Key words: HIV Herpes simplex virus, Human papillomavirus, Antiviral therapy

Over the past 15 years in the United States, HIV/AIDS has become increasingly common among women. In 1990, women made up only 11% of the newly reported cases of AIDS.¹ In 2006, 27% of newly reported AIDS cases were in women.²

Minority women have been particularly affected by HIV/AIDS. The CDC estimates that the prevalence in African American women is 20-fold higher than it is in white women. The infection rate in Hispanic women is 5-fold that of white women.² Heterosexual sex is a much more common risk factor than injection drug use. Indeed, heterosexual sex accounts for more than 80% of the newly reported cases of HIV/AIDS in women.²

Although urban areas of the Northeast historically had the greatest number of HIV/AIDS cases and the highest prevalence of HIV infection, the Northeast is no longer the geographic center of the HIV epidemic in women. Indeed, the South surpassed the North in numbers of new cases of AIDS in women as early as 1998,¹ and the HIV epidemic in southern states continues to grow. The region identified as the Deep South, which includes the states of Louisiana, Mississippi, Alabama, Georgia, South Carolina, and North Carolina, reported a 36% increase in new AIDS cases from 2000 to 2005, with a high proportion occurring among women, racial and ethnic minorities, the poor, and those persons who live in rural areas.³

Women tend to have lower viral loads than men, as noted in a number of studies.⁴ However, rates of disease progression appear to be similar, despite the difference in viral load. The natural history and progression of HIV infection, patient survival rates, and type of HIV-associated illnesses (other than those of the reproductive tract) that emerge are similar in women and men.⁵ Current treatment guidelines differ for men and women only in regard to issues related to gynecological care, contraception and pregnancy, and perinatal management. Nevertheless, equivalent clinical outcomes will only be achieved if women have equivalent access to care and support. Recent findings from the Coping with HIV/AIDS in the Southeast study (see “Social factors and HIV infection risk”) suggest that HIV-infected women are less educated, less likely to have private health insurance, less likely to be receiving antiretroviral therapy, and less likely to have a suppressed viral load than are their male counterparts.⁶ Addressing such problems will be critical to the health and survival of HIV-infected women.

HIV AND SEXUALLY TRANSMITTED DISEASES
Clinicians have long known that patients who have 1 sexually transmitted disease (STD) are more likely to have another, either concomitantly or subsequently.⁷ Herpes simplex virus (HSV) infection and human papillomavirus (HPV) infection are common in women with HIV infection; they have unique presentations and disease courses, and they require special attention.

Herpes simplex virus infection
HSV infection is a major risk factor for HIV acquisition. Indeed, the majority of women who are infected with HIV are coinfected with HSV.⁸ HSV infection increases the risk of HIV infection through several mechanisms. Lesions compromise mucosal integrity, damaging the barrier defenses of skin and mucous membranes. HSV-related lesions also cause an influx of CD4 lymphocytes, which act as potential target cells for invading HIV.⁹ Monocytes that are recruited to sites of HSV-related genital ulcerations release chemokines and increase expression of CCR5, a receptor for HIV.^10,11 A recent meta-analysis demonstrated that HSV-2 infection increases the risk of HIV acquisition 3-fold in women. This finding held true even after controlling for age and sexual behavior.¹²

Given that HSV infection is such a strong risk factor for HIV infection, there has been interest in the use of long-term HSV suppression with acyclovir, famciclovir, or valacyclovir to help prevent persons infected with HSV from becoming infected with HIV. Unfortunately, recent trials in which HSV-infected women were treated with acyclovir (400 mg bid) failed to find any benefit from this approach.^13,14 Standard doses of acyclovir showed no efficacy in reducing the acquisition of HIV infection. Novel strategies to prevent the transmission of HIV to HSV-infected persons are very much needed.

Women who are coinfected with HIV/HSV are more likely to have detectable HIV in their cervicovaginal secretions during an HSV-2 infection outbreak or an episode of asymptomatic HSV-2 shedding.^15,16 Hence, there is great interest in suppressive treatment of HSV disease in coinfected persons as a means of decreasing HIV transmission to their partners. Trials of HSV suppression in HIV/HSV coinfected persons have found that valacyclovir (500 mg bid) reduces HIV viral load in the genital tract.^17,18 Pending additional studies that look at HIV transmission, HSV suppression should be considered as a potential adjuvant to condom use in decreasing HIV transmission from persons with HIV/HSV coinfection.

In immunocompetent persons, the initial HSV infection outbreak is typically the most severe and can be accompanied by fever, malaise, or even aseptic meningitis. Subsequent outbreaks are less severe and become less frequent over time. In HIV-infected women, HSV acts as an opportunistic pathogen. Outbreaks continue to increase in frequency and become more prolonged as HIV-induced immunosuppression advances and the CD4 count falls. In the Women’s Interagency HIV Study, which has been following a cohort of HIV-infected women and women at risk for HIV infection in New York; Washington, DC; Chicago; San Francisco; and Los Angeles, women who had a CD4⁺ cell count of less than 350/µL were more likely to have an active genital ulcer.²¹ Indeed, an HSV infection outbreak that fails to resolve within a month is considered to be an AIDS-defining event.²⁰

HIV-infected women who also are infected with HSV respond well to acyclovir, valacyclovir, or famciclovir for treatment of HSV infection.²¹ These agents are nucleoside analogues that inhibit the replication of HSV and varicella-zoster virus. They are safe and well tolerated. Because they do not have significant interactions with antiretroviral medications, they also can be safely used in patients who are receiving antiretroviral therapy.

If the clinical response to initial treatment is suboptimal, the acyclovir dosage can be increased to 800 mg tid. Alternatively, valacyclovir or famciclovir can be used because they have much better oral bioavailability than acyclovir.

Resistance to these medications has developed in HIV-infected patients, but resistance remains uncommon. Testing for drug resistance in HSV isolates is usually not necessary and should be reserved for patients who have responded poorly to an adequate course of treatment. Patients in whom treatment with 1 of these agents has failed will often respond to foscarnet, but this is a much more costly and toxic alternative and must be given intravenously. Because HSV infection outbreaks are more frequent and severe in HIV-infected women, many HIV/HSV coinfected women benefit from continuous HSV suppression.

Antiretroviral therapy is associated with more rapid healing of HSV-related lesions in women. Unfortunately, the frequency of new outbreaks of lesions is not dramatically changed. Although women who have achieved measurable immunological improvement from antiretroviral therapy are less likely to have an HSV-related lesion at any given time than are HIV-infected women who are not receiving antiretroviral therapy, they are still more likely to have an HSV-related lesion than their HSV-infected HIV-seronegative counterparts.¹⁹

Data from several early trials of antiretroviral therapies suggest that HIV-infected patients who are treated with acyclovir have a survival advantage.^22,23 These findings were puzzling because acyclovir is not known to have any direct activity against HIV. Nevertheless, findings from a recent meta-analysis of randomized trials of acyclovir in HIV-infected patients confirmed that acyclovir improves both HSV infection outbreaks and overall survival.²⁴ Attempts to understand why have focused on the interplay between HSV and HIV. HSV infection outbreaks are associated with increases in HIV RNA level, both in genital secretions and systemically as measured by the HIV viral load.^16-18,25 A small study of acyclovir treatment of HSV infection in patients coinfected with HIV/HSV demonstrated a 48% decrease in HIV viral load.²⁵

A larger trial of valacyclovir in 140 women with HIV-1 infection demonstrated a 0.53 log₁₀ reduction in plasma HIV viral loads and a reduction in the frequency of detection of genital HIV-1 RNA in treated patients.¹⁷ Given that current antiretroviral regimens are effective at decreasing HIV viral load, it is anticipated that suppressive treatment of HSV would have the greatest effect on the course of HIV infection in those who are not receiving antiretroviral therapy.

Human papillomavirus infection
HPV is another problematic STD for HIV-infected women. HPV is exceedingly common in the general population, especially among young women. Most HPV infections are relatively asymptomatic, and the virus is cleared from the genital tract after a few months.²⁶ However, HPV infection is associated with a wide spectrum of manifestations ranging from genital warts to intraepithelial neoplasia and cancers of the cervix, vulva, penis, anus, and other sites. There are many genotypes of HPV that vary greatly in their cancer-causing potential.

A recently developed HPV vaccine provides protection against infection with HPV types 16 and 18 (the genotypes most commonly associated with cervical cancer) as well as with HPV types 6 and 11 (the genotypes most commonly associated with genital warts). Because the vaccine prevents infection but has not been shown to alter the course of a preexistent HPV infection, it should ideally be given before the onset of sexual exposure.^27,28

Current recommendations are to vaccinate young women between the ages of 9 and 26 years, without regard to HPV or HIV infection status. It is anticipated that immunogenicity and efficacy may be reduced in immunosuppressed women, including those with HIV infection. Clinical trials of HPV vaccination in HIV-infected women are ongoing. Furthermore, it is unclear to what extent, if any, the vaccine will protect against other HPV genotypes.

Women who are HIV-seropositive have significantly higher rates of HPV infection than women who are HIV-seronegative.^29-32 Furthermore, the prevalence of HPV infection is highest in women in whom immunosuppression is most advanced.^29,30 HIV-infected women seem to have higher levels of HPV expression, a wider spectrum of HIV types, and an increased frequency of infection with multiple HPV types simultaneously.^29,32,33 If HIV-infected women have increased susceptibility to infection with unusual HPV types, they may not benefit from the currently available HPV vaccine.

Because HIV-infected women have higher rates of HPV persistence,³⁴ especially if their CD4 counts are low, they are at higher risk for cervical neoplastic changes than their non–HIV-infected peers.³⁵ Fortunately, a Papanicolaou test adequately identifies cervical intraepithelial neoplasia in HIV-infected women.³⁶ HIV infection treatment experts recommend that women should be screened with a Papanicolaou test twice in the first year after HIV infection is diagnosed. If the test results are negative, then the test can be repeated annually thereafter.³⁷

Even mild cytological abnormalities—those read as atypical squamous cells of unclear significance (ASC-US)—can be associated with cervical intraepithelial neoplasia in these women. Consensus guidelines on the appropriate follow-up of ASC-US in HIV-infected women consider repeated cytological examinations every 6 to 12 months to detect the presence of high-risk types of HPV DNA or colposcopic examination to be safe and effective approaches.³⁸ HIV experts, however, have often favored a more aggressive approach, advocating colposcopy for HIV-infected women who have ASC-US.³⁷ It is also important that a thorough visual inspection of the vulva, vagina, and perianal areas is included and that anal cytology results be obtained in women who have cervical or vulvar neoplasia.³⁷

Unfortunately, women who are HIV-infected are also more likely to have multifocal HPV disease and to relapse after local treatment. Poor response to treatment and recurrent neoplasia is responsible for higher rates of hysterectomy among HIV-infected women.³⁹ Nevertheless, with appropriate screening and careful follow-up, HIV-related cervical cancer is a preventable disease.