Hormonal contraception and HIV risk in women: more evidence but uncertainty remains

Injectable hormonal contraception may raise the risk of HIV infection for women, but it does not appear to increase the risk of HIV disease progression in women with HIV, according to findings from two new studies presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

However, the possible increased risk from injectable hormonal contraception seen in the study presented today is unlikely to be large enough to justify further changes in advice to women. Injectable hormonal contraception makes a substantial contribution to reducing the risk of death due to unintended pregnancy or complications of childbirth.

Around 14 million women in sub-Saharan Africa use a hormonal form of contraceptive and 60% of these women use an injectable, long-lasting form of hormonal contraceptive.

Concerns about injectable hormonal contraception have arisen as a result of a number of studies showing a higher risk of HIV infection in women who are using an injectable hormonal contraceptive as a method of birth control. (See research presented in 2011 here). However, not all studies have found such an increased risk.

Last month the World Health Organization convened an expert consultation to review this evidence, but decided that “the data were not sufficiently conclusive to change current guidance. 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 always use condoms, male or female, and other HIV preventive measures”. (See full technical statement here.)

The technical review noted no evidence of a significant association between oral contraceptive use and HIV acquisition in studies that were judged to have a design that was sound enough to minimise biases in the data.

The review also noted no evidence from well-designed studies of a  significant association between use of norethisterone enanthate (NET-En) as an injectable hormonal contraceptive and an increased risk of HIV acquisition.

In the case of other injectable hormonal contraceptives (such as DMPA) the evidence was mixed, with some higher-quality studies failing to show an association with an increased risk of HIV acquisition.

New studies

The technical review did not consider the studies presented today.

The first study was a data analysis of the relationship between oral and injectable hormonal contraceptive use and HIV acquisition in the Methods for Improving Reproductive Health in Africa (MIRA) trial, a large trial that evaluated the use of diaphragm and lubricant gel in the prevention of HIV infection among women in sub-Saharan Africa. The trial was not specifically designed to evaluate the effect of hormonal contraception on HIV risk.

The trial recruited sexually active women who were followed for up to two years and the analysis presented to the conference reported on 4866 women. Participants underwent pregnancy testing and screening for HIV and for sexually transmitted infections at quarterly visits. A total of 274 women became infected with HIV during the study.

The investigators evaluated the risk of HIV infection according to contraceptive type among non-pregnant women in the study, compared to women who did not use a hormonal contraceptive. The contraceptive methods were classified as follows:

• Combined oral contraceptive pills (COC)
• Progestin-only pills
• Injectable hormonal contraceptives (DMPA or NET-En)
• Non-hormonal methods (no contraception, condoms, withdrawal, traditional methods, etc)

The investigators used several statistical approaches to their analysis. The analysis found no increase in the risk of HIV infection in women who used combined oral contraceptives (adjusted hazard ratio 0.88, 95% confidence interval 0.59-1.32) or progestin-only contraceptive pills (aHR 1.02, 95% CI 0.58-1.81) in any of their analyses.

The results for injectable hormonal contraception depended on the analysis technique. Using a Cox proportional hazards model, women who used injectable contraceptives were at 37% higher risk of HIV infection (aHR 1.37, 95% CI 1.01-1.86, p = 0.04).

However, when the two types of injectable contraceptive were analysed as separate categories, neither were associated with an increased risk of HIV infection.

However the result for injectable hormonal contraception depended on the statistical method used to control for confounding factors. A method which better controlled for factors which might vary over time and confound the association between hormonal contraception and HIV risk, such as the level of condom use, found no significant increase in the risk of infection among women using injectable hormonal contraception (aOR = 1.16 95% CI 0.97-1.53).

The use of a causal inference technique to examine the ‘direct effects’ of injectable hormonal contraception – a  statistical technique which simulated what would happen in a hypothetical randomised trial of contraceptive methods where women were constrained from using condoms – showed a similar increased risk of injectable hormonal contraception as the Cox model.

Sandra McCoy of the University of California at Berkeley, presenting the results, concluded that the findings underscore the continued importance of dual protection for women at high risk of HIV infection who use injectable hormonal contraception – which in many settings in sub-Saharan Africa could apply to the vast majority of women using this contraceptive method. She also noted that the variability in the results by statistical analysis method highlights the importance of adequately controlling for confounding (e.g., other factors that might explain the results).

The second study looked at the risk of HIV disease progression according to contraceptive type among HIV-positive women enrolled in the Partners in Prevention study, a large trial which evaluated the effect of acyclovir treatment for the herpes virus HSV-2 on the risk of HIV transmission in HIV-serodiscordant partnerships in sub-Saharan Africa.

Some evidence of a negative effect of hormonal contraception has been reported in one study, although a large cohort study of over 4500 women failed to find an increased risk, and the WHO technical review on hormonal contraception noted that a total of ten studies have now failed to find any increased risk of disease progression. Nevertheless the technical review concluded that because of limitations in the design of these studies, the overall body of evidence on hormonal contraception is 'weak' and in need of improvement.

The analysis of the Partners in Prevention study looked at the relationship between contraceptive usage and disease progression in 2236 women recruited to the study in southern and eastern Africa. Hormonal contraception of some form was being used by 18.7% of HIV-positive women at the beginning of the study, and in the majority of cases they were using an injectable hormonal contraceptive. (A separate analysis of this study, recently reported, showed that women who used an injectable method, among the study population as a whole, were less likely to become pregnant but more likely to become infected with HIV.)

 Disease progression was evaluated by two measures:

• Any one of the following: death for any reason apart from trauma or accident; the need to start antiretroviral therapy due to CD4 cell decline or clinical illness as indicated in guidelines; or a CD4 cell decline below 200 cells/mm³
• A CD4 cell decline below 500 cells/mm³ in women who became infected during the study.

The disease progression rate observed in women with HIV at baseline was 11.5 events per 100 person-years of follow-up, and 377 events were observed during the study.

The rate of disease progression was significantly lower among women using a hormonal contraceptive of any type when compared to women not using hormonal contraception (aHR 0.75, 95% CI 0.56-0.99, p = 0.03). There was no significant difference between women using injectable and non-injectable hormonal contraception.

A similar association was seen in women who became infected with HIV during the study; those who used any hormonal contraceptive method were around 75% less likely to experience a CD4 cell decline below 500 cells/mm³ (aHR 0.26, 95% CI0.07-0.97, p = 0.05).

Discussion

The findings presented today are likely to add a further layer of complexity in communicating the safety of hormonal contraceptive methods, especially to women in settings where the risk of HIV infection is high.

In its technical review of the data on hormonal contraception and HIV risk the World Health Organization’s expert advisory group stressed the importance of informing women without HIV of the need to use condoms as protection against HIV infection while using an injectable hormonal contraceptive.

The guidance further reinforces the need for closer integration of sexual and reproductive health programmes with HIV prevention activities.

However, HIV programmes also need to consider how they communicate the guidance – and the findings presented today – to women with HIV. There is a danger that the substantial potential benefit of hormonal contraception to women living with HIV could be diminished if messages about hormonal contraception do not make clear that:

• Hormonal contraceptive methods are highly effective in preventing unintended pregnancy, and therefore in reducing the risk that a child might be born with HIV, or die of other causes in settings where infant mortality is high.
• Using hormonal contraception could have an important benefit for the mother’s own health because it prevents unintended pregnancy. In settings where maternal mortality is high due to complications of pregnancy or childbirth, the efficiency of contraception is an important consideration when seeking to reduce maternal mortality rates in women with HIV.

At a population level a shift towards less effective contraceptive methods may have the paradoxical effect of increasing the total number of HIV infections over time, pointed out Dr Karen Beckerman of Albert Einstein College of Medicine, New York, if a substantial rise in the birth rate increases the number of sexually active young adults within one generation.