Women and AIDS: Selected Highlights
from The National Conference on Women & HIV
Pasadena, CA, May 4-8, 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
- Women with AIDS have more candidiasis, herpes simplex virus infections
and CMV infections (non-retinitis) than men with AIDS
Kaplan J. Prevention of opportunistic infections. Oral
presentation and abstract #210.2.
CMV Infection Common in HIV Positive Women
- 63% of 296 women from the Chicago consortium with less than 200 CD4
cells/mm3 had CMV in either saliva, cervix or urine, compared to 31%
of women with at least 200 CD4 cells/mm3
Chandler S and others. Epidemiology and natural history
of cytomegalovirus in HIV-infected women. Abstract #103.1.
100% Recurrence Rate of Invasive Cervical Cancer
- Study reports a 100% rate of recurrence of invasive cervical cancer
after successful treatment in women with HIV
Levine A. AIDS-related cancers in HIV infected women.
Oral presentation and abstract #300.1.
Nelfinavir in Women
- Nelfinavir (Viracept) in combination therapy is as effective for women
with HIV as for men
- 3 studies (505, 506, 511) included 78 women, for 11% of the total
study population
- Viral load reductions and CD4 cell count increases were nearly identical
- Side effects were similar in women and men
- Diarrhea was less common in women (10% of women vs 23% of men)
- Transient abdominal pain was more common in women (7% of women vs
2% of men)
- Itching occurred in 3.3% of women vs 0.3% of men
- Rash occurred in 5% of women vs 2% of men
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
- The adverse event profile for ritonavir differs somewhat between women
and men taking the drug
- Weakness more common in women (47% of women vs 34% of men)
- Numbness and tingling around the mouth occurred in 37% of women vs
27% of men
- Folliculitis (hair follicle infection) was 17% more common in women
- Allergic reactions (9% less), enlarged lymph glands (16% less) and
bronchitis (14% less) occurred less often in women than in men
- Nausea, vomiting and diarrhea were very common in both women and men
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
- Report describes protease inhibitor experiences of HIV positive women
at the University of Southern California
- 48 women were studied; 65% had prior experience with 3 or more nucleoside
analog drugs
- Mean baseline HIV RNA viral load was 83,970 copies/mL and mean CD4
count was 144 cells/mm3
- At baseline, 70% were taking d4T plus 3TC and 10% were taking AZT
plus 3TC
- Before starting protease inhibitor therapy, 50% of the 24 women patients
with available information had stopped their menstrual periods
- Indinavir (Crixivan) was started by 67%, saquinavir (Invirase) by
15% and ritonavir (Norvir) by 12%; 6% never started prescribed protease
therapy
- After 5 months follow-up, only 51% remained on their original protease
inhibitor
- 32% changed to a different protease inhibitor due to lack of benefit
(25% of those started on indinavir switched to ritonavir plus saquinavir,
43% started on saquinavir switched to indinavir and 16% started on ritonavir
switched to indinavir)
- 17% were no longer taking a protease inhibitor due to nausea, vomiting
or non-adherence
- Of those remaining on a protease inhibitor (data on 40 of 48 women),
54% had an undetectable viral load (limit of detection 500 copies/mL),
35% had an initial viral load decrease with a subsequent increase and
2% had no change in viral load
- 61% had an increase in CD4 cell counts and 40% had an initial CD4
count increase followed by a decrease
- 16% of the women developed diabetes mellitus (elevated blood glucose);
2 patients required insulin injections and 3 started on oral hypoglycemic
medication
- after 15 months, 1 case of CMV retinitis (in the ritonavir plus saquinavir
group), 1 case of toxoplasmosis (in the indinavir group) and 3 cases
of kidney stones (in the indinavir group) were reported.
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
- Women taking protease inhibitors had a variety of self-reported side
effects
- 23% reported menstrual changes
- 27% reported light sensitivity
- 16% reported insomnia
- 12% reported breast pain
- 12% reported some hair loss
- The study included 34 current users and 9 former users of protease
inhibitors; most of the women were on standard protease inhibitor cocktails,
with the majority taking indinavir or saquinavir
- The study had several potential confounding variables
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
- Study (0021) of AZT plus delavirdine (Rescriptor) included 139 women
(19% of total study population); 60% were AZT-naive and 40% had less
that 6 months of AZT experienced
- The combination showed equal efficacy in women and men
- 0.6 log copies/mL reduction in HIV viral load at 52 weeks
- Increase of approximately 30 CD4 cells/mm3 at 52 weeks
- Trough level (lowest blood level prior to next dose) of delavirdine
was 1.8-fold higher in women, indicating a gender difference in metabolism
- Trough level of AZT was the same for both women and men
- Rash developed in 18% of both women and men, but disappeared in 85%
within 3-14 days without discontinuing or decreasing dose of drug
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
- Study of 52 women showed no gender differences in pharmacokinetics
of 3TC (Epivir)
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
- A retrospective analysis including 16 women and 314 men showed that
the combination of 3TC plus d4T (Zerit) is as effective for women as
for men
- HIV viral load decreases and CD4 cell count increases were similar
in women and men, including when drug-naive and drug-experienced patients
were compared
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
- Hormone replacement therapy (HRT) was shown to increases survival
in menopausal women with AIDS
- 72% decreased risk of death in women on HRT (borderline significance)
- Study included 84 women with AIDS over 40 years of age
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
- Janesway device, which consists of a cotton panty with attached latex
internal condom, is designed to prevent STD and pregnancy
- Device could provide more STD protection than standard male or female
condoms because the vulva and groin are covered with latex
- A similar device for receptive anal intercourse called Rearguard is
planned
Hunnicutt J. Acceptability study of the Janesway female
condom. Poster #1.73.
Cocaine Use Increases Progression to AIDS in Women
- Immune cells and cocaine from HIV positive women's blood increases
HIV growth in vitro
- Study of 94 HIV positive African-American women in Miami
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
- Vaginal fluids from HIV positive women who had had a hysterectomy
(removal of the uterus) were found to contain HIV RNA
- Results suggest that HIV shedding is possible from vaginal cells
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.
Page last updated 3 July 1997
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