The role of women in HIV trials
05 December 2007
In the second of a three-part series on clinical trials and the search for effective HIV preventions and treatment, UNAIDS looks at why it is a scientific and ethical imperative that women and adolescent girls be adequately represented in testing and at the special issues that can surround their participation.
Women account for an increasing percentage of people living with HIV around the world. In sub-Saharan Africa, women and adolescent girls make up 61 percent of the 22.5 million people living with HIV, and young women in the 15-24 age group are three times more likely to become infected as men of the same age.
In high-income countries, some of the highest infection levels are to be found among women from ethnic minorities.
Decades after AIDS first became a global health threat, it has become clear that gender has to be a crucial consideration in medical research into stopping the spread of HIV, and for treatment. If investigators are to conduct research in those sectors of the population most exposed to HIV, which must be the case, then that means increasingly involving women, particularly in sub-Saharan Africa.
“It is important that HIV related research focus on the populations that are at most risk of HIV exposure,” said UNAIDS chief scientist Catherine Hankins.
Yet, until relatively recently, women were under-represented as participants in trials for all types of clinical interventions, including trials for HIV vaccines.
Thirty years ago the United States banned women of child-bearing age from taking part in initial phases of clinical trials. This step was taken in response to the thalidomide tragedy of the late 1950s and early 1960s when thousands of babies were born deformed in Europe. Their mothers had been prescribed thalidomide, a sleeping pill, to combat the effects of morning sickness during pregnancy.
Although the U.S. Food and Drug Administration (FDA) regulation officially referred only to women of child-bearing age, it effectively procluded all women from taking part in trials as even those unlikely to conceive, such as women using contraception, or who were infertile, celibate or lesbians. As a result, clinical trials for all preventions came to be dominated for several years, including the early 1980s which saw the recognition of AIDS as a global health danger, by the “cult of the 70-kilo man.”
But scientists soon began to ask whether research findings based on all-male trials could confidently be applied to women – particularly given the physiological differences between men and women.
Women have a lower body mass, a higher body-fat content, and a hormonal cycle and different levels of hormones to men, all of which can affect drug action, or what is known as pharmacodynamics. There are also metabolic differences. Aspirin is a case in point. When taken in small daily doses, it has been shown to reduce the incidence of heart attack in men, but not in women.
Given the under-representation of women in trials, the US Congress was lobbied to revise the law. By 1993, the FDA had reversed its ban and produced guidelines calling for data to be analysed in terms of gender.
Change did not come overnight. When the results of the first ever efficacy trial for an HIV vaccine – AIDSVAX -- were published in 1994, there were still only 309 women among the 5009 people that took part.
In contrast, in the recently stopped STEP trial of a Merck HIV vaccine candidate women accounted for 38 percent of the 3000 participants.
“Women and men are physiologically different, so results and conclusions from male-only studies cannot be assumed to be applicable to women,” said Hankins.
“It is both ethically and scientifically sound to enrol women in adequate numbers to be able to provide answers pertinent to them in all stages of human subject research,” she added.
Some of the most important recent breakthroughs in the response to AIDS have come in areas where only women can be participants. Mother-to-child transmission, where because of successful interventions infection rates have fallen as low as 1-2 percent in high-income countries, is the most obvious example.
In fact, all the most promising biomedical HIV prevention intervention trials currently underway involve both men and women, with the exception of female-initiated prevention tools. These include microbicides and barrier methods including the new female condoms, which may potentially provide protection against HIV, STIs and pregnancy.
There are currently a number of microbicides – gels, creams, films, anti-HIV releasing rings – undergoing tests in various parts of the world. Some have already passed the stage of animal testing and moved on to efficacy studies in humans.
Women are also involved in phase 3 trials – the efficacy stage -- of pre-exposure prophylaxis, herpes simplex 2 suppression and treatment, and in all stages of HIV vaccine testing.
Gaps in research
For various reasons, women may be more susceptible to HIV infection than men. Studies of sexual partners where one is HIV-positive show that women are at least twice as likely to become infected through unprotected heterosexual sex than men.
The reason may be that the vagina has a large mucosal surface area, making it more vulnerable to the virus. Women are also exposed to a greater quantity of fluids by way of male semen.
Issues such as medication dosages, drug resistance, side effects stemming from sex-based differences need to be studied. Women have highter CD4 T-cell numbers—cells that initiate the body’s response to invading micro-organisms such as viruses—and their viral loads vary with CD4 T-cell counts in a different way to men.
Clinical trials need to be designed for safety of women, her foetus, breastfed infant, and in the case of vaginal or rectal microbicides, her partner. Safety and efficacy amongst women remains one of the gaps in current research.
Vulnerability to HIV exposure is greater where women are marginalised due to their social, economic and legal status and this can influence their willingness, or ability, to take part in trials.
Women may fear being labelled within a community as an HIV risk, or be reluctant to take part because of concerns for possible harm to an unborn baby, or they may worry that it will affect their chances of getting pregnant in the future. These are important issues that researchers need to bear in mind and address when seeking to recruit amongst vulnerable communities.
Barriers for adolescent involvement
There also could be legal barriers to enrolling adolescents into trials for which they are assumed to be engaging in sexual activity.
One clinical issue for researchers is the physiological differences between women and adolescent girls. Sex hormone profiles change dramatically during adolescence and these changing sex hormones may have immunological consequences that may influence the efficacy of a given prevention tool, e.g. the immunological response to a vaccine.
Biological distinctions between age groups must be considered in research designed to assess safety, immunogenicity and efficacy. But so far there have been no HIV candidate vaccine trials involving adolescents.
There could be ancillary health advantages to involving older adolescent girls in clinical trials for female-initiated preventions such as female condoms and microbicides. These interventions can become part of routine sexual health practices and thus also give protection against other sexually transmitted diseases and unwanted pregnanacies.
Female sex workers and injecting drug users are often isolated from the general population and so demand extra effort to ensure that they become participants in HIV-related research.
Current prevention methods for sex workers and injecting drug users may not work. Sex workers may not have easy access to condoms, or may be prevented from using them by the threat of violence or may receive more money for unprotected sex.
There are also questions about whether microbicides would be effective for high frequency use by women with multiple sex partners. So prevention research continues to be particularly important for them.
Furthermore, the precarious legal status of sex workers and female injected drug users may make participation difficult and could even expose them to increased exploitation.
In recent years, HIV research has begun to afford women the attention that their exposure to HIV would warrant. Many of the most hope-inspiring avenues of scientific study, notably microbicides, rely almost exclusively on female trial participation.
Nevertheless, women most at risk from HIV are often vulnerable to social, economic and cultural pressures that can complicate their involvement in trials.
“Women should be recipients of future safe and effective biomedical HIV prevention products and therefore should be eligible for enrolment in biomedical HIV prevention trials, both as a matter of equity and because in many communities throughout the world women, particularly young women, are at higher risk of HIV exposure,” said Hankins.
The question of HIV trials, and in particular the involvement of women and adolescent girls in them, will be the subject of a two-day conference being hosted by UNAIDS in Geneva December 10-11. On Friday 7 December, part three of this special web series will preview the Geneva meeting, featuring interviews with the four organizing partners UNAIDS, The Global Coalition on Women and Girls, Tibotec and the International Center for Research on Women (ICRW).
Three-part web series
Part 1: Meeting ethical concerns over HIV trials
Part 2: The role of women in HIV trials
Part 3: Experts meet on women and HIV clinic trials
More on biomedical research
HIV Prevention Research: A Comprehensive Timeline
Global Coalition on Women and AIDS
International Center for Research on Women (ICRW)
Ethical considerations in biomedical HIV prevention trials (pdf, 750kb)
Good participatory practice guidelines for biomedical HIV prevention trials (pdf, 3.04Mb)