Published in the Bulletin of Experimental Treatments for AIDS April 1998 issue, by the San Francisco AIDS Foundation.

April 1998 Table of Contents

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Women and HIV: Recent Reports on Women and HIV from Worldwide Sources

Leslie Hanna

Obstetrics And Gynecology

Efavirenz Safety Alert

DuPont Merck Pharmaceutical Company, manufacturer of the new antiretroviral drug efavirenz (Sustiva, also known as DMP-266), recently released important safety information to the Division of AIDS (DAIDS), which widely distributed a safety alert. The information emerged from an animal study in which pregnant monkeys were given efavirenz at doses level comparable to doses used in human trials. Of 13 infants born to these monkeys, 3 had moderate to serious birth defects. One had a cleft palate (a deformity of the mouth), another had abnormally small eyes, and the third was missing one eye and its brain.

As a result, DAIDS is adding the following to the informed consent for all studies involving efavirenz:

• It is not known whether this [the defects] could happen in humans; therefore, you SHOULD NOT become pregnant while taking efavirenz
• All males and females must use barrier contraception [during the study]
• Women must use oral contraceptives or depo-progesterone [injectable contraceptives] in addition to barrier contraception

This alert is based upon preliminary data; it is not known exactly how animal study results ultimately relate to what will happen when humans take the drug. While the results do not necessarily mean the same would happen in humans, they warrant caution, since monkeys are genetically similar to humans. The company says that it will provide follow-up information as it becomes available.

Efavirenz is in the same class of anti-HIV drugs as delavirdine (Rescriptor) and nevirapine (Viramune); all are non-nucleoside reverse transcriptase inhibitors. Nevirapine is being tested in pregnant HIV positive women and their newborns to evaluate its efficacy in preventing mother-to-child HIV transmission.

Luzar MA, Chief, Regulatory Affairs, Division of AIDS. DMP 266 safety alert. March 17, 1998.

Viral Load and Mother-to-Child HIV Transmission

John Jacquez, with the Departments of Physiology and Biostatistics at the University of Michigan, reviewed data on maternal disease and perinatal HIV transmission (PHT), and developed a mathematical model to gauge the likelihood of transmission. To develop the model, he used transmission data gathered from mothers with primary HIV infection.

In brief, the model combines data on viral load with data on transmission by stage of infection, gathered in both the U.S. and in other countries. The model considers 3 possible time periods in which PHT can occur: during pregnancy, during childbirth and after birth (via breast-feeding). This staging helps consider changes in viral load at specific times. For example, the probability of PHT varies during the course of breast-feeding. During the early phase of lactation (milk production), colostrum is formed, which is rich in macrophages (white blood cells likely to be infected with HIV). This is a short phase of lactation. In later phases, colostrum ceases to be produced, and only "true milk" is formed. The later phases of breast-feeding involve lower probability of PHT.

Limitations of this model include the inability of the model to consider the impact of maternal nutritional status, variation in disease progression, concomitant sexually transmitted diseases and the use of average values for viral load. Despite these limitations, use of this model successfully supports the theory that PHT is most probable during primary HIV infection or advanced disease stages. The findings support the importance of taking into account the stage of the mother's infection in relation to the stage of pregnancy, delivery and breast-feeding.

Syndromes and Human Retrovirology 16(4): 284-292. December 1, 1997.

San Francisco Group Demonstrates the Ability of Combination Anti-HIV Therapy to Lower PHT

The Bay Area Perinatal AIDS Center (BAPAC), housed within San Francisco General Hospital (SFGH), is a coalition of doctors, physician assistants and other healthcare providers that offers prenatal care and HIV specialty care for HIV positive women, as well as pediatric care.

Recently, BAPAC proudly announced that, over the past 2.5 years, not one of the 60 women who has gone through the perinatal care program and given birth has transmitted HIV to her children. (One woman who delivered an HIV positive baby at SFGH did not know that she herself was HIV-infected, and did not receive prenatal care.) All 62 uninfected babies will be closely followed at least until they turn 2 years of age.

Karen Beckerman, MD, feels that this transmission rate owes, in large part, to the use of combination therapy by the mothers. Many women come in already on stable regimens, which they continue to use. All babies receive AZT according to the ACTG 076 regimen for 6 weeks. BAPAC strongly recommends that all babies receive prophylaxis for Pneumocystis carinii pneumonia (PCP), so it is offered to all mothers to administer to their babies.

While the results have been perhaps ideal for the children, the postpartum period may be difficult for the mothers. Some mothers have seen rises in their viral load; others have begun to experience problems with drug resistance. Compliance issues have influenced both viral load levels and resistance, and may be related to difficulty with the scheduling demands of complicated drug regimens and new motherhood.

"All of this points to the importance of counseling and offering HIV tests to all women, especially pregnant women, and then making sure HIV positive pregnant women receive prenatal care," says Beckerman. Access to care remains a huge issue for HIV positive women in general, and pregnant women in particular. Beckerman adds that outcomes improve when women receive care at centers where there is a staff who has significant experience with HIV disease and are comfortable both with the women and with the healthcare protocols. She suggests that insurers and policy makers incorporate these facts into health policies.

Beckermann K, MD, BAPAC. Personal communication. February 12, 1998.

HIV Transmission across Vaginal Tissues

Sexual transmission is by far the predominant mode of HIV transmission. Understanding how the virus penetrates the genital tract will likely lead to improved prevention methods.

Several studies have used animal models of infection, especially macaque monkeys. Usually, the animals are given an inoculation of simian immunodeficiency virus (SIV), then closely followed to see if and when they develop primary infection, what cells are affected, etc. Recent studies in female macaques indicate that HIV infection that occurs through vaginal exposure first occurs in specific white blood cells (mononuclear cells) in specific layers of the mucosa (the lamina propria, which lies underneath the surface of the vaginal lining).

In this study, researchers examined cells derived from human cervices. They wanted to try to determine whether HIV could pass through the superficial layers (the epithelium) to penetrate and infect cells at the base (the lamina propria). In the laboratory, the researchers constructed a model that essentially replicated the anatomical structure of the vagina, and added HIV to the upper compartment. At different points in time, they used p24 antigen testing in the lower portions to see if the virus had made it through.

They found that virus was able to penetrate and travel through the top layers and reach the base as soon as 1 hour after inoculation. A balance was reached around 17 hours after inoculation. The amount of virus able to reach the base during 24 hours ranged from 10-40%; the upper layers trapped about 50%. In those samples in which basal infection occurred, mononuclear blood cells were consistently infected with HIV.

These findings suggest that the vaginal epithelium may be only slightly effective as a barrier. The data support findings from other studies that show that the epithelium is not the site of infection, but rather that HIV diffuses through it to reach target cells in the lamina propria.

Fantini J and others. HIV-1 transmission across the vaginal epithelium. AIDS 11(13): 1663-1664. November 1997.

HIV in Vaginal Secretions

The latest published study of HIV in cervicovaginal (CV) secretions adds support to the notion that the presence of HIV in these secretions is correlated with the amount of HIV in the blood, or plasma viral load. This study also concluded that the amount of HIV in CV secretions is negatively correlated with CD4 cell count.

Researchers collected blood and CV specimens from 72 HIV positive women and measured their viral load. HIV RNA was detectable in blood from 61 of the women, or 85%, and in CV secretions of just 28 women, or 39%. The results were as follows:

Somewhat surprisingly, the percentages remained the same when researchers looked at the relationship between detectable CV viral load and CD4 cell count only in the group of women who took antiretroviral therapy. In the 200-500 CD4 cell range, the figure dropped to 31%; the other figures are identical.

Uvin SC and Caliendo AM. Cervicovaginal human immunodeficiency virus secretion and plasma viral load in human immunodeficiency virus-seropositive women. Obstetric and Gynecology 90(5): 739-743. November 1997.

HIV in Vaginal Secretions during Pregnancy

A team of French researchers studied 43 HIV positive pregnant women in Paris to determine the factors associated with detection of HIV in cervicovaginal (CV) secretions.

Approximately 144 specimens were gathered from these women. HIV RNA was not detected in all samples, nor in all samples from a single woman. HIV was detected in one-fourth of all the samples (36 of 144), from 37% of the women (16 women).

Three factors were associated with detectable HIV in CV secretions: having HIV subtype B, not using AZT and having a vaginal infection. In general, intermittent detection appears related to factors that include having blood or semen in the vagina, vaginal infections, use of antiretroviral therapy and the sensitivity of the PCR test used.

Investigators noted that their data offer evidence that antiretroviral therapy can reduce HIV excretion in the female genital tract. After adjusting for HIV subtype and vaginal infection, the rate of HIV detection was significantly lower in women who used antiretroviral therapy that included AZT.

Only 8 of the 144 women had fewer than 200 CD4 cells/mm3. In this study, no relationship was found between CD4 cell count and the detection of HIV in CV secretions. However, the study was too small to allow conclusions about the relationship between CD4 cell count and detectable HIV in CV secretions. In addition, the study was too small to determine the relationship between HIV in CV secretions and perinatal transmission. Three of 43 children born to the women in the study were HIV infected.

Loussert-Ajaka I and others. HIV-1 detection in cervicovaginal secretions during pregnancy. AIDS 11(13) 1575-1581. November 1997.

Women in Cote d'Ivoire Indicate Approval for Proposed Vaginal Microbicide Study

Research into female-controlled HIV prevention methods is a global high priority. Studies involving nonoxynol-9 (N9) products are underway in sites in Africa and Asia. Before proceeding with plans for another N9 study in Africa, researchers surveyed over 200 female sex workers (the population from whom participants would be recruited) in Abidjan, Cote d'Ivoire to determine the women's attitudes, and to gauge the feasibility of conducting such a trial.

The proposed trial would evaluate the use of an N9 product called COL-1492 in an intravaginal gel formulation among women with a high number of sex partners. Of the 219 women who fit the proposed study criteria and agreed to be questioned, 200 would be willing to join the trial. Of these, 62% were eligible, i.e., were over 18 years of age, had 5 or more sex partners in the past week, agree not to become pregnant within the next 6 months and agree to have a bimonthly blood sample drawn.

The researchers learned that the women would prefer to have most medical examinations conducted in the central clinic rather than at home, would like to have financial compensation for transportation and lost working hours, and would not mind home outreach visits from the study team.

The researchers concluded that acceptability of the study is high among female sex workers in Abidjan. However, the proposed eligibility criteria would exclude many of these women. Both the number of eligible participants and the study costs would increase if HIV positive women were allowed to participate, which originally was not considered desirable. Yet the study team has indicated a willingness to accept the higher costs and to gather data on the effects of the product on cervicovaginal HIV shedding.

Sexually Transmitted Diseases

High Rates of Trichomonas vaginalis Infection

A recent letter to the editors of the British journal The Lancet discussed the implications of high rates of vaginal infection with Trichomonas vaginalis among HIV positive women at a health clinic in Los Angeles. Commonly transmitted sexually, trichomonas was the most common sexually transmitted disease (STD) among women at the clinic. Certain characteristics of the infection are cause for concern, namely, that the infection is often asymptomatic and therefore often goes undetected and untreated. Having the infection taxes local immune responses in the genital areas. Half of the women observed in this study had signs of lesions in the genital region. The authors reported their belief that the lesions caused by the infection and the extended length of time of infection were likely to increase HIV transmission. Although the increase due to trichomoniasis alone may not be very high, the high prevalence rate of the STD would increase the amount of HIV transmission due to trichomoniasis.

Sorvillo F and Kerndt P. Trichomonas vaginalis and amplification of HIV-1 transmission. The Lancet 351(9097): 213. January 17, 1998.

The Human Papillomavirus-Cancer Connection

More evidence continues to accumulate to support the link between genital infection with the human papillomavirus (HPV) and genital cancers. It is also known that women with HIV have high rates of HPV infection (this STD is also common throughout the general population) and also are at higher risk for cancerous cervical conditions. A study recently published by a team of researchers from Columbia University in New York sheds more light on the natural history of HPV infection in HIV positive women.

The study evaluated data from 220 HIV positive women and 231 HIV negative women in New York City and the surrounding area. The women were similar in most respects (age, race, education and income), but the HIV positive women were less likely to be married and more likely to have a history of prostitution. All women received semiannual gynecologic examinations that included a Pap smear, a test for HPV viral DNA and a colposcopic examination.

Researchers found that over half (56%) of the HIV positive women and 31% of the HIV negative women had detectable HPV viral DNA at the time of the first examination. After 4 examinations, the number of HIV positive women with detectable HPV DNA had risen to 83%, compared to 62% of HIV negative women. Rates were high in both groups. However, the proportion of women with persistent HPV infection was strikingly different: 24% of HIV positive women and 4% of HIV negative women were coinfected with HPV. Of those with persistent HPV infection, 20% of the HIV positive women and 3% of the HIV negative women were infected with types of HPV that are considered aggressive, virulent and most associated with cancer (types 16, 18, 31, 33, 35, 45 and 58).

Another striking finding is that detection of HPV viral DNA after the first visit among HIV positive women was not associated with recent sexual activity, strongly suggesting that the virus was persistent, not new. Persistence was associated with decreasing CD4 cell count.

Persistent HPV is associated with the subsequent development of cervical cancer. Women infected with both HIV and HPV appear to have a related increase and persistence of HPV "shedding," which is thought to explain the elevated rates of cancer in these women.

Epidemiology

AIDS-Related Death Rate Falls among Chicago Area Women

In January, the Chicago Tribune reported that the local rates of AIDS-related deaths among women and among African Americans had decreased for the first time since the beginning of the epidemic. While overall decreases in the rate of death due to AIDS were noted nationwide for the first time in 1996, women and ethnic minorities, in particular African Americans, have continued to experience increases. In other words, the overall decrease in death rate has been seen primarily among white males.

Although the death rate continues to fall more rapidly among white males, Chicago area efforts to reach women and African Americans in order to increase access to care and treatment appear to be working.

Christian SE. Female, Black AIDS death rates drop. Chicago Tribune. January 14, 1998.

Nutrition And Body Weight Management

Nutritional Deficiencies in HIV Positive Women

Mariana Baum, MD, and a team of researchers from the University of Miami recently published results of an in-depth study of nutritional deficiencies. For this analysis, Baum evaluated a group of male and female HIV positive drug users.

Certain immune deficiencies that occur in HIV infection are well documented. Why and how the deficiencies occur, as well as their ramifications, are still under study. In some studies deficiencies have been associated with accelerated disease progression. In other studies, HIV positive drug users have been observed to be particularly nutrient-deficient, due possibly to poor diet and to drug/nutrient interactions. Because female HIV positive drug users were considered likely to have special needs, researchers evaluated the status of specific nutrients and overall nutrition in both women and men.

Participants were recruited from a population of street drug users who have been followed for 9 years. The women and men in the study were similar in terms of race (88% African American, 8% Latino and 4% Caucasian), income level and educational level. Cocaine use was documented for 85% of the men and 80% of the women. Immune status as measured by mean CD4 cell count was similar in men and women.

All 125 participants were evaluated at a community-based clinic every 6 months for 3.5 years. Blood was drawn between 8 and 11 am after overnight fasting and subsequently tested in a laboratory for nutrient levels. Participants also reported their dietary intake for a 6-month period. The main nutrients evaluated were vitamins A, E, B6 and B12, and zinc and selenium, as well as the proteins prealbumin, which indicates overall nutritional status, and retinol-binding protein.

Studying the dietary patterns of men and women revealed that dietary intake was at or below the U.S. recommended daily allowance. Few participants used nutrient supplements. Those who did take supplements were less likely to have vitamin E deficiency than those who did not (50% vs 26%), although status was similarly deficient in both groups for the A and B vitamins and for zinc.

Both men and women with advanced disease (or CD4 cell count fewer than 200 CD4 cells/mm3) had similar overall nutritional status. Women with advanced disease had significantly lower levels of vitamin A, vitamin E and selenium, and also of the proteins. As measured by low prealbumin levels, overall poor nutritional status was detected in 73% of women with advanced disease, compared to 25% of the men.

Severely decreased levels of the antioxidant vitamins A and E were observed in 40% and 50% of the men and women, respectively. Researchers observe that HIV positive drug-using men and women appear to have far greater relative deficiencies of these nutrients, compared with non-drug using gay HIV positive men. Zinc deficiencies are roughly equally prevalent in these 2 groups, however. The severe antioxidant deficiencies in this drug-using population are of particular concern, since antioxidant function and HIV infection are interrelated.

The study showed that female HIV positive drug users were likely to have worse overall nutritional status than their male counterparts. This discrepancy was more profound among those with advanced disease. Nutritional status may impact disease progression and survival; it remains to be demonstrated that correcting deficiencies will be of value.

Baum MK and others. HIV-1 and nutritional deficiency in women. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 16(4): 4272-278. December 1, 1997.

Page last updated 5 May 1998