The number of women with HIV (human immunodeficiency virus) infection and AIDS (acquired immunodeficiency syndrome) has increased steadily worldwide. By the end of 2005, according to the World Health Organization (WHO), 17.5 million women worldwide were infected with HIV.
According to the Centers for Disease Control and Prevention (CDC), between 2000 through 2004, the estimated number of AIDS cases in the United States increased 10 percent among females and 7 percent among males. In 2004, women accounted for 27 percent of the 44,615 newly reported AIDS cases among adults and adolescents. 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 79 percent of AIDS cases in women.
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.
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, severe pelvic inflammatory disease (PID), and an increased risk of precancerous changes in the cervix including probable increased rates 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 obtain or adhere to treatment.
To confront the growing problem of HIV infection 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 is studying the course of HIV/AIDS disease in women through the Women's Interagency HIV Study (WIHS) and supports clinical trials to investigate gender-specific differences in disease progression, complications, and treatment though the Adult AIDS Clinical Trials Group (ACTG), the Pediatric AIDS Clinical Trials Group (PACTG), and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The HIV Prevention Trials Network (HPTN) investigates non- vaccine prevention strategies.
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 through WIHS. WIHS is a multi-site, prospective cohort of predominantly minority HIV-infected and uninfected women and is currently following 2,441 women. The study recently increased enrollment to evaluate clinical outcomes in the era of highly active antiretroviral therapy (HAART), including time to develop AIDS, impact of resistance to antiretroviral therapy, the effect of co-infections such as hepatitis C and human papillomavirus (HPV), the effects of metabolic abnormalities and toxicities, the impact of hormonal factors on HIV disease, and the impact of aging on HIV disease, which includes assessing neurocognitive functioning and physical impairment.
Recently, WIHS implemented an intensive protocol to evaluate cardiovascular manifestations of HIV among women. This study was the outgrowth of a workshop held in May 2003 that was co-sponsored by NIAID and the National Heart, Lung and Blood Institute. So that gender comparisons can be made, a similar investigation is taking place in the Multi-center AIDS Cohort Study, a cohort of men who have sex with men, and the Tri-Service AIDS Clinical Consortium, a cohort of HIV-infected U.S. military personnel.
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, that ideally would be non-irritating, inexpensive, and unobtrusive. The research effort for developing topical microbicides includes basic research, preclinical product development, and clinical evaluation.
To clinically evaluate the safety of vaginal formulations of microbicide products, NIAID is supporting the adaptation of imaging technology (Optical Coherence Tomography) developed for other indications, among other techniques, and is examining the potential relevance of specific parameters, such as endometrial toxicity and vaginal innate immunity. NIAID-supported researchers continue to evaluate microbicide candidates for safety in animal models (pig tailed macaques), coordinate the results with other testing to facilitate product development, and test safety and efficacy in clinical trials. At present, NIAID is supporting the development and evaluation of 23 compounds and/or combinations through its Integrated Preclinical/Clinical Program for HIV Topical Microbicides. Some of the new products in development include a combination product using dendrimer and BufferGel, both of which have entered into clinical testing separately and the use bioengineered Lactobacillus expressing a broad range of protein-based microbicides.
In February 2005, NIAID initiated a multicenter clinical trial (HPTN 035) to examine the safety and preliminary effectiveness of BufferGel and PRO2000/5 Gel (P) to prevent HIV infection. The trial, which is the first microbicide safety and effectiveness trial of this magnitude to be supported by NIAID, is being conducted through the HPTN and represents a partnership among various research institutions in Africa and the United States. The primary objective of the trial is to evaluate the safety and effectiveness of BufferGel and PRO2000/5 Gel (P) when applied intravaginally by women at risk for sexually-transmitted HIV infection. Women are currently being enrolled at sites in Philadelphia, Pennsylvania; Lilongwe and Blantrye, Malawi; and Durban and Hlabisa, South Africa, Harare and Chitungwiza, Zimbabwe, and Lusaka, Zambia.
Another study, the HIV Prevention Preparedness Study (HPTN 055) was conducted in Zambia, South Africa, and Tanzania to assess the ability of sites to recruit and retain participants for future efficacy trials of topical microbicides. This study has helped obtain reliable data on HIV seroprevalence and seroincidence in the target populations.
Recently, NIAID-funded investigators demonstrated that combination microbicides may be more efficient than single microbicides at preventing vaginal transmission of simian HIV(SHIV) in rhesus macaques. This has important implications for future microbicide research because it is highly possible that first generation microbicides may at best be only 30 to 50 percent effective, given the complexity of HIV transmission. Thus, combinations resulting in additive or synergistic inhibition of HIV transmission could offer the potential to reduce individual microbicide concentrations resulting in a more potent and cost effective microbicide strategy. This study, which was the first to investigate the efficacy of combination microbicides, had a goal of achieving at least 50 percent protection for the monkeys. It was not only achieved, but was surpassed, in some cases, with certain combinations. This study demonstrates that combination microbicides can result in what appears to be synergistic inhibition of virus transmission in monkeys and offers support for the hypothesis that optimization of combination microbicides could result in enhanced microbicide strategies.
Another finding recently released provided proof that disrupting how the virus attaches itself to cells completely protected monkeys that were vaginally exposed to SHIV. This was done with the use of PSC-RANTES, a chemically modified form of a protein called RANTES, that works by targeting a protein in the body called C-C chemokine receptor 5 (CCR5), a receptor on human cells to which HIV binds. In addition to CD4, there are co-receptors, such as CCR5 and CXCR4. Sexual transmission of HIV is thought to predominantly involve CCR5. HIV needs CCR5 to achieve infection of any given cell.
For the virus to be transmitted during heterosexual intercourse -- the primary method the virus is spread in many parts of the world -- the virus must attach to CCR5 in cells within the vaginal mucosa. When these cells were protected with a topical microbicide containing a high enough concentration of PSC-RANTES, however, the virus could not attach to them, thus preventing transmission. This work represents the first demonstration of significant protection through a range of doses for any protein-based microbicide and demonstrated that it was possible to achieve in vivo concentrations of protein microbicides that could afford 100 percent protection of exposed individuals.
To further develop vaginal microbicides, NIAID entered into an agreement with the International Partnership for Microbicides (IPM) earlier this year to share information and expertise. This agreement draws on complementary strengths of the two organizations. NIAID brings funding resources and expertise in topical microbicide discovery and early product development for HIV and other STIs to the partnership, while IPM has enhanced capacity to design optimal microbicide formulations, manufacture pilot lots of microbicides for clinical testing, and implement clinical trials.
NIAID's Topical Microbicide Strategic Plan, which details long-range plans for advancing microbicide concepts from the laboratory to clinical trials, is available on NIAID's Web site at www.niaid.nih.gov/publications/topical_microbicide_strategic_plan.pdf.
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 diagnosed among women in the United States in 2004, CDC estimated 70 percent were attributed to heterosexual contact and 28 percent to injection drug use.
In this country, 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 examining the use of antiretroviral drugs to try to prevent transmission are also underway. For example, the HPTN (HPTN 052) has a study examining serodiscordant couples with CD4 counts above 300 cells to 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.
In the United States, approximately 25 percent of pregnant HIV-infected women who do not receive AZT or a combination of antiretroviral therapies pass 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. (There were 84 infected infants born in the US in 2004, see CDC table.)
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
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. One NIAID-sponsored study also 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.
NIAID supports research on MTCT through the PACTG, ACTG, and HPTN, and until recently, through the Women and Infants Transmission Study (WITS), a prospective cohort study that has followed HIV-infected mothers and their children since 1988. Since that time, WITS researchers have examined factors that contribute to perinatal transmission, evaluated disease progression and contributing factors during pregnancy and postpartum in HIV-infected women and their infants, and evaluated diagnostic tools for determining HIV status in infants. Sponsored by NIAID, the National Institute of Child Health and Human Development, and the National Institute on Drug Abuse, WITS will be phasing out over the coming year.
The first regimen to prevent MTCT was identified in a landmark study conducted in 1994 by the PACTG. A specific regimen of AZT (azidothymidine) 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 (NVP), 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 NVP 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 NVP-containing regimen.
Data from HIVNET 012 also showed that resistance to NVP was present in approximately 19 percent of women 6 to 8 weeks after the single dose of NVP. After 12 to 24 months, there was no NVP 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 NVP had poorer virologic outcome when treated with HAART than women who had never received NVP.
Studies are now underway to examine the effects of exposure to single dose nevirapine (SD NVP) on future treatment options for women and children. One study currently open to enrollment in Africa is evaluating the effect of previous exposure to SD NVP on the mother's future treatment options (Optimal Combined Therapy after Nevirapine Exposure, ACTG 5208). A similar trial for infants is in development (PACTG 1060). Strategies to minimize viral resistance after SD NVP are also being explored in two other studies. The first study will compare the impact of three antiretroviral strategies administered on reducing NVP resistance following SD NVP, and the second will examine the pharmacokinetics and incidence of NVP resistance in women who receive SD NVP alone or in combination with one of two other regimens.
The HPTN is also conducting a study to compare three antiretroviral regimens for post-exposure prophylaxis of HIV-uninfected infants born to HIV-infected women whose HIV status was unknown at the time of delivery and who were therefore not exposed to a prenatal or perinatal antiretroviral regimen (HPTN 040).
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 to identify effective strategies for reducing the risk of transmission through breastfeeding is underway in areas of the world where the benefits of breastfeeding outweigh the risks. This includes early weaning strategies as well as evaluating drugs or vaccines to reduce the risk of transmission from breastfeeding.
To further evaluate ways to prevent HIV transmission during breastfeeding, the HPTN is initiating a study of NVP for breastfeeding infants of HIV-infected mothers (HPTN 046). Similarly, an investigator-initiated study for preventing MTCT is underway in Ethiopia and Uganda to evaluate a 6-week regimen of NVP administered to HIV-uninfected infants born to HIV-infected breastfeeding mothers. In Uganda, another component of the study will be added to passively immunize the breastfeeding children with HIV immune globulin (HIV-Ig).
Many manifestations of HIV infection are similar in men and women. Both men and women with HIV may have non-specific symptoms even early in disease, including low-grade fevers, night sweats, fatigue, and weight loss. Anti-HIV therapies, as well as treatments for other infections associated with HIV, appear to be similarly effective in men and women. Other conditions, however, 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 had higher rates of herpes simplex infections than men.
Data from several studies conducted by the Community Programs for Clinical Research on AIDS (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 less access to anti-HIV therapies or preventive therapies for Pneumocystis carinii pneumonia, or PCP.
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 treat yeast infections with fluconazole. A CPCRA study demonstrated that weekly doses of fluconazole can also safely prevent oropharyngeal and vaginal, but not esophageal yeast infections, without resulting in drug resistance.
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.
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.
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.
CDC currently recommends that HIV-positive women have a complete gynecologic evaluation, including a Pap smear, as part of their initial HIV evaluations, or upon entry to prenatal care, and another Pap smear 6 months later. If both smears are negative, annual screening is recommended thereafter in asymptomatic women. The agency also recommends more frequent screenings-every 6 months-for women with symptomatic HIV infection, prior abnormal Pap smears, or signs of HPV infection.
Some women in the United States have poor access to health care. In addition, women may not think they are at risk for HIV infection. They may not heed symptoms that could serve as warning signals of HIV infection, such as recurrent yeast infections. PID and the other symptoms discussed above should signal health care providers to offer women HIV testing with counseling.
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.
Women whose HIV infections are detected early and receive appropriate treatment survive as long as HIV-infected men. Although several studies have shown HIV-infected women to have shorter survival times than men, this may be because women are less likely than men to be diagnosed early.
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.