Will we ever know if this widely-used contraceptive increases the risk of HIV infection?

The link between Pfizer’s Depo-Provera and HIV isn’t new. In the early days of HIV research, scientists looked at every factor they could think of that might increase infection risk. Of course, behavioral factors like intravenous drug use generated a lot of interest. But other researchers went further afield, looking at everything from insect bites, to human urine, and hormonal contraceptive use. Although most of these factors were dismissed, the injectable hormonal contraceptive DMPA, a progestin-only based method that goes by the name of Depo-Provera, continued to raise concerns. In 1998, for instance, researchers wrote that women who use DMPA exhibit higher rates of HIV infection. But like many others, this study was based on observations, and was easily overlooked.

Today, we don’t know much more. A 2013 review of the observational data estimates that DMPA might be associated with 48 to 100 percent increase in HIV acquisition risk. That would mean an additional 27,000 to 130,000 cases globally each year — 88 percent of which would occur in Sub-Saharan Africa. Still, most researchers think these numbers aren’t enough to justify a drug ban.

"I participated in several of the studies that suggested there was increased HIV risk associated with injectable progestin contraception, most specifically Depo-Provera," says Jared Baeten, an infectious disease expert at the University of Washington and one the researchers attached to the proposed trial, which has been codenamed ECHO. "And when I first saw the results, I felt tremendous concern, but also skepticism, because the data from the observations is not as rigorous of an approach as a trial would be — observational results don’t fully reflect the truth."

That’s the heart of the controversy: an old scientific debate about the value of observational studies. In medicine, these types of studies aren’t taken as seriously as controlled, blinded trials. When researchers see a link between, for instance, vitamin E and cancer prevention, what they may really be seeing is that the kind of people who take multivitamins are healthier than their peers for other reasons — maybe because they’re more affluent and have more access to care, or maybe because they engage in other behaviors, like going to the gym. After optimistic-seeming data in observational studies, controlled studies found that Vitamin E doesn’t prevent cancer — in fact, it slightly raises the risk of prostate cancer. This is a case in point for why observational data alone isn’t enough.

Every study that has linked Depo-Provera — or DMPA, as researchers call it — to HIV infection has been observational. So although a well-regarded DMPA study estimates that the contraceptive might double a woman's risk of acquiring HIV, policy-makers and charitable organizations that provide countries with contraceptives have yet to change their policy on Depo-Provera. That’s where the new trial comes in; it could provide confirmation of the observational results — or show that they weren’t reliable.

The proposed trial has its share of critics, though. Some think it would unethical to ask women to take DMPA for an extended period, because it would amount to knowingly putting them in harm’s way; these critics think the observational data already supports an immediate phasing out of DMPA. Others think a trial shouldn’t lead to a global ban on DMPA, even if results show that the drug has increased the rate of HIV infections. In most countries, removing it would ultimately cause more deaths than leaving it be, some experts say, because a greater number of women would end up dying during childbirth without it.

The most alarming explanation for the trial’s funding woes is also the hardest to prove: some HIV activists suggest that women’s health advocates are afraid of what we might learn if the trial goes ahead. If the link researchers have observed between DMPA and HIV is real, that would mean that women’s health advocacy groups are inadvertently responsible for the high HIV infection rates seen in countries like South Africa, and Mozambique — countries where over 45 percent of women rely on injectable contraceptives like DMPA.

A history of uncertainty

Part of the problem with trying to get at "the truth" is that scientists haven’t had much luck finding a mechanism that might explain how progestin-based contraceptives like DMPA make women more vulnerable to HIV infection. In 1996, researchers found that implants filled with progesterone — the non-synthetic equivalent of progestin — make the vaginal epithelium of macaques thinner, which increases their likelihood of acquiring SIV, the non-human primate version of HIV, by 7.7 times. "We do see that in macaques and in fact, in certain HIV research studies, macaques are injected with DMPA in order to make them more vulnerable to SIV, so that SIV has a greater chance of taking hold," says Chelsea Polis, an epidemiologist at the Guttmacher Institute in New York City.

This finding, however, wasn’t replicated in a recent study conducted on women who took the drug for up to two years. What researchers found instead is that DMPA seems to reduce the number of CD3-T cells — cells involved in the human immune system response — that are able to infiltrate the vaginal mucous membrane. This immunological effect hasn’t been directly linked to HIV infection, however, so little is known about how this research avenue might eventually play out.

Beaton's skepticism at his own results also stems from the fact that a number of studies have noted no difference in HIV acquisition between women who take the drug and women who don’t. For example, one 2007 study that looked at HIV acquisition in 4,200 South African women found no difference between those who didn’t use hormonal contraceptives and those who used either the Pill or injectable contraceptives. These types of contradictions aren’t unusual for observational studies, however, as results can vary based on the population sampled. Still, the World Health Organization thinks these inconsistencies are enough to raise doubts; after reviewing the evidence in 2012, it decided to continue recommending the use of DMPA, and told women who use it to use condoms. To many, the WHO’s stance was wholly disappointing.

Depo-Provera might contribute between 27,000 to 130,000 new cases of HIV each year

In an emailed statement, Pfizer said that the observational-only aspects of the Depo-Provera studies that have taken place so far can't be trusted. "Couples seeking to prevent both unintended pregnancy and HIV transmission should be strongly advised to use dual protection — condoms and another effective contraceptive method, such as hormonal contraceptives," said Pfizer spokesman MacKay Jimeson.

But convincing a partner to use a condom isn’t always easy for women, says Mitchell Warren, executive director at AVAC, an HIV prevention advocacy group. Some women don’t have the power to impose their use. That’s why he thinks the trial should take place. Although promoting condom use is right and important, it’s also key to make sure women know what kind of risks they run by taking a drug — in this case, a contraceptive. And right now, that isn’t something health care providers can do; when it comes to HIV, scientists don’t know what sorts of risks DMPA may or may not carry.

Under the trial’s current proposal, ECHO researchers would enroll 7,800 women in Sub-Saharan Africa, and assign each of them to one of three forms of contraception: the copper IUD, a contraceptive implant, and the injectable DMPA. These women would then receive regular testing for HIV over several months. This is an adequate trial formulation, Warren says. But it could have been a lot better.

When the researchers first proposed the trial, "we decided to go for the Rolls-Royce of clinical trials, and made a proposition to the Bill and Melinda Gates Foundation," says Ward Cates, one of the researchers associated with ECHO and an HIV researcher at the nonprofit FHI 360. This "Rolls-Royce" approach would have cost $80 million, enrolled 10,000 women and would have a included a second injectable contraceptive called NET-EN. But the researchers soon realized few funding agencies were willing to fund the trial.

Cates thinks the trial’s interdisciplinary nature might be to blame. Family planning agencies see the trial as an HIV trial, he says, whereas agencies that focus more on HIV think about the trial in terms of women’s health — a field that has been largely segregated from HIV prevention efforts, despite the fact that women make up 50 percent of those living with HIV worldwide. "That's the problem of this whole study," Cates says. "[We ended up seeing] this juggling of well, ‘Do you own this, do we own this, and is it your responsibility to fund it or is it ours?’"

Cates’ group chose the Gates Foundation, which has prioritized both HIV research and the distribution of contraceptive methods — DMPA included — to women in Africa. So the ECHO group was elated when the Gates Foundation pledged to fund the trial for up to $30 million in February 2013. But with a budget of $80 million, that wasn’t nearly enough; by the spring of 2014, the group had only raised an additional $10-12 million.

So the researchers decided to cut the cost of the trial down to $60 million. And then again down to $48 million in August. Today, the ECHO trial is just $1 million short of its goal, and the researchers are hopeful. The trial has managed to gather the support of a few more organizations and the South African government — but the largest funding bodies (the NIH, the WHO, and UNAIDS) aren’t among them. And as the researchers begin making plans to start the trial sometime in mid-2015, those who oppose the ECHO trial continue to make themselves heard.

Fighting the trial; defending DMPA

Warren is hesitant to say other groups don't want to know whether DMPA is responsible for increasing the rate of HIV infection among women. He does say he hasn’t seen many women’s health advocates acknowledging DMPA’s potential risk. That may be because DMPA is the focus of many reproductive health programs. A finding that firmly links DMPA and HIV would be "a significant challenge" for existing reproductive health programs, he says.

E. Tyler Crone, a human rights attorney and founder of the Athena Network, an HIV advocacy group, also thinks that some women’s health advocates have shied away from the issue. "I often feel that some people are unwilling to question DMPA… because they fear it will undo their family planning efforts," she says. No organization has publicly admitted to this. But the sense that women’s health advocates are worried about the trial’s outcome remains. "I think we all envision ourselves as being committed to family health," Crone says. But if DMPA does increase a woman's’ risk of HIV infection, "are we going to feel like we have done more harm than good?"

This has been flatly denied by other researchers. Polis has spent the last seven years researching the overlap between hormonal contraceptives and HIV, and she doubts anyone has shied away from funding it because they’re worried about how it might affect the women’s health movement. "I think it’s a pretty cynical view," she says. "Because this is such a controversial issue, my take is that the best way to serve women and couples is for us to remain very clear-headed and open-minded, and just let the data speak." Because of a previous position she held at the United States Agency for International Development, Polis declined to comment on whether she wants the ECHO trial to take place.

Then there's the ethical issue. The most recent meta-analysis — a study that compares other studies — has shown women taking Depo have a 1.5 times increased risk of acquiring HIV. "Our best guess is that it does increase the risk slightly," says Heidi Jones, a reproductive health expert at City University of New York who has written about the ethics of the trial. Given that information, asking thousands of women to take DMPA for a clinical trial would be unethical, she says. "We owe the ethical commitment to individuals in our study, and the benefit to society can never take the place of our obligation to individual participants."

Instead, Jones suggests phasing out DMPA, and making more methods of contraception available to women in Africa. She also thinks that researchers should focus on finding the mechanism that allows HIV to infect women more easily. "We should work to find evidence that [DMPA] suppresses the immune system," she says.

Jones isn’t the only one worried about ethics. "I wish there was another way, that I could wave my magic wand and we could move this issue without the trial," says Crone, Athena Network’s founder. But the WHO doesn’t appear ready to budge on this issue, she says, "so I guess I’m a reluctant supporter of it."

Polis says she rethinks her approach to the issue every time a new study is published. "There is genuine uncertainty among the experts over whether or not the link is real," she says. This uncertainty is the main reason some scientists have called for a trial. But even if the trial does show that the contraceptive puts women at moderate increased risk for HIV acquisition, she doesn’t think those results will warrant immediate discontinuation of DMPA use on a global level. Removing it might reduce the number of new HIV infections, but banning DMPA is the kind of decision that needs to balanced against other factors — like how effective it is at preventing unwanted pregnancies, and its ease of use.

Because DMPA only needs to be administered once every three months, it’s a lot easier to take reliably. It also comes with a higher efficacy rate than the birth control pill. The fact that a single dose lasts so long is also a huge advantage for women who don’t have control over condom use: they can use Depo-Provera covertly, Polis says. Although some women manage to do that with the birth control pill, hiding a long-lasting injection is far easier. In addition, the injection is more practical than implants, because unlike implants, doses of DMPA can be administered by nonmedical providers — so they’re easier to get. And when women want to start having children, they can simply let it wear off. Finally, early research suggests that DMPA might be one of the only hormonal contraceptives that doesn’t become less effective at preventing pregnancy when taken alongside drugs that treat HIV. Women who are HIV positive and don’t wish to have children therefore benefit from having the drug around.

Given these benefits, Polis says, removing DMPA in countries that don’t carry a high risk of HIV infection wouldn’t make much sense.

But this isn't just about the injectable approach; Polis also worries removing the contraceptive could increase deaths. Removing the drug would likely cause more women to become pregnant against their wishes. And because childbirth is still a life-threatening event in some developing countries, phasing out DMPA may lead to an increase in overall deaths among women — particularly in regions with high use of injectables and high rates of maternal mortality.

"If we remove DMPA all over the world tomorrow, it’s possible that a certain proportion of women would switch to this method or that method, but many would be left without alternative, accessible, and acceptable contraceptive options," she says, citing a 2013 study she published in AIDS in which she and other colleagues modeled the possible outcomes of a removal of DMPA.

There's one more thing. Polis says that removing Depo would increase HIV transmission — between mother and child. "What we found is that unless the true effect [of DMPA] more than doubles the risk of HIV, continuing to use DMPA would result in a net public benefit, with the possible exception of certain countries in southern Africa," Polis says — countries where close to half of women use injectable contraceptives and HIV infection rates are high.

Polis’ position isn’t exactly popular, and some women’s health activists have gone to great lengths to let her know. In 2013, one of her unpublished reviews, a manuscript that summarized findings from eight observational DMPA studies that was being evaluated by The Lancet Infectious Diseases, ended up in the hands of The Rebecca Project for Justice, a US-based women’s advocacy group that opposes the use of DMPA. It’s not entirely clear how this happened, but an editor’s note indicates that a reviewer might have been to blame. The Rebecca Project published the study — which was peer-reviewed and later published by the journal — by without the authors’ or the journal’s permission, because they felt that The Lancet was attempting to hide the truth about DMPA from the public.

Someone sent the group the document, because the leaker didn’t believe it would be published, says Kwame Fosu, policy director at The Rebecca Project for Justice. "[The journal’s editors] told me they were going to, but I don’t believe that."

Despite repeated requests from the journal and legal action from Elsevier, the journal’s publisher, The Rebecca Project for Justice refused to take the manuscript down (it can still be found on their website, here). "As far as we’re aware, our publishers, Elsevier, have now exhausted credible legal means of redress," said Daisy Barton, The Lancet’s media relations manager, by email. "The matter is not currently being pursued further."

A ticking clock

It’s been four years since the ECHO trial was first proposed, and although the researchers have nearly reached their goal, rumors about potential funding deadlines have surfaced. "As far are we understand it, if enough funding isn’t made available, it’s possible that the money might disappear," Warren says. "There’s a rumor that the deadline is the end of the year."

Cates says that at one time, there was a fear that funders might move on to other research questions. "But now we are hopeful," he says. "Hopefully by getting started with planning the trial, and showing the progress that we have made on whittling the budget down, those pledges won’t go away by the end of the year."

When The Verge contacted The Bill and Melinda Gates Foundation to ask about its funding of the trial, a representative said that it was "actively engaged in ongoing conversations with partners about funding and potential grantees, to ensure that the trial is fully funded." But it has yet to make any grants to support trial implementation. According to Cates, the Gates Foundation has told them they can start planning the trial. And they will keep fundraising until they reach their goal.

Meanwhile, the WHO has stayed on message: the condom is still king, regardless of concerns over women's ability to make their partners don one. "The most important message," says Mary Gaffield, a WHO epidemiologist, "is that — and we continue to say this — the only method of contraception that protects against STIs, including HIV, are condoms." Right now, she says, there are "no restrictions on these hormonal contraceptive methods for women who are at high risk for HIV," and "DMPA remains a very effective contraceptive method." Whether or not this stance is endangering women remains, in the absence of a rigorous trial, anyone’s guess.

Illustration by Dylan Lathrop