Gynecologic Care for Women With HIV Infection

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CLINICAL ISSUES

Gynecologic Care for Women With HIV Infection Ann B. Williams

The purpose of this article is to review the gynecologic conditions encountered among women with HIV and to outline elements of gynecologic care for these women. The most prevalent problems are vulvovaginal candidiasis and cervical dysplasia; however, other sexually transmitted diseases, pelvic inflammatory disease, genital ulcer disease, and menstrual abnormalities are also seen. Drug interactions may limit the effectiveness or increase the toxicities associated with hormonal contraception. Intrauterine devices are contraindicated. JOGNN, 32, 87–93; 2003. DOI: 10.1177/0884217502239805 Keywords: Anal dysplasia—Candida—Cervical dysplasia—Contraception—Genital ulcers— Gynecologic—HIV—Human papillomavirus—Pelvic inflammatory disease—Vaginitis—Women Accepted: June 2002 Women with human immunodeficiency virus (HIV) have high rates of concomitant gynecologic disease. Among one group of women hospitalized for complications of HIV, 83% were also diagnosed with gynecologic conditions (Frankel, Selwyn, Mezger, & Andrews, 1997). Although gynecologic problems are common among women who are infected with HIV, the extent to which specific conditions are directly attributable to HIV co-infection, immune suppression, or common risk factors has not been definitively established. In the United States, most women with HIV infection are of reproductive age and most acquire HIV infection through sexual activity (Centers for Disease Control and Prevention, 2001). Thus, they are at risk for other sexually transmitted infections and in need of routine reproductive health care services. January/February 2003

Many of the women in North America who are infected with HIV are members of minority and impoverished populations who may not have had regular access to preventive gynecologic care. In the absence of screening examinations and health education, they sometimes fail to recognize the abnormal nature of symptoms such as discharge and dyspareunia. As a result, treatable conditions remain undiagnosed. Among 73 HIV-positive women denying the presence of a vaginal yeast infection, 15 (20%) were found upon examination to have signs and symptoms of Candida vaginitis (Williams, Andrews, Tashima, Mezger, & Yu, 1998). Furthermore, 64% of this group reported feelings of fear and embarrassment in anticipation of a pelvic examination, potentially leading them to avoid care. Thus, it is crucial that an active protocol of gynecologic surveillance, including a regular health history and physical examinations, be followed to ensure timely diagnosis and treatment of gynecologic problems. After an initial comprehensive evaluation, the patient should be asked about gynecologic symptoms at each visit, with routine complete pelvic examinations performed annually. The purpose of this article is to review the common gynecologic conditions encountered among women with HIV and to outline the elements of gynecologic care for these women.

Gynecologic Infections Human Papillomavirus Infection Human papillomavirus (HPV) is an extraordinarily common sexually transmitted agent. Over 75% of sexually active women acquire HPV at some point in their lives (Palefsky, 2001). However, only a

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small portion of those with anogenital HPV infection develop symptoms such as genital warts. Another portion, including many who remain asymptomatic, will develop precancerous lesions known as cervical or anal intraepithelial neoplasia (Palefsky, 2001). The cervical and anal epithelia are histologically similar. Anogenital HPV infection commonly occurs in the basal level of the epithelium at the transformation zone, where squamous epithelium transforms to columnar epithelium. In the cervix, this is the squamocolumnar junction, where the exocervix meets the endocervix. Similarly, in the anal canal, the transformation zone is located at the junction between the squamous epithelium of the anus and the columnar epithelium of the rectum. These transformation zones are the locations where HPVassociated lesions, such as dysplasia and invasive cancer, are most likely to occur (Palefsky, 2001). Two factors influencing the progression of anogenital HPV from asymptomatic infection to invasive cancer are the HPV viral genotype and the woman’s immune status. HPV types 6 and 11 are associated with low-grade lesions, which rarely progress, whereas types 16, 18, 31, and 33, among others, are implicated in the development of precancerous lesions (Lungu et al., 1992). Because the association of immune suppression with cervical cancer among women receiving cancer chemotherapy was well known prior to the HIV epidemic, it should not be surprising that there is an increased incidence of cervical dysplasia among women with HIV. The frequency of dyspla-

T

he patient should be asked about gynecologic symptoms at each visit and have a routine complete pelvic examination annually.

sia is related to the extent of immune suppression, which is measured by counting the number of CD4 lymphocytes present in 1 mm3 of whole blood. The CD4 cell count, also known as the T-cell count, normally ranges from 800 to 1,200 per cubic millimeter. A CD4 cell count of 200 per cubic millimeter is associated with an increased risk for a variety of opportunistic infections, including HPV infection and dysplasia (Ho, Burk, Fleming, & Klein, 1994; Palefsky et al., 1999). Cervical HPV Infection: Screening and Management. Women with HIV are likely to have high rates of cervical HPV infection, to be infected with multiple HPV types, and to have abnormal Papanicolaou (Pap) smear tests indicating precancerous lesions as a result of HPV infection (Massad et al., 1999; Palefsky et al., 1999). Pap 88 JOGNN

TABLE 1

Cervical Pap Smear Screening Protocol for Women Infected With HIV 1. 2. 3. 4. 5.

Obtain the first cervical Pap smear as soon as possible after HIV diagnosis. Repeat the screening (if normal) in 6 months. Screen annually thereafter (if normal). Treat and repeat the screening in 3 months if inflammatory or reactive changes are present. Perform a colposcopic examination immediately if atypia or squamous changes are present.

Note. Adapted from Centers for Disease Control and Prevention, 1993, Sexually transmitted disease treatment guidelines. Morbidity and Mortality Weekly Reports, 42(RR14), 89-91.

smear screening is a well-established approach to identifying precancerous cervical lesions. In view of their increased risk for HPV-associated lesions, women with HIV should undergo careful and regular gynecologic evaluations that include cervical Pap smear tests. In the United States, the Centers for Disease Control and Prevention (CDC) has published guidelines for Pap smear screening of women infected with HIV (see Table 1). It is important to take into account each woman’s clinical history, including her immune status, previous abnormal Pap smears, and risk for advancing HPV lesions, when deciding how frequently to screen. Many women with HIV infection continue to be sexually active and have limited access to primary gynecologic care. The slightly more active program of surveillance outlined in Figure 1 is appropriate for these women at increased risk. Although the high prevalence of cervical HPV infection and disease in women with HIV is now well-known, guidelines for management of HPV-induced epithelial lesions in the context of HIV-associated immunosuppression are not established. Women whose abnormal cervical Pap smear results are confirmed by colposcopy-directed biopsy will require very close observation of low-grade lesions and immediate excisional or ablative treatment for high-grade lesions. Unfortunately, the risk for recurrence after treatment appears to be as high as 50% among women with HIV, although recurrence rates have decreased with the use of topical vaginal 5-fluorouracil (5-FU) cream for 6 months after treatment (Maiman et al., 1999). Clearly an important element in the successful screening and management of HPV cervical infection is regular care and close follow-up. It is, therefore, crucial that women participate in decisions regarding treatment and understand the pathologic basis of their infections, the goal of treatment, and the benefit of follow-up. Anal HPV Infection: Screening and Management. Among women with HIV, cervical HPV infection is assoVolume 32, Number 1

Unsatisfactory for evaluation

Repeat now

Within normal limits Cervical cytology performed q 6-12 months

Benign cellular changes

Repeat annually or more frequently if CD4 + cell count < 200. Repeat q 6 months if there is a history of anogenital HPV infection or SIL.

Infection or inflammatory

1.

Atypical squamous cells of undetermined significance (ASCUS)

2.

Low-grade squamous intraepithelial lesions: HPV, mild dysplasia/CIN 1 (LSIL)

3.

High-grade squamous intraepithelial lesions: Moderate and severe dysplasia, CIS/CIN 2 and CIN 3 (HSIL)

Epithelial cell abnormalities

Treat according to diagnosis

Repeat cytology

Treatment and follow-up guided by: Colposcopy with directed biopsy

1.

Histologic diagnosis

2.

Gynecology consultation

3.

Patient preference

FIGURE 1

Approach to cervical cytologic evaluation for women who are HIV positive.

ciated with infection at other anogenital sites, such as the vagina, vulva, and perianal area (Hillemanns et al., 1996; Williams et al., 1994). Anal HPV infection, which is associated with anal cancer, actually appears to be more common than cervical infection (Palefsky, Holly, Ralston, Da Costa, & Greenblatt, 2001; Williams et al., 1994). The pattern of infection and development of epithelial lesions parallel that of cervical infection. Therefore, the high prevalence of anal HPV infection and dysplasia among women with HIV places them at risk for progression to anal cancer. Screening for anal HPV lesions through collecting Pap smears of cells from the anal transformation zone is one approach to identifying women at risk for developing anal cancer. However, the effectiveness of anal Pap smear screening in routine practice is not yet established. The lack of experience with this technique as well as uncertainty regarding appropriate follow-up and treatment of abnormalities has slowed its entry into clinical care on a widespread basis. Nevertheless, ongoing studies suggest that a program of regular anal cytologic screening, followed by anoscopy-directed biopsy and treatment of high-grade lesions, may be warranted (Palefsky, 2001).

Vulvovaginal Candidiasis Mucosal Candida infections such as vulvovaginal candidiasis (VVC), oral thrush, and Candida esophagitis can be the first sign of the immune suppression induced by January/February 2003

HIV infection. Although oral thrush and Candida esophagitis are extremely rare in immunocompetent adults, VVC is a common gynecologic condition in the general female population. The prevalence of VVC is similar among women who are HIV negative and women with HIV whose immune systems remain intact. Its frequency increases with declining CD4 cell counts (Williams et al., 1998), however, and VVC is the source of significant discomfort for many women with HIV infection. The opportunistic qualities of Candida organisms are well recognized and may account for the increased frequency of VVC among women with advanced HIV infection. In the vagina, transformation from asymptomatic Candida colonization into clinical disease is precipitated by an alteration in host factors, including both the microflora environment and the host immune system. A lapse in host immunity permits a process of pathogenesis that moves from (a) adherence of the organism to mucosal epithelial cell walls to (b) invasion of the epithelial cells to (c) an inflammatory reaction (Vartivarian & Smith, 1993). Although standard approaches to diagnosis of VVC, including visualization of spores and pseudohyphae on wet mount, KOH [potassium hydroxide] preparations, or gram stain, should be used, it is important to remember that self-diagnosis of vaginal symptoms is frequently inaccurate. In view of their increased risks for other sexually transmitted diseases and gynecologic complications, women with HIV who have complaints of vaginal dis-

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charge, itching, and discomfort should always receive a pelvic examination. Treatment of VVC in the context of HIV infection can be carried out with standard therapies, including topical intravaginal antifungal preparations or a single oral dose of 150 mg of fluconazole. For women with CD4 cell counts of less than 200 per cubic millimeter, a longer course of topical therapy may be more effective. There are no data to suggest that oral therapy is more efficacious than topical agents, although many women prefer the convenience of a single, oral dose. Persistent or recurrent VVC represents a difficult management problem. The reasons for recurrent disease are not understood. Although some clinicians have suggested that infection with nonalbicans strains may be resistant to standard therapies (Schuman et al., 1998), this has not been demonstrated in prospective trials. It is possible that concurrent use of antibiotics for prophylaxis or treatment of opportunistic infections such as Pneumocystis carinii

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ulvovaginal candidiasis is the source of significant discomfort for many women with HIV infection.

pneumonia or Mycobacterium avium complex contributes to the risk for VVC. In a randomized controlled trial, an oral dose of 200 mg of fluconazole weekly reduced the risk of VVC (Schuman et al., 1998). However, because resistance to azole drugs can develop with chronic use and fluconazole may be needed to treat other, potentially life-threatening opportunistic infections, it may be prudent to limit its use. In another randomized controlled trial of interventions to reduce the incidence of VVC among women infected with HIV, weekly use of either intravaginal clotrimazole tablets or capsules containing Lactobacillus significantly reduced the incidence of VVC (Williams, Yu, Tashima, Burgess, & Danvers, 2001). This nonsystemic approach to prophylaxis, combined with patient education, is an alternative for women faced with frequent uncomfortable episodes of VVC.

Bacterial Vaginosis Bacterial vaginosis (BV) is a common condition resulting from the replacement of Lactobacillus flora with mixed vaginal flora, including Gardnerella vaginalis. There are no data to suggest that BV occurs more frequently among women infected with HIV, infection is associated with the CD4 count, or treatment of BV for these women should differ from treatment for women 90 JOGNN

who are HIV negative. There have been some claims, as yet unsubstantiated, that the lack of Lactobacillus organisms associated with BV contributes to the increased risk for HIV acquisition and transmission. In two studies, BV was associated with an increased risk for HIV seroconversion, which lent weight to this theory (Martin et al., 1998; Taha et al., 1998).

Genital Ulcer Disease Genital ulcers are caused by a wide variety of infectious agents and systemic conditions, including Treponema pallidum (syphilis), herpes simplex virus (HSV), Haemophilus ducreyi (chancroid), cytomegalovirus, aphthous ulcers, and drug reactions. Only HSV and aphthous ulcers are significantly increased among women infected with HIV, although these women are at risk for all the conditions listed above. Persistent and severe HSV infections are not uncommon among both men and women with advanced HIV infection and seriously compromised immune systems. The lesions are extremely painful; they can also be atypical and difficult to diagnose. The lesions are infectious, and viral shedding may be greater if there is more advanced immunosuppression. Most HSV infections respond dramatically to oral acyclovir. A dose of 400 mg three to five times a day is comparable with that used for other patients with immunocompromised conditions. Severe disease occasionally requires hospitalization for intravenous therapy. Persistent lesions suggest the development of acyclovir-resistant virus and the need for expert consultation. Herpes infections in pregnant women are of particular concern because of the potential for disseminated infection in the newborn.

Pelvic Inflammatory Disease Pelvic inflammatory disease (PID) is a significant cause of morbidity and infertility among women in all parts of the world. An upper genital tract infection, it is most often due to ascending bacterial infections as a result of a variety of sexually transmitted organisms, such as Neisseria gonorrhoeae and Chlamydia trachomatis. Women with HIV infection might be expected to have an increased incidence of PID in view of both their increased behavioral risk for sexually transmitted disease and the immune suppression that results from chronic HIV infection. However, such a pattern has not been clearly described. The majority of data come from cross-sectional studies of women hospitalized for PID or diagnosed in outpatient clinics or emergency wards. These studies, which found a prevalence of 14% to 17% HIV seropositivity among women with a diagnosis of PID, do not cast light on the risk for PID among women infected with HIV (Hoegsberg et al., 1990; Sperling, Friedman, Joyner, Brodman, & Dottino, 1991). Little data are available about the impact of HIV infection on the natural history of PID. Data suggest that Volume 32, Number 1

although clinical signs and symptoms of PID (such as fever, pelvic mass, cervical motion tenderness, and cervical friability) are more common among women with HIV than among women who are HIV negative, the etiologic agents are similar and standard antibiotic treatment is equally effective for both groups (Irwin et al., 1993; Kamenga et al., 1995). Hospitalization for intravenous therapy is frequently recommended, especially in cases of profound or advancing immunosuppression. A study in Kenya reported, however, that oral, outpatient antibiotic therapy was effective for both HIV-positive and HIVnegative women with PID (Bukusi et al., 1999).

Menstrual Abnormalities Data on menstrual abnormalities among women infected with HIV are limited. Although anecdotal reports suggest that amenorrhea, menorrhagia, and dysmenorrhea are frequent, these conditions have not been etiologically associated with HIV infection (Chirgwin, Feldman, Muneyyirci-Delale, Landesman, & Minkoff, 1996; Shah et al., 1994). Alternative explanations for these conditions include wasting, malnutrition, chronic disease, anemia, emotional stress, and opiate or other drug effects. Endocrine abnormalities, including male gonadal failure, are known to be associated with HIV infection, and it is possible that female gonadal failure may be reflected in menstrual abnormalities. Progestational agents such as megestrol acetate, used for appetite stimulation, can cause irregular vaginal bleeding. Hypermenorrhea has been reported in association with one antiretroviral agent, ritonavir (Nielsen, 1999). Whatever the cause, menstrual dysfunction is common among women with HIV infection and must be evaluated carefully according to the same protocols used for women who are HIV negative. Evaluation of missed menses should always begin with consideration of pregnancy. This is particularly important for women who are HIVpositive, who must make difficult choices regarding a pregnancy. The benefits of early identification of pregnancy are substantial. Furthermore, amenorrhea lasting longer than 6 months should not be attributed to opiate drug use without a search for another cause. Women taking daily doses of methadone, a synthetic opiate used to treat opiate dependence, frequently experience a period of amenorrhea immediately after beginning therapy. However, this side effect usually disappears within the 1st year after beginning methadone treatment. Failure to pursue a complete evaluation of amenorrhea could lead to a missed diagnosis of pregnancy or a treatable condition. The debilitating effects of chronic dysmenorrhea should not be underestimated; dysmenorrhea represents a significant source of pain and distress for many women with HIV. Correctly or not, many of these women attribute their discomfort to HIV, heightening its emotional and January/February 2003

personal significance. Use of some of the many techniques to decrease pain and cramping, including exercise, dietary adjustments, and antiprostaglandin therapy with nonsteroidal anti-inflammatory prostaglandin inhibitors, can be of great comfort and benefit.

Contraception Contraception is a critical issue for all sexually active women of reproductive age. The HIV epidemic has made it clear that contraception and prevention of sexually transmitted disease represent two separate challenges. The most effective contraceptive methods, such as hormone therapy or sterilization, do not provide protection from exposure to infectious agents, including HIV. On the other hand, the effective protection from sexually transmitted disease offered by consistent use of high-quality male and female condoms is accompanied by a contraceptive effect that may not be what the woman desires. Hence, there is great interest in the development of an effective vaginal microbicide that is not also a spermicide. To date, such an agent has not been found. Women with HIV, indeed all sexually active women, need careful contraceptive counseling that makes clear that in many instances contraception and sexually transmitted disease prevention require separate interventions. Barrier methods of contraception include male and female condoms, vaginal diaphragms, and cervical caps. The effectiveness of these methods is related to the quality of the materials, consistency of use, and correct insertion of the devices. Male and female condoms offer some protection against sexually transmitted agents and provide contraception. This is not true of the cervical diaphragm or cervical cap. The acceptability of condoms varies wide-

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ntrauterine devices are associated with an increased risk for pelvic inflammatory disease, provide no protection against sexually transmitted diseases, and are not recommended for women with HIV infection.

ly and is strongly influenced by social and cultural mores. Social marketing campaigns in many countries have been quite effective in increasing the use of condoms. Hormonal contraceptives, although widely used and effective, have remained somewhat controversial in the context of HIV disease. There has been some suggestion that hormonal agents increase the risk for acquiring HIV infection, although the data are not convincing (Martin

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et al., 1998; Wang, Reilly, & Kreiss, 1999). Hormonal contraceptives have significant drug-to-drug interactions that may decrease either the effectiveness of the contraceptive or the coadministered medication. This is of particular concern for women with HIV infection, who are prescribed numerous antiviral and antibiotic regimens to control their HIV infection and prevent opportunistic infections. Some of the agents commonly used in HIV care that are known to interact with hormonal contraceptives are listed in Table 2. Intrauterine devices are associated with an increased risk for PID, provide no protection from sexually transmitted diseases, and are not recommended for women with HIV infection.

Effects of Antiretroviral Therapy Much of what is known about the gynecologic manifestations and gender-related complications of HIV comes from research conducted before the widespread use of effective antiretroviral therapy. Early observations of genderassociated differences in survival times in North Americans with HIV most likely reflected the impact of the epidemic on a population of women from disadvantaged social and economic backgrounds. It is now clear that HIV disease progression and outcomes do not differ significantly between men and women (Phillips et al., 1994). However, intriguing differences persist at the time of primary HIV infection. While women demonstrate lower HIV RNA levels than men, particularly in the first few years of infection, these lower viral loads are not associated with slower disease progression (Sterling et al., 2001). It is likely that effective antiretroviral therapy will change the natural history of HIV-associated gynecologic conditions, but the clinical implications of those changes are not yet clear. For example, although restoration of the immune system might slow or even reverse the progression of HPV-induced cervical dysplasia, the longer life span induced by antiretroviral therapy could allow more opportunity for HPV progression. In any case, women with HIV infection will continue to require competent, compassionate, and comprehensive gynecologic care.

Conclusions Gynecologic health maintenance is an important element of primary care of women with HIV disease. Integration of gynecologic care with other primary care services is ideal for these women, who will most likely be scheduled for regular appointments to monitor their HIV disease. The availability of gynecologic care in the same setting that provides HIV management is convenient for the patient, promotes continuity of care, allows better coordination between gynecologic and medical services, and is consistent with a holistic nursing approach to 92 JOGNN

TABLE 2

Medications Commonly Used by Women With HIV Infection That Interact With Hormonal Contraceptives • Antiretroviral agents Nelfinavir Ritonavir Amprenavir Lopinavir/ritonavir Efavirenz

• Tetracyclines • Penicillin • Rifampin

patient care. However, it is important that in such an environment adequate attention be given to gynecologic evaluation and service. In most cases, it will be best to establish dedicated visits for annual comprehensive gynecologic evaluation. Whether offered in conjunction with HIV care or in a separate clinic, the foundation of a gynecologic health maintenance program for women with HIV is an annual evaluation that includes a sexual, menstrual, obstetric, family planning, and gynecologic history. Annual laboratory screening should include a cervical smear for cytology, screening for sexually transmitted disease (gonorrhea, Chlamydia, syphilis), and microscopy of vaginal secretions. These services, when offered in conjunction with thoughtful patient education, represent an important opportunity to improve the gynecologic health of women with HIV. REFERENCES Bukusi, E. A., Cohen, C. R., Stevens, C. E., Sinei, S., Reilly, M., Grieco, V., et al. (1999). Effects of human immunodeficiency virus 1 infection on microbial origins of pelvic inflammatory disease and on efficacy of ambulatory oral therapy. American Journal of Obstetrics and Gynecology, 181(6), 1374-1381. Centers for Disease Control and Prevention. (2001). HIV/AIDS surveillance report, 13(No. 1), 5-26. Chirgwin, K. D., Feldman, J., Muneyyirci-Delale, O., Landesman, S., & Minkoff, H. (1996). Menstrual function in human immunodeficiency virus-infected women without acquired immunodeficiency syndrome. Journal of Acquired Immune Deficiency Syndrome and Human Retrovirology, 12(5), 489-494. Frankel, R. E., Selwyn, P. A., Mezger, J., & Andrews, S. (1997). High prevalence of gynecologic disease among hospitalized women with human immunodeficiency virus infection. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 25(3), 706-712. Hillemanns, P., Ellerbrock, T. V., McPhillips, S., Dole, P., Alperstein, S., Johnson, D., et al. (1996). Prevalence of anal human papillomavirus infection and anal cytologic abnormalities in HIV-seropositive women. AIDS, 10(14), 16411647. Ho, G. Y., Burk, R. D., Fleming, I., & Klein, R. S. (1994). Risk of genital human papillomavirus infection in women with

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human immunodeficiency virus-induced immunosuppression. International Journal of Cancer, 56(6), 788-792. Hoegsberg, B., Abulafia, O., Sedlis, A., Feldman, J., DesJalais, D., Landesman, S., & Minkoff, H. (1990). Sexually transmitted diseases and human immunodeficiency virus infection among women with pelvic inflammatory disease. American Journal of Obstetrics and Gynecology, 163(4, Pt. 1), 1135-1139. Irwin, K., Rice, R., O’Sullivan, M., Sperling, R., Brodman, M., & Moorman, A. (1993). The clinical presentation and course of pelvic inflammatory disease in HIV+ and HIV. Paper presented at the IXth International Conference on AIDS, Berlin, Germany. Kamenga, M. C., De Cock, K. M., St Louis, M. E., Toure, C. K., Zakaria, S., N’Gbichi J. M., et al. (1995). The impact of human immunodeficiency virus infection on pelvic inflammatory disease: A case-control study in Abidjan, Ivory Coast. American Journal of Obstetrics and Gynecology, 172(3), 919-925. Lungu, O., Sun, X. W., Felix, J., Richart, R. M., Silverstein, S., & Wright, T. C., Jr. (1992). Relationship of human papillomavirus type to grade of cervical intraepithelial neoplasia. Journal of the American Medical Association, 267(18), 2493-2496. Maiman, M., Watts, D. H., Andersen, J., Clax, P., Merino, M., & Kendall, M. A. (1999). Vaginal 5-fluorouracil for highgrade cervical dysplasia in human immunodeficiency virus infection: A randomized trial. Obstetrics & Gynecology, 94(6), 954-961. Martin, H. L., Jr., Nyange, P. M., Richardson, B. A., Lavreys, L., Mandaliya, K., Jackson, D. J., et al. (1998). Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1. Journal of Infectious Diseases, 178(4), 10531059. Massad, L. S., Riester, K. A., Anastos, K. M., Fruchter, R. G., Palefsky, J. M., Burk, R. D., et al. (1999). Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1. Women’s Interagency HIV Study Group. Journal of Acquired Immune Deficiency Syndrome, 21(1), 33-41. Nielsen, H. (1999). Hypermenorrhea associated with ritonavir. Lancet, 353(9155), 811-812. Palefsky, J. (2001). Screening for anal and cervical dysplasia in HIV-infected patients. The PRN Notebook, 6(3), 24-31. Palefsky, J. M., Holly, E. A., Ralston, M. L., Da Costa, M., & Greenblatt, R. M. (2001). Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. Journal of Infectious Diseases, 183(3), 383-391. Palefsky, J. M., Minkoff, H., Kalish, L. A., Levine, A., Sacks, H. S., Garcia, P., et al. (1999). Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. Journal of the National Cancer Institute, 91(3), 226-236. Phillips, A. N., Antunes, F., Stergious, G., Ranki, A., Jensen, G. F., Bentwich, Z., et al. (1994). A sex comparison of rates

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of new AIDS-defining disease and death in 2554 AIDS cases. AIDS in Europe Study Group. AIDS, 8(6), 831-835. Schuman, P., Sobel, J. D., Ohmit, S. E., Mayer, K. H., Carpenter, C. C., Rompalo, A., et al. (1998). Mucosal candidal colonization and candidiasis in women with or at risk for human immunodeficiency virus infection. HIV Epidemiology Research Study (HERS) Group. Clinical Infectious Diseases, 27(5), 1161-1167. Shah, P. N., Smith, J. R., Wells, C., Barton, S. E., Kitchen, V. S., & Steer, P. J. (1994). Menstrual symptoms in women infected by the human immunodeficiency virus. Obstetrics & Gynecology, 83(3), 397-400. Sperling, R. S., Friedman, F., Jr., Joyner, M., Brodman, M., & Dottino, P. (1991). Seroprevalence of human immunodeficiency virus in women admitted to the hospital with pelvic inflammatory disease. Journal of Reproductive Medicine, 36(2), 122-124. Sterling, T. R., Vlahov, D., Astemborski, J., Hoover, D. R., Margolick, J. B., & Quinn, T. C. (2001). Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. New England Journal of Medicine, 344(10), 720-725. Taha, T. E., Hoover, D. R., Dallabetta, G. A., Kumwenda, N. I., Mtimavalye, L. A., Yang, L. P., et al. (1998). Bacterial vaginosis and disturbances of vaginal flora: Association with increased acquisition of HIV. AIDS, 12(13), 16991706. Vartivarian, S., & Smith, C. B. (1993). Pathogenesis, host resistance, and predisposing factors. In G. P. Bodey (Ed.), Candidiasis (2nd ed., pp. 59-84). New York: Raven. Wang, C. C., Reilly, M., & Kreiss, J. K. (1999). Risk of HIV infection in oral contraceptive pill users: A meta-analysis. Journal of Acquired Immune Deficiency Syndrome, 21(1), 51-58. Williams, A. B., Andrews, S., Tashima, K., Mezger, J., & Yu, C. (1998). Factors associated with vaginal yeast infections in HIV-positive women. Journal of the Association of Nurses in AIDS Care, 9(5), 47-52. Williams, A. B., Darragh, T. M., Vranizan, K., Ochia, C., Moss, A. R., & Palefsky, J. M. (1994). Anal and cervical human papillomavirus infection and risk of anal and cervical epithelial abnormalities in human immunodeficiency virus-infected women. Obstetrics & Gynecology, 83(2), 205-211. Williams, A. B., Yu, C., Tashima, K., Burgess, J., & Danvers, K. (2001). Evaluation of two self-care treatments for prevention of vaginal candidiasis in women with HIV. Journal of the Association of Nurses in AIDS Care, 12(4), 51-57.

Ann B. Williams, RN, EdD, is Helen Porter Jayne and Martha Prosser Jayne Professor, Yale School of Nursing, New Haven, CT. Address for correspondence: Ann B. Williams, RN, EdD, Helen Porter Jayne and Martha Prosser Jayne Professor, Yale School of Nursing, P.O. Box 9740, New Haven, CT 06536-0740. E-mail: [email protected].

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