SF AIDS Fdn: BETA Summer 2000 -- Re-Examining Treatment Recommendations for Women

Published in the Bulletin of Experimental Treatments for AIDS Summer 2000 issue, by the San Francisco AIDS Foundation.

Summer 2000 Table of Contents

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Re-Examining Treatment Recommendations for Women

Kathryn Anastos, MD

The rate of HIV infection in the United States has increased among women and individuals of color, while decreasing among White men. Women and individuals of color now represent 67% of people newly diagnosed with AIDS, 62% of individuals living with AIDS, and 69% of newly reported diagnoses of HIV infection. The highest rates of AIDS, of HIV infection, and of HIV-related deaths are among African-American women and men. Nearly 80% of HIV positive women in the United States are African-American or Latina. Thus it is extremely important to know if the recommendations for treatment of HIV positive people, developed almost entirely from data in White men, are valid for women and individuals of color.

In the last year, new information has become available suggesting that the "natural history" of HIV infection, that is, the ways in which HIV can make people sick, may be different in women and in people of color, compared with White men. However, the recommendations currently followed by doctors to determine treatment for individuals with HIV infection are based mostly on the results of studies of viral load and treatment in HIV positive White men. There are three areas in which there is evidence of differences between women and men. These include 1) levels of viral load, 2) CD4 cell counts in people with or without HIV infection, and 3) the level of CD4 cell counts at which AIDS develops. The differences found between Whites and people of color include viral load differences and differences in how fast CD4 cell levels decline.

Several ongoing studies in the United States are investigating the natural history of HIV infection in women. Two large studies include only women: the Women's Interagency HIV Study (WIHS), which has enrolled 2,059 HIV positive women and 569 HIV negative women, and the HIV Epidemiology Research Study (HERS), which includes about 800 HIV positive and 400 HIV negative women. Some studies include both men and women, usually with about four times as many men as women. This includes the AIDS Link to Intravenous Experience (ALIVE) study, which follows the course of disease in women and men enrolled in a drug treatment program in Baltimore. Nearly all (96%) of ALIVE participants are African-American.

Recent studies suggest that viral load tends to be lower in women compared with men, in people of color compared with Whites, and in those participants reporting a history of injection drug use compared with those without such a history. In addition, some data has suggested that for women with HIV infection, remaining alive (survival) is predicted better by the CD4 cell count than by the viral load. These findings have led some physicians and scientists to question whether it is appropriate to assume that information gained from studies of White men should be used to develop treatment recommendations for women and people of color.

In November 1998, researchers from the ALIVE study published findings about the viral load levels of the women and men in the study. At every level of CD4 cells, the viral loads for the women were lower than in the men. For example, in women the average level of viral load was 3,000 copies/mL but in men it was 9,000 copies/mL. Similar results had been reported about a year earlier in a much smaller group of HIV positive women and men in the U.S. military.

In early 1999, the WIHS investigators also presented results of a comparison of viral loads in the WIHS women to viral loads among the men in the Multicenter AIDS Cohort Study (MACS). The results indicated that the viral loads in women were 20% lower than in the men at any given level of CD4 cells. This information prompted other researchers to look at viral loads in women and men: some have found that there is a difference, and some have not found such a difference. The WIHS and MACS investigators also found that the viral load in people of color was 35% lower than in Whites, an even larger difference than they found between women and men.

Although it is not often discussed, it has been known for some time that the "normal" CD4 cell levels in women and men are different, i.e., regardless of HIV serostatus, women and men have different standard CD4 cell ranges. In HIV negative people, CD4 cell levels are about 100 cells/mm3 higher in women than in men: women's CD4 cell levels average around 1,100, and men's are around 1,000 cells/mm3. This established gender difference in CD4 cell counts is important when interpreting study results. HIV positive individuals are often stratified into study groups by CD4 cell count in an attempt to adjust for duration of infection; the assumption is that people with similar CD4 cell counts have been positive for the same (approximate) amount of time.

Yet that assumption may be incorrect when comparing groups of women and men. One study has shown that in HIV positive people, the CD4 cells in the women continued to average about 100 cells/mm3 higher than in the men for at least the first five years of infection. It is important to note that, even though CD4 cell counts differ by gender, they do not appear to differ by race, based on observations made in White, African-American, and Latino groups in the U.S.

The differences in CD4 cells may matter -- it may mean that women can develop AIDS or HIV-related diseases at higher CD4 cell counts than men do. Alternatively, women's higher CD4 cell counts may "protect" them by preventing the development of AIDS for a longer period of time after becoming infected with HIV. Unfortunately, few studies can help answer these questions, which would be best answered in a study that would include people whose date of infection with HIV is known, or who have been followed for a long time before they develop AIDS.

Most studies that have looked at gender differences in disease progression have followed people who are stratified by CD4 cell counts, as described above. Some studies have found no difference, some have found that women progress faster, and others have found that men progress faster. No study has been designed yet to answer this question, and the available data really leave the question unanswered. However, a very recently published study of a group of HIV positive women and men in Europe had some disturbing findings. Using a mathematical modeling of CD4 cells, the investigators demonstrated that the women developed AIDS at higher CD4 cell levels than the men.

Similarly, very little scientific information exists that could detect any differences in clinical disease between Whites and people of color. Most studies have found no difference in rates of disease progression or death by race. However, the MACS study (again, a study that enrolled men only), which includes very few men of color, found that the rate at which the CD4 cells fell was much slower in the men of color compared with the White men -- suggesting that the men of color may fare better clinically. Similarly, WIHS investigators have preliminary findings that CD4 cell counts may decline more slowly in African-American and Latina women, compared with White women.

There are three major measures that physicians or other providers use when making treatment recommendations to HIV positive individuals. These are: 1) clinical disease, or the presence or absence of HIV-related illnesses, 2) the CD4 cell count, and 3) the viral load. Clearly, highly active antiretroviral therapy (HAART) should be recommended and provided to any person with clinical disease. What is less clear is at what CD4 cell or viral load level treatment should be first recommended -- i.e., when antiretroviral treatment should be initiated. The current recommendation is that HAART be recommended for any HIV positive person with fewer than 500 CD4 cells/mm3, or whose viral load is higher than 10,000 to 20,000 copies/mL. Although most people would not develop clinical disease at these high CD4 cell and low viral load levels, the theory behind treating early is to prevent the development of clinical disease.

Because of recent information suggesting gender and racial differences in CD4 cells and viral load, there has been concern that the standard recommendations doctors and patients use to guide decisions about initiating or changing treatment may not be correct for women and people of color. Two things must be kept in mind when considering changing the recommendations.

First, because of their lower viral loads when treatment is initiated (usually because of CD4 cell levels below 500 cells/mm3), women and people of color may actually respond better to antiretroviral therapy. If this is the case, then the current recommendations may be appropriate -- or it may even be that treatment could be initiated later for women and people of color. What is most important is how people (different groups) respond clinically to treatment, not whether their viral loads differ in the absence of treatment. Thus it is critically important to determine if the differences in viral load mean that women and people of color do better or worse with treatment than White men. The scientific community is only beginning to be able to answer this question. Much more research is required.

Second, it is unclear whether the current treatment recommendations are "correct" even for White men. HAART has not been around long enough for us to know if people treated when CD4 cell levels fall below 500 cells/mm3 do better in the long run than people who wait until the CD4 cells fall below 350 or 300 cells/mm3. A recent study from Europe found that HAART was initiated at lower CD4 cell counts in people with a history of injection drug use and in people who had less formal education -- but these groups were not any more likely to develop AIDS. This suggests that people who initiate treatment later may do just as well as those who initiate treatment relatively earlier, by the current recommendations.

Again, the optimal time to initiate treatment (like the optimal time to change treatment) remains unknown for all HIV positive individuals. Therefore, it is premature to suggest that treatment recommendations for specific groups be changed now. It is not clear whether such a change would mean women or men of color would be treated earlier or later. Investigations of this question should clearly include sufficient numbers of women and of men of color to allow informed decision-making for those groups specifically.

In summary, much recently published information suggests that there are gender and/or racial differences in CD4 cell counts and in HIV viral loads. However, it is unclear whether these differences indicate that there are clinical differences by race or by gender, even in people not taking any antiretroviral treatment. The most important question is whether these differences in CD4 cell and viral load levels mean that treatment would be more or less effective in delaying or preventing clinical disease, including AIDS, for women and people of color. More study is needed to determine answers to this and to related questions.

Reprinted with permission from the Winter 1999-2000 issue of the CRIA Update.

Kathryn Anastos, MD, is the Principal Investigator for the Women's Interagency HIV Study (WIHS), NYC/Bronx consortium and Vice President and Chair of the Ambulatory Services and Primary Care Center at the Catholic Medical Centers of Brooklyn and Queens.

Page last updated 16 August 2000