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Vulvar, Vaginal, and Perianal Intraepithelial Neoplasia in Women With or at Risk for Human Immunodeficiency Virus

From the ¹Women’s Health and Fertility Branch, Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia; ²CONRAD Program, Arlington, Virginia; ³Brown University, Providence, Rhode Island; and ⁴Fred Hutchinson Cancer Research Center, Seattle, Washington.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION Appendix 1 REFERENCES

 
OBJECTIVE: To compare the incidence of vulvar, vaginal, and perianal intraepithelial neoplasia among human immunodeficiency virus (HIV)–infected women with a group of well-matched high-risk HIV-uninfected controls.

METHODS: A total of 192 HIV-infected and 88 uninfected women at high risk for HIV were followed up prospectively in Providence, Rhode Island during a 6-year period. Pap tests and cervicovaginal lavage for human papillomavirus detection and typing were performed at baseline and every 6 months thereafter. All women referred for colposcopy underwent a full colposcopic evaluation, including the vulvar, vaginal, and perianal regions. Unadjusted hazard ratios with 95% confidence intervals were calculated for development of vulvar, vaginal, and perianal intraepithelial neoplasia using univariable Cox proportional hazards models. An incidence analysis was performed by calculating Kaplan-Meier survival curves for development of intraepithelial neoplasia.

RESULTS: At baseline, 3 (1.6%) of the 192 HIV-infected women and none of the 88 HIV-uninfected women had vulvar, vaginal, and perianal intraepithelial neoplasia. During the study, 16 of 189 (8.5%) HIV-infected women and 1 of 88 (1.1%) HIV-uninfected women developed vulvar, vaginal, and perianal intraepithelial neoplasia. The incidence of vulvar, vaginal, or anal intraepithelial neoplasia was 1.96 per 100 person years for the HIV-infected women and 0.26 per 100 person-years for the HIV-uninfected women (P = .03).

CONCLUSION: Human immunodeficiency virus–infected women had more vulvar, vaginal, and perianal intraepithelial lesions compared with HIV-uninfected women. Furthermore, the incidence rates were higher than has been found in HIV-infected women in other similar cohorts.

LEVEL OF EVIDENCE: II-2

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION Appendix 1 REFERENCES

 
Women in this analysis were participants in the HIV Epidemiology Research Study, the methods of which have been described in detail elsewhere.⁴ Briefly, the HIV Epidemiology Research Study was a multicenter prospective cohort study established by the Centers for Disease Control and Prevention to study the natural history of HIV in women. Women with or at risk for HIV infection were recruited between April 1993 and January 1995 in 4 sites (the Bronx, NY; Baltimore, MD; Detroit, MI; and Providence, RI.) Eligibility criteria included the following: 1) documented HIV status within the prior 60 days or consenting to HIV testing as part of screening; 2) aged 16–55 years; and 3) a history of either injection drug use since 1985 or sexual risk behaviors (eg, having ever had more than 5 sexual partners, traded sex for drugs or money, or engaged in sex with a male injecting drug user or a man known or suspected to be HIV-infected). This third criterion was used to determine "risk cohort"; by study design, approximately one half of the women were at risk for HIV from drug use, and one half of the women were at risk for HIV from sexual behavior. All participants gave written informed consent, and the study was approved by institutional review boards at the 4 sites and by the Centers for Disease Control and Prevention.

At baseline and 6-month intervals, women underwent a standardized face-to-face interview, which included demographic, behavioral, and medical histories, including gynecologic and treatment history. For HIV-infected women, antiretroviral use at baseline was by self-report and for analysis was classified as use of any antiretroviral therapy, because enrollment occurred before the widespread introduction of highly effective combination therapy. At each visit, biologic specimens were collected and a physical examination with a complete gynecologic examination was performed. Pap test and cervicovaginal lavage for HPV detection and typing were performed. Pap tests were collected with a cytobrush and Ayre spatula from all women with a cervix and submitted as conventional slide-based specimens. All Pap tests were evaluated using the 2001 Bethesda scoring system for cervical cytology by a single commercial cytologic laboratory (Kyto Diagnostics, L.P., New York, NY), where cytopathologists were blinded to the participant’s HIV serostatus. Cervicovaginal lavage specimens were collected by irrigation of the cervix with 10 mL of normal saline solution, followed by aspiration of the lavage fluid from the posterior fornix of the vagina. Specimens were then tested for HPV by polymerase chain reaction in a single laboratory, using consensus L1 primers with amplification of the cellular ß-globulin gene as an internal control. Human papillomavirus types in the amplified product were identified by hybridization with a generic probe that was designed to recognize most HPV types as well as with HPV type-specific probes. High and intermediate risk-types included types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82; low-risk types included types 6, 11, 26, 40, 53, 54, 55, 66, 83, and 84. Samples that were deemed positive by the generic probe mix but negative by all type-specific probes were considered to represent untypable HPV types. For specimens with multiple HPV types, the specimen was placed in a single-risk category that corresponded to the highest risk HPV in the specimen.

All women in the HIV Epidemiology Research Study were referred to colposcopy for any abnormal cervical cytology, including atypical squamous cells of undetermined significance or atypical glandular cells of undetermined significance or for any visible lesion noted on physical examination. This current analysis is limited to women enrolled at the Providence, Rhode Island site, where all women referred to colposcopy underwent a full colposcopic evaluation including the vulvar, vaginal, and perianal regions. Any areas suspicious for intraepithelial neoplasia were biopsied. Vulvar, vaginal, and perianal biopsies were classified as normal or intraepithelial neoplasia grades I, II, or III (vulvar, vaginal, or anal intraepithelial neoplasia). Pathologists examining the biopsy specimens were not systematically blinded to the participant’s HIV serostatus. During the course of the study, 2 women in Providence HIV seroconverted, 1 after 2 years in the study and the other at 3.5 years. These 2 seroconverters were included in the analysis until the visit that they seroconverted. Neither of the woman had vulvar, vaginal, or anal intraepithelial neoplasia.

Statistical analyses were performed using SAS 8.2 software (SAS Institute Inc, Cary, NC). Selected demographic and behavioral characteristics were compared using ² for categorical variables. Student t tests were used to compare means between groups. Unadjusted hazard ratios with 95% confidence intervals were calculated for development of vulvar, vaginal, or perianal intraepithelial neoplasia using univariable Cox proportional hazards models. Because the number of women with the outcome of interest (vulvar, vaginal, or anal intraepithelial neoplasia) was small (n = 17), we were unable to conduct multivariable analyses. After excluding women with intraepithelial neoplasia at baseline, an incidence analysis was performed by calculating Kaplan-Meier survival curves for development of intraepithelial neoplasia.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION Appendix 1 REFERENCES

 
A total of 192 HIV-infected and 88 HIV-uninfected women were enrolled in at the Providence, Rhode Island site. Human immunodeficiency virus–infected women were significantly less likely to have graduated from high school, to have 2 or more male sexual partners in the last 6 months, to report having injected drugs in the past 6 months, or to report using crack in the past 6 months. Human immunodeficiency virus–infected women were significantly more likely to report 100% condom use in the last 6 months. Human immunodeficiency virus–infected women did not differ from HIV-uninfected women in age, race, monthly income, number of live births, current smoking status, and ever having exchanged sex for drugs or money (Table 1).

At baseline physical examination, 3 (1.6%) of the 192 HIV-infected women had vaginal, vulvar, or perianal intraepithelial neoplasia; 2 women had vulvar intraepithelial neoplasia I and 1 woman had both vulvar intraepithelial neoplasia II and vaginal intraepithelial neoplasia I. None of the 88 HIV-uninfected women had vulvar, vaginal, or anal intraepithelial neoplasia at baseline. Thus, 189 HIV-infected women and 88 HIV-uninfected women were included in the analysis of incidence of vulvar, vaginal, and anal intraepithelial neoplasia.

During the study, 16 of the 189 (8.5%) HIV-infected women and 1 of 88 (1.1%) HIV-uninfected women developed vulvar, vaginal, or anal intraepithelial neoplasia (Table 2). Total person-years of follow-up was 815.2 years for the HIV-infected women and 382.8 years for the HIV-uninfected women. The incidence of vulvar, vaginal, and anal intraepithelial neoplasia was 1.96 per 100 person-years for the HIV-infected women and 0.26 per 100 person-years for the HIV-uninfected women (P = .03). In terms of abnormal cervical histology, 10 of the 16 HIV-infected women with vulvar, vaginal, or anal intraepithelial neoplasia also had cervical intraepithelial neoplasia (CIN): 7 with CIN I, 1 with CIN II, and 2 with CIN III. The HIV-uninfected woman with vulvar intraepithelial neoplasia had a cervical biopsy with normal results. Regarding Pap tests, among the 16 HIV-infected women with vulvar, vaginal, or anal intraepithelial neoplasia, 1 had a normal Pap test, 7 had atypical squamous cells of undetermined significance, 6 had low-grade squamous intraepithelial lesions, and 2 had high-grade squamous intraepithelial lesions. The HIV-uninfected woman had a normal Pap test. The 2 women with normal Pap tests were referred for visible lesions noted on physical examination. Regarding HPV status at baseline, 15 of the 17 women had HPV detected at baseline, and 7 had multiple types detected. The most common HPV types detected were types 58, 53, 52, 16, 66, and 84. Although the HIV Epidemiology Research Study started before highly active antiretroviral therapy (HAART) was widely introduced, 97 of the 189 HIV-infected women started HAART at some point during the study. Ten women who developed vulvar, vaginal, or anal intraepithelial neoplasia reported HAART use at some point during the study, of which 5 women reported starting HAART before identification of their first lesion, and 5 reported staring HAART after their first lesion was identified. In addition to the biopsies that revealed vulvar, vaginal, or anal intraepithelial neoplasia, there were 20 vulvar biopsies (15 with normal results and 5 with condyloma), 18 vaginal biopsies (14 with normal results, 3 with condyloma, and 1 with inconclusive results due to inadequate sample), and 10 perianal biopsies (2 with normal results and 8 with condyloma).

The unadjusted hazard ratio for development of vulvar, vaginal, and anal intraepithelial neoplasia for HIV-infected women compared with HIV-uninfected women was 7.66 (95% confidence interval [CI] 1.02–57.76). Although women were followed up for up to 6 years, all women with vulvar, vaginal, and anal intraepithelial neoplasia developed their lesions within the first 4.5 years of follow-up. The median time for development of disease for HIV-infected women was 2.6 years; the HIV-uninfected woman developed disease at 2.4 years. Within 4.5 years, 23.7% (95% CI 2.7–44.8) of HIV-infected women with CD4 counts of less than 200 developed vulvar, vaginal, and anal intraepithelial neoplasia compared with 11.6% (95% CI 4.8–18.5) of the HIV-infected women with CD4 counts between 200 to 499, 4.3% (95% CI 0–10.1) of the HIV-infected women with CD4 counts 500 and greater, and 1.4% (95% CI 0–4.0) of the HIV-uninfected women (P < .01) (Fig. 1).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Kaplan-Meier survival curves for the development of vulvar, vaginal, or perianal intraepithelial neoplasia among human immunodeficiency virus (HIV)–infected women stratified by CD4 count compared with HIV-uninfected women. Jamieson. Genital and Anal Intraepithelial Neoplasia. Obstet Gynecol 2006.

Univariable analyses of risk factors associated with the development of vulvar, vaginal, and anal intraepithelial neoplasia were then conducted in the HIV-infected women. CD4 counts less than 200 cells/µL, HPV positivity, HPV high-risk positivity, and antiretroviral use at baseline were all associated with the development of vulvar, vaginal, and anal intraepithelial neoplasia. (Table 3).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION Appendix 1 REFERENCES

 
Overall, HIV-infected women had more vulvar, vaginal, and anal intraepithelial lesions at baseline and during follow-up compared with high-risk HIV-uninfected women. This is consistent with other reports that also found higher rates of these lesions among HIV-infected women.^5,6 However, unlike these other reports, we found substantially higher rates of vulvar, vaginal, and anal intraepithelial neoplasia among HIV-infected women than had previously been reported. Conley and colleagues⁵ reported 5 vulvar, vaginal, and anal intraepithelial neoplasia lesions among 385 HIV-infected women (1.3%) during 4 years of follow-up. Massad and colleagues⁶ found 28 vulvar intraepithelial neoplasia lesions among 1,562 HIV-infected women (1.8%) during 8 years of follow-up. By contrast, we found 17 vulvar, vaginal, and anal intraepithelial neoplasia lesions (in 16 women) among 189 HIV-infected women (9.0%) during the first 4.5 years of follow-up; 10 of these lesions were vulvar intraepithelial neoplasia (5.3%). This increased proportion of lesions that we found may be because of a more systematic approach to identifying lesions. At the Providence site in the HIV Epidemiology Research Study, all women referred for abnormal cervical cytology underwent a complete colposcopic examination, which included the vulvar, vaginal, and anal regions. By contrast, in the other 2 studies^5,6 women underwent colposcopic evaluation of the vulva, vagina, or anal regions only if a lesion was noted on visual inspection. This systematic approach to complete colposcopy was a strength of the HIV Epidemiology Research Study in Providence. However, a related limitation was possible surveillance bias. Because more HIV-infected women have abnormal cervical cytology compared with HIV-uninfected women, HIV-infected women were referred for colposcopy more frequently and therefore may have had a greater chance of having vulvar, vaginal, and anal intraepithelial neoplasia lesions detected. In addition, the incidence rates we report may be an underestimation of the true incidence of vulvar, vaginal, and anal intraepithelial neoplasia, because only women with abnormal cervical cytology or a visible lesion were referred; women without an abnormal cytology may have had other noncervical intraepithelial neoplasias that were not detected.

In terms of risk factors for development of vulvar, vaginal, and anal intraepithelial neoplasia among HIV-infected women, the risk factors we identified (CD4 counts less than 200 cells/µL, HPV positivity, HPV high-risk positivity, and antiretroviral use at baseline) were similar to findings from other studies. Conley and colleagues⁵ found HPV infection and low CD4 counts associated with vulvar, vaginal, and anal intraepithelial neoplasia. Similarly, Massad and colleagues found high- and medium-risk HPV positivity and low CD4 counts as risk factors for vulvar intraepithelial neoplasia.⁶ Our finding that antiretroviral use at baseline was associated with an increased risk of vulvar, vaginal, and anal intraepithelial neoplasia may be due to residual confounding in this unadjusted analysis, because women with more advanced HIV disease were more likely to be taking antiretrovirals. A limitation of our study is that due to small sample sizes multivariable analysis was not possible.

We have demonstrated that when systematically evaluated, HIV-infected women frequently have lower genital tract intraepithelial neoplasia that is not limited to the cervix. Therefore, during gynecologic exams, the vulvar, vaginal, and perianal regions of HIV-infected women should be carefully evaluated. Furthermore, when women undergo colposcopy for cervical dysplasia, the vulvar, vaginal, and perianal regions should also be evaluated colposcopically. The problem, as pointed out by others,⁷ is that there is not a consensus about how these lesions should be managed in HIV-infected women. The lesions may be multicentric and extensive and may tend to recur after treatment. In addition, punch biopsies of the lesions may not reveal underlying carcinomas.⁷ Therefore, the management of vulvar, vaginal, and anal intraepithelial neoplasia in HIV-infected women remains a clinical challenge.

	Appendix 1

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION Appendix 1 REFERENCES

 
The HIV Epidemiology Research Study Group consists of Robert S. Klein, MD, Ellie Schoenbaum, MD, Julia Arnsten, MD, MPH, Robert D. Burk, MD, Chee Jen Chang, PhD, Penelope Demas, PhD, and Andrea Howard, MD, MSc, from Montefiore Medical Center and the Albert Einstein College of Medicine; Paula Schuman, MD, and Jack Sobel, MD, from the Wayne State University School of Medicine; Anne Rompalo, MD, David Vlahov, PhD, and David Celentano, PhD, from the Johns Hopkins University School of Medicine; Charles Carpenter, MD, and Kenneth Mayer, MD, from the Brown University School of Medicine; Ann Duerr, MD, Lytt I. Gardner, PhD, Charles M. Heilig, PhD, Scott Holmberg, MD, Denise Jamieson, MD, Jan Moore, PhD, Ruby Phelps, BS, Dawn Smith, MD, and Dora Warren, PhD, from the Centers for Disease Control and Prevention; and Katherine Davenny, PhD, from the National Institute of Drug Abuse.

	Footnotes

 
*For members of the HIV Epidemiology Research Study Group, see the Appendix.

Funded by the Centers for Disease Control and Prevention (cooperative agreement U64/CCU 106795).

The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. Use of trade names is for identification purposes only and does not constitute endorsement by the Centers for Disease Control and Prevention or the Department of Health and Human Services.

Corresponding author: Denise J. Jamieson, MD MPH, Centers for Disease Control and Prevention, 4770 Buford Highway, Mailstop K-34, Atlanta, GA 30341; e-mail: djj0{at}cdc.gov.

doi:10.1097/01.AOG.0000210237.80211.ff

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION Appendix 1 REFERENCES

 
1. Ahdieh L, Klein RS, Burk R, Cu-Uvin S, Schumann P, Duerr A, et al. Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. J Infect Dis 2001;184:682–90.[Medline]

2. Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 1999;91:226–36.[Abstract/Free Full Text]

3. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2000;283:1031–7.[Abstract/Free Full Text]

4. Smith DK, Warren DL, Vlahov D, Schumann P, Stein M, Greenberg BL, et al. Design and baseline participant characteristics of the Human Immunodeficiency Virus Epidemiology Research (HER) Study: a prospective cohort study of human immunodeficiency virus infection in US women. Am J Epidemiol 1997;146:459–69.[Abstract/Free Full Text]

5. Conley LJ, Ellerbrock TV, Bush TJ, Chiasson MA, Sawo D, Wright TC. HIV-1 infection and risk of vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia: a prospective cohort study. Lancet 2002;359:108–13.[Medline]

6. Massad LS, Silverberg MJ, Springer G, Minkoff H, Hessol N, Palefsky JM, et al. Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus. Am J Obstet Gynecol 2004;190:1241–8.[Medline]

7. Baldwin P, Sterling J. HIV-1 infection and intraepithelial neoplasia of lower genital tract. Lancet 2002;359:2040.[Medline]

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