CAPE TOWN, South Africa – The most popular form of contraception in South Africa may be linked to an increased vulnerability to HIV infection, but health professionals have no guidance on what to do about it.

In a country where more than 22 percent of women aged 15-49 are HIV positive, the potential link is cause for concern among providers. The three-month injectable contraceptive, sold under the Depo-Provera brand, is provided for free by the South African government.

The latest Demographic and Health Survey showed 17.7 percent of South African women are using it. If there were a causal link between Depo-Provera and increased vulnerability to HIV, these numbers would put millions of women at risk. However, a such a link has yet to be definitively proven.

One recent study, from the Population Research Institute, showed Depo-Provera increased women’s risk of acquiring HIV by 49 percent when compared with women who did not use hormonal contraception. But other studies have not shown the same increase.

The differing results have caused confusion among healthcare providers, so in December 2016 the World Health Organisation Guidance Group, made up of scientists and researchers from around the world, reviewed 13 observational studies that showed the potential risk of increased HIV vulnerability when using Depo-Provera.

Their guidance note, issued this year, expresses concern and recommends women be told about a possible increased risk. It does not, however, suggest the withdrawal of Depo-Provera.

In South Africa, health professionals explain the popularity of Depo-Provera by the ease of its use: It is more convenient than taking a daily pill, it requires less frequent clinic visits and no supplies need to be kept at home.

“For many women, Depo-Provera has been a godsend,” says Marion Stevens, chairperson of the Sexual and Reproductive Justice Coalition. “But the challenge is that there is no policy position [in South Africa] on what to say about these potential risks.”

The South African National Contraceptive Clinical Guidelines note that “the benefits of the injectable to prevent pregnancy need to be weighed against the possible risk of HIV” but do not specify what a doctor should say to their patient when she asks about Depo-Provera.

If women are not able to use Depo-Provera, the other options are a two-month injectable, the contraceptive pill or the contraceptive implant. But not all of these methods are equally available at all facilities.

Professor Helen Rees, executive director of the WITS Reproductive Health and HIV Institute, says that early observational studies conducted in the late 2000s looking at HIV and the three-month injectable weren’t consistent.

“Some have shown increased risk and some have not,” she says. “You’ve also got problems with the methodology.” She says these studies were focused on other research – such as the efficacy of various microbicides – and not on Depo-Provera exclusively.

In addition, they were not able to isolate for all variables, for example whether the participants changed to different forms of contraception during the study.

Since then several studies have been better designed and Rees says that “the observational data as it stands at the moment tends to suggest an increased risk with Depo-Provera when compared with other hormonal methods.”

Now, scientists are trying to find a definitive answer as to why or if Depo-Provera puts women at increased risk of HIV contraction.

The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial is the first-ever randomized trial looking at three contraceptive methods and their impact on HIV vulnerability.

The study is being undertaken at 12 sites in four countries (Kenya, South Africa, Swaziland and Zimbabwe) and looks at Depo-Provera, a two-year implant called Jadelle and copper intrauterine devices (IUDs) – which are not based on hormones.

“The women who are enrolled are HIV-negative women who are seeking contraception, are sexually active and are happy to be enrolled in one of these three methods,” Rees explains.

These women receive counseling to make sure they understand the goals of the study and the benefits and risks associated with each method. They are asked to continue on the method for a minimum of 12 months, and up to 18 months.

The early results of the ECHO Trial will only be released in late 2018 or early 2019. Until then, women in South Africa will still be able to opt for Depo-Provera at their local health clinics. Given the number of South African women using Depo-Provera as a preferred method, removing it as an option while the trial is underway could put many women at risk of unwanted pregnancy.

Until the results of the ECHO Trial are out, there is no evidence that getting a Depo-Provera injection increases a woman’s risk of contracting HIV, but the observational studies are cause for concern.

This puts doctors in a difficult predicament. For Dr. Tlaleng Mofokeng, a reproductive rights activist, the crux of the matter is that women should have access to the latest and best information about contraception and be able to use their preferred option.

“At the very least, women must be given information to enable real informed consent,” she says.

This is why, Mofokeng says – like the World Health Organisation’s 2017 guidance note – women should be advised of the potential links between Depo-Provera and HIV, even before the results of the ECHO Trial are out.