International researchers are struggling to settle a 25-year-old debate about the risk of HIV infection in women who use the contraceptive injection Depo-Provera, the common name for depot medroxyprogesterone acetate, a hormone-based contraceptive administered by injection every three months.
More than two-thirds of South African women who are on birth control use Depo-Provera or a two-monthly injection of Neten as their preferred contraceptive method, according to government estimates.
The national department of health states that when used correctly, both Depo-Provera and the oral contraceptive pill, which has to be taken daily, are 99% effective in preventing pregnancy. But, based on typical use, which measures effectiveness based on how people actually use a given method, Depo-Provera is slightly more effective than the pill.
The convenience of using hormone injections can account for their efficacy, says Professor Elna McIntosh, a sexual health practitioner from the Disa Sexual and Reproductive Health clinic in Johannesburg. Unlike the pill, hormone injections do not need to be taken daily, which makes them an easier treatment for many women to adhere to, she says.
Possible linkBut evidence of a possible link between hormone contraception and the risk of HIV infection has been accumulating since the early 1990s. Some studies suggest that Depo-Provera is linked to an increased risk of HIV; many others indicate that there is no association at all.
The latest study on this association, published in January in The Lancet Infectious Diseases medical journal, revealed that women on Depo-Provera were 40% more likely to contract HIV. Researchers found no similar association with the use of the pill or the Neten injection.
Thus far, most evidence pertaining to the use of Depo-Provera and the risk of HIV-infection come from observational studies, which can reveal whether two factors are associated with each other, but cannot determine whether one is causing the other to occur. Given this limitation, some scholars are looking to develop a randomised controlled trial, an experimental study that is better at determining cause and effect. In a controlled trial, participants are randomly assigned to a specific treatment group with the purpose of comparing different groups.
The scholars advocating for the development of a controlled trial are members of the Evidence for Contraceptive Options and HIV Outcomes (Echo) consortium, a multiorganisational group that includes the Wits Reproductive Health and HIV Institute, the University of Washington, the World Health Organisation (WHO) and FHI 360, an international human development organisation.
In the proposed Echo trial, which will take approximately four years to complete, thousands of HIV-negative women in sub-Saharan Africa will be randomly assigned to receive a copper intrauterine contraceptive device, Depo-Provera, or a hormonal implant. Researchers will then compare the rate of HIV acquisition among the three groups.
Criticised But the Echo trial, which will commence later this year, has come under fire from critics who question the ethics of asking women to use Depo-Provera while the risks of doing so remain unknown. Critics also argue that existing observational data on HIV risk and hormonal contraceptives are not strong enough to warrant a lengthy and costly clinical trial.
According to Christopher Colvin, a public health lecturer at the University of Cape Town, the scientific debate over the proposed randomised controlled trial and the strength of existing observational data has become polarised and tense.
"Ultimately, it may be that a trial adds an important layer to our evidence, one that points us in a clearer direction. But it isn't likely to suddenly answer all of our questions, or be a clear and convincing arrow in one direction only," Colvin says.
He argues that researchers need to focus on expanding the debate to include more conversations about different types of research as well as short and long-term endeavours.
"We need to be thinking about all of the evidence at the same time and all of the different decisions we need to make, now and in the future," he says.
Maternal and infant deathsOne reason why the debate is so contentious is because Depo-Provera and other hormonal contraceptives are widely used and have been central in helping to lower the number of maternal deaths, unwanted pregnancies and infant deaths happening worldwide, according to international health agencies.
Maternal mortality is death that occurs during the course of pregnancy, childbirth or within 42 days following the termination of pregnancy. Infant mortality is the death of a child one year old or younger.
The WHO states that closely spaced and ill-timed pregnancies and births contribute to the unacceptably high global rates of maternal and infant mortality, but contraception helps to lower these rates by giving women more control over the timing and spacing of pregnancies and by delaying pregnancies in women who face health risks.
After examining the conflicting evidence in 2012, the WHO concluded that hormone contraceptives were still safe to use without restriction, but emphasised the importance of condom use for those using progestin-only injectables like Depo-Provera.
McIntosh says women are always "strongly advised" to use condoms when on birth control regardless of the type of birth control they use condoms are the only contraceptive that can protect against HIV and other sexually transmitted infections.
The WHO guidelines also advise healthcare providers to tell women that they may or may not be exposed to an increased risk for HIV infection when using progestin-only injectables such as Depo-Provera.
But Helen Rees, head of the Wits Reproductive Health and HIV Institute, and other researchers, health workers and women's health advocates argue that such guidelines are confusing for women and providers alike.
"Imagine you sit down with a woman [who's using Depo-Provera] and say: 'You must use a condom and you may or may not be at risk of HIV.' How can you interpret that, either as a nurse or as a user? It doesn't really mean anything."
Rees says that in the end it's crucial for researchers to find the right answer not only to improve existing guidelines but also to avoid potentially devastating effects on reproductive health programmes, women's access to contraception and rates of maternal death if researchers get the answer wrong.
"If there isn't a problem and we take Depo-Provera off the market then we stand to potentially create a serious gap in the contraceptives available to women, particularly poorer women in poorer countries. That in turn could increase maternal death, [because of a shortage of effective contraception]," she says.
"However if there is an association, by leaving Depo in countries where there is a high prevalence of HIV and where you do have the opportunity to introduce other forms of contraception as alternatives, we might be increasing the number of HIV infections unnecessarily, which in turn could also increase maternal and newborn death."
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