Treatment Issues; Vol. 9, No. 3 - March 1995
Mary Jo Hoyt, N.P.

Fundamental questions such as female-male differences in clinical manifestations and survival can be answered only by looking at large groups of HIV-infected women over time and collecting clinical, virologic, immunologic, hormonal, social and psychiatric data. The new HERS (HIV Epidemiologic Research Study) centered at Brown University and the just commenced WIHS (Women's Interagency HIV Study) at the NIH are two such natural history studies.

At the Conference's medical sessions, data from the studies that looked primarily at the manifestations of HIV infection predominated over reports from clinical trials testing disease treatments or prophylaxis. (References below refer to the conference abstract book.)

Disease Progression in Women

A report from Kenneth Mayer, M.D., and colleagues at Brown University (abstract no. TC1-98) described the clinical course of HIV disease in 108 men and 175 women with similar demographic backgrounds (age, ethnicity, risk behavior and income) and at similar stage of disease who received their health care within the same community between 1988 and 1992.

AIDS-defining illnesses occurred at the same level of CD4 cell depletion for both genders. The two most common AIDS- defining conditions were Pneumocystis carinii pneumonia and esophageal candidiasis, with candidiasis more common in women and PCP more common in men. For all other AIDS-defining illnesses, no gender differences were found. There were differences, however, in non-AIDS defining diagnoses, with women more likely to have sinusitis and genital condyloma (warts), and men more commonly experiencing skin diseases and oral hairy leukoplakia. Women also had high rates of new and recurrent vaginitis and pelvic inflammatory disease, and in situ cervical neoplasia (precancerous lesions) was detected in two percent of women during the study period.

A study of disease progression from Johns Hopkins (abstract no. TC3-147) compared 974 HIV-positive men with 416 HIV- positive women receiving care in the same clinic between July, 1989 and December, 1993. Gender was not found to be a factor associated with progression of disease in this study. In patients with early symptomatic disease, the median time to progression to AIDS was 3.1 years for women and 2.8 years for men. In patients with AIDS, the median survival time was 1.8 years in women and 1.8 years in men.

The Community Programs for Clinical Research on AIDS (CPCRA) reviewed its data on disease progression and mortality in women and men recruited from seventeen CPCRA research sites. (abstract no. TC3-146) Information was obtained from the records of 768 women and 3,779 men enrolled between 1990 and 1993 in clinical trials or the CPCRA Observational Data Base. The results revealed some important differences. Women were one-third more likely than men to experience death as the first clinical "event" after enrollment. Among the patients who survived this first incident, there was no difference between men and women in disease progression.

Women were 40 percent more likely than men to be diagnosed with bacterial pneumonia and fifty percent less likely to have oral hairy leukoplakia than men. The increased risk of bacterial pneumonia and death occurred primarily among injection drug users, possibly reflecting differences in availability of health care, more poverty or less social support.

Wasting Syndrome

A hallmark of wasting syndrome associated with AIDS is the tendency to lose crucial lean body tissue and preserve relatively useless fat tissue. Because male and female hormones are important in determining the fat-to-lean tissue ratio, it is possible that HIV wasting syndrome has major gender differences. Reports analyzing wasting in diseases such as severe skeletal trauma have shown that women lose significantly less lean body mass than men. But at this conference, two studies comparing patterns of body mass depletion in men and women reported conflicting results.

Donald Kotler, M.D., and colleagues performed a retrospective cross-sectional analysis of body composition studies in 237 HIV-positive men and women and 577 HIV-negative controls. (abstract no. WF1-25) As expected, HIV-positive men and women had lower body weight and body mass index than HIV-negative controls. Depletion of lean body mass accounted for 40 percent of the body weight difference in HIV-positive men, but less than eight percent in HIV-positive women. The researchers concluded that: 1) the composition of lost weight differs in HIV-positive men and women, 2) HIV-positive women lose disproportionately more body fat than HIV-positive men, and 3) excess losses of body fat and alterations in skinfold thickness measurements in HIV-positive women suggest the possibility of hypogonadism, analogous to the relationship of testosterone deficiency to excess lean body mass loss in HIV-positive men.

In contrast, an ongoing prospective study in San Francisco, presented by Kathleen Mulligan, M.D., (abstract no. TC1-100) so far has found no support for the hypothesis that women with HIV may preserve more lean body mass than men with the same condition. There was evidence of progressive loss of lean tissue and increased rates of resting energy expenditure compared to HIV-negative controls. These losses were of the same degree and pattern in men and women with HIV infection. Increased rates of resting energy expenditure (or "hypermetabolism") were not found in all subjects and did not appear to be related to CD4 count.

Vertical Transmission

Two studies addressing different issues related to transmission of HIV infection from pregnant women to their infants generated interest and discussion.

Barbara Weiser, M.D., of the New York State Department of Health presented a prospective study examining the relationship between levels of maternal plasma HIV-1 RNA to transmission of HIV to the offspring. (abstract no. WC3-72) Quantitative levels of plasma viral RNA from 30 women at various stages of HIV infection were measured by polymerase chain reaction (PCR) during pregnancy and again at the time of delivery. In this group, 22 women were asymptomatic with CD4 counts over 200 and eight women had CD4 counts below 200, with three of the latter having had at least one opportunistic infection. Nineteen of the women took AZT at some point during their pregnancy.

Plasma HIV-1 RNA level at delivery correlated strikingly with vertical transmission. Eight of ten women with the highest blood plasma levels of HIV (over 175,000 copies of HIV RNA per milliliter) transmitted HIV to their infants. No baby born to women with lower HIV levels became infected.

Use of AZT in this cohort did not show an effect on vertical transmission. AZT resistance was found in three women taking the drug, and all three infants of these women were infected. One woman who initiated AZT during pregnancy showed a five- fold drop in viral RNA, but at the time of delivery she had developed AZT resistance and vertical transmission took place.

In general, viral RNA titers remained stable throughout pregnancy in women who either did not take antivirals or who remained on one antiviral treatment throughout. This data indicated that: 1) maternal plasma HIV level is a major determinant of mother-to-child transmission, 2) HIV level remains generally stable during pregnancy, and 3) there is strong scientific rationale for implementing multiple strategies to interrupt transmission by reducing viral load.

A study from Malawi presented by Richard Semba, M.D., examined the relationship of levels of vitamin A in pregnant HIV-positive women to the risk of mother to infant HIV- transmission and infant mortality. (abstract no. TF1-107) In this study, 474 HIV-positive women were followed from the second or third trimester of pregnancy to twelve months post- partum, when infant HIV status was determined. Vitamin A levels were measured during pregnancy, along with body mass index and CD4 levels.

Of the women enrolled, 69.2 percent showed some deficiency in vitamin A. For the analysis, women were categorized into four groups based on vitamin levels, ranging from the most severe depletion to normal levels. Results showed that the transmission rates for the four groups, beginning with the most deficient, were 32.4 percent, 25.2 percent, 16.0 percent, and 7.2 percent.

More than a quarter of the infants (28.7 percent) died in the first year of life. Infant mortality was significantly higher among those born to vitamin A deficient women, with a rate of 93.3 percent among those born to women with the most extreme deficiency. At the healthiest vitamin A level, fourteen percent of the infants died.

Pregnancy and CD4 Count

The question of whether pregnancy may adversely affect progression of HIV disease was addressed in a study from the University of Miami that compared CD4 counts over time in three groups of HIV-positive women. (abstract no. WC3-71) Group A (39 women) had no pregnancy during the study period, Group B (49 women) had one pregnancy and Group C (18 women) had two or more pregnancies.

Investigators found no differences between the groups in CD4 or CD8 counts and CD4 or CD8 percent. Declines in CD4 and CD8 counts were related to the baseline counts and were not effected by pregnancy. There also was no statistical difference in time to progression from one CDC classification (stage of HIV infection) to another between the three groups.

Genital Tract Infection

Several studies looked at the prevalence of genital tract infections in HIV-positive women as compared with HIV- negative women. Thomas Wright and colleagues at Columbia University compared 324 HIV-positive women with 258 HIV- negative women of similar age, income and race. (abstract no. FC1-180) Women were examined every six months, and tested for six genital tract infections: gonorrhea, chlamydia, syphilis, trichomonas, candida and bacterial vaginosis. With the exception of candida infections, there were no differences between the two groups.

The HERS group reported similar results. (abstract no. FC1- 178) Candida vaginitis was significantly associated with HIV after adjusting for age, current drug use, number of sexual partners, history of trading sex for drugs or money, condom use and antimicrobials. There was no association between HIV infection and bacterial vaginosis, trichomonas vaginitis, syphilis, chlamydia, or gonorrhea.

Cervical Disease and HPV

Human Papillomavirus (HPV) is a sexually transmitted virus, certain strains of which are known to cause precancerous growths in the cervix (cervical intraepithelial neoplasia, or CIN). Previous studies have shown that CIN is more common in women with HIV infection, and that the risk of CIN increases as immune function worsens and CD4 cells decline. An important question for HIV-infected women is whether a Pap smear is an adequate screening test for CIN, or if the more invasive test, which uses a colposcopy microscope to directly examine the cervix for tissue abnormalities, is required. (See Treatment Issues, December, 1994, pp. 4-5, 7.) Once CIN is diagnosed, it is not known whether response to treatment is the same in HIV-positive women as in uninfected women. Another study by Dr. Wright's group at Columbia (abstract no. FC2-208) reported the prevalence, incidence, and risk factors for CIN, the accuracy of Pap smears, and the efficacy of loop electrosurgical excision (LEEP) as a treatment for CIN in HIV-positive women. Four hundred HIV-positive and 400 HIV- negative women underwent clinical examination and colposcopy every six months beginning in 1991.

Colposcopy-confirmed CIN was diagnosed in twenty percent of the HIV-positive group and four percent of the HIV-negative group. CIN was independently associated with HPV infection, HIV infection and CD4 counts below 200. Eighty-one percent of the HIV-positive women with CIN had positive Pap smears. Recurrent or persistent CIN was documented in 56 percent of the HIV-positive women treated with LEEP, compared to thirteen percent of another group of women in the same clinic whose HIV status was unknown.

In a report from the HERS group (abstract no. FC2-207), HPV infection was detected by PCR in 65 percent of HIV-positive women and 31 percent of HIV-negative women. Pap smear showed squamous intraepithelial lesion (a stage prior to CIN) in seventeen percent of HIV-positive women versus four percent of HIV-negative women.

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