Depo Danger

AIDS, Africa, and the UW researchers who rocked the medical world.

The world's seven billionth human was officially delivered to Planet Earth on Halloween eve in a crowded hospital in the Philippines. A healthy five-and-a-half-pound girl named Danica May Camacho, she was chosen by the United Nations to symbolize the challenges presented by the world's steadily increasing population.

The U.S. Census Bureau estimates that 255 people are born every minute, while only 106 die. That translates to an annual net gain of more than 78 million global citizens per year. First-world countries like the United States contribute disproportionately to the increase. A baby born and raised in Seattle, for example, is expected to live to age 82. A child reared in Nairobi, Kenya, will likely be dead by 50.

Life in the Emerald City is obviously easier than in sub-Saharan Africa. Grocery stores; doctors and hospitals; a coffee shop on every block. There are many reasons for the difference in average lifespan, but one stands out: HIV/AIDS. Between 1992 and 1996, it was the leading cause of death in King County for people ages 22 to 44. By the end of the decade, improved education initiatives and access to anti-retroviral drugs had helped stem the tide. Today, fewer than 30 King County residents per year die of AIDS.

Sub-Saharan Africa, too, has made progress. The virus is still responsible for 8 percent of all under-age-5 deaths in a region where children are 20 times more likely to perish prematurely. But the good news is that, according to UNICEF, about 12,000 fewer children died every day in Africa in 2010 than did in 1990.

A variety of factors surely contributed to this improvement, but one of the most critical has been improved access to contraception. Global health organizations have spent billions of dollars on condoms and other forms of birth control over the past two decades, supposing that if fewer babies are born, fewer will die. Moreover, mothers who already have children are less likely to suffer fatal complications giving birth to their third, fourth, or fifth. It seems like a win-win proposition.

But what if one of the most popular methods of contraception actually contributes to the spread of HIV?

In a cruel twist of fate, that might be the case—at least according to research published earlier this year by a team from the University of Washington's School of Public Health. After two years of observation, those researchers now suspect that birth-control injections, most commonly known by the brand name Depo-Provera, may double a woman's risk of contracting and transmitting HIV.

Though hardly definitive, the findings have rattled the global health community. Approximately 12 million women in sub-Saharan Africa currently rely on injectables like Depo-Provera to prevent unwanted pregnancies. At the same time, the region is home to nearly three-fourths of the world's HIV-positive population. Evidence that this birth-control method contributes to the spread of the disease has startling implications: Much of the continent suffers devastatingly high maternal and neonatal mortality rates (meaning that often, both mother and baby die during birth), making access to contraception literally a matter of life and death.

"It was personally challenging to see these results," says Jared Baeten, a UW physician who co-authored the study. "Thinking that a well-tolerated, highly acceptable, and effective form of contraception could not be available because of this research is terribly concerning for me."

In response to these findings and the subsequent widespread media coverage, the World Health Organization (WHO) is convening more than 60 experts on HIV, family planning, and health policy next month in Geneva. The group will determine precisely what some 150 million women worldwide who use hormonal contraception ought to be told about the possible association between their birth-control method and HIV.

The debate promises to be intense. On one hand, skeptics argue that the UW research is potentially flawed, and that any increased risk of acquiring HIV is outweighed by the tremendous benefits of the birth control. Others contend that the findings warrant new guidelines, perhaps even restrictions.

What everyone agrees on, however, is that there is no easy solution. According to Michael Worobey, a professor of ecology and evolutionary biology at the University of Arizona who follows the spread of HIV, the life-altering trade-offs revealed by the study are "about as bad as it could possibly get."

 

Years before she co-authored the study that could change the way women around the world use birth control, Renee Heffron gave a eulogy. A soft-spoken Rhode Island native with blonde hair and a slender frame, the Ph.D. student is sipping coffee at a cafe near her office at Harborview Medical Center while talking about her time in Africa.

Heffron's first experience on the continent came in 2001, when the then-22-year-old Peace Corps volunteer was stationed at a rural clinic in Burkina Faso. Two things about her new home stuck out: the primitiveness—no paved roads, no running water, no electricity—and the fear that gripped the local youth.

"People were terrified of HIV," she says.

Heffron had arrived roughly 100 years after the virus. Thanks to an archive of blood samples from the earliest AIDS patients, scientists like Worobey now estimate that HIV first jumped from chimpanzees to humans around the turn of the 20th century, when hunters in Cameroon butchered the animals for "bush meat." The virus then came to the United States around 1960, via a small group of Haitian immigrants who had previously traveled to the Congo. After that, there was no stopping it. By the time Heffron returned home from her journey to the remote village, AIDS had claimed an estimated 1.8 million lives worldwide, nearly 75 percent of those deaths occurring in Africa.

During her time working in the trenches of the HIV crisis, the cultural hurdles Heffron had to clear were high. She remembers negotiating a deal with village elders to visit a school deep in the countryside and teach kids about the risks of unprotected sex.

"They didn't have anybody to talk to or really learn about it," she says. "Having that conversation with their parents and elders just wasn't considered culturally appropriate."

Heffron cracks a smile describing "this class of elementary-school students putting condoms on their fingers." But her mood turns somber talking about Zambia. A landlocked country in southern Africa where more than a million people are infected with HIV—including one out of every five adults under age 50—Zambia presented Heffron with a familiar challenge. She was once again at a rural clinic, this time researching herpes and HIV. But now she was also working alongside one of the people she was trying to help—the employee charged with keeping local women coming back on a regular basis to answer her survey questions hadHIV, and she watched him waste away. As the boss, she was obliged by local custom to give a talk at his funeral.

"He was such a hard worker," she says, taking a long pause. "He just got really sick, and that was it."

 

Around the same time HIV leapfrogged to America, the pharmaceutical company Upjohn began selling Depo-Provera. Developed in the 1950s, it was first rejected by the U.S. Food and Drug Administration after tests on beagles suggested an elevated risk of breast cancer, marking the start of the drug's long, controversial history.

In 1967, the FDA denied approval again, just as Depo was being tested extensively for the first time on humans. Approximately 14,000 women from the Atlanta area were injected over a 10-year period. But according to a report from the Committee for Women, Population and the Environment, some of the test subjects didn't know they were guinea pigs—many were impoverished African-Americans tested by Upjohn "without their knowledge or consent."

The FDA withheld its approval of the drug again in 1978 and 1983, as even more studies on dogs and monkeys continued to show an elevated risk of breast cancer. It wasn't until labs made the shift to rats and mice that long-term studies started showing little or no cancer risk associated with Depo. (In fact, the drug has actually now been proven to reduce the likelihood of cancer of the uterus.)

By the time it received final FDA approval in 1992, more than 30 million women in 90 countries were already using Depo, thanks to Upjohn's aggressive overseas sales of the drug. Today, about 1.2 million women in the U.S. use it, for many of the same reasons that injectables have become so popular in sub-Saharan Africa: It is the ultimate low-maintenance birth control. All it takes is one dose every three months, and a woman can rest assured with 99.7 percent certainty that she will not conceive unexpectedly.

(Because it reduces sex drive in men, Depo has also been used on sex offenders for the purpose of "chemical castration." Michael Jackson allegedly took the drug at the urging of his personal physician in 2003 when the late King of Pop was in trouble for hosting sleepovers with young boys at his Neverland Ranch.)

The chemical magic behind Depo comes from a large, time-released dose of DMPA (short for depot medroxyprogesterone acetate), a synthetic form of progesterone, one of the main hormones associated with pregnancy. Injected in the form of tiny crystals suspended in solution, the medicine gradually seeps into the bloodstream, essentially duping a woman's body into thinking she is already pregnant. Then she stops ovulating—and with no eggs, there can be no baby.

Charles Morrison, senior director of clinical sciences for Family Health International, a global public-health and development organization, says the efficacy of Depo and the ease with which it can be administered—a doctor's expertise isn't required to deliver the prepackaged shots—make it a natural fit for developing nations.

"There's very little that's required in terms of equipment and training," says Morrison, one of the leading experts on the possible Depo/HIV link. "And from the client's standpoint, it's fast, it's not daily-dependent, and it can be hidden from a partner, if that's a concern."

A variety of public-health organizations have stepped up to meet the demand. According to records from the Reproductive Health Supplies Coalition (RHSC), 18 groups combined to spend more than $52 million on Depo and its generic cousins last year, at a cost of less than $1 per dose. The result, Morrison says, is that use of DMPA-based drugs have "grown faster than any other reversible birth-control method, especially among young women who are at most risk of contracting HIV."

Yet fears about Depo aren't new, and scientists have long worried that the birth-control shot actually makes women more susceptible to the lethal virus.

 

Seated in his 12th-floor office at Harborview Medical Center, a sweeping view of Elliott Bay at his back, Jared Baeten is a long way from Africa. But the 38-year-old doctor and epidemiologist says he has no trouble keeping his work in perspective—as he puts it, the virus has the same devastating impact on his Seattle patients as on those in other parts of the world.

"It reminds me every week of the reality of HIV," Baeten says. "When I travel to Kenya or Uganda or South Africa, it informs me with an understanding of the implications of our research."

Baeten spent two years in the late '90s running a woman's clinic in Mombasa, Kenya, where researchers from UW have been investigating the Depo/HIV link for nearly 20 years. A major port on the Indian Ocean and the hub of the country's coastal tourism industry, Mombasa is home to a large contingent of sex workers who frequent one local hospital, a circumstance that lends itself well to the study of HIV and AIDS.

In their profession, the women face a dramatically increased risk of contracting the virus. But not all become infected. By asking questions about sex habits, birth-control preferences, and other external factors, Baeten and his colleagues can infer whether certain behaviors make women more likely to acquire the virus. Early on, they noticed that women on Depo-Provera–type drugs tended to get sick more frequently than their peers. But because the test subjects were prostitutes and the research observational rather than clinical, their findings were frequently met with skepticism.

"Nobody ever criticized the data because it was not well-collected or scientifically unsound," says Ludo Lavreys, a former UW researcher involved in the Mombasa studies. "But that, of course, does not exclude the possibility that there's something else happening. Those who don't believe the effect say, 'Yeah, but you're working with sexual behavior, and these women are probably not telling you the truth.' "

Two decades of observational studies by Baeten's peers produced similarly inconclusive results. Lacking hard evidence to the contrary, the WHO and other global health organizations have long considered the contraceptive safe, even for women at risk of acquiring HIV.

"This has always been something we've recognized," says Mary Lyn Gaffield, an epidemiologist in the WHO's department of reproductive health and research. "We keep a close eye on it. There have been studies published, but they haven't actually documented an increased risk that was substantially worrisome."

For the UW group's most recent study, researchers turned from sex workers to a group even more suited to their needs: nearly 3,800 couples in which one person was already HIV-positive, whom they then followed for two years. Heffron, the paper's lead author, says that she inquired about each woman's sex habits and contraception use, then used sophisticated analytical techniques to compensate for factors that could potentially skew the results, like condom use.

After months of poring over the data, she and her team had their conclusions: Women using hormonal contraception became infected at a rate nearly double those who didn't (6.61 per 100 versus 3.78). Transmission of HIV to men from women who used injectables was also nearly twice as high (2.61 per 100, versus 1.51 for other contraceptive methods). And of the 73 total women who became HIV-positive during the study, 13 reported using injectables (the other 60 used a method other than hormones, or nothing at all).

For Lavreys and others involved in the prostitute study, the results came as no surprise. "As long as it was just Mombasa, I kind of thought 'OK, maybe it's just sex workers,' " he says. "But when I saw the results from Jared, now I thought 'This is confirming what we saw!' "

The UW team first presented their research this past summer at a conference in California, but the findings didn't attract widespread attention until they were published October 3 in the British medical journal The Lancet. That day, they also appeared on the front page of The New York Times.

 

Since October, Baeten says he has received "dozens and dozens" of calls from fellow academics offering suggestions or alternate ways to parse the data. Heffron has taken to carrying a printed copy of the study in her purse at hand for reference.

The intense scrutiny has been accompanied by a backlash, some of it targeted at the Times article, which was headlined "Contraceptive Used in Africa May Double Risk of HIV." In a recent issue of Nature magazine, James Shelton, science adviser for the U.S. Agency for International Development's Bureau for Global Health, complained about "alarming media accounts" regarding Depo and HIV, and took the Times to task. "The article essentially presented the increased risk as established, and focused on the conflict it presented," wrote Shelton. "Such a conflict piques interest, but ill-serves what remains a complicated and serious issue. We deserve better, from all involved."

Shelton's organization has contributed $198 million in funding for injectables since 2000, according to RHSC records, but even some of the UW crowd took issue with the way their work had been portrayed in the newspaper. Connie Celum, a longtime researcher of the correlation between Depo and HIV and co-author of the study with Heffron and Baeten, grumbles that the Times' report "was not very nuanced." "You had to read beyond the headline to understand that [our study] was observational and not the result of a clinical trial," Celum says. "Our intent is not to point fingers at Depo-Provera or take away contraception choices. It's to understand the information and give women a chance to balance fertility desires with HIV risks."

Celum and her colleagues readily acknowledge that their data has some limitations. Because the contraceptives used were not provided at research sites, it was impossible to record the exact dose and type used by each woman. Even more problematic is that many women switched birth-control methods mid-study—at least half of the participants who reported using a Depo-type drug also used a non-hormonal method at some point. Finally, the researchers once again had no choice but to take women at their word on the issue of condoms.

This last point is especially bothersome for some critics, including John Townsend, vice-president of the reproductive-health program at the Population Council, an NGO, or non-governmental organization, that conducts public-health research. "It's sort of like what you tell your dentist when he asks 'Do you use floss every day?' " Townsend says. "People tend to give answers that they feel are more acceptable, especially if they have HIV and are supposed to be using condoms."

The other big issue for skeptics is that no one—Heffron and Baeten included—is really sure why Depo might make women more susceptible to HIV. One theory is that the medicine causes the lining of a woman's vagina to thin, which could lead to easier transmission of the virus. Another possibility is that Depo might lower a woman's defenses against disease in the same way pregnancy does—the UW team determined recently in a separate study that expectant women are at increased risk of acquiring and transmitting HIV.

Citing the uncertainty and conflicting body of evidence, Morrison described the Depo/HIV connection as "an unanswered question" in an editorial that accompanied the UW research in The Lancet. He also called for a randomized trial to settle the matter once and for all, stressing that the stakes are too high for anything less. "[Injectables] could be contributing to the HIV epidemic in sub-Saharan Africa, which would be tragic," wrote Morrison. "Conversely, limiting one of the most highly used effective methods of contraception . . . would probably contribute to increased maternal mortality and morbidity and more low birth-weight babies and orphans—an equally tragic result."

 

There is no global equivalent of the FDA's "black-box warning" for Depo—the drug has been proven to reduce bone-mineral density, which can cause osteoporosis—just a list of suggested talking points. And though doctors are encouraged to discuss the medication's potential risks and benefits, surprisingly, some experts believe that African women should not be warned about the possibility that Depo increases their odds of acquiring HIV. "Some people feel the data isn't good enough, and so you're needlessly scaring people," Morrison explains.

Among the naysayers is Townsend, the Population Council official. He compares the Depo/HIV catch-22 to a similar situation that arose in the 1990s when researchers discovered that mothers could pass HIV to their children through breast milk; it was eventually decided that discouraging breast-feeding and the malnutrition that might ensue was potentially more devastating. "To give an order of magnitude," Townsend says, citing one recent estimate, "if you remove Depo from the market in South Africa . . . you'd get close to 2,000 unwanted births for every HIV infection averted."

Others maintain it is paternalistic to assume that African women aren't capable of weighing a drug's risks and rewards. From this perspective, says Worobey, it would be unconscionable to keep millions of women in the dark about a potentially fatal consequence of their method of birth control. "This is the kind of thing that ought to be disseminated so they know there's this downside," he says. "And the sooner the better, I think."

The general consensus is that an alternative to Depo ought to be developed. The challenge is to duplicate the drug's strong points: efficacy, convenience, and affordability. The IUD (short for "intrauterine device," a small, T-shaped contraption implanted in the uterus) prevents pregnancy just as well and can last for up to 12 years, but costs more up front and requires skilled providers to insert and remove.

Lavreys, the former UW researcher involved in the Kenyan sex-worker study, now works for the International Partnership for Microbicides, which he says is developing a vaginal ring that not only prevents pregnancy but also utilizes drugs that suppress HIV. The product is scheduled to be tested in Africa over the coming year, with Baeten co-leading the study. "There's still tons of pre-clinical work to be done," Lavreys says. "But the results look nice on paper."

Last year, the Bill and Melinda Gates Foundation spent $62 million on family-planning initiatives worldwide, according to spokeswoman Jenny Sorenson. About $300,000 of that went toward purchasing Depo, according to the RHSC. Gates also helped fund the UW's Depo/HIV research, and Sorenson says research on several promising non-hormonal contraception methods is being funded through the organization's Grand Challenges Exploration program.

But after years of pushing contraception as an antidote to child mortality, Gates himself has said he is reconsidering the strategy. He now believes that providing better care and nutrition for children is just as important, if not more so, as birth control. "It goes against common sense," he told Forbes during a recent interview. "Most parents don't choose to have eight children because they want to have big families, it turns out, but because they know many of their children will die."

Next month, at the pivotal WHO conference in Geneva, it will be left to Baeten to present and defend the study. Yet the doctor says that despite the controversy, he won't be lobbying for a specific outcome, but for whatever way forward helps the most amount of people.

"I want to use the skills that I have to prevent as many HIV infections as possible in my lifetime," Baeten says. "I don't think the take-home point from our work is to remove a very acceptable, highly used contraception from global use. But what I hope our research can do is open up a broad conversation to help make more choices—easier, better, safer choices—available."

khamilton@seattleweekly.com

 
comments powered by Disqus