Ladies First
Women's Bodies Pose Challenges for HIV Treatment
By Emily Bass

Women represent the fastest rising group of new HIV infections in the United States, making up 22 percent of reported AIDS cases in 1997. In spite of these rising numbers, female participation in clinical trials of anti-HIV drugs hovers at around 10 percent. This means more and more women are taking drugs whose side effects and toxicities in the female body are largely unknown. While short-term studies to date suggest that most HIV antiretroviral drugs are effective and well-tolerated in women, emerging data reveal potential gender-specific side effects, including fat-related disorders and pregnancy-related toxicities (see box, "Bringing Up Baby"). This has prompted advocates to intensify their demand that drug companies consider the effects of new drugs on women's bodies before they reach the market.

Until recently, women with HIV, particularly pregnant women, were excluded from many drug trials on the grounds that experimental compounds could cause birth defects, and that women's hormonal cycling might interfere with data collection. Drug companies fear expensive lawsuits related to birth defects, and often require women of child-bearing age seeking entry into a drug trial to take birth control. They've also been reluctant to pay for day care or transportation, factors that limit womens' participation in drug trials.

As it stands, much of the information we have gleaned about HIV drugs is based on how they affect adult male bodies. Women's body composition can impact drug potency and side effects. Women generally weigh less than men and have a higher fat and water content in their bodies. Their reproductive systems are also different. Menstrual periods, menopause, and pregnancy all cause major changes in women's body chemistry that can affect how drugs are absorbed and where they are distributed. In spite of these differences, anti-HIV drugs-and most medications in general-are dosed according to average male weight and volume.

"Yes, drugs are working, which is extremely important and saving lives," says Dr. Kathryn Anastos, a principal investigator from the Women's Interagency Health Study (WIHS), the largest study of women and HIV in the country. "But we may be blasting women with higher doses than we need to." It is also likely that women have different side effects. Gender-based studies of safety, dosing, and efficacy are complicated to do-which spells dollars-and some drug companies avoid the issue altogether, saying that pre- and postmenopausal women with HIV have no apparent hormone-related problems. Experts and women's health advocates remain unconvinced. "It's a moot point," says Dr. Kathleen Squires, an AIDS researcher at the University of Alabama at Birmingham. "We need to do well-controlled pilot studies (of hormonal influences) even if the drugs appear to be working."

Researchers are already puzzling over gender differences in lipodystrophy, a disfiguring side effect marked by unusual fat deposits, facial and truncal wasting in people taking HIV combination therapies-notably protease inhibtors. While men tend to develop big bellies and "buffalo humps" or large fat deposits in their necks, women may experience increases in their breast size and lose body fat in their thighs and buttocks (see "Side Effects"). Other pressing issues that demand a gender-based focus include HIV viral load, which may be lower in women than men (see "Viral Load"). Since viral load levels are used to determine when to start, switch, or stop treatment, the issue is critical for women considering therapy.

Given the escalating rates of HIV infection among women, including teenage girls, there's increased pressure on the Food and Drug Administration to update its drug-testing guidelines. Even so, the response has been slow. The agency waited until 1995 to start requiring drug sponsors to provide a gender breakdown of trial data: if women are included in the study, their data are analyzed separately. However, there's no requirement to enroll women (let alone study hormonal influences), so sample sizes continue to be small or non-exist-ent. A 1997 FDA attempt to enact a "clinical hold" rule that would prevent trials of drugs for life-threatening illnesses from excluding women is languishing in the proposal stage.

The research now taking place is a curious mixture of underenrolled clinical trials and high-profile "women-only" studies like Agouron's Women First, a trial that treats participants to support groups, customized pill boxes, and calendars with daily inspirational messages. These adherence tools have helped women stick with the study's demanding four-drug regimen. That's good news for women who get access to fancy planners-but even better news for Agouron. The drug company now has data showing that twice- and thrice-daily dosing of Viracept, Invirase, d4T, and 3TC is effective in reducing viral load to undetectable levels.

The hoopla surrounding trials like Women First-(when was the last time a men-only study came with a gift bag and a catchy name?)-underscores the need for a major, organized HIV women's research agenda focused on basic research. "We haven't studied women for years and years," points out Asia Russell, an activist on women's issues with ACT UP-Philadelphia. "Now we're doing elaborate studies without the context for interpreting them."

Here's a quick look at what we do know-and what we need to find out. Remember that the information may be based on small studies or limited data that can be hard to interpret. Keep an eye out for updates on these issues and discuss new developments with your health provider.

Viral Load. There's striking evidence that HIV plasma viral load-a measurement of how many copies of HIV are in the blood-may mean something different in women than men. Several studies have found that women have lower plasma viral load than men. The U.S. Public Health Service's current, gender-neutral threshhold for starting anti-HIV drugs is a viral load count of 10,000 or more. But in one study, researchers from the Johns Hopkins University School of Hygiene and Public Health found that women were 1.6 times more likely to develop AIDS than men with the same viral load. Women's viral load count was also roughly 50 percent lower than that of men with the same CD4 T-cell count.

Despite these findings, most experts are hesitant to change current treatment guidelines. "If you look at the rate at which women and men become sick, it's basically the same," says Hopkins' study co-author Dr. Joseph B. Margolick. "The factors that influence women's viral load don't have much influence on disease progression." It's also possible that having a lower viral load could give women an edge when it comes to treating HIV, making them easier to treat. "Therapies may be more effective because women have to fight less virus," says Dr. Anastos.

Other studies have found HIV in the genital fluid and lymphoid tissues of women taking combination therapy when it can't be detected in their blood. That means the virus still poses a risk for sexual and perinatal transmission of HIV. It also raises the question of how well the drugs work to suppress all virus in women, and whether additional or more sensitive tests, such as cervicovaginal viral load tests, should be used. They are now used mainly for research purposes.

Side Effects. Studies of anti-HIV drug-related side effects in women are a jumble of cohort sizes and drug combinations. Viewed together, the picture that emerges is that women's side effects are no worse, and may even be better, than men's. Women report less diarrhea with several protease inhibitors including Norvir, Viracept, and Fortovase. But some drugs also appear to cause specific side effects in women: those taking Norvir report more nausea, vomiting, fatigue, malaise, numbness, and tingling around the mouth; those taking Viracept commonly experience belly pain, itching, and skin rash. A new Austrian study found that women on Crixivan are more likely to have increased serum creatinine levels and sterile pyuria (pus in the urine)-symptoms that can be early signs of kidney trouble.

Meanwhile, studies of lipodystrophy show that 16 to 18 percent of women on protease inhibitors develop fatty deposits and abnormal blood levels of lipids, triglycerides and cholesterol, problems that increase their risk of a heart attack. They also develop high levels of glucose that increase their risk of diabetes. The drugs appear to impair the body's ability to break down fat correctly, causing a loss of peripheral fat under the skin and an increase in visceral fat, typically around the intestines and liver. These problems also affect men taking protease inhibitors and non-protease HIV drugs. But women's patterns of fat redistribution differs from men's: women have breast cup-size increases from a B to a D/D, and typically lose peripheral fat in their thighs and buttocks, rather than developing big bellies seen in men with this problem.

Recently, a Spanish group reported that the risk of HIV-related lipodystrophy appears to increase over time: The longer you take the drugs, the greater your chance of having the problem. It's too soon to tell what this trend means for women.

Hormones. Estrogen, progesterone, and other hormones are the cogs and wheels of the body's biological clock. They prepare women for menstruation (periods), pregnancy and menopause. For women with HIV, hormones may also play an important role in drug levels and distribution. In one early study, women had blood levels of Rescriptor (delavirdine) that were 1.8 times higher than men taking exactly the same doses. Scientists speculate that women's hormones delay breakdown of the drug. More recently, researchers at the State University of New York at Buffalo found "considerable variability" of Crixivan levels depending on where a woman was in her menstrual cycle. Such fluctuations could potentially have serious consequences: Excess exposure could cause severe side effects, while insufficient doses could fail to suppress HIV activity, leading to drug-resistant virus and other complications.

There's also compelling evidence that women's hormones play a role in their risk of becoming infected or getting sick. In studies of SIV, the (monkey) simian sister virus to HIV, changes in progesterone levels were linked to an increased risk of viral transmission. In human studies, the hormone causes a thinning of the vaginal membrane and increased expression of a protein receptor called CCR-5 that acts as a doorway to allow HIV to enter immune cells. Women's progesterone levels are also affected by pregnancy and birth control pills, which may interact with HIV drugs that are metabolized by the same liver pathways. But here again, we lack specific information about whether women on therapy should avoid oral contraceptives. At Johns Hopkins, scientists are investigating the possibility that estrogen may help women maintain a lower viral load.

Pregnancy. Studies are also needed to look at how drug levels are affected by the dramatic changes in hormone levels the occur during pregnancy. This means shifting some of research focus away from the fetus. "We didn't start these trials (of drugs in women) to prevent perinatal transmission," says Lynne Mofenson, a National Institutes of Health researcher. "It's important to study the drugs that women receive before they are pregnant, because they will require them when they are pregnant." Planning is also underway to study the effect of menopause on HIV therapy.