BETA June 1997.
PART I
by Leslie Hanna
For 4 days in early May, over 1,500 people including researchers, healthcare providers and more than 400 women living with HIV/AIDS convened in Pasadena, CA, for the National Conference on Women & HIV. The main program was organized into 3 basic topic areas: basic and clinical science, behavioral and prevention science, and HIV/AIDS policy. Three hundred eighty two abstracts were presented.
This report will concentrate on highlights drawn primarily from the basic and clinical science track concerning the current state of knowledge about the biological and medical aspects of HIV disease in women.
Epidemiologic Summary
According to an April 1997 report by the National Pediatric & Family HIV Resource Center in Newark, NJ, an estimated 8.8 million women and 800,000 children in the world have HIV/AIDS. Much of the report is based on statistics released by the Centers for Disease Control and Prevention (CDC).
Most women with HIV/AIDS live in sub-Saharan Africa. By the year 2000, the number of women and the number of men infected with HIV worldwide will be equal.
By the beginning of 1997, 85,500 cases of AIDS in adolescent and adult U.S. women had been reported to the CDC. Of AIDS cases reported in 1996 alone, heterosexual transmission was the primary mode of infection for women, accounting for 40% of cases.
The percentage of new AIDS cases in women has been steadily increasing: 7% in 1985, 10% in 1990, 13% in 1992, 19% in 1994 and 25% in 1996. Nearly 80% of new cases reported in 1996 were in African-American and Latina women, who comprise 21% of all women in the U.S.
The largest percentage of AIDS cases in women is reported in the Northeast (44%), followed by the South (36%), West (9%), Midwest (7%) and Puerto Rico and U.S. territories (4%). Most cases in the Northeast occur in residents of urban centers (98.6%). In comparison, over 10% of women with AIDS in the South live in rural areas. Sixty-one percent of U.S. women with AIDS live in 5 states: New York (26%), Florida (13%), New Jersey (10%), California (7%) and Texas (5%).
AIDS is now the leading cause of death in women aged 25-44 in 15 major U.S. cities, and the third leading cause of death among women these ages in the U.S. as a whole.
Conference Overview
During the conference's opening session, keynote speakers including Congresswoman Maxine Waters from Los Angeles and National AIDS Policy Director Sandra Thurman provided an overview of the current status of the HIV epidemic in U.S. women.
The AIDS epidemic among women has been neglected by researchers and policymakers, Waters opined. Following the positive news reported by CDC of an overall 13% decrease in AIDS deaths in the first 6 months of 1996, women with HIV and their advocates now must battle the public perception that the AIDS crisis is diminishing. The CDC numbers reveal disturbing gaps in care and equity for women and people of color. While CDC reported a 15% decrease in the AIDS death rate for all men from January to June 1996, they also reported a 3% increase in deaths for all women during the same period. The gender bias in the fight against AIDS is duly reflected in these figures, Waters said.
Thurman agreed that wide reports of good news about protease inhibitors have led many to falsely conclude that the AIDS epidemic is over. Many factors are at work in the epidemic of AIDS among women. "The women's epidemic has been long-forgotten, encouraged by long-term barriers of sexism, classism and prejudice, for which we are now paying the price," Thurman stated.
"It's often said that America has the best healthcare system money can buy," she concluded. "Is it any surprise that so many Americans, including young people, people of color and women, don't have access to it? We have a long way to go to make sure that the medical establishment in this country is more responsive to women's needs. HIV doesn't happen in a vacuum. We must take the politics out of public health and let science lead us. We must balance hope with reality. This epidemic is not over."
Immunology and Virology
Alan Landay, PhD, of Rush Presbyterian-St. Luke's Medical Center in Chicago, reviewed basic HIV-related immunology and discussed some significant innovations. Today, researchers are moving to new cell markers of immunologic activation and function that should contribute to better information about health and immune status. In particular, increasing interest in a laboratory cell marker called CD38 may enhance physicians' and patients' ability to track over time what is happening with an individual's immune system.
CD38 is a receptor molecule found on CD8 cells, which are a type of immune system white blood cell. The nomenclature is parallel to that related to the more familiar CD4 cell marker; CD4 is the name of a receptor molecule found on certain immune cells.
People with HIV have elevated numbers of CD38 receptors on CD8 cells. As HIV disease progresses, cells begin to express more and more CD38 antigen. The exact mechanism responsible for elevating CD38 levels is unknown, but it is thought that increased expression may occur in response to high levels of chemical messengers (cytokines) produced when HIV viral load is high. When levels of CD38 are high, the protective ability of CD8 cells is likely impaired. For example, CD8 cells with abundant CD38 tend to kill other cells indiscriminately, whether their targets are HIV-infected or not. In addition, CD8 cells that express high levels of CD38 are believed to produce factors that enhance HIV replication.
Based on a few small studies, CD38 appears to be a very strong predictor of disease progression, regardless of CD4 cell count. CD38 levels appear to indicate immune system activation, helping to gauge the complex system by which the immune system and the virus drive each other. Despite outstanding questions about triggers of immune activation and disease progression, testing CD38 levels would likely provide valuable additional information about immune status and health.
For example, a person who receives a vaccination or is infected by an opportunistic pathogen such as Mycobacterium avium, which causes MAC disease, may experience immune activation. Immune activation increases HIV viral load. Increased viral load leads to increased levels of cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1) and IL-6 which, in cyclical fashion, enhance viral replication. It is this activated state that signals or precipitates disease progression. While the mechanisms involved in this complex process are not fully understood, testing for CD38 levels along with HIV viral load testing and CD4 cell counts would help an individual monitor her status.
Many physicians are not yet familiar with this newly appreciated marker. Although the test for CD38 level is not yet available outside of research settings, it is likely to be relatively cheap and widely available before long.
Other tests of immunologic function also are being evaluated for their ability to predict disease progression. Since it appears that the best predictor of loss of immune function is immune activation, some candidates for predictors include cytokines, the levels of which change during immune activation. Landay described the basic structure of cytokine families: proinflammatory (IL-1, IL-6, IL-7, TNF), immunoregulatory (IL-2), and the newest members, the chemokines RANTES, MIP 1-alpha and MIP 1-beta, and the receptors CCR5 and CXCR4.
Normally, cytokines help to regulate a cooperative relationship between the immune system's 2 basic pathways, the cellular and the humoral. During HIV-related immune activation, dysregulation occurs, and cytokine levels are altered. Some increase, some decrease, and a dysfunctional "cascade" and disease progression are thought to occur. While research continues to define the complex mechanisms involved in immune system defense against HIV, measuring different cytokines or related cell receptor responses may help gauge an individual's health status.
Wafaa El-Sadr, MD, of Harlem Hospital Center, discussed the clinical implications of viral load. Over the past few years, as a result of research and the widespread availability of viral load tests, the understanding of asymptomatic HIV infection has changed. Now, ongoing HIV replication is believed to occur from the time of infection, necessitating early antiretroviral drug intervention to prevent or delay progression from viral replication to immune system destruction and to disease progression and death. Assays for detecting viral load are increasingly sensitive and can detect the amount of HIV in various bodily fluids and tissues, including cervicovaginal fluid, blood and lymph nodes.
HIV viral load is a marker of viral activity or replication. Data exist to suggest that viral load can be used to provide evidence of antiretroviral drug activity and overall prognosis. El-Sadr reviewed studies including one conducted by the Terry Beirn Community Program of Clinical Research on AIDS (CPCRA) of HIV RNA levels in women that showed the value of using viral load testing to monitor quality of health care. She noted that questions about how viral load relates to clinical endpoints remain unanswered, including how undetectable RNA levels ultimately will correlate with clinical disease progression and survival. Although it makes theoretical sense to fight the virus as aggressively as possible, El-Sadr cautioned that the assumption that nondetectable HIV RNA accurately predicts clinical outcome remains unproven.
El-Sadr emphasized that blood viral load levels may not correlate with viral load in other tissues. For example, a study conducted by Burns and colleagues of perinatal HIV transmission (PHT) in 160 HIV positive women showed that vaginal intercourse during the third trimester of pregnancy was associated with a higher rate of PHT, independent of plasma viral load. This finding relates in part to the fact that levels of HIV in the blood are independent of levels in cervicovaginal fluids.
Barbara Weiser, MD, of the New York State Department of Health in Albany, reviewed the biology of HIV infection in women and men. The advent of viral load testing has permitted new insights into the natural history of HIV infection. In primary infection, there is an initial burst of viral activity and viral load, followed by a decrease and the establishment of an individual's so-called viral set point, a value that remains relatively stable for years. Currently studying long-term nonprogressors, Weiser is looking for evidence to explain attenuated (weakened) infection. She believes that the origin of attenuation is likely viral, although human genetic and other host factors may contribute.
While many of the benefits of HIV viral load testing apply equally to women and men, one application is particularly significant for women. There are now abundant data to associate viral levels with risk of PHT, and maternal viral load appears to be an important risk factor for PHT. Ongoing studies continue to eludicate the relationship between maternal viral load levels in various fluids as well as strategies for reducing maternal viral load, thereby reducing PHT. So far, certain threshold levels of plasma viral load have been tentatively identified. It appears that there is a level above which risk of PHT is very high and below which risk is not as high; however, there is no absolute level below which one can presume there is no risk of PHT (abstract #100.1-100.3).
Gender and Pain Perception
Monique Kaim, PhD, from the Memorial Sloan-Kettering Cancer Center, presented results of a New York City study that concluded that women with HIV are significantly undermedicated for pain. Study participants included 451 men and women with CDC-defined AIDS diagnoses, all of whom reported a high degree of psychological distress including depression and pain. All women participants were recruited from other studies in New York.
Approximately one-third of the women were African-American, one-third Latina and one-third Causasian. Compared to the men, the women were younger, less well educated and more likely to have been infected with HIV as a result of injection drug use. Men and women had similar CD4 cell counts and similar Karnofsky scores (a measure of overall ability to function). All participants were assessed using a battery of psychological measures including the Brief Pain Inventory, the Pain Management Index and the Beck Depression Index.
Sixty-two percent of participants reported frequent, consistent pain in the 2 weeks prior to the study (68% of women and 60% of men). On average, 2.5 different pains were reported by both women and men. Women had more AIDS-related symptoms, although once gynecological symptoms were excluded, the prevalence of physical symptoms reported by women and men were similar. Women also reported a higher intensity of average pain and of pain at its worst. There were no gender differences in amount of functional impairment (mood, activity level, ability to enjoy life). Distress caused by pain was similar in women and men.
In the analysis of their findings, researchers used the World Health Organization's pain index and recommendations for analgesic therapy for cancer pain, and found that pain in both women and men was undermedicated. Less than 7% received "strong" opioids even for severe pain. However, women were even more likely than men to be undermedicated.
The main findings were that, compared to men, women had greater levels of pain intensity and more AIDS-related physical symptoms, and were more likely to have their pain undertreated. Thus, being female was a predictive factor for undertreatment of pain (abstract #103.5).
Candidiasis in Women
Mucosal candidiasis is the most common clinical manifestation of HIV disease in adults, affecting the mucosal tissues found in the mouth, throat, esophagus and vagina. In women with HIV, vaginal candidiasis is common and often recurrent or more severe than in HIV negative women. Esophageal candidiasis, now one of the most common AIDS-defining infections, is associated with decreased food intake and wasting, and occurs more frequently in women than in men.
Wafaa El-Sadr presented results of a CPCRA study that determined predictors of mucosal candidiasis (oral and vaginal) in HIV positive women. Participants were drawn from a larger CPCRA study (protocol 010) called the Women's Fungal Prophylaxis study in which 300 women with fewer than 300 CD4 cells/mm3 were enrolled from 14 CPCRA units around the country and randomized to receive weekly fluconazole prophylaxis or placebo.
Investigators analyzed data gathered from those women who received placebo in order to identify some predictors for mucosal candidiasis. A total of 161 women were enrolled in the placebo arm. The women were 66% African-American, 18% Latina and 12% Caucasian. Forty-four percent had a history of injection drug use, 25% had an AIDS diagnosis, 47% had a history of oral candidiasis and 51% had had at least 1 prior case of vaginal candidiasis (23% reported 1 prior episode and 28% reported more than 1). The median CD4 cell count was 186 cells/mm3. Also, 75% were taking antiretroviral therapy and 60% were using PCP prophylaxis.
At baseline, 36% had a positive vaginal culture for Candida. Species were 66% C. albicans, 21% C. glabrata and 21% "other." (Detection of Candida does not necessarily mean infection.) Among these women, there were 68 cases of confirmed oral candidiasis (thrush), 44 cases of confirmed vaginal candidiasis and 20 cases of confirmed or probable esophageal candidiasis.
When all factors were considered, the main risk factor for recurrence of candidiasis was a history of prior infection at that same site, or prior oral or vaginal candidiasis. Having a baseline positive culture for vaginal C. Albicans was associated with subsequent development of vaginal candidiasis. The use of PCP prophylaxis was associated with increased risk of oral candidiasis and with decreased risk of vaginal candidiasis. However, baseline CD4 cell count was not found to be an independent risk factor for mucosal candidiasis, contrary to popular belief. Use of PCP prophylaxis may reflect a differential effect on oral compared to vaginal colonization with Candida, theoretically because there are different types of cell receptors in oral compared to vaginal mucosa (abstract #103.3).
Paula Schuman, MD, from Wayne State University in Detroit, presented data from the ongoing HIV Epidemiology Research Study (HERS), a multicenter longitudinal study of HIV positive women and HIV negative women at risk for HIV infection. Approximately two-thirds of HERS participants are HIV positive (n=871) and one-third are HIV negative (n=439). Of the HIV positive women, 70% have fewer than 200 CD4 cells/mm3.
For this study, researchers evaluated the susceptibility of Candida strains to fluconazole, a common oral antifungal drug, by testing isolates from oral and vaginal secretions gathered from participants at study entry and at visit #3 (one year later). The study and results are discussed in terms of fungal "isolates," not women.
One reason for the study was to evaluate implications of treatment of candidiasis, which, when chronic and persistent, is associated with HIV infection. In recent years, concern has emerged over the widespread use of fluconazole for treatment and prevention of candidiasis and the subsequent emergence of fluconazole-resistant strains of C. albicans, the most common cause of candidiasis. Non-albicans species may also cause infection, are more common in HIV positive persons and are more naturally resistant to antifungal azole drugs, including fluconazole.
Oral and vaginal specimens were obtained from participants at baseline and one year later. Fungi were isolated and speciated, i.e., the species were identified. Then the species were tested for susceptibility to fluconazole. Of 782 baseline oral isolates, 77% were identified as C. albicans (CA). The other, non-albicans species (NAC) were found to be primarily C. glabrata (11%) and C. tropicalis (7%). Less than 1% of oral CA isolates and 24% of NAC isolates were found to be resistant to fluconazole. One year later, 72% of 479 oral isolates were CA and 1% of CA and 20% of NAC isolates were resistant.
Of vaginal isolates at baseline, 68% of 374 were CA, and less than 1% of CA and 23% of NAC vaginal isolates were resistant. One year later, 60% of 259 vaginal isolates were CA; less than 1% of CA and 20% of NAC isolates were resistant.
Investigators then evaluated results by HIV serostatus, CD4 count category (for HIV positive women) and history of candidiasis. HIV positive women were significantly more likely than HIV negative women to have resistant oral NAC isolates at baseline and one year later, and resistant vaginal NAC isolates at one year later only. CD4 cell levels among HIV positive women were not found to be significantly related to resistance among oral or vaginal NAC isolates. Women who reported a history of candidiasis were more likely to have fluconazole-resistant strains than those who did not, but the difference was not statistically significant.
Researchers concluded that fluconazole resistance in CA isolates was rare, even among HIV positive women. NAC isolates were more likely to be fluconazole-resistant and were more commonly found in HIV positive women than in HIV negative women. Over the course of one year, the rate of fluconazole resistance among the NAC isolates was relatively unchanged (abstract #103.2).
Chronic Endometritis in Acute Pelvic Inflammatory Disease
Anne Moorman of the CDC presented results of a study that examined the influence of HIV infection on endometrial pathogens (disease-causing agents in uterine tissue) in women with acute pelvic inflammatory disease (PID). The study involved 44 HIV positive women and 163 HIV negative women, all of whom were diagnosed with PID in hospital emergency rooms and clinics between 1992 and 1995. Samples of upper uterine mucosal tissue (endometria) were obtained from the women before they began taking antibiotics. The samples were tested for bacteria and viruses, and studied for other characteristics. Diagnoses of acute or chronic endometritis (inflammation of the endometrium) were made on the basis of tissue studies.
HIV positive women were found to be more likely than HIV negative women to have endometrial genital mycoplasma, a type of bacteria (50% vs 22%), streptococci, another bacteria (34% vs 17%) and cytomegalovirus (CMV) (28% vs 2%). The incidence rates were similar for HIV positive and HIV negative women for other pathogens, including those that cause gonorrhea, chlamydiasis, bacterial vaginosis and genital warts. While 17% of HIV negative women were diagnosed with acute endometritis, based on cell and tissue studies, none of the HIV positive women were so diagnosed. On the other hand, HIV positive women had higher rates of chronic endometritis than HIV negative women (54% vs 33%).
Acute endometritis is not associated with clinical PID. Although no HIV positive women were diagnosed with acute endometritis, pathogens associated with the condition in HIV negative women were detected in HIV positive women. This finding led researchers to speculate that HIV may impair the immune system inflammatory response to endometrial pathogens. However, HIV did not appear to alter a chronic inflammatory response. No clear influence of HIV on chronic endometritis or on endometrial pathogens was discerned.
The primary difference between HIV positive and HIV negative women was that HIV positive women were more likely to have mycoplasma and/or CMV. The mycoplasma were sensitive to standard PID treatment.
One of the strengths of this study is that it is the only one to use uniform methods for detecting upper genital tract pathogens in the endometrium. A limitation of the study is that only 25% of the HIV positive women had fewer than 200 CD4 cells/mm3, which would indicate advanced HIV-related immunosuppression that might better reveal any relationship between HIV and endometritis (abstract #103.6).
Wasting Syndrome
Weight loss is a common complication of HIV disease. A diagnosis of wasting is generally made when weight loss is greater than 10% of normal body weight. However, weight loss of only 5% has been associated with poor clinical outcome, and weight loss along with malnutrition increases the risk for other illnesses. (Note: adult body weight may normally vary by 3%.)
Malnutrition often precedes as well as accompanies weight loss. Over the course of infection, HIV disrupts metabolic processes, including protein breakdown, cholesterol synthesis and fat oxidation.
Substance abuse is also associated with malnutrition. Social and economic factors such as lack of money and food often contribute to wasting in women with HIV. The problems of malnutrition and wasting are exceptionally pronounced in the developing world, particularly in Africa.
Over the past few years, several advances have occurred in understanding the mechanisms of wasting and the effects of malnutrition upon the body. Some gender differences have been detected along the way. HIV is believed to differentially affect body composition in adult and adolescent women compared to men, primarily as a result of gender-related hormonal differences. Body composition studies have shown that body weight alone is not the best yardstick for measuring wasting, and that looking at the effects of HIV on body "compartments" is more productive.
The whole body may be viewed as a total structure comprised of essential compartments of fat-free mass (muscle, also referred to as lean body mass), fat, bone and water. Hormones have a major influence on differential body composition in adolescent and adult women and men. Starting at puberty, increased production of the hormones estrogen and progesterone in women cause deposition of fat, whereas adolescent men begin to gain comparatively more muscle mass as a result of increasing levels of the hormone testosterone.
Researchers studying body composition changes during HIV infection and wasting have observed that women tend first to lose proportionately more fat, in contrast to men, who first lose proportionately more fat-free or lean body mass. Researchers believe that malnutrition and wasting may result from a loss of normal hormonal effects, and are studying both women and men to better understand the mechanisms involved. Ultimately, both women and men with wasting suffer from a significant loss of lean body mass, and lower than normal testosterone levels have been reported in women as well as in men.
Nutritional support alone (dietary supplements, total parenteral nutrition) is widely regarded as insufficient for repleting body cell mass (BCM) lost through HIV-related wasting, one of the main goals of anti-wasting treatment for both women and men. Despite gender differences, recent treatment advances for wasting such as human growth hormone and anabolic steroids seem effective for both women and men, and other approaches are being tried in both sexes. These medications, particularly in conjunction with resistance exercise for strengthening, maintaining and regaining BCM, have demonstrated efficacy in both men and women with HIV-related wasting. Continuing research into hormonal and endocrinologic influences on wasting may ultimately reveal more effective prevention and treatment strategies.
A poster from a team of New York researchers presented changes in body weight and composition in HIV-infected women and men from 1984 to 1996. The study involved an analysis of data collected during that time period in the Body Composition Unit of St. Luke's-Roosevelt Hospital Center.
Data including body weight and skinfold measurements were available for 430 persons (61 women, 369 men) with HIV-related gastrointestinal and nutritional problems. BCM and body fat were determined, and compared by year of study.
No correlations were found between the year of the study and age, race or height. Both women and men with HIV were found to be malnourished when compared with same-sex HIV negative controls. Compared to HIV positive men, HIV positive women were shorter, weighed less, and had less BCM and more body fat. From 1984 through 1996, mean body weight increased, probably as a function of better medical management of HIV disease. Both men and women had increases in body fat, but only men had increases in BCM over time (abstract #P1.62).
Arlette Pharo, DO (Doctor of Osteopathy), from the New Concept Health Center in Houston, TX, presented preliminary results of a study in women of oxandrolone (Oxandrin), an anabolic steroid being investigated for use in treating HIV-related wasting syndrome. The androgenic effects of oxandrolone (i.e., masculinizing effects like body hair growth and deepening of the voice) are less pronounced than with testosterone, yet the steroid increases muscle mass. Researchers regard oxandrolone as a better candidate than testosterone, which is also under study for anti-wasting therapy, for use in women with HIV-related wasting.
Researchers evaluated 2 doses of oxandrolone in combination with nutritional counseling, resistance exercise and nutritional supplementation. They also are evaluating the effect of the treatment on viral load and CD4 cell count.
This 16-week study involved 20 HIV positive women who were randomized to receive either 10 or 20 mg of oxandrolone a day. Mean body weight at entry was 94.5% of normal. All women were enrolled in a weight training program that involved working out for 1 hour, 3 times a week. Everyone received protein drinks and micronutrient supplementation including N-acetyl cysteine (NAC), flaxseed oil, fish oils, a multivitamin, antioxidants and vitamin C. Laboratory tests of nutritional status that measured intracellular nutrient levels occurred at baseline and at the study's end, along with bioelectrical impedance tests of body composition. At entry, most women had deficiencies in the B vitamins and calcium. Other tests (e.g., hormone levels) were performed at baseline and at 2 and 4 months.
Initial results (7 weeks) indicated that oxandrolone led to increases in body weight (mean 7 pounds), body cell mass (5 pounds) and body fat (4.3 pounds), and to reported quality of life improvement. Conclusions thus far are that use of oxandrolone in women promotes weight gain, composed of both lean body mass and fat, with no adverse side effects. At the time of the conference, the study was ongoing and open to new enrollment. For more information, call Arlette Pharo in Houston at 713-626-5050 (abstract #103.4).
HIV-Related Cancers
Several presentations concerned cancers among HIV positive women. The incidence of HIV-related cancers may be increasing, in part due to improved antiretroviral therapy leading to increased longevity. The mechanisms by which cancer develops may be different in the context of HIV. One theory holds that certain viruses associated with cancer (such as Epstein-Barr virus, associated with lymphoma; KSHV-8, associated with Kaposi's sarcoma; and human papillomavirus, associated with anogenital cancer) begin over time to gain an offensive advantage against a diminishing immune system response, thus causing clinical disease.
Conference co-chair Alexandra Levine, MD, of the University of Southern California reported new data on unusual cases of breast cancer in women with HIV. The data was gathered from women in the Women's Interagency HIV Study (WIHS), a longitudinal study of the natural history of HIV disease in women that is similar to HERS, enrolling both HIV positive women and HIV negative women at risk for HIV infection.
Through an examination of medical records, researchers identified 11 of 2,069 HIV positive women and 2 of 574 HIV negative women who reported a history of breast cancer. The increased incidence was not significant, but specific findings were. Thus far, after scrutiny of medical records and follow-up examinations, histopathologic data have been obtained for 8 of the 11 HIV positive women.
Investigators are concerned with the unusual nature of the tumors and the young age at which they developed (median age 44). The report includes 2 cases of poorly differentiated carcinoma with neuroendocrine features and 2 cases of poorly differentiated invasive adenocarcinoma, which Levine considers strange and unusual. Research into these cases continues, and the women are being followed closely. Levine is currently collecting data on viral load, family history of breast cancer and treatments used by the WIHS women (abstract #123.1).
Levine said that the study findings raise the question of a possible new etiologic agent in these types of breast tumors. She noted that neuroendocrine tumors in animals can be caused by the BK virus, which is in the same family as the JC virus that is known to cause progressive multifocal leukoencephalopathy. An estimated 90% of adults are seropositive for the BK virus.
The WIHS investigators have also proposed to the National Cancer Institute (NCI) a routine mammography screening study of all WIHS participants who have fewer than 100 CD4 cells/mm3, any breast abnormality on physical exam, one-sided axillary (armpit) lymph node swelling or a family history of breast cancer, or who are over 40 years of age. Levine said that NCI has already indicated its support for the screening study, which is contingent upon funding
When to screen for breast cancer is considered controversial, regardless of HIV serostatus. Family history of breast cancer is estimated to be a factor in only about 10% of breast cancer cases. In the population of women with HIV, many lack access to screening for diverse conditions for which they are at a higher probable risk than breast cancer. Levine says,"the bottom line is that we are seeing other cancers as women live longer, like Hodgkin's disease, and cervical cancer and anal cancer. Increasing numbers and types of cancers may have implications for the CDC's definition of AIDS."
In other cancer news, a panel of researchers presented recent summary findings relating to HPV, cancer and Pap smear abnormalities in women with HIV. Jonathon Cohn, MD, from Wayne State University, discussed the use of a quantitative HPV DNA assay for cervical squamous intraepithelial lesion (CSIL) screening in HIV positive women. The hybrid capture technique identifies HPV DNA sequences and thereby provides significant information about the probability of developing high-grade CSIL. Cohn said that longitudinal studies that use both the Pap smear and DNA assays are needed (abstract #203.1).
Julia Gage, PhD, from the University of California at Los Angeles, presented results of laboratory studies using cytokines and cervical cancer cell lines which have implications for the pathogenesis of cervical cancer and, perhaps, HPV vaccine design. The studies indicated that cervical cancer cell lines in vitro produce the cytokine IL-6 which, along with TNF and HIV tat, are all part of a pathway that HPV "turns on." When IL-6 production is increased in HIV infection, in the presence of HIV tat and TNF, HPV-infected cells appear to become increasingly receptive to IL-6. The enhanced potential for growth and spread of HPV-infected cervical cells is one explanation for the increased risk of CSIL in HIV positive women (abstract #203.2).
Joel Palefsky, MD, of the University of California at San Francisco reviewed data on the epidemiology of HPV infection and cervical cancer in the context of HIV. New data exist to suggest that HPV-related cervical abnormalities in women with HIV probably are related to HPV infection that was acquired many years earlier, and possibly long before HIV was acquired. In early HIV disease, the immune response is strong and HPV is held in check. As the immune response deteriorates, HPV "turns on" and the lesions that characterize CSIL or anal SIL (ASIL) develop.
Despite increased frequency of abnormal Pap smears and low-grade CSIL in women with HIV, the rates of reported cervical cancer are not significantly elevated. To maintain lower cervical cancer rates, Palefsky advocates extremely vigilant screening and aggressive early treatment in women with HIV, who often require multiple treatments even for low-grade CSIL.
Data on anal cancer in HIV positive men provides a cautionary tale for HIV positive women, Palefsky said. (An article on human papillomavirus infection and anal neoplasia will be featured in the next issue of BETA.) Currently, Palefsky is studying the natural history of anogenital HPV infection and lesions in the era of highly active antiretroviral therapy (HAART), which may provide a paradigm for HPV-related cancer in the future. Palefsky outlines 2 possible scenarios:
1. high-grade SIL + HAART = improved response to HPV and regression of high-grade SIL to low-grade SIL or even to normal
2. high-grade SIL + HAART = no HPV-specific immune response, which permits progressive development to cancer.
Since HIV negative persons with high-grade SIL usually have progressive or persistent high-grade SIL, it seems unlikely that scenario #1 will transpire. In PalefskyÕs San Fransciso cohort of men, a preliminary analysis of men with high-grade SIL on HAART indicated no spontaneous regression of high-grade SIL. However, high-grade SIL has been controlled to date.
Rigorous screening and aggressive treatment for persons with HIV and HPV-related abnormalities is still warranted (abstract #203.3 and 203.4).
Prevention Technologies
"Every 20 seconds, a new HIV infection occurs in a woman somewhere in the world. Over 4,000 women are infected each day, with 90% of these occurring in the developing world. Thus, the worldwide prevention agenda looms large," according to Sten Vermund, MD, PhD, of the University of Alabama at Birmingham.
Vermund outlined several prevention priorities. One goal is to explore the maintenance and restoration of natural barriers to HIV and sexually transmitted diseases (STD). In brief, based on current knowledge of the normal, naturally protective vaginal environment, Vermund recommended that women avoid vaginal douching, which may be a risk factor for HIV infection, and avoid unnecessary antibiotic use. Currently, University of Pittsburgh researchers are studying the utility of intravaginal suppositories for the renewal of normal hydrogen peroxide-producing lactobacilli.
Vermund emphasized that it will be important to develop barrier technologies that both women and men like to use. Research and community interest is high in microbicides for vaginal and anal use. He regards the female condom (Reality) as a "transitional technology," the current sole occupant of the niche of female-controlled prevention methods. Vermund advocates further exploration of possible roles in HIV prevention for the diaphragm or cervical cap, contraceptive barrier methods established in the 1950s. Finally, he spoke of the need for "erotic" and "universal" condoms that would be appealing to use and would be available everywhere, e.g., in vending machines.
Since treatment for STD decreases the rate of new HIV infections, Vermund emphasized the importance of STD detection and treatment for the prevention of HIV in women. Women-friendly settings have been shown in behavioral research to increase the likelihood of women receiving successful STD treatment, he added. In addition, it is advisable to screen women in high-risk settings such as prisons or juvenile detention centers.
Vermund noted that HIV prevention specialists are concerned about anatomical risks for HIV in women. These risks range from cervical ectopy in adolescent women and women who use oral contraceptives, to female genital mutilation, a topic he believes has great relevance for HIV acquisition and should be a priority in future prevention research.
Vermund noted challenges to prevention efforts, including the fact that "successful prevention strives to attain a nonexistent event. Prevention strategies like condoms, educational interventions and vaccines cost money, but make none. While pharmaceutical companies have money for drug research and development, market forces do not drive prevention research and development. In short, prevention has few friends. It needs more."
Prevention news presented at the conference included the results of a large CDC trial of nonoxynol 9 (N-9) film in Cameroon. The carefully designed study enrolled approximately 1,000 HIV negative female sex workers and provided counseling, monthly medical exams and condoms. Half the women also received 70 mg vaginal N-9 film to use in combination with condoms. The other half received placebo film.
Researchers, who had hoped to see a 50% protective effect from the use of N-9, instead reported an equal number of seroconversions in both arms of the study, leading them to conclude that, under the conditions of this study, the N-9 film had no measurable effect on the rate of HIV infection (abstract #215.3).
PART 2
by Harvey S. Bartnof, MD
Women with AIDS have Different Profiles of Opportunistic Infections than Men
Kaplan J. Prevention of opportunistic infections. Oral presentation and abstract #210.2.
CMV Infection Common in HIV Positive Women
Chandler S and others. Epidemiology and natural history of cytomegalovirus in HIV-infected women. Abstract #103.1.
100% Recurrence Rate of Invasive Cervical Cancer
Levine A. AIDS-related cancers in HIV infected women. Oral presentation and abstract #300.1.
Nelfinavir in Women
Gersten M and others. The safety and efficacy of Viracept (nelfinavir mesylate) in female patients who participated in pivotal phase II/III double-blind randomized controlled trials. Abstract #304.1.
Ritonavir Side Effect Profile Differs in Women
Currier J and others. Gender differences in adverse events on ritonavir: an analysis from the Abbott 247 study. Abstract #304.7.
Protease Inhibitor Use in HIV Positive Women
Johnson D and Currier JS. Protease inhibitor therapy in women: experience from clinical practice. Oral presentation and abstract #227.7.
Protease Inhibitor Side Effects in Women
MacNeil N and others. Protease inhibitors: experiences of women with HIV/AIDS. Abstract #1.65 (poster).
Delavirdine Trough Levels 1.8 Times Higher in Women
Wathen L and others. Combination therapy with delavirdine plus zidovudine versus ZDV alone: demographics, HIV viral load, and CD4 changes in female patients. Abstract #304.4.
No Gender Differences in 3TC Pharmacokinetics
Moore KHP and others. Analysis of potential gender differences in lamivudine (3TC) disposition using population pharmacokinetics from 2 phase III clinical trials in HIV infected patients. Abstract #1.54 (poster).
3TC plus d4T as Effective for Women as for Men
Cohen C and others. Retrospective analysis of lamivudine (3TC) plus stavudine (d4T) combination therapy: HIV viral load and CD4 changes in women. Abstract #1.77 (poster).
Hormone Replacement Therapy Increases Survival
Clark R and other. Clinical manifestations and predictors of survival among older women infected with HIV. Abstract #123.1.
Janesway Prophylactic Panty in U.S. Trials
Hunnicutt J. Acceptability study of the Janesway female condom. Poster #1.73.
Cocaine Use Increases Progression to AIDS in Women
Shapshak P and others. Cocaine and cocaethylene accelerate HIV/AIDS progression in African-American women. Abstract #221.1.
HIV RNA in Vaginal Fluids of HIV Positive Women with Hysterectomy
Farrar D and others. Detection of HIV-1 RNA in genital secretions of HIV seropositive women who have undergone hysterectomy. Abstract 111.2
Leslie Hanna is Associate Editor of BETA. Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee at the San Francisco AIDS Foundation since 1987.
This information is designed to support, not replace, the relationship that exists between you and your doctor.