A new women’s research agenda starts to see the light of day

30 June 2001. Related: Women's health.

Emily Bass, for American Foundation for AIDS Research

Two new initiatives

Two ambitious new gender-specific research agendas at the National Institutes of Health (NIH) could launch a major new initiative to study HIV disease and treatment in women. Within two weeks last April, the Office of AIDS Research (OAR) and the Women’s Health Committee of the AIDS Clinical Trials Group (ACTG) both produced near-final versions of comprehensive gender-specific agendas. The OAR coordinates all HIV/AIDS research spending by the Institutes while the ACTG operates HIV/AIDS studies conducted by outside trial sites. If implemented, their plans would exponentially increase knowledge of HIV disease and treatment in women. Researchers will need to overcome the obstacles that have grounded previous efforts: lack of funding and leadership needed to turn good intentions into action.

Sobering statistics have driven the latest efforts to tie gender-specific research to new money. The uphill battles of the past – including the successful fight to change the CDC definition of AIDS and establish a women’s natural history study – took place at a time when women were a largely unrecognised minority of the U.S. HIV-infected population. Today, more than half of the world’s AIDS cases occur in women. Here in the United States, the epidemic is hitting poor women and women of colour harder and harder. The Centres for Disease Control and Prevention (CDC) say that women made up 23% of all new U.S. AIDS cases in 1999. In 1986, that figure was just 7%.

There is also a steady stream of papers suggesting that HIV disease and treatment are different in men and women. A recent report from Johns Hopkins found that HIV-positive women are at higher risk for pancreatitis than men. A paper on the ALIVE cohort of IV drug users found a significant difference between men’s and women’s viral load shortly after seroconversion (see below). And this year’s Retroviruses conference in Chicago was peppered with reports of gender-specific differences in toxicities, particularly metabolic disorders.

Hard-earned lessons

The ACTG and the OAR plans developed against this backdrop. They were developed independently, from distinctly different entities. Both reflect lessons learned the hard way. Lesson one: Recommendations and polite requests do not work when it comes to increasing women’s enrolment. In 1990, the National Institutes of Health tried to increase women’s overall enrolment in NIH-funded trials by encouraging investigators to include more women. After three years, nothing had changed. It took a law from Congress and a stipulation from the NIH about grant application procedures to raise enrolment.

More recently, the Women’s Interagency Health Study, or WIHS, has been hard-pressed to find basic researchers to respond to an invitation to use WIHS samples for studies of women’s pathogenesis. First posted in 1997, this program was supposed to give basic scientists access to WIHS samples for more in-depth studies. The program has yielded several projects on human papilloma virus (which is associated with cervical cancer), but gives patchy coverage to other topics, said Paolo Miotti, the WIHS Principal.

A new plan at the OAR

The OAR shaped its plan at a March meeting of scientists, advocates and representatives from organizations devoted to women and HIV/AIDS. Following the meeting, the OAR drafted a new section devoted to “Women & Girls and HIV/AIDS” in the NIH Plan for HIV Related Research. Although this area has been covered in previous Plans in the context of various scientific areas (e.g., natural history, behavioural and social research and therapeutics), never before has there been a specific section devoted to it, said Judy Auerbach, Ph.D. Auerbach, who coordinated the OAR effort, is director of the Office’s Behavioural and Social Science Program.

The plan, which should be finalized and available to the public by early summer, is the green light to submit proposals in areas that the NIH may not have funded in the past. In particular, said Auerbach, it will encourage researchers to break down traditional disciplinary boundaries and emphasize the interaction of biological, behavioural, social and cultural factors that influence risk of HIV/AIDS among women and girls.

“We are particularly interested in how sex and gender operate at all levels, and hope the plan will encourage researchers to think in more cross-disciplinary ways,” said Auerbach. This does not mean that bench scientists will have to become social theorists (or vice versa). The first two objectives of the draft plan lay out a broad range of strategies for elucidating the mechanisms of transmission and the biology of HIV. But there will also be opportunities to approach these questions from novel viewpoints. “Biology may be affected by social and cultural forces,” she said. “External environmental pressures may have an effect on disease progression.”

Similar agendas exist for racial and ethnic minorities and prevention. They have succeeded – to some degree – in promoting research in these areas. “From the NIH point of view, we will use every mechanism we have to promote [the plan],” said Auerbach. Funding for research that fulfils the plan’s mission will come from the existing NIH budget for research that focuses specifically on women and girls – which is more than $300 million dollars per year.

The ACTG agenda on gender-specific data

Susan Cohn, chair of the Women’s Health Committee (WHC) of the ACTG, said that the draft free-standing Women’s Scientific Agenda came out of a recognition that trials were not enrolling enough women to answer gender-specific questions even though investigators had been urged to do so. According to recent statistics, women’s enrolment in all adult ACTG trials combined averages 19%. The figure masks a lot of variation: studies of immune therapies, for example, enrolled 10 % in 1999. Nor are there favourable trends: In the ACTG’s most recent survey of enrolment by gender, women’s enrolment had plateaued, said Kate Squires, a University of Southern California researcher and clinician who sits on the WHC.

The WHC has always had a research agenda. This version departs from previous models in its effort to mainstream gender-specific questions. Past agendas have focused primarily on women-specific conditions, such as human papilloma virus and HIV dynamics in the reproductive tract. In contrast, the newly minted version will ask for information on gender from trials on disease, complications and immune-based therapies.

The new agenda could be an important step for a committee that has traditionally had little power to influence the course of ACTG work. Selecting trials to fund has been left to the Research Agenda Committees, or RACs, whose tasks include designing trial concept sheets, evaluating proposals and determining the “intensity scores” for each trial. These scores, which influence funding, are based on such factors as the number of site visits, diagnostic tests and staff required to run a trial.

The draft agenda details a range of gender-specific goals. A “strategies” section next to each objective lists the ACTG trials that could help meet these goals. The agenda is broken down into three sections corresponding to the three RACs: HIV Disease, Complications, and Immune-Based Therapies. This fall, when the RACs revise their agendas, each one will decide whether to incorporate the women’s scientific agenda into its official plan. For now, only the Complications of HIV Disease RAC asks would-be funding recipients to explain how their trial will address questions of gender.

The new agenda also cannot solve old problems on its own. For several years, concerned members of the WHC, including community representatives, have asked the ACTG to give preference to sites that regularly enrol more women; to give additional funding or extended enrolment deadlines when a larger number of women is to be enrolled; and to increase the intensity scores given to trials that enrol more women. All of these measures would help compensate for the well characterized gender-specific barriers to trial enrolment. Among these are the need for on-site child care, transportation fees, and “one-stop shopping” clinics that provide care and conduct research at the same site.

So far, the ACTG has refused to make these adjustments. This is, in part, because of an entrenched distinction between clinical trials and social services. While some ACTG sites also provide primary care, many others are exclusively devoted to research. “The ACTG’s mission has been to develop drugs. It has not been in the business of managing and caring for women,” observed Susan Cohn of the Women’s Health Committee.

But these are exactly the measures that the ACTG will need to take if it is to follow the spirit as well as the letter of the new agenda. Although the agenda’s strategies section lists several existing trials next to each objective, WHC members said this can be misleading. In a letter to the WHC, Heidi Nass, a representative from the ACTG’s Community Constituency Group (CCG) wrote, “We have concern regarding the extent to which the studies identifiedÉ adequately meet the corresponding objectives.”

“In May, the ACTG began to discuss plans for RAC “SWAT teams” on gender-specific studies. These teams would be made up of experts from each RAC. They would be charged with designing protocols to answer the WHC agenda questions. In the past, WHC members have shouldered most of the responsibility for addressing these issues. Involving experts from each field would be a major step forward, said Susan Cohn.

A need for leadership

The two proposed women’s initiatives come on the heels of fresh evidence of gender differences in the course of HIV disease. A March paper in the New England Journal of Medicine found that gender differences in the initial viral load set point could lead to dramatic disparities in eligibility for antiretroviral therapy.1 Current government guidelines suggest initiating therapy early in HIV disease only when viral loads exceed 55,000 copies/mL. Shortly after contracting HIV, the 156 men in the study had viral loads that stabilized at a median of 50,766 copies mL, whereas the women’s median viral load stabilized at only 15,103 copies/mL. Yet their decrease in CD4 count and progression to AIDS was identical over the next seven years.

The NEJM report is the latest to examine the issue of gender differences. It is the first to suggest that the current guidelines may be failing women. According to current guidelines, 74% of the men but only 37% of the women would have been eligible for antiretroviral therapy at the first visit after seroconversion – in spite of the fact that men and women in the study had the same risk of progressing to AIDS.

The findings suggest a range of follow-up studies, such as basic science research on the underlying causes of women’s lower viral load; definitive studies of gender differences in immune parameters, including CD4 counts; and long-range trials to determine whether there are gender differences in the outcomes of alternate strategies, such as deferred or immediate treatment.

The existing structures that could do such follow-up have a poor track record of looking at gender in general studies. The network of sites for studying primary infection (the acute syndrome that appears in the weeks immediately following contracting HIV) would be an ideal setting for further examination of the question, said Kate Squires.

This network is currently up for funding renewal. But so far, there has been no request that its sites draw up plans for looking at how gender affects the virus-immune system relationship in this critical period. Nor have any of the sites provided such plans on their own initiative. Squires has gone so far as to offer to help recruit recently infected women for possible studies. No one has taken advantage of her assistance.

The unknowns cannot be answered by what has been called the “bikini sciences” approach to women’s health, which limits the study of women to the specifically female organs. Instead, scientists who have not done a Pap smear since medical school must start thinking about gender in the context of their own work. For now, there is no single organization – or activist group – that has taken on a watchdog role for this massive task.

This coordination is also needed to ensure that important areas of research are well covered. When the WHC put together its agenda, for example, it decided to eliminate research on microbicides (vaginal or rectal agents for preventing HIV transmission) from the list of objectives. “We had to take out what’s not in our purview,” said Cohn, adding that other institutions have taken the lead in the field.

The best laid plans

Making gender-specific research a matter of course, and not of special interest, is a mighty task. The OAR and ACTG efforts are promising steps in this direction. Both have important elements in common. One is the need to create new interdisciplinary partnerships between clinicians and bench scientists, social scientists and biologists, and trial designers and service providers. Another is to put the most pressing questions on paper and – where possible – to provide specific funding for the trials and services needed to answer these questions.

Without specific budget lines and clear-cut requirements, the new plans could falter. “The rhetoric is right. Rhetoric leads to meetings where agendas get set and ideas get clarified,” said Geeta Rao Gupta, president of the International Council of Research on Women and co-chair of the recent OAR meeting on women and girls, “The question is how to get from meeting to action. One big stumbling block is funds.”

Another critical element is pressure from activists and advocates. Today, advocates are cautiously enthusiastic about the new momentum. They warn that true commitment is needed for good results. Heidi Nass attended the March meeting that discussed the WHC agenda. “I felt like the RAC chairs were saying, ‘Bring us the studies’ and the community was there chanting, ‘If you build it they will come,’ ” she said. “Before the ACTG can legitimately say it’s so difficult to enrol women, they need to design studies that women actually want, and they need to make sure the sites are invested.”

Source: amfAR Treatment Directory.