Gynecologic Care of HIV-Infected Women
Deborah Cohan and Abner P. Korn
Table Of Contents
Deborah Cohan, MD, MPH
Abner P. Korn, MD
GENDER DIFFERENCES IN HIV AND AIDS
LOWER GENITAL TRACT NEOPLASIA
INVASIVE CERVICAL CANCER
SEXUALLY TRANSMITTED INFECTIONS
PELVIC INFLAMMATORY DISEASE
OSTEOPENIA AND OSTEOPOROSIS
There are nearly 20 million women living with HIV worldwide, accounting for approximately half of all infections.1 Although the goal of this chapter is to describe the gynecologic care of the HIV-infected woman in industrialized settings, it is critical to understand that the burden of the epidemic lies within resource-limited areas, particularly sub-Saharan Africa.
In 2001, the Centers for Disease Control and Prevention reported 141,048 cumulative cases of AIDS among women in the United States The most common risk factor for HIV acquisition in women was heterosexual contact.2 In the United States, there is dramatic geographic variation in the prevalence of HIV/AIDS among women, with the highest prevalence of AIDS cases in the northeast and southeast regions of the country. In 2001, AIDS prevalence was 9.1 per 100,000 women in the United States. New York had the highest frequency, with 30.3 AIDS cases per 100,000 women.3 AIDS incidence and the proportion of AIDS cases are increasing yearly among American women, particularly women of color. Although most HIV infections in the United States are among men, an estimated 29% of infections are among women.3
Gynecologic diseases are commonly encountered when caring for HIV-infected women.4 HIV infection may impact on the occurrence or clinical severity of a variety of gynecologic conditions. When encountered, clinical care for women with these conditions may prove to be challenging. In general, these conditions are more common and severe among more immunosuppressed women.5
|GENDER DIFFERENCES IN HIV AND AIDS|
Women and men appear to have similar rates of disease progression and survival, once accounting for access to care, use of antiretrovirals, and stage of disease.6,7,8 Nonetheless, women appear to have less access to care and are less likely than men to receive antiretrovirals and opportunistic prophylaxis.9,10,11 Most studies addressing gender differences have found that women, on average, have lower plasma HIV RNA levels at any given CD4 count as compared with men.12,13 In their systematic review of the published literature, Gandhi and associates found that women's CD4-adjusted HIV RNA levels were approximately two-fold to six-fold (.13 to .78 log10) lower than those of men.13 The meta-analysis by Napravnik and associates confirmed this finding, calculating the CD4-adjusted HIV RNA summary estimate to be 41% lower (.23 log10) among women as compared with men.12 There are apparent cyclic alterations in viral load among women as well. Greenblatt and associates noted a .16-log10 decrease in median HIV RNA levels from the early follicular to mid luteal phase among ovulatory women.14 Nonetheless, menopause does not appear to have an impact on CD4 counts.15 Whereas the full implication of these findings remain uncertain, it suggests that decisions to initiate antiretrovirals using viral load levels should use different threshold values among women and that, perhaps, the timing of these viral loads in relation to the menstrual cycle should be noted.
|LOWER GENITAL TRACT NEOPLASIA|
Women with HIV infection have approximately a four-fold to six-fold increased risk for squamous intraepithelial lesions (SIL) or cervical intraepithelial neoplasia (CIN) compared with uninfected women.16,17 In one of the ongoing, large, multicenter cohorts of HIV infected and uninfected women, SIL was detected in 17.4% (2.5% high-grade squamous intraepithelial lesions [HSIL]) of HIV-infected women compared with 3.5% of HIV-uninfected women (p < .001).18 With 5-year follow up, 73% of HIV-infected women had an abnormal Pap smear test result. Human papillomavirus infection (HPV) is also more commonly detected and more likely to be persistent in HIV-infected compared with uninfected women.18,19
A 30-month prospective study of women with no evidence of cervical disease in New York City showed incident cases of SIL in 20% of HIV-infected and in 5% of HIV-uninfected women.20 No women had cervical cancer during the study. A multivariate analysis showed a significant association between HIV infection, transient and persistent HPV infection, and young age with development of SIL. Incidence of cervical disease is correlated both with low CD4+ cell count and increased HIV RNA level.16 Antiretroviral therapy (mostly zidovudine) was not protective against development of SIL (RR = 1.0; 95% confidence interval [CI]: .5, 2.0). In another study of 168 HIV-infected women, the 96 who received highly active antiretroviral therapy (HAART) had twice the likelihood of regression of CIN during a 12-month follow-up period compared with those who did not use HAART.21 In a larger study, the Pap smears of women who received HAART were less likely to have progression to a higher grade (OR = .68; 95% CI: .52 to .8) and more likely to have regression.22 Other studies have not shown a significant effect of HAART on regression of SIL.23
Vulvar, vaginal, and anal intraepithelial neoplasia appear to be prevalent among HIV-infected women. In a well-controlled prospective study, vulvar and vaginal condyloma were found in 5.6% of HIV-infected versus .8% of HIV-uninfected women. Vulvar intraepithelial neoplasia (VIN) was noted in only two of 396 (.5%).6 Incident vulvovaginal intraepithelial neoplasia lesions were 16-times more frequent in a prospective study of HIV-infected women compared with uninfected women.24 In this study, after a median follow-up of 3.2 years, 2% of all HIV-infected women had high-grade VIN and one patient had invasive vulvar carcinoma. Cigarette smoking and injection drug use were independently associated with vulvovaginal and perianal lesions in HIV-infected women.
Human papillomavirus (HPV) infection of the anus and epithelial abnormalities on anal Pap tests are common in persons with HIV infection.25,26 In a prospective study of 319 women, 26% of the HIV-infected women and 8% of the HIV-negative women had abnormal anal cytology.27 The likelihood of having abnormal anal cytology increased with the degree of abnormality of cervical cytology. Colposcopically directed biopsy showed high-grade lesions in 6% of the HIV-infected and in 2% of the HIV-negative women. HIV-infected women have a nearly eight-fold increased risk for in situ and a nearly seven-fold increased risk for invasive anal cancer compared with HIV-negative women.28
Although vulvar, vaginal, and anal cancers are infrequently reported in HIV-infected women, these conditions may become more common as improved medical care of HIV leads to women living with immunosuppression and intraepithelial neoplasia for longer periods of time. In women with immunosuppression after organ transplantations, a 100-fold increase in vulvar cancer has been reported occurring after an average of 107 months.29
Most controlled studies have shown Pap smear sensitivity and specificity rates similar to those reported for HIV-negative women.30,31 Screening colposcopy does not appear to be warranted, at least in populations with a low prevalence of cervical disease.18 Some investigators, however, advocate screening colposcopy based on their findings in populations with a higher prevalence of dysplasia.32 A cost-effectiveness study comparing semi-annual cervical cytology with colposcopic screening of HIV-infected women in a Markov model showed that colposcopy added little and increased costs markedly.33 On the basis of the predominant findings, routine colposcopy is not recommended in published guidelines for screening of HIV-infected women.34,35 Because of the high prevalence of HPV in HIV-infected women, HPV typing (by polymerase chain reaction) may not be a useful means of triage of abnormal cervical smears.18 HPV testing by hybrid capture technique may be more useful in HIV-infected women. In a study from Hannover, Germany, HPV testing identified 16 of 17 (94%) of the lesions classified as CIN2 or higher with a specificity of 70%. Cervical cytology identified 11 of 17 (65%) of the lesions classified as CIN2 or higher with a specificity of 98%.36 The performance of HPV testing in a prospective study of a large cohort of HIV-infected women has yet to be reported.
Pap smears must be interpreted slightly differently among HIV-infected women than among uninfected women. Mild cytologic atypia and inflammation on Pap smear are more frequently associated with dysplasia in HIV-infected compared with HIV-uninfected women.37 Colposcopic examination is warranted after a single Pap showing cytologic atypia and may be warranted after a single smear showing severe inflammation. In the latter case, an alternative would be to search for an infectious cause of inflammation, such as Neisseria gonorrhea, Chlamydia trachomatis, herpes simplex virus (HSV), or Trichomonas vaginalis, and to perform colposcopy only if the inflammation fails to resolve after treatment of the infection. All HIV-infected women who have SIL on their Pap smears should have a colposcopic examination.
The optimum method of screening for noncervical lesions in HIV-infected women has not been determined. At a minimum, careful inspection of the vulva and perianal region should be performed during pelvic examinations. It may be possible to improve detection of VIN lesions by application of dilute acetic acid to the vulva followed by examination using low-power magnification (such as by hand-held magnifying glass). Optimally, the acetic acid must remain in contact with the vulva for approximately 5 minutes before examination.
High-resolution anoscopy (the use of a colposcope to examine the anal canal) is indicated for anal Pap smears that show atypical squamous cells, low-grade squamous intraepithelial lesions (LSIL) or HSIL. Approximately half of high-grade anal intraepithelial neoplasia (AIN) lesions will have only mild cytological abnormalities on cytology.27
Clinical Course and Treatment
The clinical course of CIN in HIV-infected women may be characterized by more progression and less regression than in HIV-negative women.38 A prospective study of women with SIL followed-up for 5 months in the Ivory Coast showed persistence in 76% of HIV-infected compared with only 18% of HIV-uninfected women (RR = 4.3; 95% CI: 2.4, 7.7).39 In the WIHS study, cytological progression was associated with HPV infection and with elevated HIV RNA level but not with HIV serostatus.16 Persistence of CIN after treatment is common in HIV-infected women.38 High recurrence rates (40% to 100%) of CIN after ablative or excisional therapy are reported in HIV-infected women, especially those with immunosuppression.30,40,41,42 Invasive cervical carcinoma has been reported 32 months after a cold-knife conization for CIN3 (with negative margins).40 A possible explanation for the increased treatment failure is the high likelihood of persistent HPV infection in HIV-infected women.19 The elevated HPV viral burden may lead to treatment failure.
HIV-infected women may also be more likely to have bleeding or infections after treatment for CIN than noninfected women.43 However, in this study, no patient required blood transfusion and all infections were vaginal, except for one case of pelvic inflammatory disease (PID).
Treatment of VIN in HIV-infected women is difficult. In one study, these women uniformly had recurrence of VIN after excisional or ablative therapy.44 The outcome of surgical treatment of AIN in HIV-infected patients appears to be similar, with approximately 80% having persistent or recurrent disease.45
While the high frequency of recurrence of intraepithelial neoplasia after therapy in HIV-infected women is concerning, it is important to keep in mind that the only clinically important treatment failure is that which leads to invasive cancer. Invasive cancer occurs rarely in HIV-infected women who are treated for cervical dysplasia. HIV-infected women with dysplasia need careful follow-up after treatment and often need second or third therapeutic procedures. Adjuvant 5-fluorouracil after excisional or ablative therapy for high-grade cervical dysplasia reduced the recurrence at 18 months from 47% to 28% in a randomized, controlled, clinical trial (ACTG 200).46 In this study, women in the treatment arm received 5% 5-fluorouracil cream twice weekly (2 grams per vagina) for 6 months. The 5-fluorouracil not only reduced the frequency of recurrence but also reduced the proportion of recurrences that were high-grade. An additional finding of this study was that women who were receiving antiretroviral therapy had less recurrence, whereas those with lower CD4+ cell counts had more recurrence. Only one of the treated women had signs or symptoms that could definitely be attributed to the 5-fluorouracil. Isotretinoin did not significantly prolong time to progression from LSIL to HSIL in a randomized, controlled trial.47 A randomized, controlled trial of topical 5% imiquimod cream, an immune-response modifier, in treatment of anogenital warts showed some efficacy in a group of mostly males with HIV-infection.48 Several small studies have shown a modest response of high-grade VIN to topical imiquimod.49
|INVASIVE CERVICAL CANCER|
HIV infection is more clearly associated with invasive cervical cancer in studies performed in Europe and the United States than in most studies performed in Africa.50 The association noted could be confounded by factors such as injection drug use or lack of cervical cancer screening among HIV-infected women in the European and American studies.51 The prevalence of cervical cancer among more than 23,000 HIV-infected women in France, Italy, and Spain was 3.2% among those whose mode of HIV acquisition was injection drug use versus 1.8% among those who acquired HIV through sex.52 The CDC has detected no increase in the prevalence of invasive cervical cancer between 1992 and 1997 in their surveillance for AIDS-defining opportunistic illnesses in the United States.53 In contrast, in the United States Cancer Match Registry for 1978 to 1996, there was an increased risk for cervical cancer (RR = 5.5), vaginal and vulvar cancer (OR = .8), and anal cancer (OR = 6.8) among HIV-infected women.54 In the New York State AIDS Registry, the risk for invasive cervical cancer was found to be increased by a relative risk of 6.5 (95% CI: 4.1 to 9.7).55
Maiman and associates reported that HIV-infected women with cervical cancer were more likely to present at advanced clinical stage than were HIV-negative women.56 A review of invasive cervical cancer at two hospitals in New York City showed an HIV seroprevalence of 18%. Sixty-nine percent of HIV-uninfected women had stage I or II compared with 42% of HIV-infected women.57 In a multivariate analysis, risk factors associated with advanced cervical cancer were symptom duration more than 3 months and more than 3 years since last Pap smear. HIV infection was not correlated with advanced cervical cancer (OR = .8; 95% CI: .2 to 3.4). Thus, the advanced stage of cancer seems to reflect behavioral rather than biological factors.
Consideration should be given to counseling for HIV testing of women who have CIN, and those who have invasive cervical cancer and VIN. Most of the available evidence indicates that lower genital tract neoplasia in women with HIV is extremely common and in many cases may be refractory to standard treatment, especially in the presence of severe immunosuppression. Further investigation is needed to clarify optimum methods of screening for and treatment of lower genital tract neoplasia in HIV-infected women. We recommend frequent (semi-annual) Pap screening with colposcopic evaluation if the Pap shows dysplasia or atypia. After several normal Pap results, the screening interval may be increased.
|SEXUALLY TRANSMITTED INFECTIONS|
Epidemiologic synergy describes the mutually amplifying epidemics of sexually transmitted infections (STIs) and HIV.58,59 In particular, the presence of an STI, particularly an ulcerative STI, increases the risk of HIV acquisition of HIV by two-fold to five-fold.58 The proposed mechanisms include the recruitment of HIV target cells, including CD4 cells, Langerhans cells, and macrophages, to the genital tract in the setting of an STI and the disruption of genital mucosa. There is also evidence of increased transmission of HIV in the presence of an STI, likely related to both increased genital viral load and increased plasma load associated with STIs.60 Several studies have now demonstrated that treatment of STIs decreases the likelihood of incident HIV acquisition and transmission.60,61 Mbopi-Kéou and colleagues found an association between HSV-2 DNA and genital HIV-1 RNA levels among co-infected women who shed HSV-2.62,63 Thus, all providers caring for HIV-infected women should obtain a thorough sexual history (including type and number of partners, specific sexual activities, condom and other barrier use, HIV-status of partner(s), reproductive desires, past STIs and current STI symptoms), and undergo routine screening for STIs and treatment as indicated.64 Appropriate STI screening should be guided by a woman's sexual behavior and local epidemiology in addition to standards of care established for HIV-infected individuals.65
Clinical management of STIs among HIV-infected women often differs from that of HIV-uninfected women. For instance, women co-infected with HIV and herpes simplex virus (HSV) may have more persistent and/or recurrent HSV as compared with HIV-negative women.64 Such women often benefit from suppressive therapy with acyclovir or valacyclovir.66 While acyclovir-resistant HSV is uncommon, it should be considered in HIV-infected women with persistent lesions despite adequate antiviral therapy. In such cases, a viral isolate should be obtained for sensitivity testing. Because valacyclovir has the same active metabolite as acyclovir, patients with verified acyclovir-resistant strains should be treated with foscarnet under the supervision of an expert in the field as recommended by the Centers for Disease Control.64 Similarly, HIV appears to alter the clinical course of granuloma inguinale and lymphogranuloma venereum (LGV).
For the treatment of granuloma inguinale among HIV-infected individuals, some experts recommend the addition of parenteral aminoglycoside to the typical 3-week regimen of oral doxycycline or trimethoprim-sulfamethoxazole.64 Similarly, women co-infected with HIV may experience prolonged disease course despite therapy. Treatment includes a 3-week regimen of oral doxycycline, which may need to be extended in cases of protracted LGV.64 However, treatment recommendations for gonorrhea, Chlamydia, trichomonas, pediculosis pubis, and scabies are the same for HIV-infected and uninfected women.64
For most co-infected individuals, HIV does not appear to alter the clinical course of syphilis. Nonetheless, HIV-infected individuals appear to be at slightly increased risk for both neurosyphilis and persistent disease despite treatment, although overall the absolute risk of these events is low.64 The CDC recommends treating HIV-infected patients with primary, secondary, and early latent syphilis with the standard single dose of 2.4 million units of intramuscular benzathine penicillin. In the absence of neurological signs or symptoms, pretreatment cerebral spinal fluid (CSF) assessment is not necessary. Because of the increased risk of treatment failure, it is important to monitor these patients clinically and serologically using a nontreponemal antibody titer at 3, 6, 9, 12, and 24 months after initial treatment. Cases in which nontreponemal titers do not decrease four-fold by 6 months after treatment should be considered treatment failures, undergo a CSF evaluation, and, if normal, treated with weekly benzathine penicillin injections for 3 weeks. Women with late latent or latent syphilis of unknown duration should undergo a pretreatment CSF examination and, if normal, receive weekly benzathine penicillin injections for 3 weeks. These women should be monitored clinically and serologically at 6, 12, 18, and 24 months. Neurological symptoms or a four-fold increase in nontreponemal titers necessitate a repeat CSF evaluation and treatment as indicated. Those women in whom the nontreponemal titer does not decrease by four-fold by 12 months should also undergo a repeat CSF evaluation and treated accordingly. Neurosyphilis may occur at any stage of syphilis. Treatment includes intravenous aqueous crystalline penicillin G 3 to 4 million units every 4 hours for 10 to 14 days. The CSF should be monitored at 6-month intervals until the cell count normalizes.
Hepatitis B (HBV) is a vaccine-preventable STI. Among those with HIV, HBV is more likely to proceed to chronic infection. It is, therefore, particularly important to vaccinate HIV-infected individuals against HBV with the three-part vaccination series over the course of 6 months (0, 1, and 6 months). Because immunization may be impaired in immunocompromised hosts, clinicians should obtain an HBV surface antibody (HBsAb) approximately 1 to 2 months after the third vaccine injection to confirm immunity. Those women found to be nonimmune despite a full series should undergo a second round of three HBV vaccinations with appropriate postvaccination surface antibody confirmation.
As with all STIs, sexual partners of infected patients should be evaluated and treated appropriately. For those clinicians who do not regularly treat STIs, the CDC maintains updated treatment guidelines that are easily accessible.35
|PELVIC INFLAMMATORY DISEASE|
Because HIV and the organisms associated with PID are sexually transmitted, it is not surprising that these conditions are frequently coincident. Because HIV seroprevalence among women with PID ranges from 6.7% to 22%, serologic testing for HIV infection should be offered to women with a diagnosis of PID.67
HIV appears to alter the clinical presentation of PID. Recent studies have noted the following among HIV-infected women with PID when compared with HIV-uninfected women with PID: lower white blood cell counts, higher erythrocyte sedimentation rate, more syphilis, more frequent tubo-ovarian abscesses/adnexal masses, less gonorrhea, less Chlamydia, more bacterial vaginosis, and more plasma cell endometritis.68,69,70,71 The latter findings suggest that there is an impaired defense against ascent of vaginal flora to the upper genital tract in HIV-infected women. These data also suggest that an antibiotic regimen with strong anaerobic coverage would be optimal for treatment of PID in HIV-infected women. While these studies suggest a more severe presentation of PID among HIV-infected women, the prospective studies show little difference in response to antibiotic treatment (combined with drainage of abscesses greater than 4 cm in some of these studies) compared with HIV-uninfected women. Outpatient treatment of PID has been used with success in HIV-infected women.68,69,70,71 However, some degree of caution is in order in caring for HIV-infected women with PID; there is a significant minority among them (approximately 15%) who will require surgical means to diagnose or treat their infections. Inpatient treatment is indicated for a woman with PID who would be unlikely to adhere to a regimen of outpatient therapy.
The available data suggest that the clinical course of PID may be altered by symptomatic HIV infection and that such patients have blunted local immune defenses, resulting in slower or inadequate response to medical therapy. The current data support the use of the antibiotic treatment recommendations published by the CDC.35 We recommend vigilance for treatment failure in patients with severe immunosuppression and suggest use of antibiotic regimens with optimal anaerobic coverage in this group.
HIV-immune suppression can impact on frequency and/or severity of vaginal infections. In turn, these infections could influence HIV acquisition/transmission by several mechanisms, including altering HIV shedding, increasing inflammatory cells in the cervico/vaginal epithelia, or by adverse effects on protective vaginal microflora. Vaginal isolates of Candida albicans from HIV-infected women produce higher levels of secretory aspartyl proteinase, a virulence enzyme, than do those of HIV-uninfected women.72 A recent study from Providence, Rhode Island showed an association of HIV-RNA levels in cervico-vaginal secretions with bacterial vaginosis (BV) but not with Candida albicans infections.73 In contrast, a study performed in Mombassa, Kenya showed a decrease in cell-associated and cell-free HIV after treatment of Candida vaginitis, a decrease only in cell-free HIV after treatment of trichomonas vaginalis, and no effect on cell-free or cell-associated HIV after treatment of BV.74 In this report, the most significant decrease in genital-tract HIV occurred in women with Candida who had vulvar erythema and in women with trichomonas who had more than 10 neutrophils per high-power field on vaginal Gram stain.
Bacterial vaginosis has been associated with HIV seropositivity.59 With BV, the vagina has a higher pH, which is more favorable to HIV than the normal acidic pH. It is unclear whether bacterial vaginosis may increase female susceptibility to heterosexual transmission of HIV, whether immunosuppression may lead to increased susceptibility to bacterial vaginosis, or both.
Lower genital tract mucosal inflammation caused by trichomonas vaginalis infection could lead to increased shedding of HIV in seropositive women and increased susceptibility to infection with HIV in seronegative women. To date, studies show an inconsistent association between trichomonal infection and HIV.59 A study from South Africa showed an association between trichomonas vaginalis and a clinical diagnosis of PID in HIV-infected women.75 The authors postulated that proteases produced by trichomonas might degrade the cervical mucous barrier-facilitating ascent of microorganisms into the upper genital tract.
Prevalence and Incidence
The association between HIV infection and vaginal candidiasis is debated.76,77 A prospective cohort of HIV-infected and uninfected women showed no difference in prevalence of vaginal Candida albicans colonization, unless there was immunosuppression, in which case the rates of colonization and symptomatic infection tripled.78 The proportion of nonalbicans isolates did not differ among groups. In this study, candida colonization was not associated with antibiotic or oral contraceptive use. In contrast, in a cross-sectional study of patients referred to a vaginitis clinic, HIV was associated with nonalbicans Candida infection.79 In a 2-year follow-up study, there was a very slow incremental increase in nonalbicans yeast (mostly Candida glabrata) isolated from the vaginas of HIV-infected women.80 In this study, the HIV-infected women reported recent vaginal candidiasis approximately 50% more often than did the HIV-uninfected women. A large prospective study (HERS) with 4.5 years of follow-up showed a significantly higher incidence of vulvovaginal candidiasis among HIV-infected than among uninfected women.81 The 4.5-year cumulative frequency of vaginal candidiasis in the HIV-infected cohort who did not have VVC at the baseline visit was as high as 64.5% depending on how VVC was defined. The risk of acquiring VVC was elevated among women who had severe immunosuppression with CD4+ cells less than 200 cells/μL and for those with elevated HIV viral load. In addition, systemic antifungal use and older age were associated with reduced risk of VVC, whereas diabetes and pregnancy were most strongly associated with increased risk of VVC. Interestingly, antibacterial drug use did not increase the risk of VVC. In this study, VVC was more likely to persist among HIV-infected women but was no more severe than VVC in HIV-uninfected women. There is no evidence from controlled studies that the severity or clinical presentation of vaginal candidiasis is different in HIV-infected compared with HIV-uninfected women.
In a large cross-sectional study, there was a similar prevalence of trichomonas vaginalis and bacterial vaginosis among the HIV-infected and uninfected participants and no association with CD4+ cell count.82 A longitudinal study showed a higher prevalence and more persistence of BV among HIV-infected women than HIV-uninfected women.83 In this study, prevalence and severity, but not incidence, of BV were correlated with degree of immunosuppression.
When vaginal candidiasis is encountered in HIV-infected women, a variety of treatment options are available. These include topical antifungal agents such as clotrimazole, miconazole, terconazole, boric acid vaginal suppositories (600 mg twice daily for 2 weeks) and single-dose, oral fluconazole. For immunosuppressed women who have recurrent vaginal candidiasis, fluconazole (200 mg/week) is an effective means of prophylaxis.84 Unfortunately, there is evidence that this regimen leads to an increase in vaginal colonization with nonalbicans yeast85 and an increase in the proportion of fluconazole-resistant nonalbicans yeast over time.80 The decision to use long-term fluconazole, especially for primary prophylaxis, must be carefully considered because of the risk of development of resistance, the effectiveness of therapy for acute disease, the negligible incidence of serious invasive disease, and the possibility of drug–drug interactions.86 Clotrimazole powder (100-milligram capsules) used intravaginally once weekly reduced the rate of vaginal candidiasis in a cohort of HIV-infected women.87
A prospective study showed no difference in the treatment outcome of trichomonas but a significant decrease in cure rates of bacterial vaginosis among HIV-infected compared with HIV-uninfected women.88
Vaginal infections play an important role in transmission of HIV. Treatment of vaginal Candida infections can be challenging in HIV-infected women. Antifungal prophylaxis may be necessary but should be administered judiciously.
A key element of providing care to an HIV-infected woman includes reproductive counseling with provision of contraception or preconception care. Most studies have found that individuals continue to be sexually active after receiving an HIV diagnosis.89,90,91,92,93,94 The reasons individuals and couples decide to use contraception, conceive, and continue or terminate a pregnancy are complex, particularly in the setting of HIV.91,95,96,97,98,99,100,101
While consistent hormonal contraception allows excellent pregnancy prevention, there are several issues relevant to the HIV-infected woman. Hormonal contraception appears associated with increased genital shedding of HIV-1.102,103,104 Mostad and colleagues found an association between hormonal contraceptives and cervical HIV-1 shedding.104 In particular, this study detected a significant association between cervical HIV-1 shedding and high-dose oral contraceptives (50 μg estradiol) (adjusted odds ratio [aOR]: 12.3; 95% CI: 1.5 to 101), low-dose oral contraceptives (aOR: 3.8; 95% CI: 1.4 to 9.9), and depot medroxyprogesterone acetate (DMPA) (aOR: 2.9; 95% CI: 1.5 to 5.7). More recently, Baeten reported an association between DMPA and both a higher baseline viral load and increased viral diversity.105 As a result, HIV-infected women using DMPA may be at increased risk for faster progression of HIV disease, although this has not been definitively studied. While no studies have evaluated Norplant and HIV shedding in humans, Marx and associates noted an increase in simian immunodeficiency virus (SIV) DNA-positive cells in the vaginal lamina propria of infected macaques with subcutaneous progesterone implants.106
In addition to biological implications, there may be behavioral consequences of hormonal contraceptives among HIV-infected women. Women using hormonal contraception, regardless of their HIV status, are often less likely to concurrently use condoms. Not surprisingly, one study found that HIV-infected women using oral contraceptives were significantly less likely to use condoms, putting them at risk for acquiring STIs and transmitting HIV to uninfected partners.107
Lastly, there are interactions between ethinyl estradiol (EE)/norethindrone acetate (NE) and some of the antiretrovirals. In particular, amprenavir, atazanavir, efavirenz, and indinavir all appear to increase levels of EE/NE.108 However, lopinavir/ritonavir, nelfinavir, nevirapine, and ritonavir decrease levels of EE/NE, likely by inducing CYP450 metabolism.108,109,110 There is also limited evidence that EE/NE may alter levels of antiretrovirals. Concurrent administration of 0.035 mg EE and 1 milligram NE with amprenavir 1200 milligram twice daily for 1 month, for instance, is associated with decreased levels of amprenavir.108
While there are theoretical concerns of the use of an intrauterine device (IUD) among HIV-infected women, no study has found an increase in viral shedding or incident infections associated with its use.111 Among 98 HIV-infected women in Kenya, there were no differences in HIV-1 DNA cervical shedding before and after IUD insertion.112 Sinei and associates found no significant differences in overall complications, incident pelvic inflammatory disease, and overall infection-related morbidity between 156 HIV-infected and 493 HIV-uninfected women who underwent IUD insertion.113 While it is often difficult to find the ideal method of contraception for any woman, it is crucial to assist the HIV-infected woman in weighing the risks and benefits of all options and choosing a realistic method for her circumstances.114
Often overlooked is an HIV-infected woman's desire to conceive.115 Because people with HIV are living longer, healthier lives, and because antiretroviral therapy has dramatically decreased the likelihood of vertical transmission, some HIV-infected women choose to conceive.96,97 As with all women with chronic medical conditions, ideal pregnancies are planned while in care of a medical provider. While optimizing the HIV-specific needs of infected women is clearly outside the realm of most gynecologists, there are several issues that obstetricians/gynecologists can and should address with their HIV-infected patients considering pregnancy. Goals of preconception care include identifying risk factors for adverse maternal and neonatal outcomes, treating and stabilizing medical conditions and psychosocial problems before conception, and providing patient-specific health education. In particular, medications should be reviewed and teratogenic agents discontinued or changed. Medications with teratogenic potential include the antiretrovirals efavirenz and amprenavir and lipid-lowering agents such as HMG-CoA reductase inhibitors.116,117,118 Additionally, women using stavudine and/or didanosine should switch to another antiretroviral regimen, if possible, given the association between these medications and fatal maternal lactic acidosis.119,120,121,122,123 In addition to optimizing the medication profile, it is important to confirm that all vaccination series are up-to-date. Both hepatitis A and hepatitis B vaccines are safe among HIV-infected individuals. While measles-mumps-rubella (MMR) is a live-attenuated vaccine, the Advisory Committee on Immunization Practices (ACIP) recommends MMR vaccination for all susceptible, asymptomatic HIV-infected individuals in the absence of severe immunosuppression.124 There are limited data on the safety of varicella vaccination in the setting of HIV. Brady and associates reported on the safety of varicella vaccine among HIV-infected adults with CD4+ cell counts more than 400 who had been previously infected with varicella-zoster virus.125 There are no data specifically addressing the safety and efficacy of varicella vaccination in HIV-infected, susceptible women in the preconception period. Clearly, the provision of high-quality preconception care requires eliciting a thorough sexual and reproductive history, including goals for conception.
There is a growing body of literature addressing the ethics and science of providing assisted reproduction techniques to HIV-infected women and HIV-serodiscordant couples, both for infertility treatment and for HIV transmission prevention.126,127,128,129 Reasons for withholding infertility treatment among HIV-infected women and affected couples include the life-threatening nature of HIV and the unacceptably high risk of HIV transmission to the infant. In recent years, however, HIV has evolved into a chronic medication condition and transmission risk is less than 1% among women with maximally suppressed virus at the time of delivery.130 Infertility management is typically not withheld from women with other chronic conditions, such as diabetes, hypertension, and lupus, that may have more significant implications for the health of the woman or baby. Similarly, couples known to be carriers of autosomal recessive diseases, such as cystic fibrosis, Tay-Sachs and sickle-cell anemia, have at least a 25% chance of transmitting this condition, which is significantly higher than that for HIV.
Furthermore, there is evidence that assisted reproductive therapy, such as sperm washing with intrauterine insemination (IUI) or in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI), may decrease the risk of HIV acquisition in HIV-uninfected women attempting pregnancy with HIV-infected male partners.131,132,133,134,135,136,137,138 Several clinical programs, most notably in Europe and New York, offer these techniques to discordant couples to increase the likelihood of conception with HIV transmission to the uninfected woman. To date, more than 2800 sperm washing per IUI cycles have been performed on nearly 1100 patients, leading to 470 pregnancies and no cases of perinatal HIV transmission.133,134,135,139,140,141,142,143 Similarly, 93 cycles of IVF have been performed on 75 patients, resulting in 28 pregnancies and no cases of HIV transmission.140,143 Moreover, nearly 250 cycles of IVF-ICSI have been performed on 164 patients with 90 resultant pregnancies and, again, no cases of HIV transmission.136,138,140,143
Recently, the Ethics Committee of the American Society for Reproductive Medicine stated, “Unless health care workers can show that they lack the skill and facilities to treat HIV-positive patients safely or that the patient refused reasonable testing and treatment, they may be legally as well as ethically obligated to provide requested reproductive assistance.”144
Menstrual abnormalities are prevalent among women infected with HIV.145,146,147,148,149 It is not clear, however, whether HIV, per se, is a risk factor for such disorders. Several studies have found no difference in menstrual patterns between HIV-infected and uninfected women.147,150 However, one study demonstrated a higher prevalence of amenorrhea among 248 HIV-infected versus 82 high-risk HIV-uninfected women, after adjusting for age, ethnicity, and drug use (aOR: 7.1; 95% CI: 1.1 to 1000).145 Another study found a higher frequency of amenorrhea among HIV-infected women with late wasting (38%), defined as less than 90% ideal body weight, as compared with infected women without wasting (17%).151 In the large combined HERS and WIHS prospective cohorts, polymenorrhea, defined as fewer than 19 days between cycles, was seen more often among HIV-infected women (aOR: 1.45; 95% CI: 1.00 to 2.11) as compared with HIV-uninfected women, adjusting for age, ethnicity, body mass index, psychotropic medication, and drug use.150 Polymenorrhea was particularly evident among women with HIV viral load values above 168,000 copies/mL. A separate analysis of the same cohort found an independent association between psychotropic medication and both amenorrhea and polymenorrhea.152 Not surprisingly, they also found an association between both methadone maintenance and injection drug use and amenorrhea. Regardless of whether HIV is independently associated with menstrual disorders, prevalence of such menstrual irregularities is high; therefore, it is crucial to inquire about menstrual function among HIV-infected women seeking care.
|OSTEOPENIA AND OSTEOPOROSIS|
There is a growing body of literature addressing metabolic alterations among HIV-infected individuals. While most of the attention has focused on changes in central fat accumulation and peripheral subcutaneous fat loss, researchers are now turning their attention to altered bone metabolism.153,154,155,156,157,158 Some authors report an association between HIV and diminished bone density.159 Other authors attribute this apparent bone loss to antiretroviral therapy, most likely protease inhibitors, not HIV infection.160,161 The epidemiology of osteopenia and osteoporosis among HIV-infected women is a rapidly evolving field and much of the research thus far has generated more questions than answers. Nonetheless, as HIV-infected women live longer lives and more of these women reach menopause, the clinical management of osteopenia and osteoporosis in this population will become only more relevant.
Recent well-designed prospective studies have shed some light on the interactions between HIV and gynecological diseases, but our understanding is far from complete. The most significant challenges ahead seem to be the development of microbicidal agents that could prevent HIV transmission and development of better treatment methods for lower genital tract neoplasia. Gynecological diseases are frequently encountered when caring for HIV-infected women, especially those with greater degrees of immunosuppression. Most gynecological conditions in HIV-infected women will respond to standard therapy but require increased vigilance for treatment failure. Some will require multiple courses of treatment or use of innovative treatment methods. All HIV-infected women deserve careful evaluation for and treatment of gynecological diseases.
5. Watts DH, Spino C, Zaborski L, et al: Comparison of gynecologic history and laboratory results in HIV-positive women with CD4+ lymphocyte counts between 200 and 500 cells/microl and below 100 cells/microl. J Acquir Immune Defic Syndr Hum Retrovirol 20:455-462, 1999
16. Massad LS, Ahdieh L, Benning L, et al: Evolution of cervical abnormalities among women with HIV-1: Evidence from surveillance cytology in the women's interagency HIV study. J Acquir Immune Defic Syndr 27:432-442, 2001
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39. La Ruche G, Leroy V, Mensah-Ado I, et al: Short-term follow up of cervical squamous intraepithelial lesions associated with HIV and human papillomavirus infections in Africa. Int J STD AIDS 10:363-368, 1999
48. Gilson RJ, Shupack JL, Friedman-Kien AE, et al: A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. Imiquimod Study Group AIDS 13:2397-2404, 1999
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73. Cu-uvin S, Hogan JW, Caliendo AM, et al: Association between bacterial vaginosis and expression of human immunodeficiency virus type 1 RNA in the female genital tract. Clin Infect Dis 33:894-896, 2001
75. Moodley P, Wilkinson D, Connolly C, et al: Trichomonas vaginalis is associated with pelvic inflammatory disease in women infected with human immunodeficiency virus. Clin Infect Dis 34:519-522, 2002
80. Sobel JD, Ohmit SE, Schuman P, et al: The evolution of Candida spp And fluconazole susceptibility among oral and vaginal isolates recovered from human immunodeficiency virus (HIV) seropositive and at-risk HIV-seronegative women. J Infect Dis 183:286-293, 2000
81. Duerr A, Helig CM, Meikle SF, et al: Incident and persistent vulvovaginal candidiasis among human immunodeficiency virus-infected women: Risk factors and severity. Obstet Gynecol 101:548-556, 2003
82. Greenblatt RM, Bacchetti P, Barkan S: Lower genital tract infections among HIV-infected and high-risk uninfected women. Findings of the Women's Interagency HIV Study (WIHS) Sex Transm Dis 26:143-151, 1999
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91. Wilson TE, Massad LS, Riester KA, et al: Sexual, contraceptive, and drug use behaviors of women with HIV and those at high risk for infection: Results from the Women's Interagency HIV Study. AIDS 13:591-598, 1999
92. Zierler S, Mayer K, Moore J, et al: Sexual practices in a cohort of US women with and without human immunodeficiency virus. HERS Study. HIV Epidemiology Research Study J Am Med Womens Assoc 54:79-83, 1999
99. Wilson TE, Minkoff H: Brief report: Condom use consistency associated with beliefs regarding HIV disease transmission among women receiving HIV antiretroviral therapy. J Acquir Immune Defic Syndr 27:289-291, 2001
104. Mostad SB, Overbaugh J, DeVange DM, et al: Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet 350:922-927, 1997
105. Baeten JM: The influence of vitamin A and hormonal contraception on HIV transmission and disease progression in women: Abstract #116. 10th Conference on Retroviruses and Opportunistic Infections. Boston 2003
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109. Mildvan D, Yarrish R, Marshak A, et al: Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-infected women. J Acquir Immune Defic Syndr 29:471-477, 2002
124. Measles, mumps, and rubella–Vaccine use and strategies for elimination of measles, rubella and congenital rubella syndrome and control of mumps. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 47:1-57, 1998
125. Brady KA, Levin M, Weinberg A, et al: Safety and immune response to varicella vaccine in HIV-infected adults previously infected with varicella. 9th Conference on Retroviruses and Opportunistic Infections. Seattle 2002
130. Shapiro DE, Tuomala R, Samelson R, et al: Mother-to-Child HIV Transmission Rates According to Antiretroviral Therapy, Mode of Delivery, and Viral Load (PACTG 367): Abstract #114. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA. 2002
131. Sauer MV, Chang PL: Establishing a clinical program for human immunodeficiency virus 1-seropositive men to father seronegative children by means of in vitro fertilization with intracytoplasmic sperm injection. Am J Obstet Gynecol 186:627-633, 2002
136. Loutradis D, Drakakis P, Kallianidis K, et al: Birth of two infants who were seronegative for human immunodeficiency virus type 1 (HIV-1) after intracytoplasmic injection of sperm from HIV-1-seropositive men. Fertil Steril 75:210-212, 2001
137. Marina S, Marina F, Alcolea R, et al: Human immunodeficiency virus type 1–serodiscordant couples can bear healthy children after undergoing intrauterine insemination. Fertil Steril 70:35-39, 1998
141. Pasquier C, Daudin M, Righi L, et al: Sperm washing and virus nucleic acid detection to reduce HIV and hepatitis C virus transmission in serodiscordant couples wishing to have children. AIDS 14:2093-2099, 2000
142. Tur R, Buxaderas C, Martinez F, et al: Comparison of the role of cervical and intrauterine insemination techniques on the incidence of multiple pregnancy after artificial insemination with donor sperm. J Assist Reprod Genet 14:250-253, 1997
145. Chirgwin KD, Feldman J, Muneyyirci-Delale O, et al: Menstrual function in human immunodeficiency virus-infected women without acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr Hum Retrovirol 12:489-494, 1996
149. Clark RA, Mulligan K, Stamenovic E, et al: Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis 184:1325-1327, 2001
152. Harlow SN SD, Cohen M, Ohmit SE, et al: Substance use and psychotherapeutic medications: A likely contributor to menstrual disorders in women who are seropositive for human immunodeficiency virus. Am J Obstet Gynecol 188:881-886, 2003
159. Aukrust P, Haug CJ, Ueland T, et al: Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: Indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab 84:145-150, 1999
160. Tebas P, Powderly WG, Claxton S, et al: Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. Abstract #114. 7th Conference on Retroviruses and Opportunistic Infections. Alexandria, VA 2000
161. Hoy J, Hudson J, Law M, et al: Osteopenia in a randomized, multicenter study of protease inhibitor substitution in patients with the lipodystrophy syndrome and well-controlled HIV viremia. Abstract #208. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco 2000