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Home > Knowledge Base > Cervical Neoplasia
Clinical Management of Lower Genital Tract Neoplasia among Women with HIV
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Introduction
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HPV Infection and Progression of Dysplasia in Women with HIV
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transparent imageImmunosuppression and HPV Prevalence
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transparent imageHPV Expression and Types
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transparent imageCofactors for HPV Infection
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transparent imageIncidence, Persistence, and Progression of HPV Infection
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transparent imageMultifocal Disease
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transparent imageCervical Cancer
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transparent imagePapanicolaou Smear Screening
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transparent imageAdherence to Screening and Follow-Up
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Clinical Management
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transparent imageCervical Papanicolaou Smears in HIV-Infected Women
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transparent imageTreatment of Genital Warts
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transparent imageHPV DNA Screening
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Monitoring and Treatment of Cervical SIL
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transparent imageMonitoring of ASCUS and LSIL
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transparent imageTreatment of HSIL
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transparent imageManagement of Abnormal Papanicolaou Smear Results in Pregnancy
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transparent imagePatient Education
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Conclusions
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References
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Introduction
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Cervical cancer, an AIDS-defining condition, is the culmination of a series of detectable and treatable stages of neoplasia caused by human papillomavirus (HPV). Screening for HPV infection and for the development of squamous intraepithelial lesions (SIL) therefore is one of the most important gynecologic issues for HIV-infected women. SIL can be persistent, multifocal, and progressive in nature, especially among women with immune suppression. Findings from natural history studies involving large cohorts of women such as the Women's Interagency HIV Study (WIHS) and HIV Epidemiology Research Study (HERS) provide insight into the clinical course of HPV among HIV-infected women. This chapter will review current information and offer guidance for the clinical management of lower genital tract neoplasia among women with HIV.

HPV is the most common sexually transmitted infection. Epidemiological studies suggest that more than 60% of sexually active women will become infected with HPV in their lifetime.(1) The number of lifetime sexual partners consistently has been shown to be a risk factor for the acquisition of HPV.(1) Most HPV infections are subclinical and do not manifest with clinical signs or symptoms such as venereal warts or abnormal results from Papanicolaou smears.

More than 120 types of HPV have been identified, and about 40 of those infect the anogenital tract.(2) Low-risk types such as type 6 and type 11 are found in benign lesions such as genital warts (condylomata acuminata) and low-grade SIL (LSIL). There are approximately 15 high-risk or oncogenic types of HPV(3) with types 16, 18, 31, and 45 accounting for 80% of cancers.(4) Most HPV infections appear to clear spontaneously although, theoretically, they may remain latent at undetectable levels.(2) Persistence of oncogenic HPV types is the critical factor leading to development of precancerous lesions.(5) In addition, it is likely that cofactors such as impaired cell-mediated immunity, smoking, multiparity, long-term oral contraceptive use, and presence of other sexually transmitted infections or inflammation contribute to carcinogenesis in conjunction with HPV.(6) Nutritional factors may play a role in the development or prevention of cervical cancer but their role has not been elucidated completely.(7) Specifically, carotenoids and tocopherols may have a protective effect in the prevention of early carcinogenesis, but well-designed prospective trials are needed to confirm this.(8)

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HPV Infection and Progression of Dysplasia in Women with HIV
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Immunosuppression and HPV Prevalence
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The prevalence of HPV infection among HIV-infected women is higher than it is among uninfected women, and is associated with degree of immune suppression. The HERS, which compared 767 HIV-infected women with 390 women at risk for HIV infection, found that women with HIV were more than twice as likely as women without HIV to have HPV (64% vs 28%, respectively).(9) High HIV viral loads and low CD4 cell counts among women with HIV also were associated with HPV infection. Data from the WIHS cohort and other studies have shown a strong association between HIV viral load and CD4 count and both prevalent and incident HPV infection.(10,11)

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HPV Expression and Types
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HIV-infected women also are more likely to have a high level of HPV viral expression and to be infected with HPV of multiple types.(12,13,14) Both of these conditions are associated with risk of SIL. Specifically, higher HPV type 16 DNA loads have been found to be associated with both LSIL and high-grade SIL (HSIL) in women with HIV.(15) In a study of 225 HIV-infected women followed over 56 months, 81% were found to be HPV positive at some point, and 52% were infected with more than 2 types.(16) Being infected with multiple HPV types increased the risk of SIL and persistence of HPV infection. In a European study, HIV-infected women were found to have a high prevalence of high-risk HPV types (68%) and SIL (26%).(17) HIV-infected women also have been found to have rarer types of HPV compared with HIV-uninfected women.(12)

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Cofactors for HPV Infection
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Other factors found to be associated with an increased incidence and prevalence of HPV infection are bacterial vaginosis (18) and smoking.(19) Having bacterial vaginosis or trichomoniasis may increase the risk of acquisition, or induce reactivation, of HPV. A positive vaginal culture for Candida was associated with HPV infection in the HERS cohort.(9) WIHS data showed that HIV-infected women had many of the same risk factors for HPV infection as did HIV-negative women, including African American ethnicity, smoking, and young age.(11)

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Incidence, Persistence, and Progression of HPV Infection
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Women with HIV are more likely than HIV-negative women to have new HPV infections, persistent HPV infection with an oncogenic type of HPV, and progression of SIL.(20) In one study, the cumulative prevalence of HPV infection after 3 years of follow-up was 90% among HIV-infected women with CD4 counts <200 cells/µL and 55% among HIV-negative women.(13) In the HIV-infected women, persistence of HPV infection was 1.9 times greater if the CD4 count was <200 cells/µL vs a CD4 count >500 cells/µL, underlining the relationship between immune suppression and HPV persistence. The increased incidence as well as prevalence of HPV infection among HIV-positive women, especially those without recent sexual activity, suggests reactivation of HPV, particularly in those with more severe immune suppression.(10) The inability to determine whether the HPV detected in these studies represents persistent infection, reinfection, or reactivation of previous infection is a challenging aspect of conducting research in this area.

Early studies pointed to the relationship between immune deficiency and the increased development of SIL.(21,22) The prevalence of abnormal Papanicolaou smear results in one study was 33%, 4.3-fold higher than in uninfected women.(23) These findings have been further supported in more recent studies. The WIHS monitored women every 6 months for up to 5 years and found 73% of the HIV-infected women (n = 1,639) vs 42% of HIV-negative women (n = 452; p < .001) had at least 1 abnormal Papanicolaou smear result showing atypical squamous cells of undetermined significance (ASCUS ) or higher-grade lesion.(24) Only 5.9% were ever found to HSIL, but slightly higher rates of HSIL have been reported in other studies.(23,25) Progression was more likely to occur among the women who were the most immune compromised. Similarly, in the HERS, SIL were 3.9 times more common among HIV-infected women (n = 709) than noninfected high-risk women (n = 341).(26) In addition, SIL were more likely to occur in conjunction with high- and intermediate-risk HPV types as well as with greater immune suppression. Other studies also have shown that SIL was associated with decreased CD4 count and increased HIV viral load.(14,27,28) More recent data from the WIHS give us additional insight into the role of immune suppression in the development of SIL.(29) At 2 years, the rate of SIL was similar (4% and 3%, respectively) among HIV-positive women with CD4 counts >500 cells/µL (n = 855) and HIV-negative women (n = 343) if baseline cytology was normal and HPV test results were negative. None of the HPV-negative women developed HSIL within 3 years. The development of SIL is more common among HIV-positive women than HIV negative-women infected with HPV, and the development of HSIL among HIV-infected women appears to be related to degree of immune suppression.

The apparent role of antiretroviral therapy (ART) in the progression or regression of SIL differs from one study to another. Women on combination ART who participated in the WIHS, especially those women with higher CD4 counts, were found to have increased regression of SIL.(30) Before the introduction of effective ART regimens, the rate of regression in this cohort was 0%, and after these regimens were introduced it increased to 12.5%. In a prospective study of 168 HIV-infected women, SIL regressed in 40%, with the probability of regression greater in HSIL than in LSIL.(31) The rate of regression was found to be twice as high for women on ART when there was an increase in CD4 count. Similarly, earlier WIHS data showed that women on combination ART were 40% more likely to demonstrate regression and less likely to have progression.(32) In contrast, 2 studies found that, although HPV infection and development of SIL were inversely related to CD4 count, there was no relationship with ART use.(17,25) There are a number of factors to take into account when considering these conflicting results. It is probably not just taking ART but improvement in immune status that affects the course of SIL among HIV-infected women. In some earlier studies, use of combination ART may have been a marker for later-stage disease; women on ART regimens were sicker and had lower CD4 counts. Aspects of ART use that should be considered when measuring its impact on SIL progression or regression include the timing and duration of therapy in relation to SIL status, adherence to therapy, and level of antiretroviral resistance.

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Multifocal Disease
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HPV infection and the development of SIL in the lower genital tract have a greater propensity to be multifocal among women with HIV infection, and may involve the vaginal, vulval, and perianal areas in addition to the cervix. Women with HIV infection have a greater prevalence of genital warts and infection with HPV types 11 and 16, especially with increasing immune deficiency.(33) In a review of the literature, lower genital tract neoplasia was found to be multifocal in 28-50% of women with HIV.(34) This study combined data from the WIHS and HERS cohorts and found rates of genital warts were 3.2 and 2.7 times higher among HIV-infected women in the WIHS and HERS, respectively. The prevalence of HPV types 11 and 16 was 5.6 and 3.6 times higher among HIV-infected women in the WIHS and HERS, correspondingly. In the WIHS cohort, the incidence of genital warts was 1.31 vs 5.01 per 100 person-years among seronegative and seropositive women, respectively.(35) In addition, the incidence of vulvar intraepithelial neoplasia (VIN) was 1.1 vs 4.67 per 100 person-years among seronegative and seropositive women, correspondingly. Abnormal cervical cytology was the strongest predictor of VIN, illustrating that women with cervical disease are likely to have disease in other locations in the genital tract. It is notable that ART use did not alter the course of high-grade VIN among this cohort of women. One study found that, of 8 patients examined with high-resolution anoscopy, all of the women had previous treatment for cervical SIL and 5 had high-grade VIN.(36) In a recent literature review, 9 cases of vulvar cancer among HIV-infected women were reported, and 8 of the 9 cases were in women under age 40.(37) Anal SIL is a significant problem for women with HIV disease as well and this is discussed further in the HIV InSite Knowledge Base chapter "Anogenital Neoplasia and HIV." In one study, the incidence of abnormal anal cytology was 22 per 100 person-years.(38) Factors associated with increased risk for abnormal anal cytology included CD4 count <500 cells/µL, infection with high-risk anal HPV types, and smoking. The multifocal nature of lower genital tract neoplasia emphasizes the importance of conducting a comprehensive examination of the entire anogenital tract in women with HIV.

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Cervical Cancer
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Invasive cervical cancer (ICC) is an AIDS-defining condition, and tends to be more advanced at diagnosis and more likely to persist or recur in HIV-infected women.(39) The recurrence rate was 88% (n = 28) in one study.(40) A study in New York City showed a 24-month survival rate after a diagnosis of cervical cancer of 64% vs 79% for women without HIV infection.(41) Infection with an oncogenic type of HPV is critical to the development of ICC.

A study linking AIDS and cancer registries in the United States found the incidence of ICC to be 8.8 times higher in women with AIDS than in the general population.(42) The incidence of ICC in the general population is 8.9 per 100,000 persons.(43) The incidence for ICC was 1.2 per 1,000 person-years among HIV-infected women in both the WIHS and HERS.(44,45) The incidence of ICC increased among Italian women with AIDS from 1.5% in 1993-1996 to 2.4% in 1997-1998.(46) It may be that the cervical cancer incidence in HIV studies such as the WIHS and HERS is even lower than expected because the participants receive the frequent monitoring, which leads to the identification and treatment of precancerous conditions before ICC can occur.

Surprisingly, no clear association has been found between immune status and the development of ICC. For instance, although the overall risk for HPV-associated invasive and in situ anogenital cancers was increased among women and men with HIV, invasive cancers did not increase during the 10 years spanning the onset of AIDS in the group studied.(47) This suggests that immune status did not play a significant role in late-stage cancer invasion. In the HERS cohort, all of the women with ICC had CD4 counts >200 cells/µL.(45) Another study found that CD4 count was not related to the cervical cancer rate.(42) Two other studies showing an increase in the incidence of ICC did not find that effective ART had made any impact.(48,49) Further research is needed to delineate the clinical course of ICC among women with HIV and AIDS. It may be that the development of ICC has more to do with host factors in relation to HPV oncogenesis than with immune suppression and HIV disease.

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Papanicolaou Smear Screening
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Although questions have been raised about the utility of this method, Papanicolaou smear screening is an adequate tool for detecting cytologic changes in women with HIV, a group at increased risk for SIL. Compared with biopsy as a standard, the sensitivity and specificity of Papanicolaou smear cytology for HSIL were 83% and 74%, respectively, in 248 women with HIV.(23) In another study with 398 HIV-infected women, the sensitivity of cytology was 81% and the specificity was 87%.(50) In the HERS cohort, the sensitivity for abnormal cytology on Papanicolaou screening was 87% for HIV-infected women and 94% for HIV-negative women (not statistically significant).(51) The specificity was 66% for HIV-infected women and 88% for HIV-negative women (p < .01). The positive predictive value (PPV) was 36% vs 28% (not statistically significant) for HIV-infected and HIV-negative women, respectively. These recent data suggest that the accuracy of Papanicolaou smear screening is similar in HIV-infected and HIV-uninfected women.

Concerns have been raised about discordance between cervical cytology and biopsy results among women with HIV. In a study examining the cytologic and histologic samples of a cohort of HIV-infected women with LSIL, the cytology and histology were discordant in 39%.(52) The sensitivity of cytology for HSIL was only 19%, suggesting that follow-up cytology is unreliable and that colposcopy and biopsy are warranted. In contrast, when Papanicolaou smear, colposcopy, and biopsy results were compared in the WIHS with a much larger sample of women, the PPV of cytology was 72% for HIV-positive women and 60% for HIV-negative women.(53) The PPV of colposcopy was 71% for HIV-positive women and 55% for HIV-negative women. The correlations among cytology, colposcopy, and biopsy were poor for both infected and uninfected women. In the HERS, 189 HIV-infected and 95 HIV-negative women with normal Papanicolaou smear results had biopsies, and agreement between cytology and histology was high.(51) Women with HIV were significantly more likely than uninfected women (14% vs 1%, respectively) to have SIL on biopsy when the Papanicolaou smear was normal. All but 2 of these biopsies showed LSIL. Predictors of discordant findings were detection of HPV and CD4 count <500 cells/µL. Of note, 95% of the women had abnormal Papanicolaou smear results within 1 year of the discordant results, suggesting that current guidelines recommending Papanicolaou screening of women with HIV on an annual basis are adequate for the detection of SIL.

In a recent study, there was no statistically significant difference in the number of SIL detected using liquid-based cytology compared with conventional smears among HIV-infected women. There may be a higher likelihood of finding significant SIL on follow-up after detection of ASCUS on liquid-based cytology, reinforcing the need for colposcopy in all HIV-infected women with ASCUS detected by any cytologic method.(54)

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Adherence to Screening and Follow-Up
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Cervical cancer is a preventable disease if women receive regular screening and timely follow-up and treatment after an abnormal Papanicolaou smear result. A national survey distributed by the HIV Cost and Service Utilization Study found that 81% of HIV-infected women had obtained a Papanicolaou smear within the past 12 months.(55) Women who received primary care and gynecologic care at same site were almost twice as likely to have had Papanicolaou smears. Of the women who reported abnormal results, 15% had not received their repeat Papanicolaou smear or colposcopy. Among the general population, nonadherence rates for follow-up of abnormal Papanicolaou smear results range from 15% to 42%.(56) In the WIHS cohort, nonadherence to colposcopy follow-up was 36% for HIV-infected women and 27% for uninfected women (p = .188).(57) Women were less likely to adhere if they had substance abuse or domestic violence issues. In one study, 63% of the HIV-infected patients who had carcinoma in situ did not return for a follow-up Papanicolaou smear.(58) A qualitative study involving HIV-infected women with abnormal results found 5 key factors affecting follow-up: fear, the asymptomatic nature of the problem, life circumstances, participant perspectives on health, and provider qualities such as "trustworthy," "respectful," "listens," "offers emotional support," and "competent."(59) Fear was prominent especially among women who had a history of sexual abuse. Physical and sexual abuse has been reported to occur in up to 68% of women with HIV, making this a critical issue to be considered.(60) Another factor, inhibited coping style, as measured by the Millon Behavioral Health Inventory, predicted poorer adherence to appointments among women with HIV in one study.(61) The problem of adherence is multifactorial in nature and may require tailored interventions created for different patient populations.(56) Successful interventions tested in the general population included providing education, economic incentives, telephone counseling, or using intensive tracking systems. One study found that a computerized reminder system significantly increased the rate of Papanicolaou screening among HIV-infected women.(62) Interventions to improve adherence among HIV-infected women should be designed, taking into account the unique needs of this population, including issues such as sexual abuse.

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Clinical Management
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Cervical Papanicolaou Smears in HIV-Infected Women
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Recommendations for Papanicolaou smear screening and colposcopies are available in the U.S. Health Resources and Services Administration's "Guide to the Clinical Care of Women with HIV, 2005 Edition." [Also, see the "2001 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities."(63)] These recommendations can be summarized as follows:

  • When HIV infection is first diagnosed, women should have a thorough gynecologic examination, including a Papanicolaou smear and pelvic exam.

  • If the initial smear result is normal, then a second screening should be done at approximately 6 months. If both results are normal, then women should have a Papanicolaou smear annually. Consider more frequent screening among women with:
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    • Previous abnormal Papanicolaou smear result

    • Known HPV infection

    • Prior treatment for dysplasia

    • Symptomatic HIV infection or CD4 count <200 cells/µL

Recommendations for anal Papanicolaou smear screening are not included in standard guidelines. However, the following the cervical cancer screening guidelines are suggested: anal Papanicolaou smear at initial visit, repeated at 6 months, and then annually if results are normal. Patients with ASCUS or higher cytologic changes should be referred for high-resolution anoscopy.

Indications for colposcopy include:

  • Any cytologic abnormality or atypia--ASCUS or AGUS (atypical glandular cells of undetermined significance) or higher changes

  • Recurrent or untreated dysplasia

  • History of multifocal disease (vulvar, vaginal, or anal)

  • Poor adherence to follow-up of Papanicolaou smear screening

The entire genital tract (cervix, vagina, vulva, and perianal area) should be evaluated at the time of colposcopy because multifocal disease is a common problem among HIV-infected women. Women who have had hysterectomies should be monitored with vaginal Papanicolaou smears only if they have a history of cervical SIL. One study showed 63% of HIV-infected women had SIL on vaginal Papanicolaou smears following hysterectomy,(64) indicating that vaginal Papanicolaou smears should not be neglected in this group. CD4 counts <200 cells/µL and viral loads >10,000 copies/mL were predictive of SIL on vaginal cytology.

Objectives of colposcopy:

  • Visualize cervix, vagina, vulva, and perianal areas.

  • Identify squamous columnar junction and transformation zone.

  • Assess lesions for severity of disease and formulate colposcopic impression.

  • Biopsy the most suspicious areas.

  • Determine adequacy of examination.

Women with an unsatisfactory colposcopy result, suspected HSIL/ICC, or AGUS on Papanicolaou smear should have an endocervical curettage (ECC).

After colposcopy:

  • Correlate Papanicolaou smear and pathology results with colposcopic impression to make diagnosis.

  • Consider risk factors for the development of cervical cancer.

  • Determine the best treatment and follow-up plan for individual patient.

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Treatment of Genital Warts
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Genital warts (condylomata) that are not typical in presentation or those that are suspicious for VIN (flat and/or pigmented) should be biopsied before treatment is initiated. Vulvar or perianal warts can be treated with a variety of methods outlined in the U.S. Centers for Disease Control and Prevention's Sexually Transmitted Diseases Treatment Guidelines 2002. Most treatments for genital warts rely upon destruction or removal of the warts. Imiquimod is unique because it works as an immune enhancer and is applied by the patient. Treatment of warts has not been shown to reduce progression of dysplasia.

Provider-initiated treatment methods:

  • Liquid nitrogen

  • Trichloroacetic aid

  • Podophyllin 15-25%

  • Cryotherapy

  • Electrocautery

  • Excision

Patient-applied treatment methods:

  • Imiquimod 5%

  • Podofilox 0.5%

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HPV DNA Screening
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Consensus guidelines developed by the American Society for Colposcopy and Cervical Pathology and others endorse the use of molecular HPV DNA testing of cervical brush specimens for high-risk HPV types in conjunction with the Papanicolaou smear in women over the age of 30,(65) and for the triage of ASCUS detected with Papanicolaou smears.(63) From a cost-effectiveness standpoint, one study found that starting with a Papanicolaou smear and HPV test every 6 months in the year after HIV diagnosis then modifying Papanicolaou smear screening based on these results was more effective and cost effective than annual Papanicolaou smears in women with HIV.(66) Cytology and biopsy histology were discordant in 43% of cases but, when Papanicolaou smears were combined with HPV testing, the discordancy rate was only 5%, indicating that the two tests together are superior to cytology alone for detecting SIL.(67) It is not standard practice at present to include HPV testing along with Papanicolaou smears for screening women with HIV infection but this may change as more data on the utility of that practice among this group of women become available.

The usefulness of HPV testing for triage of ASCUS detected with Papanicolaou smears was explored among HIV-infected women in the WIHS cohort (n = 270).(68) High-risk HPV DNA was detected in 30% of the women with ASCUS. The sensitivity of high-risk HPV DNA detection for HSIL on colposcopy among women with ASCUS was 50%, the specificity was 71%, and the PPV was 6%. Only 4% of the women had HSIL on colposcopy and 30% were positive for high-risk HPV. In contrast, a smaller study of 102 women with ASCUS found the sensitivity of high-risk HPV DNA testing for HSIL was 100%, the specificity was 70%, and the PPV was 31%. The rate of HSIL among women who had colposcopy was 12%, and 32% of the women with ASCUS had high-risk HPV DNA.(69) The conflicting results of these studies signify the need for further investigation into the usefulness of HPV testing in HIV-infected women with ASCUS.

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Monitoring and Treatment of Cervical SIL
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Monitoring of ASCUS and LSIL
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Even though SIL is recurrent and persistent in HIV-infected women, the risk for progression to HSIL and, more importantly, cancer, is relatively low. Women with ASCUS or LSIL should be followed with observation in conjunction with the standard recommendations for the general population.(63) A cohort of HIV-positive (n = 391) and HIV-negative (n = 103) women with ASCUS or LSIL and negative colposcopy was followed every 6 months for 4 years in the WIHS.(70) HIV-infected women were at higher risk of progression but the absolute risk of progression over the course of 4 years was only 12%, suggesting that monitoring LSIL was sufficient. In an earlier study with the WIHS cohort, HIV-infected women with LSIL showed only a 4% progression rate to HSIL and a regression rate of 33% vs 67% among HIV-negative women (p < .001).(71) When HIV-infected women and a matched control group of uninfected women with LSIL either were treated with loop electrosurgical excision procedure (LEEP) (n = 47, HIV infected; n = 45, HIV uninfected) or observed (n = 28, HIV infected; n = 30, HIV uninfected), the risk for recurrence or progression was 4-5 times higher among HIV-infected women, regardless of treatment assignment.(72) Women with a CD4 count <200 cells/µL were significantly more likely to have recurrence or progression of SIL. Taken together, this evidence shows no clear benefit to treating LSIL. HIV-infected women with LSIL therefore should be monitored with Papanicolaou smears with referral to colposcopy for biopsy of suspicious and/or persistent lesions.

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Treatment of HSIL
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There are a variety of treatments available for HSIL: cryotherapy, LEEP, laser conization or ablation, cold knife cone biopsy, and vaginal 5-fluorouracil (5FU). The selection of treatment modality is dependent upon a number of factors, including the size and location of the lesion(s), expertise of the clinician, availability of treatments, health care reimbursement, and patient preference. There is a high rate of recurrence of SIL after treatment among HIV-infected women, reinforcing the need to reserve treatment for women with HSIL, who are at highest risk for progression to cancer. The recurrence rate of SIL after treatment among women with HIV has ranged from 54% to 78%.(73-79) The recurrence rate in women with CD4 counts <200 cells/µL was 87% in one study, suggesting that women with more severe immune suppression are at additional risk for progression.(76) The high rate of recurrence underscores the importance of close follow-up after treatment for HSIL.

There appear to be higher failure rates (ie, persistence or recurrence of SIL) among women with HIV following any treatment modality. The failure rates for cryotherapy among women with HIV have ranged from 48% to 78%.(79) The failure rate among the general population has been found to be 7% in patients with HSIL.(80) One study found that women with HIV who had LEEP were significantly more likely than women with unknown serostatus to have recurrences.(79) Some studies have found that HIV-infected women were more likely after excisional procedures to have residual disease such as positive ECC (79) or positive margins after cone biopsy.(74) There were no significant differences in the progression to HSIL in HIV-infected women with LSIL who were given oral isotretinoin compared with those who were observed.(81) Recurrence rates were decreased and delayed when HIV-infected women previously treated for HSIL received 5FU cream for biweekly intravaginal use.(82) The available data are insufficient to determine whether one treatment modality is more effective than another among women with HIV.

There have been some concerns about pregnancy outcomes in women who have had excisional treatment procedures. In a case-controlled study, there was no increase in the risk of preterm birth or low birth weight or among women who had LEEP unless the size of the loop was relatively large.(83) In contrast, a recent metaanalysis of the literature on pregnancy outcomes after excisional procedures found that both cold knife cone and large-loop excision of the transformational zone increased the risk for preterm delivery and low birth weight.(84) Laser conization showed a marginally significant effect for preterm delivery and laser ablation did not show a significant effect on pregnancy outcomes. Excisional procedures should be used judiciously among women of reproductive age, with the goal to preserve as much cervical tissue as possible.

Women who have been treated for HSIL should be followed with Papanicolaou smears every 4 months until 3 consecutive normal results have been obtained and then they can return to screening every 6-12 months. All women found to have abnormal smear results after treatment should be referred for further evaluation with colposcopy.

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Management of Abnormal Papanicolaou Smear Results in Pregnancy
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Consensus guidelines for the management of abnormal Papanicolaou smear results during pregnancy have recently been published.(85) These guidelines do not specifically address women with HIV infection. Pregnant women should be referred for colposcopy or followed with cytology using the same guidelines as nonpregnant women. Because few studies have included pregnant women, the clinical courses of HPV and SIL in pregnancy are poorly understood. Colposcopy should be performed by a colposcopist experienced in evaluating changes in the cervix during pregnancy. Biopsies should be obtained only when HSIL or invasive cancer are suspected. An ECC should not be performed during pregnancy. Unless ICC is identified, no treatment should be performed during pregnancy. The risk of progression to cancer during pregnancy is low, whereas treatment could jeopardize the pregnancy. A Papanicolaou smear and colposcopy should be conducted no sooner than 6 weeks postpartum in women who had SIL in pregnancy.

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Patient Education
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There are a number of issues that can be addressed with patients who have lower genital tract neoplasia. First, smoking cessation and avoidance of secondhand smoke should be discussed with all patients. As mentioned earlier, smoking has been shown to be a cofactor in SIL progression. It is also important to discuss the use of condoms to reduce exposure to HPV. All patients should be counseled about the need for long-term follow-up after an abnormal Papanicolaou smear result and the importance of adherence to prevent the development of cancer. In one study, life stress increased the odds of SIL progression and/or persistence by 7 times in HIV-infected women followed over a 1-year period.(86) Engaging in stress reduction activities such as progressive muscle relaxation, meditation, and exercise therefore may be helpful. Eating plenty of fruits and vegetables that provide essential nutrients for healthy cell development and immune response also could be helpful. Inclusion of cruciferous vegetables containing indole 3-carbinol (I3C) may be especially beneficial in combating HPV. One randomized clinical trial using I3C supplementation showed significant regression of SIL.(87) Patients who have inadequate nutrition may benefit from a multivitamin supplement so that very basic nutrient needs are met. It is important to address psychosocial issues such as fear, anxiety, sexuality, and culture that may affect a woman's experience of having an abnormal Papanicolaou smear result and her adherence to follow-up. Resources such as Web sites, printed material, and social support should be offered.

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Conclusions
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HIV-infected women face many challenges including a greater risk of recurrent, persistent, and sometimes progressive lower genital tract neoplasia. Close monitoring with Papanicolaou smears and referral of all women with abnormal results for colposcopy are important aspects of clinical management. Women with HSIL should receive treatment and frequent monitoring upon follow-up. Fortunately, cervical cancer often is a preventable disease when women receive appropriate Papanicolaou smear screening and follow-up for abnormalities.

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References

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1.   Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol 2005; 32 Suppl 1:S16-24.
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2.   Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine 2005.
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