Immune Suppression and the Risk for Cervical Dysplasia

These studies appear to suggest that a lower CD4 count and HPV may be risks for cervical dysplasia. Does HAART decrease these risks and decrease the risk for cervical dysplasia? It appears that results from studies done to date are mixed, and more research is needed and planned to address this question.. At Retrovirus, a study was presented showing HAART improved CIN:  Dr. Heard and colleagues reported that biopsy-proven CIN either reverted to normal or regressed to a lower grade at a significantly higher rate in a group of HIV-infected women followed in France receiving HAART-based regimens (Abstract 518):
"Genital Human Papilloma Virus Infection and Cervical Intraepithelial Neoplasia; consider routine biopsy" (from "HIV Infection in Women").

Cancer 2001 Apr 25;93(2):111-4

CD4 T-cell count, viral load, and squamous intraepithelial lesions in women infected with the human immunodeficiency virus
     Cardillo M, Hagan R, Abadi J, Abadi MA. Department of Pathology, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.

BACKGROUND:
Recent studies have reported an increased incidence of squamous intraepithelial lesions in women infected with the human immunodeficiency virus (HIV). However, to the authors' knowledge there are scarce data regarding the relation between the CD4 T-lymphocyte count (CD4+), HIV viral load, and the development of cervical dysplasia as evidenced by cervicovaginal cytology. The objective of the current study was to examine the association between cervicovaginal smears (with and without squamous lesions) from HIV-infected women and their CD4+ counts and HIV viral load.

METHODS:
Two hundred ninety-six cervicovaginal smears from 108 HIV-infected women were reviewed and classified according to the Bethesda system. Abnormal cytologies (n = 74) were followed by colposcopy and/or biopsy. CD4+ counts and HIV viral loads were available at the time of the cytologic evaluation. Statistical analysis was performed using the Student t test and the Mann-Whitney U test.

RESULTS:
The control group (n = 222) had significantly higher CD4+ counts (378 vs. 246 cells/microL; P < 0.001) compared with the group with cervical lesions. There was no apparent difference between the CD4+ counts from women with low grade lesions and those from women with high grade lesions. The HIV viral load was significantly higher in patients with cytologic abnormalities than in those with negative Papanicolaou smears (P = 0.006).

CONCLUSIONS:
The degree of immunosuppression may contribute to the development of intraepithelial lesions in HIV-positive women, but once the lesion is established disease progression may not be affected by the CD4+ counts.

Gynecol Oncol 2001 Mar;80(3):350-4

Cervical dysplasia in women infected with the human immunodeficiency virus (HIV): a correlation with HIV viral load and CD4+ count
     Davis AT, Chakraborty H, Flowers L, Mosunjac MB. Department of Pathology and Laboratory Medicine, Emory University, Grady Memorial Hospital, Atlanta, Georgia 30335, USA.

OBJECTIVES:
The incidence of cervical dysplasia and carcinoma is known to be increased in HIV-infected women. In addition, there is a positive correlation between HIV viral load (VL), CD4+ count, and opportunistic infections, as well as the incidence of various malignancies. This study compares HIV VL and CD4+ count with the presence of cervical dysplasia, as well as with the degree of severity of dysplasia.

METHODS:
A retrospective chart review of 350 HIV-infected women with polymerase chain reaction (PCR) quantitation of viral load was performed to identify 82 women with biopsy-proven cervical dysplasia and 25 women without any significant cervical pathology. The highest plasma VL within a year of the patients' cervical pathology and corresponding CD4+ count was selected and compared with cervical pathology. Univariate and multivariate statistical analysis using Student's t test and logistic regression analysis was used to analyze the significance of other risk factors such as age, race, smoking history, history of illicit drug use, and prior sexually transmitted disease as well as of viral load and CD4+ count.

RESULTS:
Of 82 cases of cervical dysplasia, 33 (40.24%) were mild (CIN I), 47 (57.32%) were either moderate or severe (CIN II-III) dysplasia, and 2 demonstrated invasive squamous cell carcinoma (2.44%). A significant statistical difference was found when comparing either HIV plasma VL or CD4+ T-cell counts with the presence of cervical dysplasia on biopsy (P < 0.005). However, only CD4+ count was identified as an independent risk factor for the presence of cervicaldysplasia after multivariate analysis.

CONCLUSION:
In our population, there is a significant correlation between VL and CD4+ count and the presence of cervical dysplasia. However, VL does not appear to be an independent risk factor for cervical dysplasia in this population of HIV-infected women.

Gynecol Oncol 1998 Mar;68(3):233-9

Prevalence, risk factors, and accuracy of cytologic screening for cervical intraepithelial neoplasia in women with the human immunodeficiency virus
     Maiman M, Fruchter RG, Sedlis A, Feldman J, Chen P, Burk RD, Minkoff H. Department of Obstetrics and Gynecology, State University of New York-Health Science Center at Brooklyn 11203, USA.

OBJECTIVES:
The objective was to evaluate the sensitivity and specificity of cervical cytology in women infected with the human immunodeficiency virus (HIV), risk factors for abnormal cytology in HIV-infected and uninfected women, and risk factors for histologic diagnosis of cervical intraepithelial neoplasia (CIN) in HIV-infected women.

METHODS:
Methods included a cross-sectional analysis of cervical cytology, colposcopic impression, and histology in 248 HIV-infected women and multivariate analyses of risk factors for abnormal cytology in 253 HIV-infected and 220 uninfected women and risk factors for CIN in 186 HIV-infected women.

RESULTS:
The sensitivity and specificity of cytology for all CIN grades were 0.60 and 0.80 and, for high-grade CIN, 0.83 and 0.74. The prevalence of abnormal cytology was 32.9% in HIV-infected and 7.6% in HIV-negative women. Independent risk factors for abnormal cytology were immunodeficiency [odds ratio (OR) 8-17, P < 0.001] and human papillomavirus (HPV) infection (OR = 5, P < 0.001). The prevalence of CIN on histology was 32% in HIV-infected women, and the only independent risk factor for CIN was oncogenic HPV type (OR = 5, P = 0.005).

CONCLUSION:
Given the high prevalence of abnormal cytology and CIN in HIV-infected women, cytologic screening has significant limitations. Both immunodeficiency and type of HPV infection are important risk factors.

J Natl Cancer Inst Monogr 1998;(23):43-9

Management of cervical neoplasia in human immunodeficiency virus-infected women
     Maiman M., Department of Gynecologic Oncology, State University of New York-Health ScienceCenter, Brooklyn 11203, USA.

The existence of cervical neoplasia in women with human immunodeficiency virus (HIV) represents one of the most serious challenges in the oncologic care of immunosuppressed patients. While the development of most cancers in the immunosuppressed patient can be attributed solely to immune deficiency, the relationship between squamous cell neoplasia of the cervix and HIV is quite unique because of common sexual behavioral risk factors. Screening strategies in HIV-positive women must take into account the high prevalence of cervical dysplasia in this subgroup as well as the limitations of cytologic screening. Cervical dysplasia in HIV-positive women may be of higher grade than in HIV-negative patients, with more extensive involvement of the lower genital tract with HPV-associated lesions. The presence and severity of cervical neoplasia in HIV-positive women correlate with both quantitative and qualitative T-cell function. Standard therapies for preinvasive cervical disease have yielded suboptimal results with high recurrent rates. While poor treatment results of standard ablative and excisional therapies warrant unique therapeutic strategies, one must recognize that close surveillance and repetitive treatment have been successful in preventing progressive neoplasia and invasive cervical carcinoma. The disease characteristics of invasive cervical carcinoma may take a more aggressive clinical course in HIV-infected women. HIV-positive women with cervical cancer have higher recurrence and death rates with shorter intervals to recurrence and death than do HIV-negative control subjects. CD4 status does influence subsequent outcome. In general, the same principles that guide the oncologic management of cervical cancer in immunocompetent patients should be applied. However, extremely close monitoring for both therapeutic efficacy and unusual toxicity must be instituted.

Obstet Gynecol 1998 May;91(5 Pt 2):848-50

Rapid progression to invasive cervix cancer in a woman infected with the human immunodeficiency virus
     Holcomb K, Maiman M, Dimaio T, Gates J., Department of Obstetrics and Gynecology, State University of New York-Health Science Center at Brooklyn, USA.

BACKGROUND:
Previous studies have shown an increased risk of cervical dysplasia in women infected with human immunodeficiency virus (HIV), as well as an increased risk of progression to higher-grade lesions. It is not known whether the rate of progression is accelerated over that in immunocompetent women.

CASE:
During September 1991, an HIV-positive woman underwent conization of the cervix showing carcinoma in situ. The surgical margins and endocervical curettings were negative for dysplasia. Papanicolaou smears 4 and 7 months after the conization also were negative. She then presented 33 months postconization with a stage Ib2 cervical carcinoma, which proved resistant to chemotherapy and pelvic radiation.

CONCLUSION:
Immunosuppression caused by HIV infection may cause a more rapid progression of cervical intraepithelial lesions to carcinoma.

Obstet Gynecol 1994 Oct;84(4):591-7

Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study
    Wright TC Jr, Ellerbrock TV, Chiasson MA, Van Devanter N, Sun XW., Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York.

OBJECTIVE:
To define the prevalence of cervical intraepithelial neoplasia (CIN), the validity of Papanicolaou tests, and the associations between CIN and risk factors for cervical disease in human immunodeficiency virus (HIV)-infected women.

METHODS:
In this cross-sectional study, we enrolled 398 HIV-seropositive and 357 HIV-seronegative women from two HIV-AIDS clinics, two sexually transmitted disease clinics, a methadone clinic, and a clinic for participants in an HIV heterosexual transmission study. Each woman was interviewed and underwent a cytologic and colposcopic evaluation, and was tested for human papillomavirus (HPV) DNA.

RESULTS:
Eighty (20%) of the 398 HIV-seropositive women compared to 15 (4%) of the 357 seronegative women had colposcopically confirmed CIN (odds ratio 5.7; P < .001). No invasive cancers were found. The sensitivity and specificity of Papanicolaou tests in seropositive women were 81 and 87%, respectively. By multiple logistic regression analysis using a model that included behavioral and biologic risk factors for CIN, CIN was independently associated with HPV infection (odds ratio 9.8), HIV infection (odds ratio 3.5), CD4+ T-lymphocyte count less than 200 cells/microL (odds ratio 2.7), and age greater than 34 years (odds ratio 2.0).

CONCLUSIONS:
Cervical intraepithelial neoplasia is a common finding in HIV-infected women. However, the results of this study suggest that Papanicolaou tests should be effective for detecting cervical disease in this population.

Am J Epidemiol 2000 Jun 15;151(12):1148-57

Cervical neoplasia and repeated positivity of human papillomavirus infection in human immunodeficiency virus-seropositive and -seronegative women
     Ahdieh L, Munoz A, Vlahov D, Trimble CL, Timpson LA, Shah K., Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.

Increased risk for cervical intraepithelial neoplasia (CIN) in human immunodeficiency virus (HIV)-infected women may be explained by repeated positivity of human papillomavirus (HPV) infection facilitated by HIV infection and related immunosuppression. As part of a longitudinal study with semiannual examinations, 268 women in Baltimore, Maryland (of whom 184 were HIV+), provided 1,426 cervicovaginal lavage specimens tested for HPV DNA by a polymerase chain reaction-based assay between 1992 and 1998. HPV positivity and time to HPV clearance according to HIV serostatus and CD4+ cell count were compared using models for correlated binary data and survival analysis. Of the 187 participants who had at least one positive measurement, the probability of subsequent HPV positivity among HIV- women and HIV+ women with CD4+ > or =200 and <200 cells/microl was 47.5%, 78.7%, and 92.9% (p < 0.001). Within-women HPV results were correlated (i.e., clustered) in each group (p < 0.01). Compared with HIV-participants, the relative incidence of HPV clearance was 0.29 and 0.10 among HIV+ women with CD4+ > or =200 and <200 cells/microl (p < 0.001). At the end of follow-up, 11 women had biopsy-confirmed CIN. The association of HIV and CIN (p = 0.014) was fully explained by repeated HPV positivity induced by HIV infection (p = 0.648). Reversal of immunosuppression following potent antiretroviral therapy must be expected to have a dramatic impact on HIV-related CIN.