Women and HIV: a population at risk.

In July 2006, a colleague called me to discuss a case that troubled him. He was following a young African-American woman, Gina, who had been diagnosed with pancytopenia (low red cells, white cells, and platelets) 1 year previously. He had undertaken an extensive evaluation at the time that did not yield a diagnosis. Her past medical history included a biopsy of an enlarged supraclavicular node, which was interpreted as hyperplastic on histology, and cervical dysplasia. Despite cytokine treatment, her cell counts remained low and a repeat bone marrow biopsy was non-diagnostic. A second round of evaluations included HIV testing, which was positive. He questioned the diagnosis of HIV infection and asked me to see the patient in consultation. The patient was not only surprised by the results but was also distraught. She could not understand how she had acquired this infection. She did not believe that she was at risk for HIV since she had never used drugs or "slept around."

It is a little-remembered fact that the first cases of AIDS occurring in women were reported within months of the often cited initial 1981 Morbidity and Mortality Weekly Report (MMWR) publication detailing the presentation of Pneumocystis carinii pneumonia in gay men residing in Los Angeles. However, for much of the ensuing decade, homosexual activity and to a lesser extent, intravenous drug use, were the overriding and almost exclusive risk factors associated with transmission or acquisition of HIV/AIDS. When we thought about HIV and women, the discussion centered on women as transmitters of infection, either to their fetuses (mother-to-child transmission, MTCT) or their male partners. Gender-related research was pursued to define: 1) modalities to decrease MTCT and 2) risk factors associated with increased risk for heterosexual transmission primarily involving groups of commercial sex workers residing in international settings. In the early 1990s, when it became apparent that HIV was being diagnosed in increasing numbers of women in this country and around the world, there was a shift in gender- and sex-based research to define the natural history of HIV in women.

Now, in 2007, HIV infection is a global disease, transmitted primarily by sexual activity and intravenous drug use. The burden of this disease affects both sexes; in many regions of the world, the number of cases in women exceeds those reported in men. The vast majority of girls and women acquire HIV through heterosexual activity. As compared to the late 1990s, the increase in new infections has disproportionately affected young women who are becoming infected as they become sexually active. There are biologic and societal reasons why young women are susceptible and more vulnerable to HIV infection. Biologically, the cervix of young women is immature, lined with columnar epithelium which is friable and easily disrupted during trauma, increasing the risk of HIV acquisition during coitus. Socially, the gender inequality that is the status quo in most areas of the world renders all women more vulnerable to HIV infection: lack of financial security, intimate-partner violence, male control in the woman's current relationship, and lack of legal status. It is this last factor specifically that impedes our ability to significantly change the scope of the epidemic among women.

Strong, committed leadership on the part of governmental and medical authorities, together with a change in the legal and financial status of women in many parts of the world, are necessary and critical to empower women to exert control over factors that increase their risk of acquiring HIV. On a global basis, women and girls comprise more than 50% of individuals who are HIV-positive. It is critical for both public health officials, who work to craft and implement prevention strategies, and clinicians, who evaluate and manage HIV-infected persons, to recognize the unique impact of HIV infection on women.

Most HIV-infected women are of child-bearing potential. Therefore, issues of fertility, fertility potential, and MTCT are particularly germane to this patient population. It is not unusual for women to receive their diagnosis of HIV infection while undergoing a prenatal evaluation. In addition, especially where antiretroviral therapy (ART) is widely available, women with an established diagnosis of HIV infection may choose to have children, reassured by statistics that suggest the risk of MTCT is 1% to 2% when taking ART. While pregnancy does not appear to have an impact on the progression of HIV disease, some studies have suggested that HIV may negatively affect fertility, primarily in women residing in resource-limited settings, suggesting that other factors such as nutritional status and routine access to health care may also be implicated. In these very settings, it is of critical importance on a societal level for women to bear children; however, less than 10% of HIV-infected pregnant women receive therapy and most of them receive short-course, single-agent, single-dose regimens. A 50% reduction in HIV-transmission is achieved with this approach, but with the substantial risk of antiretroviral resistance and subsequent compromise of therapy when it is later indicated for these woman.

A number of gynecologic conditions occur with increased frequency in HIV-infected women. For instance, genital HPV infection, a sexually transmitted disease that is caused by human papillomavirus, occurs with increased frequency in HIV-infected individuals; accelerated rates of progression or persistent infection are associated with more profound immunosuppression. Optimal management strategies for HIV-infected women must include routine gynecologic evaluation as part of a comprehensive treatment approach.

The preponderance of data from patient cohorts and clinical trials suggest that women and men derive equal benefit from ART. However in some studies, factors such as impaired access to health care, high rates of depression, substance use, and decreased rates of adherence have been associated with worse outcomes for women. Poor adherence has been linked in turn to increased rates of side effects and higher off-treatment rates for women. Women have experienced higher rates of virologic failure in a number of observational studies, although the causes for these results are not clear. In order to ensure maximal benefit of ART for women, studies to determine which drug regimens are best tolerated and most effective need to be undertaken.

Gina was indeed HIV-positive. Several factors in her presentation and past history strongly suggested HIV infection as an underlying, unifying diagnosis. Her sex was the confounding variable for the clinicians who saw her; they did not make the association between any one factor and HIV infection in this female patient. She did not see herself as being at increased risk of HIV infection; she was not aware of US demographics that indicate African-American women have a significantly increased risk of acquiring HIV infection. Gina has been in counseling, participates in regular group sessions, and has disclosed her status to her sister who is very supportive. She has responded well to ART and is working full-time.

Women acquire HIV infection primarily through heterosexual activity. They represent the fastest growing segment of the epidemic globally. Effective prevention of this infection in women requires a commitment to significantly improving their social and financial status, crafting and disseminating information about risk factors in a culturally sensitive format, and organizing comprehensive, specialized medical services that can be easily accessed. Ultimately, prevention measures that the woman can control will be most successful in reducing the impact of this virus on women. Although there is much interest and active research efforts in the area of microbicides and vaccines, women currently have few such methods available to them.

Kathleen E. Squires is Professor of Medicine and Director of the Division of Infectious Diseases at Jefferson Medical College of Thomas Jefferson University in Philadelphia.