INTRODUCTION — Screening for cervical cancer is of particular importance for patients with HIV infection or in other immunocompromised states. Studies suggest that the incidence of cervical intraepithelial neoplasia (CIN), as confirmed by colposcopy, is four to five times higher in patients with HIV compared with patients without HIV but with high-risk sexual behaviors [1-3]. CIN is common in patients with HIV because [4-8]:
●Human papillomavirus (HPV) infection, the leading pathogen of most cervical cancers, is endemic among sexually active individuals.
●Patients with HIV are more likely to have persistent HPV infection.
●Persistent infection with one or more oncogenic HPV subtypes is a major factor in the pathogenesis of premalignant and malignant cervical disease.
Despite advances in management of patients with HIV and increases in HPV vaccination, screening for cervical cancer continues to require attention. One study reported that as many as one-fourth of patients with HIV do not get an annual Pap test despite seeing a primary care clinician during that time period, underscoring the need for continued emphasis on cervical cancer screening in this population .
Specific issues regarding screening for cervical cancer and evaluation of abnormal screening results in patients with HIV or other immunocompromised states will be reviewed here.
Management of CIN in patients with HIV and general issues regarding screening for cervical cancer in patients without HIV are discussed separately.
OUR APPROACH TO SCREENING — Multiple expert groups have devised consensus guidelines for cervical cancer screening in patients with HIV [10-15]. Our approach to screening for cervical cancer in patients with HIV is consistent with those published by the United States Department of Health and Human Services along with the National Institutes of Health .
Initial screening — Our approach to the initial screening visit for cervical cancer screening in patients with HIV is as follows :
●Cervical cancer screening is initiated at the time of HIV diagnosis, but no sooner than 21 years of age. This is similar to patients without HIV, in whom cervical cancer screening is also initiated at the age of 21 years. (See "Screening for cervical cancer in resource-rich settings", section on 'Screening in average-risk patients'.)
While historically earlier screening (ie, prior to age 21 years) was performed, the risk of developing cervical cancer prior to the age of 21 years is rare. In a report from the 2002 to 2016 HIV/AIDS Cancer Match Study including over 160,000 females with HIV, of the 552 patients who developed invasive cervical cancer, no cases occurred in patients <25 years of age . Thus, screening beginning at age 21 years provides a several-year window prior to age 25 years, when the risk of cervical cancer begins to increase.
●For patients 21 to 29 years, cervical cytology is used for screening. For patients ≥30 years, either cervical cytology or co-testing (cervical cytology and human papillomavirus [HPV] testing) is acceptable for screening. Primary HPV testing (HPV testing without cervical cytology) is not approved for use in patients with HIV. (See 'Cytology' below and 'Cotesting' below.)
●We perform a screening colposcopy at this visit. This is discussed in more detail below. (See 'Routine colposcopy' below.)
●Given the high rate of multifocal HPV disease and HPV-associated neoplasms, the examination also includes a thorough visual inspection of the anus, vulva, and vagina [17,18].
Subsequent screening — Our approach to subsequent cervical cancer screening for patients with HIV in whom initial screening is normal is as follows :
●If screening with cervical cytology (all patients 21 to 29 years and those ≥30 years being screened with this method):
•Cervical cytology is performed every 12 months for a total of three years. Although it is not our practice, some clinicians perform cervical cytology six months after the baseline test since cervical intraepithelial neoplasia (CIN) is not uncommon and can develop rapidly in these patients [2,11,19] and because high-grade lesions may be missed with a single test .
•If the results of three consecutive cervical cytology tests are normal, follow-up with cervical cytology is performed every three years.
●If screening with co-testing (those ≥30 years being screened with this method):
•Repeat co-testing is performed every three years; unlike with cervical cytology, consecutive testing every 12 months prior to increasing the interval to three years is not required.
●We do not perform routine colposcopy at subsequent follow-up visits. This is discussed in more detail below. (See 'Routine colposcopy' below.)
●We perform annual follow-up, which includes thorough visual inspection of the anus, vulva, and vagina [17,18].
●Screening continues throughout a patient's lifetime (and does not end, as in the general population, at 65 years old).
However, the incidence of HIV-related infection and cervical cancer appears to peak by age 54 years. In a cohort study including patients with HIV in South Africa, patients ages 30 to 44 years compared with other ages had higher rates of HIV-related infection (54 percent) and cervical cancer (53 percent); the incidence of infection-unrelated cancers surpassed infection-related cancers beginning at age 55 years . Thus, screening for non-HIV-related cancers should not be overlooked.
Patients with advanced HIV disease are more likely to have persistent HPV and CIN than those with early HIV infections. In our practice, we perform more frequent screening if the patient's HIV-related disease is poorly controlled or begins to progress (as measured by rising viral load, falling CD4 level), or if the patient is noncompliant with antiretroviral therapy (ART). However, there are no objective data showing that more aggressive screening is indicated for these patients or that this affects outcome, and there are no national guidelines that promote more frequent screening in this setting.
In addition, it has been suggested that the use of ART may reverse or lessen the severity of CIN in patients with HIV as is the case with other AIDS-related malignancies [22-24]. However, multiple studies of this hypothesis have yielded mixed results, and the incidence of invasive cervical cancer appears to be unchanged despite increasing success of HIV viral suppression with ART [25-27].
Patients in whom initial screening is abnormal are managed differently. This is discussed in detail below. (See 'Evaluation of abnormal results' below.)
RATIONALE AND EVIDENCE FOR SCREENING METHODS
Cytology — Cervical cytology appears to be a reliable primary screening tool for cervical cancer in patients with HIV, though the data regarding the reliability of this technique are conflicting [1,20,26,28-31]. Either conventional Pap smears or liquid-based cervicovaginal preparations may be employed for screening [32,33]. (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing".)
In a multicenter study of 1534 patients with HIV (median age 33 years) in Europe and South Africa, patients were followed with cervical cytology, human papillomavirus (HPV) testing, and colposcopy (with histopathology when indicated) at six-month intervals; median follow-up was approximately two years . Cytology (atypical squamous cells of undetermined significance [ASC-US] or greater) and colposcopy had equivalent sensitivity for detecting patients with cervical intraepithelial neoplasia (CIN) 2 or worse (100 and 98 percent, respectively). HPV testing compared with colposcopy had similar sensitivity (91 percent) but was less specific (50 versus 63 percent). Based on these findings, the authors concluded that cytology was preferable to HPV testing or colposcopy for cervical cancer screening in patients with HIV.
In addition, patients with HIV and a history of three negative Pap test results can be screened at three-year intervals. In a prospective study of 942 patients with HIV and three consecutive negative cytology results, after 15 months, there were no cases of precancer (CIN 2,3, atypical glandular cells favor neoplasia, or adenocarcinoma in situ), and after 39 months, precancer was found in 2 percent of participants .
Cotesting — The use of co-testing (ie, HPV testing and cervical cytology) to determine the frequency of subsequent screening in patients with HIV is a reasonable approach in patients ≥30 years.
In a cohort study of 855 patients with HIV (mean age 36 years) and CD4 counts over 500 cells/microL, the risk of developing a squamous intraepithelial lesion (SIL) in the subsequent three years after normal cervical cytology and HPV-negative test results was low (6 percent, 95% CI 2-10 percent) and was equivalent to that of patients without HIV . However, patients with CD4 counts less than 200 cells/microL and those between 200 and 500 cells/microL had higher rates of SIL (29 percent, 95% CI 15-44 percent and 14 percent, 95% CI 8-20 percent, respectively).
Similarly, in a study of 103 patients with HIV infection and CD4 counts less than 500 cells/microL, the presence of a high-risk HPV subtype, although strongly associated with the presence of any CIN, only slightly improved the sensitivity and predictive value of baseline screening when compared with cytologic screening alone . The lack of substantial benefit was most likely due to the high prevalence of HPV infection in patients with HIV. It appears that patients with HIV are more likely than other patients to be infected with high-risk HPV subtypes other than 16 and 18 and are likely to have persistent infection [36,37].
Primary HPV testing (ie, HPV testing alone without concurrent cervical cytology), however, is not a recommended screening method for patients with HIV. Primary HPV tests (ie, cobas and BD Onclarity) have not been adequately studied in patients with HIV, and we, therefore, cannot endorse the use of these tests as a standalone screening technique for this population. In one prospective study including 865 patients with HIV (mean age 46; median CD4 count of 592 cells/microL) undergoing cervical cancer screening, primary HPV testing and primary HPV testing with reflex HPV 16/18 genotyping led to fewer colposcopy referrals (35 and 24 percent, respectively) compared with co-testing (40 percent), but had similar sensitivities . Additional clinical trials are needed to determine if these tests can be used for patients with HIV.
Routine colposcopy — In our practice, we perform a screening colposcopy along with cervical cytology at the initial examination; however, there are no national guidelines that promote this practice. Colposcopic examination of the vagina and vulva, as well as the cervix, should be included in the evaluation because of the higher risk of multifocal disease [17,18]. We base the need for subsequent colposcopic examinations on cervical cytology results. (See 'Evaluation of abnormal results' below and "Colposcopy".)
Although not our practice, some clinicians perform annual colposcopy in patients with HIV. The rationale for routine colposcopy is as follows:
●These patients are usually seen in the health care system more often than once a year for other reasons, so they would not require an additional visit (with its associated costs and inconvenience) just for screening.
●The rate of cervical dysplasia is high; thus, the potential need for a return visit for colposcopy is eliminated.
●A higher rate of concurrent vulvar, vaginal, and anal neoplasias occurs in this group [17,18].
●Even mildly abnormal smears are associated with a high rate of histologic CIN (38 percent in one series) .
However, one retrospective study of 189 patients with HIV did not find that routine colposcopy improved outcomes . In this study, patients received cervical cancer screening with cytology and colposcopy and were followed for six years; agreement between cytologic findings and colposcopic and histologic findings was high. Of the 19 patients with normal cytology but abnormal biopsy, 95 percent developed abnormal cervical cytology (most commonly ASC-US) within one year; this led the authors to conclude that the routine use of colposcopy in these individuals was not necessary.
EVALUATION OF ABNORMAL RESULTS — The American Society for Colposcopy and Cervical Pathology consensus guidelines advise that patients with HIV at any age with abnormal screening results be managed as follows [12,13,41]:
●Cytology-negative, human papillomavirus (HPV)-positive – Repeat co-testing in one year (unless genotype testing for 16 or 16/18 is positive).
•If the initial HPV results identify HPV 16 or HPV 16/18, then colposcopy is recommended.
•If either of the co-tests at one year is abnormal (ie, abnormal cytology or HPV-positive), colposcopy should be performed.
●Atypical squamous cells of undetermined significance (ASC-US).
•If reflex HPV testing is positive, colposcopy should be performed.
•If HPV testing is not available or not done, repeat cytology in 6 to 12 months.
•For any result equal to or more severe than ASC-US on repeat cytology, colposcopy should be performed.
●Low-grade squamous epithelial lesion (LSIL) or more severe lesions (including high-grade squamous intraepithelial lesion [HSIL], atypical squamous cells cannot exclude HSIL [ASC-H], or atypical glandular cells [AGC]) – Colposcopy should be performed.
Although rates of cytologic glandular abnormalities appear to increase with the degree of immunosuppression in patients with HIV, glandular neoplasia is rare. This was illustrated in a large cohort study that included almost 50,000 Pap tests . Rates of glandular abnormalities on cervical cytology did not differ significantly in patients with (0.8 percent) and without (0.6 percent) HIV. Among patients with HIV, on the other hand, the rate of cytologic glandular abnormalities increased significantly with decreasing CD4 lymphocyte count (>500 cells/microL: 0.6 percent; 250 to 500 cells/microL: 0.8 percent; <250 cells/microL: 1.0 percent). Ultimately, cervical biopsy found adenocarcinoma in only one patient with HIV and glandular atypia in one patient without HIV; other patients had negative histology or squamous abnormalities and showed no significant difference by HIV serostatus.
Screening after hysterectomy — In our practice, for medically stable patients with HIV who have undergone hysterectomy for benign disease and who have no history of cervical intraepithelial neoplasia (CIN), we do not perform routine cervical cancer screening. However, if the patient's HIV-related disease begins to progress (as measured by rising viral load, falling CD4 level, opportunistic infection), or viral suppression with antiretroviral therapy (ART) cannot be achieved or maintained, we perform a Pap test or co-testing and pelvic examination, as well as annual screening from then on.
For patients with HIV who have undergone hysterectomy for a reason other than CIN or invasive cancer, there are few data regarding the risk of developing vaginal intraepithelial neoplasia (VaIN) or vaginal cancer [43,44], and no formal guidelines regarding Pap smear screening are available.
In a retrospective cohort study of 238 patients with HIV and prior hysterectomy with no history of abnormal Pap smears who underwent follow-up for a median of 16 years, 31 percent (74 patients) were found to have abnormal cytology . Of these patients, 54 had vaginal biopsies with the following distribution of results: normal (28 percent), VaIN 1 (43 percent), VaIN 2 (16 percent), and VaIN 3 (13 percent); no patients had invasive vaginal cancer. Patients who did not require ART at any point after hysterectomy were more likely to have normal compared with abnormal cytology results (91 versus 9 percent).
Immunosuppressed patients without HIV — Patients without HIV who are on long-term immunosuppressive therapy also have decreased rates of clearance of human papillomavirus (HPV) infection and increased rates of cervical dysplasia and cancer [14,45-50]. These include patients with:
●Allogeneic hematopoietic stem cell transplant .
●Systemic lupus erythematosus [14,45,47-50,52].
●Inflammatory bowel disease requiring current immunosuppressive treatments [14,53]. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Cancer screening'.)
●Rheumatologic disease (eg, rheumatoid arthritis) requiring current immunosuppressive treatments .
●Presumed hypothalamic-pituitary-adrenal axis (HPA) suppression from long-term or high-dose glucocorticoid use. (See "Glucocorticoid withdrawal", section on 'Identifying patients with HPA suppression'.)
As with patients with HIV, patients on long-term immunosuppressive therapy and normal screening results are candidates for subsequent screening every three years. In one retrospective study including 310 patients (ages 18 to 60 years) with benign cervical cancer screening after solid organ transplant, 284 patients (92 percent) continued to have normal screening results through 60 months . Of the 26 patients with abnormal cervical cytology, 17 had low-grade lesions, five had high-grade lesions, and four had atypical glandular or endometrial cells; no patients developed cervical cancer during the study period.
Patients not actively on immunosuppressive therapy — Patients with inflammatory bowel disease or rheumatoid arthritis not actively on immunosuppressive therapy, as well as those with type 1 diabetes mellitus, are not at higher risk for cervical cancer and should follow cervical cancer screening guidelines for average-risk patients (table 1) . (See "Screening for cervical cancer in resource-rich settings", section on 'Screening in average-risk patients'.)
Patients with barriers to screening — Barriers to cervical cancer screening include lack of access to gynecologic care and fear of a pelvic examination. Some HIV clinics offer cervical cancer screening, allowing patients with HIV to omit a separate visit for a pelvic examination. Although one study in HIV-positive patients suggested that self-collected primary HPV testing may be an effective screening strategy, primary HPV is not approved for screening in patients with HIV . Further study is needed to determine if primary HPV testing, as well as self-collection of HPV samples, is an option for patients with HIV. (See "Screening for cervical cancer in resource-rich settings", section on 'Relative risks and benefits of each method' and "Screening for cervical cancer in resource-rich settings", section on 'Types of screening and frequency' and "Screening for cervical cancer in resource-limited settings", section on 'Self-collected samples'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary care of adults with HIV" and "Society guideline links: Cervical cancer screening, prevention, and management".)
SUMMARY AND RECOMMENDATIONS
•For patients with HIV, cervical cancer screening starts at the time of HIV diagnosis, but no sooner than age 21 years; the risk of developing cervical cancer prior to the age of 25 years is rare. (See 'Initial screening' above.)
•For all patients with HIV presenting for their initial cervical cancer screening visit, we suggest the addition of screening colposcopy to cervical cytology or co-testing (Grade 2C). The need for subsequent colposcopies is based on cervical cytology results. (See 'Initial screening' above and 'Routine colposcopy' above.)
●Type of screening and screening intervals
•For patients 21 to 29 years, we suggest cervical cytology for screening rather than co-testing (Grade 2C). For patients ≥30 years, either cervical cytology or co-testing (cervical cytology and human papillomavirus [HPV] testing) is acceptable.
•If using cytology alone, annual cervical cytology is performed every three years; if results of the three consecutive cytology results are normal, cytology is then performed every three years.
•If using co-testing and the results of both cytology and HPV are negative, co-testing is performed every three years.
●Lifelong screening – Cervical cancer screening in patients with HIV should continue throughout a patient's lifetime (and not end, as in the general population, at 65 years old). (See 'Subsequent screening' above.)
●Management of abnormal screening results
•Repeat cytology is performed in one year for the following – Cytology-negative, HPV-positive (but negative for 16/18); atypical squamous cells of undetermined significance (ASC-US), HPV-unknown. (See 'Evaluation of abnormal results' above.)
•Colposcopy is performed for any of the following results – HPV 16/18; ASC-US, HPV-positive; low-grade squamous epithelial lesion (LSIL) or worse. (See 'Evaluation of abnormal results' above.)
●Immunosuppressed patients without HIV – Patients without HIV who are on long-term immunosuppressive therapy (eg, solid organ transplant, allogeneic hematopoietic stem cell transplant, systemic lupus erythematous, and those with inflammatory bowel disease or rheumatologic disease requiring current immunosuppressive treatments) have decreased rates of clearance of HPV infection and increased rates of cervical dysplasia and cancer. For these patients, we follow the same cervical cancer screening guidelines as for patients with HIV infection (table 1). (See 'Immunosuppressed patients without HIV' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟