May 2004

HIV Infection in Women

OVERVIEW

By the end of 2002, 159,271 adolescent and adult women in the United States were reported as having AIDS. Based on cases reported to the Centers for Disease Control and Prevention (CDC) through December 2002, more than 57,376 women have been infected with HIV. Among adolescent and adult women, the proportion of AIDS cases more than tripled from 7 percent in 1985 to 26 percent in 2002. Nonetheless, AIDS cases in adolescent and adult women have declined by 17 percent and have plateaued in the past 4 years, reflecting the success of antiretroviral therapies in preventing the development of AIDS.

Worldwide, more than 90 percent of all adolescent and adult HIV infections have resulted from heterosexual intercourse. Women are particularly vulnerable to heterosexual transmission of HIV due to substantial mucosal exposure to seminal fluids. This biological fact amplifies the risk of HIV transmission when coupled with the high prevalence of non-consensual sex, sex without condom use, and the unknown and/or high-risk behaviors of their partners.

Younger women are also increasingly being diagnosed with HIV infection, particularly among African-Americans and Hispanics. Through December 2002, women aged 25 and younger accounted for 9.8 percent of the female AIDS cases reported to CDC.

HIV disproportionately affects African-American and Hispanic women. Together they represent less than 25 percent of all U.S. women, yet they account for more than 82 percent of AIDS cases in women.

Women suffer from the same complications of AIDS that afflict men but also suffer gender-specific manifestations of HIV disease, such as recurrent vaginal yeast infections and severe pelvic inflammatory disease, which increase their risk of cervical cancer. Women also exhibit different characteristics from men for many of the same complications of antiretroviral therapy, such as metabolic abnormalities.

Frequently, women with HIV infection have great difficulty accessing health care, and carry a heavy 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.

CURRENT RESEARCH

NIAID is studying the course of HIV/AIDS disease in women primarily through two cohort studies: the Women's Interagency HIV Study (WIHS) and the Women and Infant's Transmission Study. Clinical trials to investigate gender-specific differences in disease progression, complications and/or treatment are also being conducted by the Adult AIDS Clinical Trials Group (AACTG), the Pediatric AIDS Clinical Trials Group (PACTG), and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

Natural History and Epidemiological Research

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 treatment regimens for them.

The WIHS, a multi-site, prospective cohort of predominantly minority HIV-infected and uninfected women, is conducting research on the natural history of HIV among women and has increased the number of women enrolled in their study. The increase in participants will enable WIHS to evaluate the natural history and clinical outcomes in the era of highly active antiretroviral therapy, or HAART, such as

• Time to AIDS
• Impact of other infections such as hepatitis C
• Therapy use and treatment effects in women
• Impact of aging on HIV disease
• Impact of hormonal factors on HIV disease

The expansion is now complete, and projects have 2,580 women under active follow-up.

A study conducted in the WIHS compared the rates of AIDS and/or death prior to (October 1994 to April 1996) and after (April 1996 to March 1999) the introduction of HAART (highly active antiretroviral therapy). Mortality declined 21 percent for women with AIDS and 11 percent for those without AIDS at the start of WIHS. The researchers also quantified the level of immune reconstitution and viral suppression. Women with AIDS at study entry saw the greatest improvements in their CD4+/CD8+ cells and viral load.

In another study, WIHS researchers showed that a baseline measurement of serum albumin (the main protein in the blood) was a strong predictor of 3-year survival in HIV-infected women. Women with serum albumin levels in the low-normal range had a higher risk of death compared to those with higher levels of serum albumin. This information could have important implications for women's treatment decisions, and given the low cost and availability of this measurement, it may have applications in resource-poor settings.

Moreover, another study showed that after adjusting for age, serum albumin levels, body mass index, CD4 lymphocyte counts, and HIV-1 RNA levels, higher C-reactive protein levels (> 0.4 mg/dL) were associated with shorter survival. C-reactive protein, an inflammatory marker, may be a useful and inexpensive predictor of HIV disease mortality in women.

In a study co-funded by the National Institute on Drug Abuse and NIAID, researchers found that the initial HIV viral load in women tends to be lower than in men regardless of CD4+ T cell count. Investigators need to do additional research to determine the significance of this finding because the rate of progression to AIDS in women appears to be similar to that in men.

Topical Microbicides

Because HIV is spread predominantly through sexual transmission, the development of chemical, biological, and physical barriers that can be used intravaginally or intrarectally to inactivate HIV and other sexually transmitted infection (STI) pathogens is critically important for controlling HIV infection.

Scientists are developing and testing new chemical and biological compounds that women could apply before intercourse to protect themselves against HIV and other sexually transmitted organisms. These include creams or gels, known as topical microbicides, which ideally would be non-irritating, inexpensive, and unobtrusive. The research effort for developing topical microbicides includes basic research, preclinical product development, and clinical evaluation. There are several promising investigational topical microbicides, such as PR02000/5 Gel (P), Cellulose Sulfate Gel, and PMPA Gel, currently in clinical trials in the HIV Prevention Trials Network (HPTN).

Less than 10 percent of the participants reported symptoms that could have been attributable to the product, and upon pelvic examination, approximately 90 percent had no visible vaginal or cervical abnormalities. Currently, researchers are planning a Phase III trial which will evaluate the effectiveness of Carraguard. (Carraguard is a gel derived from seaweed that prevents infection of appropriate target cells by HIV and other STIs.) In addition, HPTN has initiated several Phase I trials to study the safety and acceptability of other candidate microbicides and will be conducting a Phase II/IIb trial of two other promising microbicide candidates for vaginal use.

Scientists are no longer studying nonoxynol-9 (N9) as a potential microbicide due to safety concerns and the potential for increased risk of HIV infection as reported at the 13th International Conference on AIDS in Durban, South Africa, in July 2000.

TRANSMISSION

In the United States, most women are infected with HIV 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 the new HIV infections among women in the United States, in 2002, the CDC reported 42 percent were attributed to heterosexual contact and 21 percent to injection drug use.

In the United States, studies have shown that during unprotected heterosexual intercourse with an HIV-infected partner, women have a greater risk of becoming infected than uninfected men who have heterosexual intercourse with an HIV-infected woman. In other parts of the world, however, this is not necessarily true. In Uganda, for example, one study demonstrated that the risk of HIV transmission from woman to man was the same as from man to woman. This difference may be due to the lack of circumcision in Ugandan men.

Studies in both the United States and abroad have demonstrated that STIs, particularly infections that cause ulcerations of the vagina (for example, genital herpes, syphilis, and chancroid), greatly increase a woman's risk of becoming infected with HIV. NIAID-sponsored cohort studies in the United States have also 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.

Consistent and correct use of male latex condoms greatly reduces the risk of becoming infected with HIV. In studies of heterosexual couples, in which one individual was HIV-positive and the other uninfected and regular condom use was reported, the rate of HIV transmission was extremely low.

Studies using antiretroviral drugs to try to prevent transmission will be starting soon in the United States and internationally. HPTN Trial 052, which will be conducted in the United States and five other countries, will study approximately 1750 serodiscordant couples with CD4 counts above 300 cells. The trial will determine whether HAART, when given to the infected partner along with prevention counseling and interventions like condoms, prevents HIV transmission to the uninfected partner better than prevention counseling and prevention services alone. Another trial using an antiretroviral drug (tenofovir) to try to prevent HIV transmission in HIV negative sex workers in Cambodia will begin soon.

Mother-to-Child Transmission (MTCT) of HIV

In the United States, approximately 25 percent of pregnant HIV-infected women who do not receive AZT or a combination of antiretroviral therapies pass on the virus to their babies. If women do receive a combination of antiretroviral therapies during pregnancy, however, the risk of HIV transmission to the newborn drops below 2 percent.

The risk of MTCT is significantly increased if the mother has advanced HIV disease, high amounts of HIV in her bloodstream, or fewer-than-normal amounts of the CD4+ T cells.

Other factors that may increase the risk include

• Drug use, such as heroin or crack/cocaine
• Severe inflammation of fetal membranes
• A prolonged period between membrane rupture and delivery

One NIAID-sponsored study found that HIV-infected women who gave birth more than 4 hours after rupture of the fetal membranes were nearly twice as likely to transmit HIV to their babies, as compared to women who delivered within 4 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 babies as compared to HIV-infected women who did not use drugs.

Most MTCT, an estimated 50 to 70 percent, probably occurs late in pregnancy or during birth. Although the exact ways the virus is transmitted are unknown, scientists think it may happen when the mother's blood enters fetal circulation or by mucosal exposure to the virus during labor and delivery.

Research is underway to identify the mechanisms of MTCT and to develop interventions to reduce it. Notably, NIAID-funded investigators have identified regimens that reduce MTCT. The first regimen to prevent MTCT was identified in a landmark study conducted in 1994 by the PACTG. A specific regimen of AZT given to an HIV-infected woman during pregnancy and to her baby after birth was shown to reduce mother-to-child HIV transmission by two-thirds.

In another NIAID-sponsored study (HIVNET 012) in Uganda, researchers identified a highly effective and safe drug regimen for preventing transmission of HIV from an infected mother to her newborn that is more affordable and practical than any other course of therapy examined to date. The study demonstrated that a single oral dose of the antiretroviral drug, nevirapine, given to an HIV-infected woman in labor and another dose given to her baby within 3 days of birth reduces the transmission rate by about half compared with a course of AZT given only during labor and delivery. Additional data from this study demonstrated the continued benefit and safety of nevirapine in reducing MTCT up to 18 months, even in a breastfeeding population. This study suggests that women in the United States who are identified as HIV-infected very late in pregnancy or at the time of labor and delivery could lower the rates of HIV transmission to their babies by following a nevirapine-containing regimen.

Data from HIVNET 012 also showed that resistance to nevirapine was present in approximately 19 percent of women 6 to 8 weeks after the single dose of nevirapine. After 12 to 24 months, there was no nevirapine resistance detectable in these women using standard methods of HIV resistance testing. Nevertheless, these data are of concern because preliminary data from a small, uncontrolled trial presented at the 2004 Retrovirus Conference in San Francisco by Jourdain et al. showed that women who had received previous single dose nevirapine had poorer virologic outcome when treated with HAART than women who had never received nevirapine.

Additionally, data from an AACTG study showed that subjects who had prior nevirapine, efavirenz, or delaviradine treatment (the anti-HIV drug class abbreviated "NNRTI") had poorer virologic outcomes than those who were NNRTI naïve. The conclusion was that low level, previously unidentified drug resistance can lead to future treatment failure. Given these data, researchers are planning several randomized clinical trials to assess the impact of prior single dose nevirapine on treatment outcomes in the mother, as well the infant, and to assess various strategies to prevent the emergence of drug resistance after single-dose nevirapine used for MTCT.

HIV may also be transmitted from a nursing mother to her child. A series of studies have determined that breastfeeding increases the risk of HIV transmission by about 14 percent. Currently, the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommends that HIV-positive women be educated and counseled so they can make an informed decision about how to best feed their children. Research is underway in areas of the world where the benefits of breastfeeding outweigh the risks to identify effective strategies for reducing the risk of transmission through breastfeeding. This includes early weaning strategies, as well as evaluating drugs or vaccines to reduce the risk of transmission from breastfeeding.

Studies are also underway or planned to determine if antiretroviral drugs given to the uninfected infant or to the infected, breast-feeding mother will prevent HIV transmission to the infant. An example is HPTN 046, which will evaluate the effects of nevirapine on uninfected infants born from HIV infected mothers who are breastfeeding.

SIGNS AND SYMPTOMS OF HIV INFECTION

Data from several studies conducted by CPCRA found that HIV-infected women were also more likely than HIV-infected men to develop bacterial pneumonia. This finding may be explained by factors such as a delay in seeking care among HIV-infected women as compared to men, and/or less access to anti-HIV therapies or preventive therapies for Pneumocystis carinii pneumonia, or PCP.

Woman-Specific Symptoms of HIV Infection

Women also experience HIV-associated gynecologic problems, many of which 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 WIHS suggest that these infections are considerably more frequent in HIV-infected women. Health care providers commonly use a drug called fluconazole to treat yeast infections. A CPCRA study demonstrated that weekly doses of fluconazole can also safely prevent oropharyngeal and vaginal, but not esophageal yeast infections, 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 STIs such as gonorrhea, chlamydia, and trichomoniasis.

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

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

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

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 WIHS survey, women with CD4+ T-cell counts below 50 per cubic millimeter (mm3) of blood were more likely to report no periods than were uninfected women, or HIV-infected women with higher CD4+ T-cell counts.

GYNECOLOGIC SCREENING

EARLY DIAGNOSIS

Early diagnosis of HIV infection allows women to take full advantage of antiretroviral treatments and preventive medicines for opportunistic infections when their health care providers think it is appropriate. Both appropriate therapy and preventive drugs can forestall the development of AIDS-related symptoms and prolong life in HIV-infected women as well as men. Early diagnosis also allows women to make informed reproductive choices. Health care providers should be alert to early signs of HIV infection in women. In addition, all women should consider HIV testing if they have engaged in behaviors that put them at risk of infection.

SURVIVAL AMONG HIV-INFECTED WOMEN

In an analysis of several studies involving more than 4,500 people with HIV infection, women were 33 percent more likely than men to die within the study period. The 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 may have been important factors.

MORE INFORMATION

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REFERENCES FOR STATISTICS

CDC HIV/AIDS Surveillance Report, Vol. 14, No.2, December http://www.cdc.gov/hiv/stats/hasr1402.htm

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News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

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