Published in the Bulletin of Experimental Treatments for AIDS Winter 2001 issue, by the San Francisco AIDS Foundation.

Infection Rate in Women Increasing at an Alarming Pace

Winter 2001 Table of Contents

Main Page

beta@sfaf.org

Lessons Learned from Natural
History Studies in Women

Targeted Studies of Women

The lion's share of what is known about the pathogenesis (development) of HIV disease has been obtained through studies involving men-often, studies involving only men. Early in the epidemic, investigators mined the San Francisco Gay Men's Health Study for insights into HIV disease. The all-male Multicenter AIDS Cohort Study (MACS) provided the essential information used by John Mellors, MD, for developing a gold standard for viral load testing. In addition, many of today's treatments for HIV disease were approved on the basis of studies that primarily enrolled males.

Generally, HIV disease is known to affect adult men and women in many similar ways. Approved treatments for HIV work similarly well (or not so well) for both genders. Yet some disease characteristics are unique to women, and so the need to better understand the pathogenesis of HIV disease in women has been a long-standing item on the women's research agenda. Closely related and still incompletely answered are questions about how antiretroviral treatments impact women relative to men, i.e., with respect to such factors as lower average body weight, body composition differences, hormonal or endocrine differences (not to mention pregnancy), and variable immunologic and viral effects.

Some of these questions have been addressed already by research now concluded or underway. Many trial sponsors have worked hard to enroll numbers of women proportionate to epidemiologic measures (i.e., in numbers that reflect what is happening throughout the population at large). Nevertheless, diverse impediments to enrolling women remain in place and women continue to be underrepresented in clinical trials. Barriers include eligibility criteria that bar women of childbearing age and factors related to the lifestyle of many HIV positive women, who as mothers need childcare and as urban poor need committed assistance to access the health-care system. Thus, many fundamental issues remain only partially if at all elucidated.

The above notwithstanding, nearly ten years ago, with the express goal of addressing these sorts of concerns, two large, government-sponsored, all-women clinical trials began. The HIV Epidemiology Research Study (HERS) began enrolling in 1992 and provided much valuable information by its official conclusion last year; while since then HERS has been "on hold," a torrent of data may be forthcoming because funding to continue data analysis, reportedly, was recently approved. The Women's Interagency HIV Study, or WIHS (pronounced "wise"), opened in 1993. Now closed to enrollment, WIHS nonetheless continues both to collect and to produce data.

This edition of Women & HIV will report on the information and insights gleaned through the efforts of thousands of women with HIV, investigators, and others whose commitment to these particular trials made them possible.

Growing Numbers of Women with HIV

In the early '90s there was a new and increasing awareness of a growing epidemic in women and the consequent need for better information. A December 1990 national conference on women and HIV, sponsored by the U.S. Public Health Service (PHS) and the first of its kind, provided the National Institute of Allergy and Infectious Diseases (NIAID) the initial impetus and direction for targeted research. A steering committee assembled for that meeting that included women living with HIV as well as health and social service providers made a series of recommendations to PHS and NIAID.

Thus, NIAID and the U.S. Centers for Disease Control and Prevention (CDC) decided to collaborate to establish the first large-scale natural history studies of women and HIV infection. The NIAID branch of the study became known as the Women's Interagency HIV Study (WIHS) and the CDC component of the study, cosponsored by NIAID, was called the HIV Epidemiology Research Study (HERS). Both were designed as multicenter, prospective (forward-looking) studies of the natural history of HIV infection in U.S. women. Both enrolled women who were HIV positive and women who were HIV negative but "high risk" because of behaviors such as intravenous (IV) drug use, non-monogamy (high numbers of sexual partners), and unsafe sexual practices (e.g., exchanging sex for money or shelter). All participants had biannual examinations that included an interview, physical exam, and blood tests.

The HIV negative women constituted an important control group because in most ways other than HIV serostatus, the women in both groups were quite similar, allowing researchers to better discern sequelae (resulting conditions) of HIV. Results from analyses are often discussed in terms of these two groups: HIV positive women and the HIV negative, control group of women.

The overarching purpose of both studies was to identify clinical signs of HIV infection in women, to describe the pattern and rate of immune system decline, and to examine potential cofactors that might affect disease progression. Investigators also looked specifically at issues affecting length of survival and quality of life for women with HIV infection. Since the majority of American women with HIV infection live in inner cities and have traditionally experienced great difficulty in obtaining access to health services, both studies but HERS in particular emphasized the evaluation of psychosocial and cultural factors influencing women's access to health care.

In order to investigate the clinical, laboratory (i.e., immunologic, virologic), and psychosocial aspects of HIV infection in women in a multicenter, prospective fashion, a significant investment was needed to develop the complex infrastructures of these trial networks. Such an undertaking requires a period of several years of collaborative research and cohort follow-up for maximum scientific benefit to accrue. In addition, changes in the natural history of HIV and associated conditions occurring as a result of treatment advances and longer survival also had to be monitored. Over the course of both studies, progress in HIV/AIDS research and treatment meant that both studies had to build in flexibility to modify goals and adjust the infrastructure to reflect new knowledge and state-of-the-art methodology.

Key Recent Reports

The following sections summarize fuller reports made last year. Many were made this past summer in Durban, South Africa, at the XIII International AIDS Conference.

Non-AIDS Deaths among Women in WIHS

Mardge Cohen, MD, founder and director of the Women and Children HIV Program at Cook County Hospital in Chicago, and others evaluated causes of death in women in the WIHS cohort who did not die of HIV-related causes. They also compared causes of death pre- and post-HAART to see if any relevant factors had changed since women began taking HAART. To analyze trends, investigators reviewed death certificates and when possible consulted primary providers to pinpoint the causes of death for 308 women. While there were 407 deaths reported among the total of 2,059 women with HIV infection who were enrolled in the WIHS between October 1994 and October 1999, cause of death for over 100 women could not be adequately determined. Therefore, accurate information was available only for 76% of women who died.

A formula that considered cause of death and CD4 cell count at last study visit helped classify deaths as having been caused by HIV/AIDS or not. Thus it was determined that 227 of 308 (74%) deaths (with known cause) were HIV/AIDS-related; 67 (22%) were not related to HIV/AIDS and 14 (4%) were ultimately indeterminate. Among women who did not die of HIV, some causes of death were as follows: liver failure (9), drug overdose (10), pneumonia (7), lung disease (9), non-HIV-related malignancies (7), and violent death, such as murder, suicide, or accident (7).

Investigators also compared the most recent median viral load of women who died of HIV with that of women who died of other causes. For WIHS women who died of non-HIV-related causes, the last median viral load prior to death was 33,000 copies/mL, compared to 250,000 copies/mL for those with HIV/AIDS-related deaths. Hepatitis C (HCV) infection was present in 72% of women who died of non-HIV-related causes, and 45% of those with HIV/AIDS-related deaths. History of injection drug use also was significantly higher among women who died of other causes (70% vs 39%).

Overall, fewer women died of any cause in the HAART era (July 1996 and afterward) compared with the pre-HAART period (October 1994-June 1996). Still, the incidence of death due to non-HIV/AIDS causes remained stable. Thus, researchers concluded, a substantial minority of deaths among HIV positive women in the U.S. (16% of all deaths and 22% of deaths with known cause in WIHS women) may be non-HIV/AIDS-related, and due to causes including liver failure (often associated with hepatitis C), malignancy, violence, and illicit drug use. Since the number of deaths from AIDS has significantly decreased since the advent of HAART, non-AIDS deaths now make up a higher proportion of deaths among women with HIV.

CCR5 Genotype and HIV-1 in Women

On behalf of a large team from the Wadsworth Center, part of the New York State Department of Health in Albany, S. Philpott presented findings from their gene studies in WIHS women. They evaluated the role of "D32," the mutated form of human gene CCR5, a coreceptor for HIV-1. Previous studies have shown that having a mutated CCR5 gene affects susceptibility to HIV infection. (Studies have shown that people homozygous for D32 [having two copies of the same gene variant] are unlikely to be infected. However in studies of mostly male cohorts, D32 heterozygotes [people with only one gene mutation at the site in question] were not protected against transmission. Yet small studies with both men and women have found that D32 heterozygotes exhibit partial protection.)

To better understand the links between this gene and HIV among women, investigators determined the CCR5 genotype (i.e., the specific genetic makeup or "blueprint") for 2,047 HIV positive and 558 HIV negative participants in WIHS. Then they analyzed the relationship of CCR5 genotype to HIV status, ethnicity, transmission risk, disease stage, and response to HAART.

The CCR5 D32 allele (mutated CCR5) was found in 3% of the women overall and, as seen in other studies, much more commonly in Caucasians. The deleted form was found at the rate of 1.8% in African-Americans, 2.4% in Latinas, 7.1% in Caucasians, and 3.4% for other groups. (Of 2,605 women included in this analysis, 54.9% were African-American, 24.6% Latina, and 17.6% Caucasian; 2.8% were "other ethnicities.") The D32 gene was found in 4.0% of HIV negative and 2.6% of HIV positive women, adding to the evidence that the heterozygous genotype may confer partial protection. Like others before them, these investigators speculate that greater genetic susceptibility may in part explain the rapid spread of HIV-1 in sub-Saharan Africa and parts of Asia.

Mental Health Status and HAART

Judith Cook, PhD, from the University of Illinois at Chicago Mental Health Services Research Program, and others presented findings from a study of the impact of mental health status on women's likelihood of taking HAART. Investigators used longitudinal data (gathered over an extended period of time) from 1,668 HIV positive women. These data were collected through a total of 6,500 biannual study visits, from April 1996, when protease inhibitors became widely available, through August 1998. Investigators used the Center for Epidemiological Studies-Depression scale (CES-D) and a version of the Medical Outcomes Study Short-Form 36 (SF-36) to assess mental health status.

HAART was defined as any combination antiretroviral regimen that met published National Institutes of Health (NIH) guidelines. Fixed covariates were age, race/ethnicity, history of IV drug use, education, and study center. Factors that changed over time were mental health status, CD4 cell count, viral load, clinical symptoms, income, health insurance, current drug/alcohol use, participation in clinical trials, and utilization of mental health services.

Of 51% of women who used HAART, almost three-quarters (73%) exceeded the cut-off score on the CES-D that indicates clinical depression, and a full half (50%) reported use of mental health services. Women with depression and poorer general mental health were significantly less likely to report using HAART during the study period, even though by then it had become widely available. However, use of mental health services was associated with greater likelihood of HAART use, regardless of level of depression and general mental health. This study suggests that women's unmet needs for mental health services may inhibit both treatment decision-making and use of the most up-to-date antiretroviral therapies. The study also suggests that efforts to address psychological needs may increase women's access to HAART, since depressed women who were receiving help for their mental problems also managed to successfully take HAART regimens.

Factors Associated with Discontinuing HAART

L. Ahdieh, of the Department of Epidemiology at the School of Hygiene and Public Health of Johns Hopkins University in Baltimore, and others looked at why some women who start taking HAART either subsequently "downgrade" to less potent regimens or quit taking antiretroviral therapy altogether. The study included WIHS women who started taking combination antiretroviral therapy between October 1995 and March 1999. Investigators checked in at six-month intervals to see whether or not women were still taking their initial regimens, and evaluated factors like CD4 cell count and viral load for any associations with HAART continuation or discontinuation. (The levels and changes of these markers were assessed at two time points: immediately preceding and following discontinuation of HAART.)

Of 1,002 women who initiated HAART during the study period, 195 (19.5%) downgraded and 177 (17.7%) discontinued during follow-up. Women with low CD4 cell counts, high viral loads, and increases in viral load were significantly more likely to discontinue HAART at any point in time-decisions that appeared to reflect lack of treatment success. However, in the last period (by June 1999), women with poor prognostic indicators were nearly as likely to discontinue HAART as were women with indicators associated with a good prognosis. More importantly, in the last period, individuals who discontinued potent antiretroviral therapy did not exhibit changes in markers towards progression (i.e., whose health did not appear to be any worse, at least according to blood tests of viral load, etc.), in contrast to what was seen previously.

Therefore it was seen that over the three years of study follow-up, an increasing proportion of women taking potent antiretroviral therapy quit their regimens, sometimes for unclear reasons. Differences in CD4 cell count and viral load did not consistently predict discontinuation. Immediate immunologic and virologic negative consequences of discontinuation were not present in the last calendar period. These observations suggest that women over time discontinued their potent regimens for reasons other than treatment failure, which were not determined in this study-perhaps body fat changes-reasons that need to be elucidated so as to optimize treatment decision-making.

HAART, Anemia, and Survival

Anemia (reduced ability of blood to carry oxygen due to a low hemoglobin level, or reduced number of red blood cells, often manifesting as fatigue and weakness) is common in HIV positive women. Anemia has been found to correlate with higher plasma viral levels, lower CD4 cell counts, clinical AIDS (i.e., disease progression), use of AZT (Retrovir), and African-American (AA) ethnicity. In this analysis, Alexandra Levine, MD, of the University of Southern California (USC), and others wished to determine the effect of (1) anemia on survival and (2) the effect of HAART and other variables over time on hemoglobin (Hb) levels in HIV positive women. A total of 2,078 WIHS participants who completed a baseline visit between October 1994 and November 1995, and a last follow-up visit after April 1996, when HAART became widely used, were included.

A total of 1,575 HIV positive women were not anemic at baseline. Subsequent development of anemia was found to be associated with the following factors: African-American ethnicity, low CD4 cell count, high viral load, clinical AIDS, and AZT use in the previous six months. HAART use for 18 months or longer was significantly associated with a reduced risk of developing anemia. Among the 503 HIV positive women who were anemic at baseline, increasing CD4 cells and use of HAART for 18 months or longer were associated with resolution of anemia. Continued use of AZT prevented the improvements in hemoglobin level. The development of anemia was associated with a statistically increased risk of death (relative risk [RR] 2.58, or increased by approximately two and one-half times) while resolution of anemia was associated with a decreased RR of death (RR=0.47, meaning nearly reduced by half).

Investigators concluded that anemia is an independent risk factor for decreased survival in HIV positive women; that HAART has a protective effect against the development of anemia; and that use of HAART in anemic women is associated with improvements in hemoglobin levels over time. Elsewhere, erythropoetin (Procrit) has been used successfully to treat anemia in women.

Satisfaction with Health Care

While treatment of HIV/AIDS in the U.S. is believed to have improved for most people with HIV, less is known about the satisfaction of women with HIV. Many women with HIV have a low income, and many are members of an ethnic minority group that historically has had poor access to and dissatisfying health care. Jane Burke, MS, of the University of Illinois Chicago Mental Health Services Research Program, and others used an established measure of satisfaction, the RAND PSQ-18, to determine WIHS participants' satisfaction with care. Investigators were especially curious to see how reliable the test results would be among low-income, minority women, so they compared the results with data from a normative sample of the general U.S. population. Overall, they wanted to evaluate the validity of this measure for the WIHS population and the applicability of specific items.

As part of the normal participant follow-up, 16 of the 18 items of the PSQ-18 are administered annually in the WIHS. Data were taken from interviews with 1,303 women with HIV at two time points. Exploratory and confirmatory factor analyses were conducted, and statistical reliability computed. Investigators found that the means of each RAND factor were generally higher in the WIHS data than in the normative data, meaning that the responses given by WIHS women were likely overestimates of satisfaction. As it turns out, in other words, this measure was not very useful for this group of patients. Investigators recommended adjusting established measures to develop a test that more accurately captures the experiences of all women with HIV.

Risk of AIDS and Death Varies According to When HAART Is Initiated

Kathryn Anastos, MD, Associate Professor of Medicine at Albert Einstein College of Medicine in New York, and others looked at some factors associated with progression to AIDS or death. Among the 893 HIV positive women whose date of initiating HAART was known within six months, investigators examined time from HAART to AIDS and death (by July 1999) as well as potential cofactors like ethnicity, age, CD4 cell count, viral load, and whether or not women were antiretroviral-naïve when they began taking HAART.

Among 474 women who were AIDS-free at HAART initiation, 44 developed AIDS and 18 died within a 2.2-year median follow-up period. Compared with women who had more than 350 CD4 cells/mm3 at initiation, the relative risk for progression with 200-350 CD4 cells/mm3 and fewer than 200 cells/mm3 were 1.06 (not statistically significant) and 2.89 (highly significant), respectively. In other words, the risk of disease progression tended to be only slightly higher for women who began HAART with 200-350 CD4 cells/mm3 but significantly greater for women who waited to begin HAART until they already had fewer than 200 CD4 cells/mm3.

Over time, however, outcomes diverged for the two groups who had higher CD4 cells at initiation. After 18 months, those who began with more than 350 CD4 cells/mm3 appeared to have a somewhat better outcome than those who began with 200-350 CD4 cells/mm3.

Researchers also looked at the women's viral load at the time they began HAART, and compared levels with outcomes. Women who began HAART with fewer than 5,000 copies/mL fared best; women who began with 5,000-50,000 copies/mL were comparatively more likely to progress; women who began with a viral load greater than 50,000 copies/mL were most likely to progress.

Of 60 women who died, 42 had pre-existing clinical AIDS (illness): survival after HAART was strongly and negatively associated with preceding AIDS diagnosis. There was an upward trend for risk of AIDS with increasing age, too. In addition, a strong, but not statistically significant, protective effect from death was shown among women whose first antiretroviral regimen was a HAART regimen. (Since only 10% of the women were antiretroviral-naïve, it is hard to draw definitive conclusions.) Ethnicity was not associated with disease progression or death.

Investigators concluded that women who waited to initiate HAART until their CD4 cell count was between 200 and 350 cells/mm3 had similar progression to AIDS for the first one and one-half years as women who initiated earlier, when their CD4 counts were 350 cells/mm3. However, after the first year and one-half, the group who started later seemed somewhat more likely to progress thereafter. Longer-term follow-up (at least three years) will be necessary to determine the actual benefit of initiating HAART earlier.

Highlights of Earlier Findings

Psychosocial Factors

Over the years WIHS and HERS have generated a wealth of data and insights not only into clinical and scientific issues relating to HIV in women, but also psychosocial factors affecting women with HIV.

In one sub-study Rosemarie Gottlieb interviewed 44 women about their health beliefs, to see if those beliefs could be related to women's perceived quality of life. For these urban women, Gottlieb says, it was clear that having a positive attitude (reflected by reporting positive health beliefs such as "a person can have HIV but not get sick") was directly related to self-reports of positive quality of life. For instance, women with positive health beliefs also reported that they were in "excellent health" and that they were happy. Women who reported a so-called negative belief system (reporting, e.g., that they believed that there is nothing a person can do if she doesn't have good health care or that adherence "wasn't worth [following] a difficult health plan") generally also reported negative quality of life. These women were likely to report "feeling bad lately" or "feeling tired lately." While Gottlieb reported a clear association, she was unable to ascertain cause and effect; it is unclear which develops first-a negative quality of life, e.g., feeling sick, or a negative set of a priori (preexisting) beliefs. However, this report suggests that health-care providers spend some time talking with women with HIV about their feelings to encourage feelings of optimism and good health, which may translate into improved adherence, and to assess and treat clinical depression.

Multiple reports have described a high prevalence of domestic violence and childhood abuse in women with HIV. In one such sub-study, Judith Cook analyzed data from 1,220 HIV positive and 340 HIV negative WIHS participants. Half of the women reported a history of sexual abuse, and 80% of those (women who reported sexual abuse) reported abuse during childhood. While HIV serostatus was not significantly related to domestic violence or to physical or sexual abuse, all three were significantly related to HIV risk behaviors, including injecting drugs and exchanging sex for drugs, money, or shelter.

Jean Richardson evaluated depression in-depth among the entire WIHS cohort, using the CES-D tool described earlier in this article. She concluded that elevated levels of depression were common among HIV positive women and that they were similar to levels of depression in HIV negative women, although depression in HIV negative women was unrelated to CD4 cell count, as it was with HIV positive women. In both groups of women, depression was related to lower income, current drug use, alcohol use, and to sexual and physical abuse. Thus, depression among the WIHS cohort was found to be more likely to reflect social and cultural stressors such as poverty, violence, and substance use, than sequelae of HIV infection.

Experiences with the Health-Care System

Researchers from WIHS and HERS as well as other investigators have reported that HIV positive women have a wide range of experiences with the health-care system. Women have been noted to commonly enter care at a later stage of HIV disease than do men and, compared with men with HIV in this country, to have personal factors that reduce their chances for optimal health care. For instance, compared to men women tend to be relatively poor, to have less formal education, to be members of ethnic minorities, and to lack health insurance: all factors associated with sub-optimal health care. When it comes to taking HAART, however, both women and men report mixed experiences with treatment decision-making and with satisfaction. Alice Kim evaluated women in Chicago, who stated that positive experiences with HAART include clinical improvements like higher energy and better health, higher CD4 cell counts and lower viral loads, and increased hope and self-esteem. Negative experiences include side effects, difficulties taking complicated regimens that demand taking large numbers of pills at strict time points each day, and general emotional distress such as despair over health. Many women feel ambivalent about taking HAART, appreciating its efficacy but disliking its negative impacts on quality of life. Women also report that it is their combined feelings and experiences with HAART that influence their likelihood to continue or not, rather than a single factor such as changes in viral load.

Gynecologic Issues

Over the years investigators from both WIHS and HERS have made many reports on gynecologic conditions in women with HIV. For instance, a wealth of data clearly show that immunosuppressed women are more likely than their HIV negative counterparts to experience recurrent or severe vaginal candidiasis. One of the less straightforward topics has concerned menstruation in women with HIV. Anecdotally, many women have reported changes or abnormalities in their cycles, ranging from amennorhea (missed or absent periods) to severe and prolonged bleeding to unusually severe cramping. The results of investigations over the years have been inconclusive but generally have offered no scientific evidence of HIV-related differences (to the frustration of many HIV positive women, who assert perceived differences).

According to Sioban Harlow of the Department of Epidemiology at the University of Michigan, who evaluated menstrual function among WIHS and HERS women, being HIV positive was slightly associated with very short (e.g., less than three weeks) or very long cycles (longer than three months). Overall, however, HIV serostatus had little effect on menstruation. Body mass index (weight divided by height squared) and substance use seemed to have more bearing than HIV status on characteristics of menstrual cycles. In this sub-study, data were gathered through women's "menstrual diaries"; as with any study tool involving the need to record promptly and faithfully, there may be problems with accuracy. In another analysis, the only HIV-related effect on menstruation was a correlation between amenorrhea and severe immune deficiency, detected in 13% of women with fewer than 50 CD4 cells/mm3.

Many reports also have been made over the years about increased frequency of vaginitis and herpes in HIV positive women. Ruth Greenblatt, MD, Associate Professor of Clinical Medicine in the Department of Epidemiology and Biostatistics at the University of California, San Francisco and others published a report about the prevalence of lower genital tract infections and associated symptoms in the entire cohort. Results showed that HIV positive women were significantly more likely than HIV negative women to report gonorrhea (34% vs 22%), syphilis (20% vs 11%), genital herpes (25% vs 9%), and trichomoniasis (38% vs 27%). HIV infection was associated with having vaginal candidiasis (15% in HIV positive women vs 9% in HIV negative women) and genital warts (10% vs 1%). Bacterial vaginosis (bacterial overgrowth) was the most prevalent vaginal condition among all women but was not associated with HIV status (45% vs 42%). Researchers analyzed the data in different ways to take into account the impact of age, frequency of sexual intercourse, number of partners, condom use, and HIV factors including antibody status and CD4 cell count. They concluded that HIV positive women were more likely than HIV negative women to have histories of STD but less likely to currently have an acute STD. For HIV positive women, having a chronic viral STD (e.g., herpes, human papillomavirus or HPV) was associated with CD4 cell depletion. In another analysis, HERS data showed that HIV positive women relative to HIV negative women had more persistent HPV infection. HPV, the virus that causes genital warts, has been linked with genital cancer. (For more information on HPV and cervical cancer, see "Cervical Intraepithlial Neoplasia" in the June 1996 BETA. Also see "Anal Neoplasia: A Growing Concern" in this issue.)

Studies of genital (cervicovaginal) fluids and viral load have shown that HIV viral load in the genital tract varies widely (e.g., depending on a woman's hormonal levels, on whether she is actively menstruating, and on her overall immune status). Also, viral load in cervicovaginal secretions appears to correlate with viral load in blood plasma, both of which are related to HAART.

Cancer

Joel Palefsky, MD, Associate Professor of Laboratory Medicine at the University of California, San Francisco, has extensively studied HPV infection and cervical squamous intraepithelial lesions (CSIL), a precursor to cervical cancer, and cancer among WIHS women. His findings confirmed other reports that HIV positive women are at higher risk of HPV infection with multiple HPV types, although Dr. Palefsky reported little difference in the spectrum of types between HIV positive and negative women. Forty-two percent of HIV positive women showed infection with multiple HPV types, compared with 16% of HIV negative women. Among HIV positive women, lower CD4 cell counts, younger age, and current cigarette smoking were associated with elevated risk for HPV infection. According to Dr. Palefsky, infection with single or multiple HPV types was likely to reflect an immune-activated increase in replication of low-level HPV infection, rather than recent acquisition of new types through sexual activity. In a related evaluation, A.L. French of Chicago found a high prevalence of vitamin A deficiency in HIV positive women with cervical squamous intraepithelial lesions.

Alexandra Levine, MD, and others from USC described unusual cases of breast cancer in relatively young HIV positive women. Researchers examined the medical records of women who, at study entry, reported a history of breast cancer. Over the next year of follow-up, only two more HIV positive women and no HIV negative women reported a new diagnosis of breast cancer. Records of the seven pathology-confirmed cases (tissue biospy-positive) indicated that the median age at diagnosis was 47 years; median CD4 cell count at study entry was 196 cells/mm3. The odd and striking feature in HIV positive women was the observation of follicular hyperplasia (excessive growth of normal cells in a tissue or body part, which may increase its size) seen in adjacent lymph nodes.

The Future of Women-Specific HIV Research

Not so long ago, there was great enthusiasm over the commencement and proceedings of both HERS and WIHS. Now that HERS has ended and WIHS is no longer enrolling, has anything new taken their places? Has enough been learned about the basics of HIV in women that women-specific research has become obsolete?

Not exactly, to both questions. Some newer clinical trials involving women are currently enrolling, such as the Antiretroviral Therapy Looking at Sex and Treatment (AT LAST) study. AT LAST will enroll approximately 200 women and men with HIV who have been taking but not responding well (unable to tolerate or unable to suppress viral load below 500 copies/mL) to antiretroviral therapy that did not include a protease inhibitor. All participants will begin a new regimen consisting of indinavir (Crixivan), ritonavir (Norvir), d4T (Zerit), and ddI (Videx) to see if it is safe, tolerable, and effective and then results will be compared between women and men. Gender-specific data will be collected including body fat measurements, blood lipids, hormone levels, and pharmacokinetic (relating to the action of drugs in the body, including the processes of absorption, metabolism, transformation, distribution to tissues, and elimination) information. Study sites are in Berkeley, Boston, Dallas, Ft. Lauderdale, Los Angeles, Nashville, Rio Piedras (PR), New Orleans, New York, Newark, Rochester (NY), San Juan (PR), and Tampa. In the San Francisco Bay Area (where the study was still enrolling when BETA went to press), call Cindy Hopewell at EBAC at 510-204-1870. For general information about the study or to inquire about sites outside the Bay Area, call Ana Rodriguez at Women Alive at 800-554-4876.

The DYNAMIC Study, which is looking specifically at gender effects, is also enrolling both women and men. Researchers are investigating the potential influence of reproductive hormones (e.g., hormonal levels that vary during the menstrual cycle) on HAART pharmacokinetics. The study is open to women and men of varying CD4 cell levels but with a viral load greater than 10,000 copies/mL. Participants must be protease inhibitor-naïve. Women must be between 18 and 45 years of age and having regular menstrual cycles. For more information, call Sarah Ellison in San Francisco at 415-502-8056.

Other trials addressing newer research questions are ongoing or in the design and development phases. These include studies of the pathogenicity (disease-causing potential) and transmissibility of HIV and different HIV subtypes, and their interaction with specific sites in the body. Other studies are gauging the impact of widespread use of HAART on the way HIV develops in women compared to men, notably in evaluations of body fat and metabolic changes. (See "Metabolic and Body Fat Abnormalities: Does Gender Matter?" in the Autumn 2000 issue of BETA for key recent reports on "lipodystrophy" syndrome.) There also are a wide spectrum of prevention modalities relevant to women that are being studied or planned for study, such as microbicides (anti-HIV topical gels and lubricants) to prevent the acquisition of HIV and other STDs, and strategies to prevent mother-to-child HIV transmission.

Still, not all of the answers to older questions are in yet. Many questions remain about the interactions of anti-HIV drugs with female sex hormones and with the body during pregnancy. Studies of the natural history of HIV in women remain important, e.g., to actively and accurately survey malignancies in HIV-infected women. Finally, one of the most basic questions remains unanswered: how to increase the numbers of women participants in clinical trials so that study populations reflect what is happening in the epidemic? This question will continue to plague researchers, particularly as incidence rates continue to increase dramatically among women.

It would be tragic not to continue building upon the sound foundation provided by WIHS and HERS.

Leslie Hanna is Editor of BETA.

Related article by the same author:

Selected Sources

Ahdieh, L. and others. Factors associated with the discontinuation of potent antiretroviral therapy in a large cohort of HIV-infected women. XIII International World AIDS Conference. Durban, South Africa. July 9-14, 2000.

Alice, K. and others. HAART: personal experiences reflected in the Chicago Women's Interagency HIV Study (WIHS). 1999 National Conference on Women and HIV/AIDS. Los Angeles. October 9-12, 1999.

Cohen, M.H. and others. Non AIDS-deaths among women in the WIHS cohort: increasingly important in the HAART era. 12th International World AIDS Conference. Durban, South Africa. July 9-14, 2000.

Cook, J.A. and others. Impact of HIV-seropositive women's mental health status on their use of highly active antiretroviral therapies. XIII International AIDS Conference. Durban, South Africa. July 9-14, 2000.

Cook, J.A. The Women's Interagency HIV Study (WIHS): correlates of childhood sexual violence and HIV risk. National Conference on Women & HIV. Pasadena, CA. May 4-8, 1997.

DeHovitz, J. and others. Trends in CD4 count by response to HAART: a report from the Women's Interagency HIV Study (WIHS). 37th Annual Meeting of the Infectious Diseases Society of America. Philadelphia. November 18-21, 1999.

French A.L. and others. Association of retinol deficiency with cervical squamous intraepithelial lesions (SIL) in the Women's Interagency HIV Study (WIHS). 6th Conference on Retroviruses and Opportunistic Infections (CROI). Chicago. January 31-February 4, 1999.

Gottlieb, R. and others. Health beliefs and relationships to quality of life in a sample of HIV-seropositive women. 1999 National Conference on Women and HIV/AIDS. Los Angeles. October 9-12, 1999.

Greenblatt, R.M. and others. Lower genital tract infections among HIV-infected women and high-risk seronegatives: the Women's Interagency HIV Study (WIHS). XI International Conference on AIDS. Vancouver, B.C. July 7-12, 1996.

Harlow, S.D. and others. Menstrual function among women participating in the HIV Epidemiology Research Study (HERS) and the Women's Interagency HIV Study (WIHS). 6th CROI.

Levine, A.M. and others. Unusual cases of breast cancer in HIV-infected women: the data from Women's Interagency HIV Study (WIHS). National AIDS Malignancy Meeting. April 28-30, 1997.

Palefsky J. and others. Cervicovaginal human papillomavirus infection in HIV-positive and high-risk HIV-negative women. National Conference on Women & HIV. Pasadena, CA. May 4-8, 1997.

Page last updated 20 March 2001