Chapter VI
Gynecologic Problems

Silvia Abularach, MD, MPH and
Jean Anderson, MD

I. Introduction  TOP

Gynecologic problems are common among HIV-positive women and are frequently present at the time of initial presentation for evaluation and care. Minkoff et al. found that 46.9% of 262 HIV-infected women had a least one incident gynecologic condition with serial assessment (Minkoff, 1999). In a study of women admitted to an inpatient AIDS service, although only 9% were admitted with a primary gynecologic problem, 83% had coexisting gynecologic disease when evaluated (Frankel, 1997). Some gynecologic issues are unrelated to the patients’ serologic status, whereas others are directly related to HIV disease and associated immunosuppression. Still others are associated epidemiologically with HIV because of common risk factors, such as sexual behavior or substance abuse.

In 2002, women accounted for 26% of the adult AIDS cases and 32% of the adult cases of HIV infection reported in the United States (CDC, 2002). Moreover, women have had the greatest increase in AIDS incidence in recent years when compared with other US population groups. With this background and the fact that HIV infection primarily affects women during their reproductive years, gynecologic and reproductive health care will play an increasingly important role in the overall care of the HIV-infected woman. With improved longevity and quality of life, gynecologic problems may be encountered more commonly or may be more prominent. With these issues in mind, the goal of this chapter is to use a problem-oriented approach in reviewing the most common gynecologic complaints together with their differential diagnosis, evaluation, management, and relationship to HIV.

II. Abnormal Uterine Bleeding/Amenorrhea  TOP

A. WHAT IS CONSIDERED “ABNORMAL” BLEEDING?

A normal menstrual period should occur every 21 to 35 days and last between 2 and 6 days. The average blood loss during menses is 20 to 60 mL, but up to 14% of healthy women have blood loss greater than 80 mL and are more likely to be anemic because of this (Mishell, 1997a).

Amenorrhea represents a sort of abnormal bleeding in that it is the lack of menstruation. Primary amenorrhea is defined as the absence of menses by age 16. Secondary amenorrhea is the absence of menses for a variable period of time, for at least 3 mo and usually 6 mo or longer, in a woman who has previously menstruated.

B. RELATIONSHIP TO HIV DISEASE

Menstrual disorders are frequently reported by HIV-positive women. However, controlled studies have yielded conflicting evidence regarding whether HIV or HIV-related immunosuppression exerts a clinically significant direct effect on these reported disturbances (Chirgwin, 1996; Ellerbrock, 1996; Shah, 1994) and more definitive studies are needed. A recent large study of HIV-positive and high-risk HIV-negative women from the HERS and WIHS prospective cohorts found that HIV serostatus has little overall effect on amenorrhea or menstrual cycle length or variability. However, higher viral loads and lower CD4 counts were associated with increased cycle variability and polymenorrhea. (Harlow, 2000). Clark et al, using measurement of serum progesterone and follicle-stimulating hormone (FSH) levels, found higher than expected occurrence of anovulation and premature menopause in a small study of women 20-42 years old who participated in selected ACTG protocols.(Clark, 2001). Although numbers were too small to reach statistical significance, these menstrual disorders were more common among women with lower CD4 cell counts.

In the setting of HIV infection, menstrual disorders may be related to confounding variables, such as weight loss, chronic disease, substance abuse, or use of psychotherapeutic medications (Harlow, 2003) and progestational agents used for appetite stimulation or contraception. The impact of antiretroviral therapy on menstruation has not been well studied but hypermenorrhea, or excessive menstrual blood loss, has been reported with ritonavir (Nielsen, 1999). The effect of HIV-RNA levels on menstrual function is unknown.

C. HISTORY

• Characteristics of bleeding: date of last normal menstrual period, duration and frequency of menses, amount of bleeding (number of pads/tampons used per day); presence of clots or associated pain/cramping; duration and pattern of menstrual irregularities or amenorrhea; presence of intermenstrual or postcoital bleeding.
• Other bleeding sources: gastrointestinal (GI) or bleeding from the urinary tract (vs. from a gynecologic source); history of easy bruising, nose or gum bleeds.
• History of gynecologic problems/other symptoms: abnormal Pap smears; uterine fibroids or polyps; prior ectopic pregnancy; abnormal vaginal discharge.
• Medical history: timing of diagnosis of HIV/AIDS and existing comorbid conditions; clinical symptoms of HIV; CD4 count and viral load; history of platelet disorders (thrombocytopenia is frequently diagnosed in HIV infection, particularly in individuals with more advanced stages of disease (Sloand, 1992); medications; history of substance abuse.
• Sexual history: last sexual intercourse and use of contraception and condoms.

D. PHYSICAL EXAM

A careful and comprehensive abdominal and pelvic examination should be performed. The presence of abdominal tenderness or mass should be noted. The external genitalia, vagina, and cervix should be inspected for evidence of actively bleeding lesions (e.g., lacerations, condylomata, polyps) or inflammation. Bimanual and rectovaginal examinations assess the presence of pelvic tenderness, enlarged uterus, or other pelvic mass.

E. DIFFERENTIAL DIAGNOSIS

• Pregnancy. Pregnancy must be considered in any woman of reproductive age with irregular bleeding or amenorrhea. Pregnancy may be either intrauterine or ectopic (usually tubal); bleeding with an intrauterine pregnancy may indicate threatened or incomplete abortion or miscarriage or a serious obstetric complication in later pregnancy.
• Anovulation. Anovulation is the most common cause of abnormal uterine bleeding among reproductive-aged women. Typically, the woman has a history of menstrual irregularity and may go several months with no bleeding, followed by the onset of prolonged and heavy bleeding. Anovulatory bleeding is a diagnosis of exclusion, and organic, systemic, and iatrogenic causes of bleeding must be ruled out. Anovulation and oligoovulation are more common among perimenopausal women and adolescents soon after menarche.
• Perimenopause. In addition to anovulation/oligoovulation, women in perimenopause may have irregular menses because of declining estrogen levels.
• Uterine fibroids. Fibroids are common benign uterine tumors that are most often asymptomatic, but may cause heavy and/or prolonged periods.
• Cancer. Malignant processes in every part of the female genital tract (vulva, vagina, cervix, uterus, fallopian tubes, and ovaries) can potentially present with abnormal bleeding; most common in postmenopausal women.
• Genital tract infections. Cervicitis, endometritis, and even vaginitis and vulvitis may present with abnormal vaginal bleeding or spotting. Associated symptoms, including pain/tenderness, discharge, fever, and other signs and symptoms of infection, will aid in making the diagnosis. In very immunosuppressed patients, consider opportunistic processes, including tuberculous or cytomegalovirus (CMV) endometritis.
• Medical conditions. Thyroid disorders (hypothyroidism or hyperthyroidism), coagulopathy (including platelet disorders), cirrhosis, chronic illness/wasting.
• Substance abuse. Drug use (including methadone) can lead to disturbances of the hypothalamic-pituitary axis, with resulting irregular bleeding or amenorrhea.
• Medications. Progestational agents, such as those used for contraception (e.g., Depo-Provera, Norplant) or for appetite stimulation (e.g., Megace) frequently cause irregular vaginal bleeding. Consider antiretroviral agents as a potential cause of abnormal bleeding. Medications that can affect prolactin concentrations and possibly result in amenorrhea include psychotropic drugs (tricyclic antidepressants, phenothiazines, opiates) and metoclopramide. Thalidomide has been also been associated with development of secondary amenorrhea (Frances, 2002).

F. EVALUATION

The basic evaluation includes the following:

• Pregnancy test (urine or serum): perform on all women with abnormal bleeding/amenorrhea within reproductive age range
• Laboratory tests:
  • Complete blood count (CBC), platelet count
  • Thyroid-stimulating hormone, prolactin levels — consider with any irregular bleeding/amenorrhea without apparent cause
  • Follicle-stimulating hormone (FSH), estradiol — with oligomenorrhea/amenorrhea and/or signs/symptoms of decreased estrogen production (hot flashes, vaginal atrophic changes). These tests are particularly helpful in distinguishing ovarian failure (low estradiol, high FSH) and hypothalamic amenorrhea (e.g., with wasting) (low estradiol, low/normal FSH)
  • Coagulation profile — if evidence of systemic bleeding, to rule out coagulopathy
• Cervical testing: for gonorrhea and chlamydia
• Pelvic ultrasound: with abnormal exam (uterine enlargement, adnexal mass, significant tenderness) or positive pregnancy test; ultrasound using the transvaginal approach is used commonly in the evaluation of abnormal bleeding to assess endometrial thickness, especially in peri- and postmenopausal women, or to look for other possible abnormalities (e.g., polyps, fibroids)
• Endometrial biopsy: indicated with postmenopausal bleeding, prolonged amenorrhea followed by onset of irregular or heavy bleeding, persistently irregular bleeding. Used liberally with any form of abnormal bleeding if no cause is found otherwise and bleeding does not respond to conservative (e.g., progestins, oral contraceptives) management. It is helpful in diagnosing endometritis, endometrial hyperplasia, and uterine cancer; endometrial tissue necessary to diagnose CMV or tuberculosis (TB) endometritis—alert your pathologist if these are considerations
• Pap smear: do not perform with active bleeding; if cervical lesion seen, biopsy is required.Further evaluation or referral is indicated based on results of these tests, severity of the problem, and response to basic management.

G. MANAGEMENT

Management depends on the diagnosis and results of testing. All women with a positive pregnancy test require referral to a specialist. If anovulatory bleeding is suspected, medical management may be attempted with oral contraceptive pills or cyclic progestins (medroxyprogesterone acetate 10 mg po qd for 10–14 days each month). These therapies help restore regular menstruation, reduce possible anemia, and protect the endometrium from prolonged estrogenic stimulation, which can cause hyperplasia or neoplasia. Oral contraceptive pills will also provide effective contraception, but are contraindicated in heavy smokers over the age of 35, with hypertension or other cardiovascular disease, and in diabetics and women with markedly abnormal liver function.

With severe bleeding and anemia, pelvic mass, findings suspicious for malignancy, or bleeding that is not resolved with conservative measures, referral is indicated.

III. Abnormal Pap Smear  TOP

In the setting of HIV infection 30–60% of Pap smears exhibit cytologic abnormalities and 15–40% have evidence of dysplasia; these rates are 10–11 times greater than those observed among HIV-negative women (Maiman, 1998).

A. INTERRELATIONSHIP OF HIV AND HUMAN PAPILLOMAVIRUS

• Human papillomavirus (HPV) infection plays a causative role in lower genital intraepithelial and invasive neoplasia. The spectrum of HPV disease includes subclinical disease, classic genital warts and other HPV-related skin lesions, lower genital tract intraepithelial neoplasia, and invasive cancers of the lower genital tract. There are over 100 HPV subtypes, which are divided into low, intermediate, or high risk, based on oncogenic potential; nevertheless, these categories are not exclusive and “low-risk” HPV types have been described in cervical carcinomas.
• HPV is an extremely common infection; current evidence suggests that over 50% of sexually active adults have been infected with one or more genital HPV types, but most HPV infections are transient (Evander, 1995; Ho, 1998). Studies have shown that HIV-infected women have higher prevalence of HPV, higher incidence of HPV (Branca, 2003; Ahdieh, 2001), higher HPV viral load (Jamieson, 2002), longer persistence of HPV (Ahdieh, 2000; Sun, 1997), higher likelihood of multiple HPV subtypes (Jamieson, 2002), and greater prevalence of oncogenic subtypes (Minkoff, 1998; Uberti-Foppa, 1998) than HIV-uninfected women. HPV viral load is independently associated with HPV persistence (Ahdieh, 2001).
• In HIV-positive women the prevalence and persistence of HPV infection increases with decreasing CD4 count and increasing HIV RNA levels (Palefsky, 1999) and some studies show that oncogenic HPV types may be more common with lower CD4 counts and/or higher viral loads. (Luque, 1999; Minkoff, 1998). Higher HPV viral loads are also associated with lower CD4 counts (Heard, 2000).
• Sun et al. (Sun, 1995) have suggested that the presence of immunosuppression shifts the ratio of latent:clinically expressed HPV infections from 8:1 in the general population to 3:1 in HIV-positive women with CD4 >500/mm³ to 1:1 in HIV-positive women with CD4 <200/mm³.

B. HIV AND CERVICAL DYSPLASIA

• Abnormal cervical cytology is more common among HIV-infected women and is associated with the presence of HPV infection and the degree of immunosuppression. Both frequency and severity of abnormal Pap smears and histologically documented dysplasia increase with declining CD4 counts and have also been associated with higher HIV-RNA levels (Garzetti, 1995; Shah, 1996; Davis, 2001). Incidence of abnormal Pap smears is increased in HIV-infected as compared to -uninfected women, and is associated with lower CD4 counts; progression and regression of Pap smear abnormalities have been associated with level of immunesuppression and plasma viremia, as reflected in CD4 count and HIV viral load (Massad, 2001; Schuman, 2003). Increased HPV viral load, seen in women with more advanced HIV, is also associated with increased frequency, severity, and incidence of cervical dysplasia (Heard, 2000; Weissenborn 2003; Cohn, 2001).
• In HIV-positive women dysplasia is associated with more extensive cervical involvement and is more likely to involve other sites in the lower genital tract, such as the vagina, vulva, and perianal region (Hillemanns, 1996; Korn, 1995; Maiman, 1990; Petry, 1996; Williams, 1994) as compared with HIV-negative women.
• Recent studies have shown increased incidence of oncogenic HPV types (Minkoff, 1998) and increased incidence of biopsy-proven cervical dysplasia (Ellerbrock, 2000) in HIV-positive women compared with HIV-negative controls. A French study found an increased likelihood of progression of cervical abnormalities in HIV-positive women, although analysis was based on Pap smear results only (Six, 1998). A recent study also found an association between progression of abnormal Pap smears and high plasma HIV RNA levels (>100,000 c/mL) (Sewell, 2000). Presently there is little evidence for increased rates of progression to invasive cancer, particularly if adequate screening and treatment programs are in place.

C. HIV AND ANAL HPV/DYSPLASIA

• Anal HPV-DNA has been reported in up to 76% of HIV+ women and, when concurrent anal and cervical HPV data were available, anal HPV was more prevalent in both HIV-infected and high-risk HIV-uninfected women (Palefsky, 2001a). Anal HPV is more common with lower CD4 counts and with presence of cervical HPV. Multiple HPV types and oncogenic types are common (Lacey, 1999).
• Abnormal anal cytology or anal squamous intraepithelial lesions (ASIL) are reported in up to 26% of HIV-infected women; risk factors include lower CD4 count, increased HIV viral load, high HPV viral load, history of receptive anal intercourse, and concurrent abnormal cervical cytology (Holly, 2001; Kiviat, 1993).
• Sensitivity of anal Pap smears appears to be similar to cervical cytology, although grade of anal dysplasia may not correlate well with histology (Palefsky, 1997)
• Risk for invasive anal cancer is increased in patients with HIV/AIDS (Grulich, 2000).

D. INVASIVE CERVICAL CANCER IN HIV DISEASE

• In 1993, the CDC expanded the case definition of AIDS to include invasive cervical cancer.
• Oncogenic HPV types play a central role in the relationship between HIV and cervical cancer. Recent African data found that without high-risk HPV present, the risk ratio for cervical cancer between HIV-positive and HIV-negative women was approximately 1 (Hawes, 2003).
• Although there is little evidence that HIV infection is having a large effect on cervical cancer rates, linking of US AIDS and cancer registries has found that observed cervical cancer cases in HIV-infected women are up to 9-fold higher than the expected number of cases ; however, the likelihood of cervical cancer was not related to CD4 count (Mbulaiteye, 2003). In an analysis of women in the HER study, the rate of invasive cervical cancer was 1.20/1000 person-years in HIV-infected women as compared to 0/1000 person-years in high-risk HIV-negative women (Phelps, 2001). Mean CD4 cell count was 443 cells/mm³ at time of diagnosis of cervical cancer in women with HIV. Women with HIV and cervical cancer tend to be younger and less immunosuppressed compared with HIV-positive women with other AIDS-indicator conditions. Women with HIV and cervical cancer tend to be younger than HIV-negative women with cervical cancer (Lomalisa, 2000). A prospective cohort study from Italy found that the incidence of invasive cervical cancer as a first AIDS-defining condition continued to increase after the introduction of HAART, possibly due to the decrease seen in incidence of other AIDS-defining diseases after HAART (Dorrucci, 2001).
• HIV-positive women with invasive cervical cancer appear to present at more advanced stages (especially with CD4 < 200/mm³), may metastasize to unusual locations (e.g., psoas muscle, clitoris, meningeal involvement), have poorer responses to standard therapy, and have higher recurrences and death rates, as well as shorter intervals to recurrence or death, compared with HIV-negative women of similar stage (Klevens, 1996; Maiman, 1990).

E. SCREENING TESTS

• A single Pap smear is associated with false-negative rates of 10–25%; accuracy is significantly improved with regular periodic screening. Controlled studies have not demonstrated a decrease in sensitivity or specificity with standard cervical cytology in HIV-positive women compared with HIV-negative controls (Adachi, 1993; Spinillo, 1998).However, a prospective cohort study found that HIV-infected women were significantly more likely to have abnormal biopsy results with normal Pap smears as compared with high-risk HIV-uninfected women; predictors of discordant histology and cytology included presence of HPV by PCR and CD4 count <500/mm³. In this study 17 of 19 women with discordant results had abnormal Paps within one year of these results, using current guidelines for Pap smear screening (Anderson 2002).
• Newer Pap smear screening techniques using liquid-based media appear to increase sensitivity, decrease inadequate smears, and reduce, but not eliminate, false-negative results; they also offer the possibility of direct HPV testing on collected specimens. They are more expensive than conventional Pap tests. A recent review of over 400 HIV-infected women who underwent both conventional and liquid-based cytologic screening found a significant decrease in the proportion of smears diagnosed as ASCUS/AGUS as well as the ASCUS/SIL ratio, with liquid-based preparations (Swierczynski, 2002).
• HPV testing can identify both oncogenic and nononcogenic viral types; HPV testing for cancer-associated types can play an important role in the evaluation of women with atypical squamous cells on Pap smear (Solomon, 2001).
• The role of HPV DNA testing as an alternative or addition to the Pap smear in HIV-positive women is unknown. One analysis suggested that adding HPV testing to standard Pap smear screening may be a cost-effective strategy if this allows modification of screening intervals (Goldie, 2001). A recent German study examining HPV DNA testing as a primary screening method for cervical dysplasia in 94 HIV-positive women found that HPV DNA testing identified high-grade cervical dysplasia more accurately than Pap smear (Petry, 1999).
• Pap smear results are reported according to the Bethesda System (Solomon, 2002) (Table 6-1).

F. RECOMMENDATIONS FOR PAP SMEAR SCREENING AND COLPOSCOPY

• HIV-infected women should have a complete gynecologic evaluation, including a Pap smear and pelvic exam, as part of their initial evaluation (US Public Health Service (USPHS)/Infectious Diseases Society of America (IDSA) 2001 accessed at http://www.aidsinfo.nih.gov).
• A Pap smear should be obtained twice in the first year after diagnosis of HIV infection. If these results are normal, annual examinations are then indicated.
• More frequent Pap smears should be considered:
  • with previous abnormal Pap smear
  • with HPV infection
  • after treatment for cervical dysplasia
  • in women with symptomatic HIV infection (including CD4 counts <200/mm³)
• The American College of Obstetricians and Gynecologists recommends Pap smears every 3–4 mo for the first year after treatment of preinvasive cervical lesions, followed by Pap smears every 6 mo (ACOG, 1993). Vaginal Pap smears should be obtained after hysterectomy for persistent or recurrent cervical dysplasia.
• Women receiving gynecologic and primary HIV care at the same location are more likely to have had Pap smear screening within the previous year (Stein, 2001).
• The role of anal cytology remains unclear and recommendations for routine anal Pap smear screening are not currently part of standard guidelines. However, the approach suggested by experts in this field is similar to recommendations for cervical Pap smear screening:
  • perform anal Pap as part of initial evaluation and, if normal, repeat in 6 months
  • if these results are normal, repeat annually
  • more frequent anal Pap smears should be considered:
    • with CD4<500/mm³
    • presence of cervical dysplasia
    • with previous abnormal anal Pap smear
    • after treatment for anal dysplasia
  • anal Pap smears with ASCUS or SIL should be evaluated with anoscopy and biopsy
• Anal Pap smears are performed by inserting a moistened Dacron swab 1–1.5 inches into the anal canal and rotating as it is slowly withdrawn over 15–20 seconds, maintaining contact with the mucosa; both rectal columnar and anal squamous cells must be obtained to have an adequate specimen. The swab should then be vigorously shaken in liquid–based cytology media.
• Indications for colposcopy are outlined in Table 6-2.

• ASC (atypical squamous cells) represents the mildest cytologic abnormality in the Bethesda system; however, in the general population 5–17% of women with ASC have underlying CIN2-3 and approximately 0.1% have invasive cancer (Solomon, 2001). The 2001 Bethesda system stratifies ASC into two categories: atypical squamous cells of undetermined significance (ASC US) and atypical squamous cells-cannot exclude HSIL (ASC-H), with 24-92% of women with ASC-H having CIN2-3 confirmed with biopsy (Wright,2002). In a study of women with ASCUS, Wright (Wright, 1996) found that HIV-positive women were approximately twice as likely to have underlying dysplasia compared with HIV-negative women; a recent cross-sectional analysis of 761 Pap smears from HIV-positive women found that 27% were diagnosed as ASCUS; 15% had underlying high-grade dysplasia (Holcomb, 1999a). Immunosuppression did not appear to increase the frequency of dysplasia associated with ASCUS on Pap smear. Incidence of ASCUS is increased in HIV-infected women (Massad, 2001). Referral for colposcopy is recommended for all HIV-infected women with ASC, irrespective of CD4 cell count, HIV viral load, or antiretroviral therapy (Wright, 2002).

• The risk of underlying pathology with a diagnosis of atypical glandular cells (AGC) is significant. The 2001 Bethesda system stratifies AGC into 3 categories: atypical glandular cells, either endocervical, endometrial, or “not otherwise specified” (NOS); atypical glandular cells, favor neoplastic; and endocervical adenocarcinoma-in-situ (AIS). Overall, various studies have found that 9–54% of women with AGC have CIN on biopsy, 0–8% have AIS on biopsy, and up to 9% have invasive cancer (Wright, 2002). The risk of a significant abnormality increases with the severity of the AGC reading. Colposcopy is indicated with any AGC on Pap, as well as endocervical sampling. Endometrial sampling is indicated with presence of atypical endometrial cells or AGC-NOS, in women older than 35 years, and in younger women with AGC who have unexplained vaginal bleeding (Wright, 2002). Because of the significant risk of invasive disease with AGC, favor neoplasia or endocervical AIS, women with these results should undergo diagnostic cervical conization if initial evaluation is negative for invasive cancer (Wright, 2002).
• Biopsies should be obtained at the time of colposcopy to confirm cytologic abnormalities and/or if abnormal areas are visualized.
• Because of the multicentric nature of lower genital tract intraepithelial neoplasia in the setting of immunosuppression, it is recommended that the entire lower genital tract (vagina, vulva, and perianal region) be examined at the time of colposcopy.

G. MANAGEMENT OF CERVICAL AND OTHER LOWER GENITAL TRACT LESIONS

Management of abnormal Pap smears is outlined in Table 6-4. Documentation of a high-grade cervical lesion requires treatment. Standard excisional or ablative treatment is recommended, although HIV-positive women have an increased incidence of recurrence after treatment (over 50% recurrence rate), correlated with degree of immunosuppression (Fruchter, 1996; Holcomb, 1999b). Cryotherapy has had the highest rate of recurrences and should be avoided, if other treatment methods are available. Hysterectomy as treatment for recurrent or persistent cervical dysplasia has also been associated with significant recurrence rates in the vagina (Tate, 2002). Recurrences have been associated with detectable HIV RNA in plasma and higher mean HIV RNA levels (Keller, 2002) and may also be related to positive surgical margins with excisional treatment, which appear to be more common in HIV-positive women compared with HIV-negative women (Boardman, 1999). Abstinence should be emphasized until complete healing has occurred after treatment for cervical dysplasia, since the treatment has been shown to dramatically increase genital tract HIV shedding (Wright, 2001) and may increase risk of sexual transmission of HIV.

Topical vaginal 5-fluorouracil (5-FU) cream (2 g biweekly for 6 mo) was shown to reduce recurrence rates after standard treatment for high-grade cervical dysplasia in HIV-positive women in a recent clinical trial; over 18 mo of follow-up, 31% of women who were only observed developed a recurrent high-grade lesion compared with 8% of women receiving 5-FU. Disease recurred more slowly in women who had received antiretroviral therapy, compared with those who were antiretroviral-naïve (Maiman, 1999).

5-FU may play a role in secondary prophylaxis of preinvasive cervical lesions in some cases. However, clinical experience with this therapy is too limited to provide a recommendation for routine use. 5-FU may have significant mucosal toxicity and concerns have been raised about the potential for increased risk for transmission of HIV or other sexually transmitted infections (STIs) with this therapy.

Women with documented vaginal, vulvar, or anal dysplasia should be managed in consultation with a gynecologic specialist. Treatment options include observation, excisional biopsy, use of cavitational ultrasonic surgical aspiration, or laser vaporization; 5-FU has been used successfully for treatment of vulvar and vaginal lesions and recent small studies suggest a possible role for topical 1% cidofovir gel with lower genital tract HPV-related lesions (Koonsaeng, 2001; Snoeck, 2001a; Snoeck, 2001b). Regardless of type of treatment, recurrence rates are increased in HIV-infected women and close follow-up is needed (Chang, 2002).

The role of highly active antiretroviral therapy (HAART) and immune reconstitution in the management of lower genital tract precancerous lesions remains unclear. In one study use of HAART was associated with increased likelihood of regression of cervical dysplasia after treatment for 12 months (Heard, 2002). In the Women’s Interagency HIV Study (WIHS), after adjustment for CD4 count and Pap status, use of HAART was associated with increased regression and decreased risk of progression of cervical cytologic abnormalities (Minkoff, 2001). On the other hand, Palefsky found no effect of 6 months of HAART on anal HPV or ASIL (Palefsky, 2001b). With 15 months of follow-up, persistence of high-risk HPV and progression of SIL were comparable among women without antiretroviral treatment, those treated with nucleoside analogues only, and those treated with HAART (Lillo, 2001). Duerr and colleagues found no differences in regression of abnormalties on Pap smear, HPV acquisition or persistence after up to 24 mo on HAART compared with untreated women or women receiving non-HAART treatment. However, new abnormal Pap smear results were less likely in the HAART group (Duerr, 2000).

At the current time, HIV-positive women should continue to be followed closely for evidence of lower genital tract neoplasia, regardless of antiretroviral therapy or viral load.

IV. Genital Ulcers  TOP

A. HISTORY

Duration and location of lesion(s); previous history of genital ulcers, syphilis, or genital herpes; associated symptoms (pain, pruritus, fever, etc.); medications and timing of ulcers relative to initiation of new medication; sexual history (including condom use); and CD4 counts and HIV RNA levels.

B. PHYSICAL EXAM

Dimensions and location of lesion(s); presence of pigmentation, edema, erythema, or induration; presence of associated exudate or tenderness; presence of oral lesions; associated lymphadenopathy or rash.

C. EVALUATION

• Syphilis serology or darkfield examination
• Culture or antigen test for herpes simplex virus (HSV)
• Biopsy: with unclear diagnosis, lack of response to treatment; consider special stains, if indicated (CMV, acid-fast bacillus)
• Culture for Haemophilus ducreyi: not widely available commercially; diagnosis of chancroid generally made with typical clinical presentation, after excluding syphilis and HSV

D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT
(See recent review Rosen, 2003)

Infections

Herpes Simplex Virus

• most prevalent infectious cause of genital ulcers in the United States
• two distinct serotypes of HSV (HSV-1 and HSV-2), most cases of recurrent genital herpes (60–95%) are caused by HSV-2
• Since the late 1970s, the seroprevalence of HSV-2 infection has increased by 30%; infection is now detectable in 21.9% of people aged 12 or older nationwide (Fleming, 1997). Most people with HSV-2 do not know that they are infected, since they have mild or unrecognized symptoms; however, they may shed virus intermittently in the genital tract and transmit infection to their sexual partners. Age-adjusted HSV-2 prevalence is significantly higher among women than in men (Xu, 2002).
• typically lesions present as painful vesicles that ulcerate and heal without scarring
• primary infection often associated with systemic symptoms (fever, photophobia, headache); duration of lesions and viral shedding more prolonged with primary infection; after primary episode latency established in sacral dorsal root ganglia
• nonprimary first episode herpes occurs in individuals with antibodies to HSV-2 or HSV-1 but no previous clinical symptoms of HSV; milder, shorter episode
• recurrent episodes occur at variable frequency; more localized lesions, shorter duration compared with first episodes (primary or nonprimary)
• viral shedding and sexual transmission can occur during asymptomatic periods
• HIV-positive patients:
  • more frequent, prolonged, and/or severe episodes common with progressive immunesuppression; lesions may be atypical in appearance or location
  • HSV viral shedding increases with declining CD4 counts (Augenbraun, 1995) and higher plasma HIV viral load (Wright, 2003); may be more common in oral contraceptive or Depo-Provera users and in women with severe vitamin A deficiency (Mostad, 2000); most viral shedding asymptomatic
  • HSV is associated with increased risk for HIV transmission/acquisition (Heng, 1994). Higher levels of cervical HSV have been associated with increased HIV shedding in the genital tract (McClelland, 2002) and plasma HIV viral load is increased during HSV reactivation (Schacker, 2002).
• Treatment: See Table 6-5.
  • HIV-positive women often need higher doses and longer treatment courses, particularly with more advanced immunosuppression, and may benefit from suppressive therapy.
  • Daily suppressive therapy reduces the frequency of recurrences by 75% among patients who suffer from frequent HSV episodes (i.e., six or more recurrences per year). Suppressive treatment reduces but does not eliminate viral shedding. Safety and efficacy with daily acyclovir for over 10 years.
  • Acyclovir-resistant HSV: Usually cross-resistant to famciclovir, valacyclovir. The prevalence of resistant HSV in immunocompromised patients has remained stable at approximately 4–7% (Bacon, 2003). Most of these isolates are susceptable to foscarnet IV or topical cidofovir. Factors associated with acyclovir resistance are low CD4 counts and long-term exposure to acyclovir.

Syphilis

• systemic disease caused by Treponema pallidum
• definitive methods for diagnosing early syphilis are darkfield examination and direct fluorescent antibody test of lesion exudate or tissue
• presumptive diagnosis is possible using two types of serologic tests for syphilis: VDRL or RPR (nontreponemal) and a confirmatory FTA-ABS or MHA-TP (treponemal)
• nontreponemal test antibody titers usually correlate with disease activity and are used to assess treatment response; serial assessment during follow-up after treatment should use the same type of nontreponemal test
• HIV-infected patients may have abnormal serologic test results (e.g., unusually high titers, false negatives or delayed seroreactivity). However, generally serologic tests can be interpreted in the usual manner. If clinical findings suggest syphilis but serology is nonreactive, biopsy, darkfield examination, or direct fluorescent antibody staining of lesion material should be considered. The clinical presentation of syphilis is very variable at all stages; atypical manifestations may be seen in the setting of HIV disease. Neurosyphilis should be considered in the differential diagnosis of neurologic signs or symptoms in HIV-infected individuals (CDC, 2002).
• Treatment: See Table 6-6.

Chancroid

• caused by H. ducreyi
• endemic in some areas of the United States; also occurs in discrete outbreaks
• 10% of patients with chancroid have coinfection with T. pallidum or HSV
• initial presentation typically consists of a tender papule that becomes pustular and then ulcerative; the ulcer is usually well demarcated, with ragged undermined edges
• probable diagnosis can be made if the patient has one or more painful ulcers, there is no evidence of T. pallidum or HSV infection, and the clinical presentation appearance of ulcers and regional lymphadenopathy is typical for chancroid
• Response to treatment may be diminished in the HIV-infected patient; may require longer courses of therapy, increased risk for treatment failure
• Treatment:
  • Azithromycin 1 g po (single dose), OR- Ceftriaxone 250 mg IM (single dose), OR
  • Ciprofloxacin 500 mg po twice a day for 3 days, OR
  • Erythromycin base 500 mg po four times a day for 7 days.
  • Note
    • In HIV-positive patients use single-dose therapies only if follow-up can be ensured;
    • Some experts recommend the 7-day erythromycin regimen in the setting of HIV infection.

Cytomegalovirus

• should be suspected in severely immunocompromised patients
• diagnosis requires biopsy of lesion with immunohistochemical stains
• cervical shedding of cytomegalovirus is associated with low CD4 counts (Clark, 1997)
• Treatment:
  • Ganciclovir 5 mg/kg IV twice a day for 2–3 wk, OR
  • Foscarnet 60 mg/kg IV q 8 hr or 90 mg/kg q 12 hr for 2–3 wk.

Other Infectious Causes of Genital Ulcers

• Lymphogranuloma venereum: rare in United States; associated with tender, usually unilateral inguinal or femoral lymphadenopathy, proctocolitis, rectal fistulas/strictures; diagnosis with serology and exclusion of other causes; treatment: doxycycline or erythromycin for 3 wk; HIV-positive individuals may require more prolonged treatment
• Granuloma inguinale (donovanosis): rare in United States; painless, progressive ulcers which bleed easily on contact, without regional lymphadenopathy; diagnosis with biopsy or tissue crush preparation; treatment trimethoprim-sulfamethoxazole or doxycycline for 3 wk or until all lesions healed; CDC recommends adding aminoglycoside to regimen in HIV-positive patients
• Tuberculosis (Giannacopoulos, 1998): genital TB is generally a secondary manifestation of primary (usually pulmonary) disease. In the United States, the incidence of genital disease is <1% diagnosis is established by biopsy. Genital tuberculosis should be treated as is extrapulmonary disease; expert consultation is necessary.

INFLAMMATORY CONDITIONS

Crohn's Disease

• This disease may be easily misdiagnosed because its principal clinical features (i.e., fever, abdominal pain, diarrhea, fatigability, weight loss) are often found in patients with HIV disease. Crohn’s disease may also present with genital ulcers, rectal fissures, perirectal abscesses, or intestinal fistulas. Sigmoidoscopy or barium enema is essential in making this diagnosis. Manage with expert consultation.

Behçet's Syndrome

• This is a multisystem disorder that presents with recurrent oral and genital ulcerations as well as uveitis, arthritis, and vasculitis. Vaginal ulcers are usually painless, whereas lesions on the external genitalia are generally painful. Ulcers range between 2 and 10 mm in diameter, and they can be shallow or deep with a central yellowish necrotic base; either a single lesion or crops of lesions may be evident. Diagnosis is established based on the clinical presentation and biopsy. Treatment consists of topical or systemic corticosteroids.

Hidradenitis Suppurativa (Droegemueller, 1997)

• This is a chronic, refractory condition involving the skin, subcutaneous tissues, and apocrine glands. Lesions are painful and are associated with a foul-smelling discharge. Eventually, a deep-seated chronic infection of apocrine glands develops, with multiple draining abscesses and sinuses. A biopsy is necessary to establish the diagnosis. In the early stages of disease, treatment options include antibiotics, topical steroids, antiandrogens, and isotretinoin. Treatment of advanced disease requires surgical intervention.

Neoplastic

• any nonhealing genital ulcer must be biopsied to rule out a neoplastic process
• squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, melanoma, lymphoma, Kaposi’s sarcoma
• refer to oncologist

Drug Reaction

• has been described as rare side effect of treatment with zalcitibine and foscarnet

Aphthous Genital Ulcerations (Anderson, 1996)

• no specific etiology (typical or opportunistic organism) is identifiable
• similar to aphthous ulcers seen in the gastrointestinal tract
• most patients are significantly immunosuppressed (median CD4 count 50/mm³)
• lesions can be painful, multiple, deep, and extensive (size 1–6 cm)
• associated morbidity includes immobility, bleeding, and superinfection
• most have been reported to be chronic and/or recurrent or relapsing
• oroesophageal ulcers coexist in about one third of cases and one fifth were associated with genital fistula formation
• Treatment:
  • Consider empiric therapy for HSV.
  • If empiric therapy fails, systemic steroids (prednisone 40–60 mg/day for 1–2 wk, then taper) have been moderately successful.
  • Thalidomide (200 mg/day for 2–4 wk) has been used in similar ulcers in the oropharynx or esophagus with complete healing in 55–73% of these ulcers (Jacobson, 1997, 1999); there has been similar success anecdotally in genital apththous ulcers. (Warning: this drug is a powerful teratogen and should only be used in women of reproductive age after appropriate counseling and pregnancy testing and in the setting of reliable contraception or abstinence.)

Trauma

• history of traumatic injury
• consider possibility of sexual violence

V. Vaginal Discharge  TOP

A. HISTORY

Duration and characteristics of discharge, associated symptoms (e.g., pruritus, malodor, burning, pelvic pain), sexual history (including condom and other contraceptive use), history of sexually transmitted diseases, history of douching, recent antibiotic use, CD4 counts and HIV-RNA levels, medications.

B. PHYSICAL EXAM

Complete genital inspection and bimanual pelvic examination; document the characteristics and amount of discharge as well as the presence of erythema, edema, and tenderness.

C. EVALUATION

• saline wet mount
• 10% potassium hydroxide (KOH) preparation
• vaginal pH determination
• testing for gonorrhea and chlamydia
• fungal culture, if indicated (signs/symptoms of yeast infection with negative findings on microscopy; chronic/recurrent yeast infections)

D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT

Bacterial Vaginosis (BV)

• most prevalent cause of vaginal discharge or malodor
• results from replacement of normal Lactobacillus dominant vaginal flora with increase in prevalence and concentration of mixed flora, including anaerobic bacteria, Gardnerella vaginalis, and Mycoplasma hominis
• 18–42% prevalence among HIV-infected women; BV is more prevalent and persistent as compared with HIV-negative controls and prevalence, persistence and severity increase with lower CD4 counts (Cu-Uvin, 1999; Greenblatt, 1999; Jamieson, 2001). Use of antiretroviral drugs has been associated with lower prevalence of BV (Warren, 2001)
• Some studies suggest that BV or BV-associated organisms (or lack of vaginal lactobacilli) may enhance HIV transmission (Martin, 1999; Olinger, 1999). BV has been associated with increased HIV expression in the genital tract (Cu-Uvin, 2001).
• associated with increase in several obstetric and gynecologic complications, including pelvic inflammatory disease (PID), postabortion and posthysterectomy infections, preterm labor
• standard diagnosis by clinical criteria; requires three of the following: 1) a homogeneous grayish or yellowish discharge (may coat vaginal walls); 2) clue cells on microscopic examination; 3) vaginal pH >4.5; 4) a positive whiff test (i.e., fishy odor of discharge before or after addition of 10% KOH)
• Treatment: See Table 6-7.

Vulvovaginal Candidiasis

• Most commonly caused by Candida albicans; the prevalence of infections due to non-albicans species is increasing
• 75% of all women will have at least one episode of candidiasis, and 40–45% will have two or more episodes; less than 5% of women experience recurrent episodes of candidiasis
• Typical symptoms: thick, white discharge and pruritus; other symptoms include vulvar burning, vaginal soreness, dyspareunia, and external dysuria
• Prevalence among HIV-infected women is 3–15%; most studies suggest no significant difference in prevalence of infection between relatively immunocompetent HIV-positive women and HIV-negative controls; recent longitudinal analysis from the HER Study found that vulvovaginal candidiasis occurred with higher incidence and greater persistence, but not greater severity, among HIV-infected as compared to high-risk HIV-uninfected women. Lower CD4 count and higher viral load were associated with vulvovaginal candidiasis (Cu-Uvin 1999;Duerr, 2003).
• Possible confounding factor for HIV-positive women is more frequent use of antibiotics; pregnancy is also a predisposing factor for candidiasis irrespective of HIV status.
• Most studies show increased rates of vaginal (also rectal, oral) colonization in HIV-positive women, particularly with declining immune function.
• In HIV-positive women 26–27% of vaginal isolates are non-albicans strains (Schuman, 1998); available studies are conflicting on the proportion of non-albicans strains in HIV-positive compared with HIV-negative women; most common is Candida glabrata. No association found to date between strain diversity and HIV progression. In general conventional antifungal therapies are not as effective against non-albicans species and 10–14 days of therapy with a non-fluconazole azole drug is recommended as first-line therapy.
• Diagnosis is made by identifying budding yeast or pseudohyphae on a wet mount or KOH preparation or Gram stain of vaginal discharge; positive identification can also be accomplished by means of culture
• Treatment: See Table 6-8.
  • Special considerations in HIV-positive women:
    • Topical therapies may be more effective when given for at least 7 days; fluconazole may be more effective when given in two sequential 150 mg doses 3 days apart.
    • Consider prophylactic use of topical antifungals when antibiotics are given
    • Randomized, placebo-controlled trial of fluconazole 200 mg po weekly for prophylaxis of candidiasis in women with CD4 <300/mm³ (median CD4 15/mm³): effective in preventing oropharyngeal candidiasis (relative risk .50, p<.001) and vaginal candidiasis (relative risk .64, p=.05), but not esophageal candidiasis (Schuman, 1997). Consider in selected cases with recurrent vaginal candidiasis.
    • Recent study found that ritonavir and indinavir (and possibly other protease inhibitors) strongly inhibited secretory aspartyl proteinase (proteolytic enzyme produced by pathogenic Candida species, considered a virulence factor) activity and production in a dose-dependent fashion, and exerted a therapeutic effect in an experimental model of vaginal candidiasis, with efficacy similar to fluconazole (Cassone, 1999).
  • Azole resistance:
    Concerns have been raised about extensive use of oral azoles and promotion of azole resistance, possibly limiting use of these agents for other HIV-related indications. Current information about development of resistance is limited.
    • ACTG 816: annual incidence of clinical failure to fluconazole (persistence of oral candidiasis after 200 mg/day or higher dose for 14 days) 5.8% (median CD4 15/mm³); C. albicans primary etiology
    • Community Programs for Clinical Research on AIDS—randomized, placebo-controlled trial of fluconazole 200 mg weekly for prophylaxis of candidiasis (described above) (median CD4 15/mm³): after median 29 mo follow-up, fluconazole resistance <5% resistance in both fluconazole and placebo groups (Schuman, 1997a)
    • HIV Epidemiology Research Study (HERS): overall fluconazole resistance rare among C. albicans isolates with no evidence for progressive reduction in susceptibility over time; however, resistance frequent in non-albicans isolates from vagina and oral cavity; fluconazole resistance with non-albicans species more likely in HIV-positive women (Sobel, 2001). There was a trend towards more in vitro azole resistance in non-albicans species (all C. glabrata) in women with CD4 <300/mm³ who were receiving weekly fluconazole prophylaxis vs placebo. (Vazquez, 2001).
    • 139 isolates from vulvovaginal candidiasis in HIV-positive women: 95–98% susceptibility of C. albicans to fluconazole, itraconazole, clotrimazole; C. glabrata: 44% resistance to fluconazole, 72% resistance to itraconazole and clotrimazole. Twenty percent of 90 relapses/persistence were with same organism; emergence of drug resistance was not observed between sequential isolates. Twelve percent had recurrent infection with different strains or species (Li, 1997).

There are no current data to suggest that intermittent therapy with a single dose of fluconazole increases development of azole resistance. Similarly, weekly prophylaxis with fluconazole was associated with infrequent development of resistance, which was not significantly different from placebo recipients. Nevertheless, long-term use of fluconazole may select for more resistant and difficult-to-treat non-albicans species and should be used with caution. Further study is needed.

• Recurrent candidiasis (four or more symptomatic episodes per year):
  • Evaluation:
    1. establish diagnosis — fungal culture may be needed
    2. identify/eliminate predisposing factors, if possible: uncontrolled diabetes, corticosteroid use, topical or systemic antibiotics, spermicides
       (conflicting data), tight-fitting synthetic underwear, douching, pregnancy, immunosuppression
    3. speciation/susceptibility testing
  • Management options:
    1. longer duration of standard treatment regimen
    2. chronic intermittent therapy (e.g., with perimenstrual episodes)
    3. restriction of orogenital/anogenital sexual contact (anecdotal evidence only); double-blind, placebo-controlled trials of topical therapy for male sexual partners showed no benefit (Sobel, 1999)
    4. possible role for boric acid vaginal capsules, gentian violet
    5. maintenance therapy: initial intensive regimen (e.g., 7–14 days of topical therapy or a 150 mg oral dose of fluconazole repeated 3 days later) followed by a maintenance regimen for at least 6 mo:

       a. fluconazole* 100–150 mg po every wk
       b. itraconazole* 400 mg po every month or 100 mg po every day
       c. clotrimazole 500 mg suppository per vagina every wk
       d. ketoconazole* 100 mg po every day (associated with rare but significant hepatotoxicity-monitor liver function; significant
       drug interactions with some antiretrovirals (see Chapter XIV on Pharmacologic Considerations in HIV-infected Pregnant Patients)

    6. immune reconstitution; potential benefit with protease inhibitors

       *Note: avoid concomitant use with terfenadine, astemizole, cisapride secondary to cardiotoxicity.