogesterone and so may carry less risk).
Importance of accessing antiretroviral therapy—A recent (unpublished) small cohort study showed no change in HIV infectivity (assessed indirectly by viral load) in HIV positive women taking antiretroviral therapy who started medroxyprogesterone, leading the authors to recommend priority initiation of antiretroviral therapy in women intending to use hormonal contraception.23
We should not deny medroxyprogesterone to women who want to use it, as there is insufficient evidence against its use; preventing unintended pregnancy must continue to be at the forefront. Some healthcare providers might be reluctant to discuss the possible risks, for fear that patients will abandon medroxyprogesterone without seeking an alternative method of contraception. It is important help providers understand the evidence in context and equip them to counsel women effectively, as well as to train them to provide alternative methods such as intrauterine devices. Involving male partners in contraception counselling may make simultaneous use of condoms or use of less familiar methods more acceptable.
Contextualising any potential risk with hormonal contraception is of the utmost importance; it must be balanced against the risks of maternal morbidity and mortality, infant morbidity and mortality, and unsafe abortion24—risks that are substantial in sub-Saharan Africa.25
Recommendations for further research
Population—Couples who are serodiscordant for HIV-1. Consider younger women (who might be at higher risk10) and high risk groups such as commercial sex workers.
Intervention and comparisons—Ideally use randomised trial design to clarify impact of different hormonal contraceptive methods on HIV acquisition and infectivity, using non-hormonal methods (such as copper intrauterine devices) as controls (in view of ethics of randomising to use of male condoms only). Consider methods that have not yet been adequately explored (such as progestogen-only pills) and newer methods (such as contraceptive ring, patch, implant, or intrauterine device with progestogen). Consider medroxyprogesterone and norethisterone separately.
Outcome—HIV acquisition and infectivity as assessed directly (rather than with surrogate markers). Minimise differential method discontinuation, which could compromise results, by careful counselling of participants.
Much of the current evidence is observational and derived from studies that were not designed for purpose. Should a randomised controlled trial be carried out, it would be easier to counsel women with confidence. However, the trial would be a logistical challenge and would likely take many years for results to be obtained.
Cite this as: BMJ 2013;347:f6695
This is one of a series of occasional articles that highlight areas of practice where management lacks convincing supporting evidence. The series adviser is David Tovey, editor in chief, the Cochrane Library. To suggest a topic, please email us at email@example.com.
Contributors: SLG conceived of and designed the article, undertook the initial literature search, and wrote the initial draft. Both authors interpreted and revised the data, and approved the final article.
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; externally peer reviewed.