The number of women with HIV and AIDS in the United States is steadily rising. From 1985 to 1995, the proportion of reported U.S. AIDS cases occurring among women increased from 7 percent to 19 percent. HIV infection is now the third leading cause of death among women ages 25 to 44 and the leading cause of death among black women in this age group.

In addition to conditions such as Pneumocystis carinii pneumonia that afflict HIV-infected people of both genders, women suffer gender-specific manifestations of HIV disease, such as recurrent vaginal yeast infections and pelvic inflammatory disease.

Women with HIV frequently have great difficulty accessing health care, and carry a large burden of caring for children and other family members who may also be HIV-infected. They often lack social support and face other challenges that may interfere with their ability to adhere to treatment regimens.

To confront the growing problem of HIV and AIDS in women, the National Institute of Allergy and Infectious Diseases (NIAID) has made woman-focused research an important component of the Institute's AIDS research program.

NIAID supports studies in the United States and abroad of the natural history and manifestations of HIV infection in both non-pregnant and pregnant women, as well as the factors that influence the transmission of HIV to women. Investigators are studying the unique features of HIV/AIDS in women, and developing new treatment regimens for women with these conditions.

Scientists also are developing and testing new methods to prevent women from becoming infected with HIV. These include creams or gels that women would apply before intercourse to protect themselves from HIV as well as other sexually transmitted organisms.

In addition, researchers are studying the mechanisms of mother-to-child HIV transmission and are devising interventions to reduce such transmission. Notably, NIAID-funded investigators have shown that a specific regimen of zidovudine (AZT), given to an HIV-infected woman during pregnancy and to her baby after birth, can reduce mother-to-infant HIV transmission by two-thirds. Researchers now are assessing other antiretroviral regimens that may prove even more effective, as well as simpler and less costly regimens that may have more relevance to the developing world.

Scope of the Problem

A recent analysis from the National Cancer Institute estimates that between 107,000 and 150,000 women in the United States are living with HIV infection (many of whom have not developed AIDS).

As of Dec. 30, 1995, the Centers for Disease Control and Prevention (CDC) had received reports of 71,818 cases of AIDS among female adults and adolescents in the United States, 40,658 of whom have died. Minority women in the United States are disproportionately affected by AIDS: in 1995, 56 percent of reported female U.S. AIDS cases were among black women, and 21 percent among Hispanic women. These women tend to be poor, young and residents of disenfranchised communities in inner-city neighborhoods.

Approximately 42 percent of the 21 million adults living with HIV/AIDS worldwide are women, according to the World Health Organization (WHO).

Transmission of HIV to Women

In the United States, most HIV-infected women are exposed to the virus during sex with an HIV-infected man or while using HIV-contaminated syringes for the injection of drugs such as heroin, cocaine and amphetamines.

Of U.S. AIDS cases among women reported in 1995, 38 percent were attributed to heterosexual contact and 38 percent to injection drug use; most of the other cases reported in 1995 were attributed to "no known exposure." In recent years, the majority of such unclassified cases upon further investigation have been reclassified as cases attributable to heterosexual exposure.

Worldwide, the WHO estimates that about 90 percent of HIV infections are due to heterosexual transmission of the virus.

During unprotected heterosexual intercourse with an HIV-infected partner, women in general appear to be more easily infected with the virus than do men. Studies in the United States and abroad have demonstrated that other sexually transmitted diseases (STDs), particularly infections that cause ulcerations of the mucosal surfaces (e.g., syphilis and chancroid), greatly increase a woman's risk of becoming infected with HIV. Anal sex also increases a woman's risk of becoming HIV-infected.

NIAID-sponsored cohort studies in the United States have found a number of other factors to be associated with an increased risk of heterosexual HIV transmission including alcohol use, history of childhood sexual abuse, current domestic abuse and use of crack/cocaine.

The consistent use of condoms greatly reduces the risk of becoming infected with HIV. In studies of discordant heterosexual couples (one individual HIV-positive, the other HIV-negative) who report regular condom use, HIV transmission rates have been extremely low.

Signs and Symptoms of HIV

Many manifestations of HIV disease are similar in men and women. Both men and women with HIV may have nonspecific symptoms even early in disease, including low-grade fevers, night sweats, fatigue and weight loss. In the United States, the most common AIDS-associated condition in both women and men is a lung infection called Pneumocystis carinii pneumonia (PCP). Anti-HIV therapies, as well as treatments for the infections associated with HIV (so-called opportunistic infections), appear to be similarly effective in men and women.

Other conditions occur in different frequencies in men and women. HIV-infected men, for instance, are eight times more likely than HIV-infected women to develop a skin cancer known as Kaposi's sarcoma. In some studies, women have had higher rates of esophageal candidiasis (yeast infections of the windpipe) and herpes simplex infections than men.

Data from a study conducted by NIAID's Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) found that HIV-infected women were more likely than HIV-infected men to develop bacterial pneumonia. This finding may be explained by factors such as a delay in care-seeking among HIV-infected women as compared to men, and/or less access to anti-HIV therapies or preventive therapies for PCP.

Woman-Specific Symptoms of HIV Infection

Women also experience HIV-associated gynecologic problems, many of which also occur in uninfected women but with less frequency or severity.

Vaginal yeast infections, common and easily treated in most women, often are particularly persistent and difficult to treat in HIV-infected women. Data from the NIAID-supported Women's Interagency Health Study (WIHS) suggest that these infections are considerably more frequent in HIV-infected women.

A drug called fluconazole is commonly used to treat yeast infections. A recent CPCRA study demonstrated that weekly doses of fluconazole can also safely prevent vaginal and esophageal candidiasis, without resulting in resistance to the drug.

Other vaginal infections may occur more frequently and with greater severity in HIV-infected women, including bacterial vaginosis and common STDs such as gonorrhea, chlamydia and trichomoniasis.

Severe herpes simplex virus ulcerations, sometimes unresponsive to therapy with the standard drug, acyclovir, can severely compromise a woman's quality of life.

Idiopathic genital ulcers -- those with no evidence of an infectious organism or cancerous cells in the lesion -- are a unique manifestation of HIV disease. These ulcers, for which there is no proven treatment, are sometimes confused with those caused by herpes simplex virus.

NIAID is currently assessing, in a study known as AIDS Clinical Trials Group (ACTG) 842, the prevalence of idiopathic genital ulcer disease in HIV-infected women and the effect of thalidomide treatment. Thalidomide has previously proven effective in the treatment of oral aphthous ulcers in HIV-infected people.

Human papillomavirus (HPV) infections, which cause genital warts and can lead to cervical cancer, occur with increased frequency in HIV-infected women. A precancerous condition associated with HPV called cervical intraepithelial neoplasia (CIN) also is more common and more severe in HIV-infected women, and more apt to recur after treatment.

Three studies within NIAID's ACTG address CIN in HIV-infected women. A study known as ACTG 200 is assessing topical vaginal 5-fluorouracil maintenance therapy to prevent the recurrence of moderate-to-severe cervical dysplasia. ACTG 293 is evaluating oral isotreninoin for prevention of progression of low-grade (mild) dysplasia to high-grade dysplasia or invasive cancer of the cervix in HIV-positive women. ACTG 866 is assessing the effect of the protease inhibitor indinavir on the progression of cervical dysplasia and HPV infections in HIV-infected women, and on the amount of HIV in vaginal secretions.

Pelvic inflammatory disease (PID) appears to be more common and more aggressive in HIV-infected women than in uninfected women. PID may become a chronic and relapsing condition as a woman's immune system deteriorates.

Menstrual irregularities frequently are reported by HIV-infected women and are being actively studied by NIAID-supported scientists. Although menstrual irregularities were equally common in HIV-infected women and at-risk HIV-negative women in a recent WIHS survey, women with CD4+ T cell counts below 50 per cubic millimeter (mm³) of blood were more likely to report amenorrhea (no menses within the last three months) than uninfected women, or HIV-infected women with higher CD4+ T cell counts.

Because megace, an FDA-approved drug often prescribed for HIV-associated wasting, can cause significant, irregular vaginal bleeding in HIV-infected women, NIAID is planning a trial to assess an alternate drug, nandrolone, in women with HIV-associated weight loss.

Gynecologic Screening

The Public Health Service currently recommends that HIV-positive women have a complete gynecologic evaluation, including a Pap smear, as part of their initial HIV evaluation, or upon entry to prenatal care, and another Pap smear six months later. If both smears are negative, annual screening is recommended thereafter in asymptomatic women. However, more frequent screening -- every six months -- is recommended for women with symptomatic HIV infection, prior abnormal Pap smears, or signs of human papillomavirus infection.

Early Diagnosis Important

Some women in the United States have poor access to health care. In addition, women may not perceive themselves to be at risk for HIV infection. Because of these reasons and other psychosocial factors, symptoms that could serve as warning signals of HIV infection -- such as recurrent yeast infections -- may go unheeded. PID, CIN and the other symptoms discussed above should signal caregivers to offer women HIV testing accompanied by counseling.

Early diagnosis of HIV infection allows women to take full advantage of antiretroviral therapies and preventive drugs for opportunistic infections, both of which can forestall the development of AIDS-related symptoms and prolong life in HIV-infected men and women. Early diagnosis also allows women to make informed reproductive choices. Health care workers should be alert to early signs of HIV infection in women, and all women should consider HIV testing if they have engaged in high-risk activities.

Survival Among HIV-Infected Women

Women whose HIV infections are detected early and who receive appropriate treatment survive as long as infected men. However, because women may be less likely than men to receive an early diagnosis and treatment, survival times for women as compared to men have been shorter in several studies.

In the largest of these, a CPCRA study of more than 4,500 patients, HIV-infected women were one-third more likely than HIV-infected men to die within the study period. The CPCRA investigators could not definitively identify the reasons for excess mortality among women in this study, but they speculated that poorer access to or use of health care resources among HIV-infected women as compared to men, domestic violence, homelessness and lack of social supports for women may have been important factors.

Perinatal Transmission of HIV

In the United States, approximately 25 percent of pregnant HIV-infected women not receiving AZT therapy have passed on the virus to their babies.

Most perinatal transmission, an estimated 50 to 80 percent of infections, probably occurs late in pregnancy or during birth. Although the precise mechanisms are unknown, scientists think HIV may be transmitted when maternal blood enters the fetal circulation, or by mucosal exposure to virus during labor and delivery. The role of the placenta in maternal-fetal transmission is unclear and the focus of considerable research.

The risk of perinatal transmission is significantly increased if the mother has advanced HIV disease, large amounts of HIV in her bloodstream, or few of the immune system cells -- CD4+ T cells -- that are the main targets of HIV.

Other factors that may increase the risk of perinatal transmission are maternal drug use, severe inflammation of fetal membranes, or a prolonged period between membrane rupture and delivery. A recent study sponsored in part by NIAID found that HIV-infected women who gave birth more than four hours after the rupture of the fetal membranes were nearly twice as likely to transmit HIV to their infants, as compared to women who delivered within four hours of membrane rupture. In the same study, HIV-infected women who used heroin or crack/cocaine during pregnancy were also twice as likely to transmit HIV to their offspring as HIV-infected women who did not use drugs.

HIV also may be transmitted from a nursing mother to her infant. A recent analysis suggested that breast-feeding introduces an additional risk of HIV transmission of approximately 14 percent. However, the WHO still recommends breast-feeding of infants in developing countries because the benefits are believed to far outweigh the potential risk of HIV transmission.

A role for AZT. A study conducted by NIAID's Pediatric AIDS Clinical Trials Group demonstrated that AZT, given to HIV-infected pregnant women who had very little or no prior antiretroviral therapy and CD4+ T cell counts above 200/mm³, reduced the risk of maternal-infant transmission by two-thirds.

In the study, known as ACTG 076, AZT therapy was initiated in the second or third trimester and continued during labor, and infants were treated for six weeks following birth. AZT produced no serious side effects in mothers or infants; long-term follow-up of the infants and mothers is ongoing.

Researchers have subsequently shown that this AZT regimen has reduced perinatal transmission in other populations in which it has been used.

The AZT regimen used in ACTG 076 is too expensive and logistically demanding for general use in less-developed countries. Therefore, NIAID also is supporting studies of simpler and less costly strategies for preventing mother-to-infant transmission of HIV.

Because a significant amount of perinatal HIV transmission occurs around the time of birth, and the risk of maternal-fetal transmission depends, in part, on the amount of HIV in the mother's blood, it may be possible to reduce transmission using drug therapy only around the time of birth. Two NIAID studies that test this hypothesis have been funded. One study will test the effectiveness of a shortened course of AZT given to HIV-infected pregnant women in Ethiopia. Another study, in Uganda, will assess whether a single dose of nevirapine, given to a mother in labor when she arrives at the hospital, can prevent infection in newborns. One dose of this drug has been shown to dramatically reduce the amount of HIV in the blood.

NIAID-supported researchers also are studying whether immunoglobulin preparations containing large quantities of antibodies to HIV can prevent perinatal HIV transmission when given to the mother and/or the neonate. This strategy -- known as passive immunization -- has been used successfully in reducing perinatal transmission of hepatitis B virus. An NIAID-funded trial using such an HIV hyper-immune product, which is given to mothers late in pregnancy and to their neonates, has begun in Uganda.

Source:
Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services