Objective
The purpose of this study was to assess the prevalence of and risk factors for abnormal anal cytology and human papillomavirus (HPV) infections in women who are human immunodeficiency virus (HIV) positive.
Study Design
We conducted an observational single center study of 100 HIV-infected women with cervical and anal specimens that were obtained for cytologic and high-risk HPV testing with Hybrid Capture 2.
Results
Seventeen women had abnormal anal cytology; 16 women had anal HPV; 21 women had abnormal cervical cytology, and 24 women had cervical HPV. Abnormal anal cytology was associated with cervical HPV infection, abnormal cervical cytology, and anal HPV infection in univariate analysis. In multivariate analysis, abnormal anal cytology was associated with a CD4 count <200 cells/mm 3 , a history of sexually transmitted disease, and concurrent cervical cytologic abnormality.
Conclusion
HIV-infected women are at high risk for abnormal cytology and HPV infections of both the anus and cervix. Risk factors for abnormal anal cytology include abnormal cervical cytology, cervical and anal HPV infections, and low CD4 count.
Anal cancer rates in human immunodeficiency virus (HIV)-infected individuals in the United States have continued to increase over the past decade, despite the widespread use of highly active antiretroviral therapy (HAART). HIV-infected men who have sex with men (MSM) appear to be at highest risk of the development of anal cancer; the current incidence is >90 per 100,000 person-years. HIV-infected women have at least 7 times the risk of the development of anal carcinoma or carcinoma in situ, compared with their HIV-negative counterparts.
Anal and cervical cancers have many similarities that include association with human papillomavirus (HPV) infection, occurrence in an epithelial transformation zone, and coexistence with high-grade squamous intraepithelial lesions. HPV has been detected in 99% of cervical cancers and 80-90% of anal cancers. It is possible that the pathogenesis of anal cancer is similar to that of cervical cancer: that is, anal HPV infection, in conjunction with other yet to be determined factors, leads to the development of high-grade anal intraepithelial neoplasia (HGAIN), which is a likely precursor to anal cancer.
Because programmatic screening for cervical cancer with cytology has been associated with markedly decreased incidence and mortality rates of cervical cancer, anal cytology has been evaluated as a screening method for anal neoplasia in high-risk individuals (eg, HIV-infected MSM). Individuals with abnormal anal screening cytology are referred for a colposcopic evaluation of the anus called high-resolution anoscopy (HRA), in cases for which directed biopsies may diagnose HGAIN. If HGAIN is detected, potential treatments include ablation of HGAIN lesions by electrocautery, infrared coagulation, cryotherapy, or trichloroacetic acid.
Despite the considerable data on cervical neoplasia and HPV infection in HIV-infected women, there are limited data on anal neoplasia and anal HPV infection in this population. Most studies were performed in the 1990s, with reported abnormal anal cytologic rates of 14-31% and anal HPV infection rates of 29-79% with a wide range of risk factors.
We conducted a cross-sectional study to assess the prevalence of anal cytologic abnormalities and anal HPV infection and their relationship to associated abnormal cervical cytology and cervical HPV infections in a cohort of HIV-infected women at a single institution.
Materials and Methods
Study population
This was a cross-sectional study that was conducted at the Center for Infectious Diseases, which is the primary site of HIV care at Boston Medical Center (BMC), an inner city hospital in Boston, MA. English-speaking, HIV-infected women between the ages of 18 and 64 years who had not had a cervical or anal Papanicolaou test, colposcopy, or HRA in the previous 6 months were eligible to participate. The exclusion criteria included pregnancy, use of chronic anticoagulation medication, and life expectancy of <1 year. The protocol for the study was approved by the BMC Institutional Review Board.
Study design
After written informed consent was obtained, each subject provided a detailed history of routine gynecologic healthcare and risk factors for the development of anal cytologic abnormalities. This assessment by questionnaire included history of anal intercourse; number of sexual partners; history of sexually transmitted diseases; cervical cytologic abnormalities; vulvar warts; cervical, vulvar, or vaginal cancers; solid organ transplantation; chronic corticosteroid use; history of cigarette smoking; drug and alcohol use, and an in-depth HIV history. Additional medical and laboratory data were collected from the electronic medical record that included most recent cervical cytologic results before enrollment, CD4 T-cell count and HIV viral load performed within the previous 6 months.
After the questionnaire and history were completed, a visual examination of the lower genital tract was performed and samples were collected for cervical and anal cytology and HPV testing with Hybrid Capture 2 (HC2; Qiagen Corporation, Gaithersburg, MD). These specimens were sent to the BMC Pathology Laboratory for processing. Anal and cervical Papanicolaou test samples were collected with the BD SurePath Papanicolaou Test (Becton Dickinson and Company, Franklin Lakes, NJ). HC2 is a Food and Drug Administration-approved commercially available test for the detection of oncogenic HPV in the cervix and has been shown to increase sensitivity and negative predictive value when used as an adjunct to cervical cytology for the detection of high-grade cervical dysplasia in select patient populations. The HC2 assay assesses the presence of 13 types of high-risk associated HPV infection (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). HC2, however, has not been validated for detection of HPV in the anus.
Follow-up examination was determined by the anal and cervical results. Women with cervical cytologic abnormalities (low-grade squamous intraepithelial lesion [LSIL] and high-grade squamous intraepithelial lesion with or without a positive high-risk HPV test results) were referred for colposcopic examination that involved microscopic visualization of cervical lesions with biopsy. Women with Papanicolaou test results that showed atypical squamous cells of unknown significance and a high-risk associated HPV type by HC2 testing were also referred for colposcopic examination. Women with a positive cervical high-risk HPV test and normal cytology were not assessed with colposcopy but were recommended for cytology and HPV testing in 6-12 months.
Subjects with any grade of anal cytologic abnormality were referred for examination with HRA. The protocol was amended during the study to refer participants with high-risk anal HPV that was detected by HC2 for HRA, regardless of the anal cytologic result to assess whether subjects with a positive high-risk anal HPV testing with normal anal cytology had evidence of anal dysplasia. This change in protocol affected only 4 women. All colposcopy and HRA procedures were performed by a gynecologist with expertise in colposcopy and HRA.
Participants who were identified with high-grade dysplasia of the anus, cervix, vagina, or vulva were referred for treatment as recommended. Subjects with no evidence of anal or cervical high-grade dysplasia were to be followed with anal and cervical cytologic testing at 6- to 12-month intervals for a total of 3 visits.
Statistical analysis
In the Center for Infectious Diseases at BMC, 545 women with HIV infection were seen in 2003-2004. It was estimated that a sample size of 100 women would be feasible for this pilot study to complete enrollment over 6 months. Analysis was performed with Fisher’s exact test to determine associations between cervical HPV infection, abnormal cervical cytology, anal HPV infection and abnormal anal cytology. Adjusted and unadjusted measures of association were assessed between abnormal anal cytology and selected variables with the use of the Student t test, χ 2 test, Wilcoxon rank-sum test, odds ratios (ORs), and logistic regression as appropriate. Multiple logistic regression model selection was conducted with forward selection with a cutoff probability value of .10 or evidence of confounding for inclusion in the final model. Variables that showed evidence of colinearity were not included in the final multivariate model. Statistical analysis was performed with SAS software (version 9.1; SAS Institute, Inc, Cary, NC).
Results
One hundred women who were receiving HIV care in Center for Infectious Diseases at BMC were enrolled in the study between October 2006 and May 2007. The median age at enrollment was 40 years; 56% of the women were born outside of the United States (primarily in Haiti and Africa). Seventy-eight percent of women were black; 67% of the women reported no HIV risk factors other than heterosexual contact. Thirty-seven percent of the women were known to be HIV-infected for <5 years. At the time of enrollment, 11% of the women had a CD4 count of <200 cells/mm 3 ; 62% of the women had an undetectable HIV viral load, and 79% of the women were currently receiving HAART. Only 5 women reported having undergone a previous anal Papanicolaou test.
Forty-six percent of the women reported ≥6 lifetime sexual partners; 35% of the women reported the onset of sexual activity at ≤15 years old. Twenty-two percent of the women reported a history of receptive anal intercourse. Ten percent of the women reported a history of vulvar dysplasia; 27% of the women had a history of treatment for cervical dysplasia. Twenty-three percent of the women were active cigarette smokers; 25% and 15% of the women had a history of alcohol ingestion or intravenous drug use, respectively.
Of 83 women for whom a documented previous cervical cytologic result was available, 13 women (15.7%) had a cytologic abnormality on the most recent previous Papanicolaou test. The cervical abnormalities were high-grade squamous intraepithelial lesion in 3 women (3.6%), LSIL in 9 women (10.8%), and high-grade squamous intraepithelial lesion in 1 woman (1.2%). Six of 12 women (50.0%) with a positive anal HPV test result had a history of an abnormal cervical Papanicolaou test, compared with 7 of 71 women (9.9%) with no anal HPV detected ( Table 1 ).
| Risk factor | Anal human papillomavirus result, n (%) | Odds ratio (95% CI) | |
|---|---|---|---|
| Positive (n = 16) | Negative (n = 84) | ||
| Concurrent anal cytologic result (n = 99) | 18.10 (5.06–64.71) a | ||
| NILM | 6 (37.5) | 76 (91.6) | |
| ASCUS | 6 (37.5) | 4 (4.8) | |
| LSIL | 4 (25.0) | 3 (3.6) | |
| Cervical HPV positive (n = 99) | 11 (68.8) | 13 (15.7) | 11.85 (3.53–39.79) |
| Concurrent cervical cytologic result | 7.71 (2.41–24.65) a | ||
| NILM | 7 (43.8) | 72 (85.7) | |
| ASCUS | 0 | 8 (9.5) | |
| LSIL | 8 (50.0) | 4 (4.8) | |
| HSIL | 1 (6.3) | 0 | |
| Most recent previous cervical cytologic results (n = 83) | 9.14 (2.31–36.14) a | ||
| NILM | 6 (50.0) | 64 (90.1) | |
| ASCUS | 0 | 3 (4.2) | |
| LSIL | 5 (41.7) | 4 (5.6) | |
| HSIL | 1 (8.3) | 0 | |
| Current cigarette smoker | 6 (37.5) | 17 (20.2) | 2.36 (0.75–7.42) |
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