Women as Likely to Get HIV on DMPA as Other Contraceptives

Heather Boerner

June 17, 2019

Women who use long-acting, progestin-only injectable contraception are no more likely to acquire HIV than those using other long-acting methods, according to results from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial (NCT02550067).

Some previous studies have shown a twofold increase in the risk for HIV acquisition among women using injectable depot medroxyprogesterone acetate (DMPA, Depo-Provera), "but this trial clearly rules this out," said Jared Baeten, MD, from the University of Washington in Seattle.

ECHO is the first and, researchers say, potentially last, randomized multicenter open-label trial to compare HIV acquisition rates in women using one of three methods of contraception: copper intrauterine device (IUD), intramuscular injection of DMPA, and levonorgestrel implant (Norplant).

The highly anticipated results drew crowds that watched the presentation remotely on YouTube and Zoom.

The findings are "reassuring," said Baeten, who added that women and their physicians can now feel confident that all three contraceptive methods are safe, effective, and do not increase HIV risk.

Baeten, along with the rest of the ECHO team, presented results during a satellite session at the South African AIDS Conference 2019 in Durban. The study was also published online in the Lancet.

Although this study is completed, the work is not over, Baeten said. Now, more contraceptive options, HIV prevention medication, and integrated HIV and family planning services need to be made available to women around the world.

From Signal to Randomization

When Baeten and his colleagues started ECHO in 2015, they were not sure what they would find because previous results had been mixed.

Studies had shown that intramuscular injections of DMPA and sometimes other progestin-only injectable contraceptives could double the rate of HIV acquisition (Lancet Inf Dis. 2012;12:19-26) or halve it (Contraception. 2007;75:461-467).

This led policy groups, like the World Health Organization, to issue hazy recommendations on how physicians should talk to patients about the use of contraceptives. And it led to the birth of the ECHO consortium, which was comprised of researchers, policymakers, women living with HIV, and clinicians.

To have an 80% chance of correctly assessing the impact of the contraceptives on HIV acquisition, the researchers calculated that they would need 250 HIV incidents during the 18-month study. And that meant they needed 7800 women. Previous study populations numbered in the hundreds and were not randomized, so the team was concerned that they would not be able to recruit enough women, or that the women would not stay on the contraceptive assigned to them.

It turned out that it "wasn't that challenging at all," Baeten told Medscape Medical News.

In fact, 99.4% of the women accepted the contraceptive they received, and 93.0% stayed on their assigned method to the end of the trial. And more than 80% of the study participants had enough contraceptive drug in their system to show that they hadn't discontinued use during the trial.

Notable, but Not Statistically Significant

Average age of the 7829 women, enrolled at 12 sites in sub-Saharan Africa, was 23 years. The women were selected primarily because they lived in areas with high rates of HIV, not because they engaged in behavior that put them at higher risk for HIV.

During the study period, 397 women acquired HIV: 138 in the IUD group, 143 in the DMPA group, and 116 in the levonorgestrel group.

Subanalyses showed no association between HIV risk and contraceptive type in women with more partners, women with herpes simplex virus 1, women younger than 25 years, or women older than 25 years.

Interestingly, the risk for HIV was 4% higher in the DMPA group than in the IUD group (P = .72), 18% higher in the IUD group than in the levonorgestrel group (P = .19), and 23% higher in the DMPA group than in the levonorgestrel group (P = .097).

The annual incidence rate of HIV in the study cohort was 3.8%, but there was no noncontraception control group, so Baeten could not say whether that rate was higher than in the general population.

Reassurance, Not Relief

"As a woman and as a Kenyan, I am very happy and very relieved with these results," said Maricianah Onono, ECHO site investigator at the Kenya Medical Research Institute, who added that the study participants were relieved as well.

But not everyone felt the same. "The results raise more questions than answers," said Janneke van de Wijgert, PhD, from the University of Liverpool, United Kingdom.

The lack of a contraception-free control group makes the results hard to interpret, she told Medscape Medical News. The comparison between groups is interesting, but without a control, "we are comparing apples with oranges with pears."

"Admittedly, it would have been difficult to include such a control group for many reasons, but this then begs the question whether the trial should have been conducted in the first place," she explained. "The funding could have been used to expand the contraceptive and HIV prevention methods mix."

In fact, there is a stark contrast between what women in the study received — contraceptives, HIV pre-exposure prophylaxis after it was approved for women late in the study period, and HIV testing and services — and what women in day-to-day life throughout much of Africa receive, said Lilian Mworeko, executive director of the International Community of Women Living with HIV in Eastern Africa.

"It seems like there is some sort of comfort in terms of the status quo," she told Medscape Medical News. "But it doesn't give relief, especially for women in Africa," where DMPA is often the only option.

We need as many safe and effective contraceptive methods in Southern Africa as possible.

The fact that women now know these options could work for them is reassuring, said Ava Avalos, MD, from of the Botswana–Harvard AIDS Institute, who was not involved in the study.

But, she said, the ECHO conversation reminded her of the discussion last year on the signal between the antiretroviral medicine dolutegravir and neural tube defects in infants.

In the case of dolutegravir, the immediate response in many African nations was to prohibit women of reproductive age from using the drug, even though it was more effective and had fewer adverse effects. This led women to flood the halls of the AIDS 2018 conference with protests and admonitions to trust African women, as reported by Medscape Medical News.

Eventually, most governments relented on dolutegravir, but "you would be surprised how many African countries still are not allowing women access to dolutegravir," Avalos reported.

The dolutegravir signal also pointed out the urgent need to help women avoid pregnancy when they do not want to become pregnant.

"Now that the neural tube signal appears to be fading, hopefully the demand for contraception will not be lost," Avalos told Medscape Medical News. "We need as many safe and effective contraceptive methods in Southern Africa as possible."

ECHO was funded by the Bill and Melinda Gates Foundation, the US Agency for International Development, and the President's Emergency Plan for AIDS Relief, among other organizations. Baeten reports receiving consulting fees from Gilead Sciences, Merck, and Janssen. Onono, van de Wijgert, Mworeko, and Avalos have disclosed no relevant financial relationships.

South African AIDS Conference 2019. Presented June 13, 2019.

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