Standing Trial
What happens when women lend their bodies to science?
by Emily Bass

If you're a woman with HIV, science wants your body. Flattered? Probably not. Much of what springs to mind in connection with "medical research"—Tuskegee, thalidomide, human guinea pig—is enough to make anyone steer clear of studies altogether. These days, though, doctors trying to get their hands on women's bodies have better intentions. Highly active antiretroviral therapy, or HAART, is on its way to turning HIV into a chronic infection like diabetes or some cancers. And the way scientists do research has changed to reflect this. The majority of studies look at how well and long drugs work, rather than what the disease does in the absence of treatment. Such studies are shorter—often lasting less than a year—and may be fueled by the pharmaceutical industry's desire to get the next best thing on the shelves as quickly as possible.

There's no reason why women shouldn't jump on or at least benefit from the breakthrough bandwagon. HAART therapy seems to work as well in men as it does in women, and new infections in women are on the rise. Unfortunately, women's status in the world of medical research hasn't kept up with the leaps and bounds of HIV treatment. Scientific progress has been speedy, but what about the pace of social change?

Here, it's less like the autobahn and more like life in rush hour traffic. If you merge the streams of scientific progress and social change, it becomes clear that a maddening game of catch-up is going on, and that many groups, including women, minorities, and the poor are losing. Not everyone is benefiting equally from the new knowledge, nor has everyone been included in the research, particularly in clinical trials, the basic building blocks of medical inquiry. Women have lagged far behind in clinical trials participation, especially those testing new, experimental therapies. With the bulk of research accelerating in exactly that direction, advocates worry that the next era of HIV research may, once again, leave women in the dust.

"In some ways I'm more concerned than in years past," says veteran activist Dawn Averitt, about the current status of HIV-positive women in the research world. "The closer we get [to a cure], the more lackadaisical we're becoming about designing studies that answer the most important questions." For example, we're still in the dark about how these drugs interact with hormones, pregnancy, aging, and a woman's reproductive system. We also know that women make up an estimated 20 percent of HIV infections in the United States, and nearly a third of all new HIV infections each year; that those getting infected are often poor and most likely to be black or Latina; and that women are much less likely than men to have access to today's state-of-the-art medical care. The hard truth is that runaway infection rates don't translate into representation in clinical trials. There are more women than ever to study, more urgent questions to be answered. With the realistic possibility of living a normal lifespan, the stakes have never been higher. What's to be done?

Advocates, researchers, and, yes, some drug companies, urge women to take their place in an immense medical experiment-one with life or death consequences. "We're all guinea pigs," says Beri Hull of the National Association of People with AIDS. She means it in a good way. Just about every piece of official information about treating HIV started as a question in a clinical trial-a large test of a particular strategy, anything from drugs to exercise to herbal remedies. It's also possible to gather information through observational or "natural history" studies, which simply watch what a disease does in lots of people over a long period of time. A growing number of women like Hull are demanding good medical care and real answers in exchange for their participation. It's the physical, as well as the personal, that's political, after all.

Drug companies eager to test a promising compound often bankroll these studies. They are also carried out by government scientists and researchers at academic centers and through smaller, community-based organizations. Many trials are conducted at multiple sites, allowing enrollment of the large numbers of people needed to generate relevent answers. Individual doctors also conduct ad-hoc studies.

Steering through the complicated paths of medical research can be overwhelming if not impossible for women who may be caring for other infected family members, or simply trying to put food on the table. Getting started can also be difficult. One small study found that while 48 percent of women's doctors thought their patients would be good candidates for clinical trials, only 14 percent had actually discussed the trials with them. Without day care, compensation for their time and travel, and sympathetic medical staff, many women who do learn about trials simply can't, or won't, sign up. The numbers reflect this.

Right now, women's clinical-trial enrollment is woefully low. The NIH-sponsored Adult AIDS Clinical Trials Group, part of the largest research network in the country (see "Trial, Not Error"), is settling for an average of roughly 18 percent female participation. And that is an overall figure: Broken down by specific research areas, the AACTG's figures offer even less encouragement. From 1997 to 1999, women constitued a mere 10 percent enrollment in immunology trials and substudies. That's a 2 percent drop from 1993 to 1997 and this at a time when immune-based therapies have gained ground as a crucial part of less toxic long-term strategies for managing HIV.

Of course, 10 years ago, women made up a mere 6.7 percent of research subjects in AACTG clinical trials. It's taken the efforts of a small group of tireless activists-and 10 long years-to increase female representation by roughly 12 percent. Along the way, this same group of angry women and their allies also forced the Centers for Disease Control and Prevention to expand its definition of AIDS to include the conditions that afflict women, and overthrew the Food and Drug Administration's rule banning women from drug trials because of their reproductive capability. But with the National Institutes of Health and the CDC balking at setting specific threshholds for women's participation in most trials, today's numbers don't add up. "The winning of a battle doesn't signify the end of the struggle in any way," says Dr. Paula Schuman, an HIV physician at Wayne State University in Detroit and an outspoken women's advocate. "Things can drift back."

If the goal and design of clinical trials is to paint as complete a picture as possible of the course of HIV disease and the consequences of treatment, accepting current rates of enrollment is equivalent to filling in the background of the Mona Lisa while leaving her chair conspicuously empty. To get into the picture-or the driver's seat-women need to rev their engines for yet another race against time.

Broad Strokes
The first major women-specific study was the CDC-funded HIV Epidemiology Research Study (HERS). Launched in 1992, HERS enrolled 2,000 HIV-positive and -negative women, following up with twice yearly visits to see who got sick, what some of the risk factors were for becoming infected, and which opportunistic infections emerged. It did not offer its participants medications-individual doctors provided those. The study simply collected information about their emotional and physical health. Then, as now, these were the areas that posed the most questions.

Even HERS left room for more scientific research on the disease's progression in women. For this, women activists and a handful of concerned physicians took on the NIH. "Several of us went to the AACTG meetings," recalls Mary Lucey, a long-term survivor of AIDS politics who recently helped organize the 1999 National Conference on Women and HIV/AIDS. "We couldn't even get a room. So we sat in the hallway with Sten Vermund, then head of epidemiology at NIAID, and Diane Hartel, who became the first NIAID project officer for WIHS, and said, 'We just don't know the direction of this disease in women.'" It wasn't an easy sell. "Every day for nine months we got called and asked: Why do we need this study?" Finally, the Women's Interagency Health Study or, WIHS, was born.

Over the past eight years, both WIHS and HERS have filled in useful pieces of the puzzle. From WIHS came data about possible gender-based differences in viral load, women's barriers to accessing care, and more. HERS supplied papers about depression, poverty, and having other STDs as important predictors of HIV infection. At the same time, both studies have weathered a barrage of criticism about the rate and scope of their research. It's broad strokes, say some. Broad strokes painted too slowly.

The NIH and the CDC are each grappling with the place of natural history studies in a treatment-driven world-and have come up with strikingly different answers. The HERS trial closes in April. The CDC is shifting HERS's funding into nonwomen specific studies of access to healthcare in minority and drug-using communities. The rationale: "A lot of the questions that required longitudinal study of natural history specific to women had already been answered, and so the question became 'What are we going to find out in the next five years that justifies that kind of expense?'" says Dawn Smith, HERS project director at the CDC.

Plenty, say researchers over at WIHS, which also boasts an enrollment of more than 2,000 women. Rather than closing up shop, WIHS has revamped its research tools, gathering real-world information about women in treatment, tracking its long-term efficacy and side effects of the dizzying array of currently available HAART combinations.

Even with its new mission, WIHS can't make up for the women missing from clinical trials. Drug-driven research may allow underserved populations and unpopular questions, particularly about long-term side effects, to fall through the cracks. Drug companies favor neat-and-tidy 48 week studies that focus on specific questions about drug efficacy or side effects. Such time-limited studies can give quick answers and end before troubling toxicities are likely to turn up. They're not so good for such open-ended questions as, What happens to men and women after half a lifetime on treatment? "Once [drug companies] do a Phase III trial and get approval, who's going to be sitting on them to make sure that they invest money in looking at long-term sequelae?" asks Dr. Kenneth Mayer, an HIV physician and HERS investigator at Brown University. And, just as important, who's going to make sure that there are women on board when they do?

Stand Up and Be Counted
When it comes to women in trials, playing the numbers game means playing hardball with expectations. Most activists ask only that enough women be included for meaningful conclusions to be made-not that numbers of men and women have to match in every study. "It's not about equal work for equal pay," says ACT UP-Philadelphia's Julie Davids, who draws a clear line between "equity and justice" and "scientific" rationales for women's trial participation. What it boils down to, say Davids and others, is: How many women do we need to get the data? Unfortunately, all too often the answer is, more than we've got. Take lipodystrophy, or fat redistribution. Among the many complications that have emerged as a result of long-term use of HAART therapy, perhaps none is as devastating and in need of urgent attention as the drastic changes in body shape-ballooning bra size, "buffalo humps," peripheral wasting-and lipid profiles that threaten to turn thirtysomethings into prime candidates for heart disease and diabetes. Research strongly suggests that the problem looks different in men and women, both in how and where fat is lost and gained and in blood chemistry changes.

A hot research area that's exactly in sync with women's deepest concerns about their bodies should make getting women into lipo trials a breeze, right? Wrong. Trial AACTG 5082 is one of four new studies touted as having a woman-specific research objective. Scheduled to begin in early 2000, AACTG 5082 will study two drugs, metformin and rosiglitazone, for fat redistribution and insulin resistance. When the study is over, it will be able to tell only how well these drugs work in men.

To answer the 5082 trial question in both genders, you'd need the same number of women as men in the study, says Dr. Rebecca Clark, former chair of the AACTG Women's Health Committee. "Meeting that target would probably be prohibitive in terms of the time and cost." The 5082 researchers say they may reevaluate the size of the women's sample, depending on findings from the initial descriptive analysis. It's not an uncommon problem, Clark says, adding that researchers are left in the difficult position of "weighing how critical is it to look at [a problem] only in women or whether a lot of the information can be generalized to women."

Instead, 5082 will generate detailed descriptions of these problems in women. It's useful information. Researchers have hardly reached the point at which any information about HIV-positive women can be discarded, but 5082 is also planted squarely in the realm of observational research, the one area where WIHS at least is coming through.

The state of the research on fat disorders typifies many other areas, and is a prime example of the Catch-22 bedeviling those on both sides of the examining table: Without sufficient numbers of women in trials, researchers can't conduct studies the way they would like to; and without sufficient resources and supports, women can't enroll in trials, no matter what the topic is.

At the AACTG, the design process for all studies, including metabolic trials, involves number-crunching to pinpoint the minimum number of women needed for "statistical power"—researcher-speak for how many people are needed to draw a meaningful conclusion. The number of women required for statistical power differs for every study, but the fact remains that without it, women's participation threatens to become tokenism, even in the case of a well-intentioned trial like 5082. "[The AACTG] is using women as research subjects, but [that data] is not integrated into the larger picture," observes Iris Long, a medicinal chemist and longtime activist watchdog of trials on women.

Sleeping With the Enemy
Again, what's to be done? Holding the AACTG accountable for it's numbers is a start. Every woman can ask her trial coordinators if there will be enough women enrolled to answer the study question. Many of the simplest measures for upping enrollment—child care, carfare, and peer support groups—take money. And many HIV-positive women think the answer lies in getting pharmaceutical companies to ante up.

Mary Lucey and other positive women have spent the last two years working with Bristol-Myers Squibb and outside researchers on the design of the Antiretroviral Trial Looking at Sex and Treatment, or AT LAST, the latest industry-funded trial with a catchy name (see Agouron's Women First and Hoffmann-LaRoche's Being Alive) to emerge with the explicit goal of getting answers about how drugs work in women. "Of course, it's smart marketing strategy, but what have the feds funded?" asks Lucey. "Call NIAID and ask, 'What AIDS treatment studies do you have specifically for women?' They'll be at a loss."

In fact, AT LAST is the first such study to involve HIV-positive women in its experimental design. The result is a 48-week trial looking at first-use of a PI-containing regimen in 100 men and 100 women. Having a male cohort will allow investigators to gather meaningful data about gender differences. AT LAST has also pulled out all the stops in providing resources for participants: travel reimbursement, 24-hour peer support at every site, child care, the works.

But the AT LAST template-a fairly straightforward, none-too-costly set-up-won't be coming soon to a Phase I or II study near you. "Currently, AT LAST is the only trial that BMS is participating in that incorporates a peer education and peer support component," says Jill Greytok, the AT LAST rep and manager of immunology clinical trials at Bristol-Myers Squibb, adding that "BMS will consider incorporating such models into future clinical studies." For now, this remains another industry promise.

The same goes for Glaxo Wellcome, which is launching its Women's Study to track the emergence of metabolic problems in women on their first HAART regimen. Here again, peer advocates and a site budget for transportation and other services have been put in place to help guarantee full participation. Again, the trappings are far from standard practice. "Having a peer support person is brand new," says Dr. Keith Pappa, senior clinical program head in charge of the study. "The standard way that research is done provides patients with nominal amounts. These efforts are above and beyond our usual practice."

That's not to say that cash infusions from industry are all bad, simply that women need to demand that such "special services" become standard practice. With more and better drugs entering the pipeline, it's crucial that women be incorporated into early stages of trials, like Phase I studies that determine correct dosing of a new drug. These studies often require overnight stays, which can be incredibly difficult for women with children. It may be possible to gather information over a shorter, say 10-hour, period, but if the drug companies don't see a system as broken, they're none too likely to fix it.

Unlike earlier days in the epidemic, women are a hot commodity in today's research enviroment. Officials agree that it's becoming more and more important that trial sites come through. "When sites put in their application, they are much more competitive if they have those issues [about women's enrollment] addressed," explains the AACTG's Clark. "We can't mandate that you have to provide a stipend or transportation. That's up to the sites, although certainly it's been recommended again and again."

Unfortunately, being the new demographic on the block won't be enough to catapult women into equal standing. Nor will competition and heightened awareness be enough to safeguard underserved sites and individual researchers whose priorities don't match those of the powerful AACTG committees. For Paula Schuman, shutting the doors on the Detroit HERS site means losing valuable funding for a struggling hospital in an econmically depressed city. What happens to sites like these when the system for allocating funds leaves little room for altruism? "Not only will a project embraced by the community come to an abrupt end but enormous amounts of data collected from women will remain unpublished as statistical staff lose funding and investigators have to seek salary support elsewhere," says Schuman. "When a multisite study comes to an end, it's every man for himself. No one gets tenure points for collaborating with sites with fewer resources."

Women's Work
The good news is that around the country, women are looking for ways to bypass some of the competition to create new systems that support their research agendas. Dr. Alexandra Levine, a leading researcher on HIV and cancer, is currently working with Dr. Joel Palefsky and others on a possible collaboration between WIHS, the AIDS Malignancy Consortium, and the Women's Health Committee of the AACTG that would pool resources to answer questions about human papillomavirus. "Since each of the groups has been unsuccessful in accruing large numbers of women, and since we think we might be able to do better by working together, we're linking together and trying to force additional types of funding to occur," she explains. "We're giving it a try."

Meanwhile, Clark and other members of the Women's Health Committee are working to build bridges between the AACTG and its counterpart, the Pediatric AIDS Clinical Trials Group, for looking at HIV disease and transmission in infants and children. "There's an increasing interest in maternal health above and beyond transmission," says Clark. Women, particularly women of color, are significantly more likely to enroll in a pediatric study than in an AACTG trial. Cosponsoring trials and enrolling women in PACTG trials into AACTG trials could keep more women from harder-to-reach communities hooked into the system.

As usual, progress requires struggle, and it will likely take women activist warriors raising their voices to drag the trials system into the next millennium. If today's trial participant isn't sitting with her hands crossed in the foreground of a pretty research picture, it's probably because she's on the frontlines herself, kids and all, demanding trials that take her life, her language, her unique experience into account. Says Mary Lucey, "We're not dead, we're not giving up, and we're not going away."

• Trials for pregnant women
• Trials for children
• Information gathering studies

Emily Bass wrote about HIV drug development in our Dec./Jan. issue.