Worldwide, there are approximately 18.5 million women living with HIV/AIDS. 1 Approximately 33–38% of HIV-infected women have abnormal cervical cytology. 2,3 Women infected with HIV have been shown to have a greater risk for cervical intraepithelial neoplasia (CIN) 4–7 and a greater rate of recurrence after treatment of this problem 8–10 compared with HIV-uninfected women. Routine surveillance by Papanicolau test for cervical dysplasia is advised for both HIV-uninfected and -infected women. Increased rates of vulvar and vaginal intraepithelial neoplasia (VAIN) in HIV-infected women 7,11–13 suggest that genital tract human papillomavirus (HPV) disease may be less localized in these women. If this is indeed the case, HIV-infected women may still be at risk for vulvovaginal disease after excision of cervical lesions.
In 2002, the American Cancer Society advised that women with a prior hysterectomy continue follow-up screening with vaginal Papanicolaou smears if they had a history of CIN 2/3, cervical carcinoma, or in utero exposure to diethylstilbestrol. 14 The risk of VAIN in women with no history of invasive gynecologic malignancy is low and the cost-effectiveness of cytologic screening has been questioned. 15,16 The American College of Obstetrics and Gynecology recommends that, after hysterectomy, women should undergo periodic cytologic screening of the vagina if they have ≥1 of 11 risk factors, which include HIV infection. 17 Little is known, however, about the rate of vaginal dysplasia in HIV-infected women after hysterectomy.
We used data from the HIV Epidemiology Research (HER) Study, an observational study of women with HIV or at risk for the infection, to investigate the association of HIV infection with the frequency of abnormal vaginal Papanicolau results after hysterectomy. We studied factors associated with incidence of abnormal vaginal Papanicolaou smears in women who had hysterectomies during the study. We investigated the proportion of women with abnormal vaginal cytology and histology during follow-up and assessed the prevalence of risk factors for abnormal cytology.
The methods have been described in depth by Smith et al. 18 Briefly, between April 1993 and January 1995, 871 HIV-infected and 439 at-risk women were enrolled at 4 US sites: Baltimore, MD; Detroit, MI; Bronx, NY; and Providence, RI. Each site contributed approximately one-fourth of the participants. HIV-infected women without AIDS-defining conditions and HIV-uninfected women were selected to give approximately a 50:50 ratio between those with risk from injection drug use (IDU) and those with increased risk due to sexual behavior but not IDU. Women were followed for approximately 6.5 years. Semiannual research visits included core interviews on medical history, obstetric and gynecologic history, substance use, and sexual behavior. Participants also had a physical examination that included a pelvic examination. Institutional review boards approved the study protocol at each site and at the Centers for Disease Control and Prevention (CDC), and all participants gave informed consent. This analysis included all HER participants who had a hysterectomy before or during the study (76 HIV-infected and 35 HIV-uninfected women had had a hysterectomy before the study; 28 and 11, respectively, had this procedure during the study). Women who had a hysterectomy were identified by self-report and medical record abstraction. They were confirmed to have had a hysterectomy by physical examination. Two of the 28 HIV-infected women who had a hysterectomy during the study did not have follow-up after hysterectomy. One died 3 months after her surgery because of end-stage HIV disease; the other had a hysterectomy late in the study and did not have a follow-up vaginal Papanicolaou test.
Women without a cervix had vaginal Papanicolaou smears at each semiannual visit; the smears were collected with an Ayres spatula from the vaginal cuff. All Papanicolaou smears were evaluated using predefined criteria by a single commercial cytologic laboratory (Kyto Diagnostics, LP, New York, NY). Women with low-grade squamous intraepithelial lesion (SIL) or higher on cytology or had 2 semiannual Papanicolaou smears with atypical cells of undetermined significance (ASCUS) were referred for colposcopy. An abnormality, such as condyloma noted on physical examination, was also a cause for colposcopy referral. However, a uniform treatment protocol was not implemented across study sites. Colposcopy and biopsy results were obtained from medical record abstractions.
For analysis, the Papanicolaou smears were categorized into 3 groups: normal, ASCUS, and SIL; the last included both high-grade and low-grade SIL (HGSIL, LGSIL).
Cervical vaginal lavage specimens were collected semi-annually as a 10-μL saline wash, frozen, and tested for HPV using polymerase chain reaction (PCR) at a central laboratory as previously described. 19 HPV risk types were determined using type-specific probes, with classification of types by oncogenic risk, which was based on the prevalence in cervical cancer. 6,20 Specimens with multiple types were placed in a single category based upon the highest risk detected. Categories were as follows: high-risk types 16, 18, 31, 45; intermediate risk 33, 35, 39,51, 52, 56, 58, 59, 68, 73, 82; and low risk 6, 11, 26, 53, 54, 55, 66, 83, and 84.
CD4 T lymphocytes were calculated at each visit and were grouped by cells/μL: <200, 200–499, and ≥500. HIV viral load was tested at each visit and was determined via a third-generation branched DNA signal amplification assay (Chiron Corp., Emeryville, CA) with a lower quantification limit of 50 copies/mL. Antiretroviral use was ascertained by self-report at each visit. Regimen classifications were adapted from the US Department of Health and Human Services guidelines for preferred or alternative combinations, with unclassed regimens included if they were believed to have a high likelihood of effective and sustained viral suppression. 21 For analysis, a 3-category variable was created for current antiretroviral use: highly active antiretroviral therapy (HAART), antiretroviral use not defined as HAART, and no antiretroviral use.
Time since hysterectomy was calculated for all women who had had a hysterectomy. Women who had had a hysterectomy before the study were asked the month and the year of when they had had their hysterectomy. For women who had a hysterectomy during the study, the date of hysterectomy was taken from medical record abstraction. Time since hysterectomy was calculated for each visit after hysterectomy and computed in years.
For the women who had a hysterectomy during the study period, pathology reports and other information about this procedure were abstracted from medical records. Type of hysterectomy performed was defined as total abdominal hysterectomy, radical hysterectomy, or vaginal hysterectomy. Evidence of CIN before or at hysterectomy was defined using surgical pathology reports, cervical biopsy information, and self-reported history of cervical cancer before the study. Categories were CIN I, CIN II, CIN III/CIS (carcinoma in situ), CA (invasive cervical cancer), and self-report of cervical cancer before the study. Values at hysterectomy for CD4 count and viral load and the presence of HPV were from results obtained at the last semiannual visit before the procedure. The median age of women who had a hysterectomy during the study was used to categorize women below or above median age at hysterectomy.
Data were analyzed using SAS (SAS Institute, Inc.) and S-Plus (Mathsoft, Cambridge, MA). χ2 or Fisher exact tests were used to compare proportions, and Student t tests were used to compare means between groups. The Wilcoxon rank sum test was used for variables that were not normally distributed. Cox proportional hazard models were used to calculate unadjusted hazard ratios for variables of interest in the 26 HIV-infected women with follow-up who had a hysterectomy during the study.
Multiple logistic regression models that corrected for repeated measures were used to identify correlates of abnormal vaginal cytology in all 102 HIV-infected women who had follow-up. Inferences were based on standard errors estimated by robust methods using an m-dependent working correlation structure (which assumes that the correlation depends only on how far apart 2 events were in time). Univariate analysis was used to screen variables for a possible association with SIL vaginal smears; variables with a moderate association (P < 0.20) were considered for inclusion in the final multivariate model.
The 102 HIV-infected women did not differ significantly at enrollment from the 46 HIV-uninfected women in risk cohort (IDU vs. sexual), age, education, live births, monthly income, current smoking status, having ever had sex for drugs or money, current IDU, or “crack” cocaine use (Table 1). HIV-infected women, however, were more ethnically diverse, more likely to have used condoms in the 6 months before enrollment, and less likely to have had >1 male sex partner in that time.
Previous Cervical Intraepithelial Neoplasia
Twenty-six HIV-infected women had a hysterectomy during the study, 19 (73%) had evidence of CIN before or at hysterectomy (one CIN I, 2 CIN II, 11 CIN III/CIS, 3 CA, and 2 self-reported a diagnosis of cervical cancer before the study). The remaining 7 women had a hysterectomy for the following conditions: 4 (15%) had uterine leiomyomata; one (4%) had endometrial carcinoma; one (4%) had endometriosis; and one (4%) had urinary stress incontinence. Of the 11 HIV-uninfected women who had a hysterectomy during the study, the indications were as follows: one had CIN III; 8 had uterine leiomyomata; one had pelvic pain; and one had uterine prolapse. For the 76 HIV-infected women and 35 HIV-uninfected women who had had a hysterectomy before the study, information on prior CIN was unavailable (Fig. 1).
Frequency of Abnormal Vaginal Cytology
Median follow-up for 26 HIV-infected women who underwent a hysterectomy during the study was 2.9 years (range: 0.2–5.9). Their highest-grade vaginal Papanicolaou smears were as follows: 3 (12%) HGSIL/CIS, 9 (35%) LGSIL, 2 (8%) ASCUS, and 12 (46%) normal. Twelve (63%) of the 19 women with CIN before or at hysterectomy had an SIL vaginal Papanicolaou as their highest-grade Papanicolau test during follow-up, but none of the 7 women without CIN before or at hysterectomy had this result (P < 0.01). Of the 12 women who ultimately developed SIL, 11 first had an ASCUS or SIL vaginal Papanicolau test in the first 18 months after hysterectomy (Fig. 2).
For the 76 HIV-infected women who had had a hysterectomy before the study, the highest-grade vaginal Papanicolaou smears were as follows: 33 (43%) had LGSIL; 17 (22%) had ASCUS; and 26 (34%) had normal. Median time of follow-up was 5.4 years (range: 0.5–6.7).
None of the HIV-uninfected women had an SIL vaginal Papanicolau test during the study. ASCUS was found for 2 (18%) of the 11 HIV-uninfected women who underwent a hysterectomy during the study, vs. 11 (31%) of the 35 HIV-uninfected women who had had a hysterectomy before the study. Median time of follow-up was 1.8 years (range: 0.3–4.6) for the 11 HIV-uninfected women who had a hysterectomy during the study, and 5.4 years (range: 1.0–6.4) for the 35 HIV-uninfected women who had had a hysterectomy before the study.
The rate of SIL vaginal cytology in the HIV-infected women who had hysterectomy during the study was 11.0 per 100 person-years compared with 0 per 100 person-years among HIV-uninfected women (P < 0.01).
Predictors of SIL Vaginal Cytology After Hysterectomy
Hazard ratios were calculated for the risk of SIL vaginal cytology during follow-up among the 26 HIV-infected women with a hysterectomy during the study (Table 2). Women with CD4 counts of <200 cells/μL at the time of hysterectomy had a greater risk of SIL than women with CD4 count ≥200 cells/μL. Women with viral loads of >10,000 copies/mL at hysterectomy also had a greater risk of SIL than women with viral loads ≤10,000 copies/mL. Since no woman without evidence of CIN before or at hysterectomy developed SIL, a hazard ratio was not possible, but the log-rank test was significant (P < 0.01). Age at hysterectomy was not significant, perhaps due to low power; a trend toward an increased risk was seen for women with HPV infection at hysterectomy (P = 0.10). A trend toward an increased risk was seen for women who had a vaginal hysterectomy as compared with women who had a total abdominal hysterectomy (P = 0.07).
All 19 HIV-infected women who had evidence of CIN before or at hysterectomy were HPV positive before hysterectomy, and 12 (63%) women had the same HPV type after hysterectomy. Seven (53%) of the 12 women had high- or intermediate-risk types (18, 31, 33, 45, 51, 52, and 58) that were persistent, whereas the other 4 had low-risk types (6, 53, 58, 66, 68, 84, and 84) that were persistent. This persistence did not predict development of an SIL vaginal Papanicolaou result.
In the 7 HIV-infected women who did not have evidence of CIN before or at hysterectomy, 3 were HPV positive before hysterectomy. None of these 3 women had the same HPV type after hysterectomy.
Factors Associated With Prevalent SIL Vaginal Cytology
Among all 102 HIV-infected women, univariate logistic analysis found no association between SIL vaginal Papanicolaou at a visit and any of the following risk factors measured at the same visit: age, race, risk cohort (history of IDU vs. sexual risk), HIV viral load, cigarette use in the past 6 months, IDU in the past 6 months, crack use in the past 6 months, laboratory diagnosis of bacterial vaginosis, trichomoniasis, lifetime number of sexual partners, condom use in the past 6 months, and time since hysterectomy. A univariate association was found with number of live births, number of male sexual partners in the past 6 months, less than a high school education, current CD4 count, HPV risk type detected at the same visit, current HAART use, and vulvar or vaginal condyloma present at the time of Papanicolau test. In the final multivariate model, the risk factors that remained associated with SIL vaginal Papanicolaou test were CD4 count, HPV risk type, current HAART use, less than a high school education, and vulvar or vaginal condyloma present at the time of Papanicolaou test (Table 3). A generalized estimating equation model restricted to HIV-infected women who had a hysterectomy during the study did not find an association between prevalent SIL vaginal cytology and with time since hysterectomy.
Colposcopy data were available for 29 of the 45 HIV-infected women with SIL vaginal cytology; 11 women had normal colposcopic findings. The remaining 18 women had the following biopsy results: one normal biopsy, 6 VAIN I, 3 VAIN II, 4 VAIN III, 2 no biopsy taken, and 2 biopsy information missing. Of the 19 HIV-infected women with ASCUS vaginal cytology, 8 had colposcopy data. Six of these women had a normal colposcopic finding: one had a normal biopsy, and one had VAIN I. Of the 38 HIV-infected women with normal vaginal cytology, 9 had colposcopy performed because of physical findings. Seven of these women had normal colposcopic findings, and 2 had VAIN I. In total, 46 of the 102 HIV-infected women had colposcopy because of abnormal vaginal Papanicolau test or physical findings. Biopsy information is available for 18 of these women, 16 of whom had VAIN histology. Nine of the 46 HIV-uninfected women had colposcopy. None had findings consistent with dysplasia and no biopsies were taken.
Thus, 16 of 102 HIV-infected women (16%) had VAIN during follow-up. This represents a minimum estimate, because biopsy information was missing for 4 women with abnormal colposcopies, and abnormal histology may have been detected if biopsies had been taken in HIV-infected women with normal colposcopies. The rate among HIV-infected women was significantly higher than the estimate for HIV-uninfected women (0/46; P < 0.01).
In this study we observed that a high proportion (63%) of HIV-infected women with evidence of CIN before or at hysterectomy experienced SIL vaginal cytology during follow-up; no SIL was observed among 7 HIV-infected women with no prior evidence of CIN. Prevalent SIL vaginal cytology was also associated with low CD4 count, HPV infection, current HAART use, low educational attainment, and vulvar/vaginal condyloma present on examination. Although histologic data were not available for all the HIV-infected women, VAIN was detected in 16 (16%), 7 (44%) of whom had VAIN II/III. A high percentage of HIV-infected women had evidence of CIN at time of hysterectomy.
We were unable to distinguish how many of the HIV-infected women who had had a hysterectomy before the study had a history of CIN, but we noted a very high frequency of SIL vaginal cytology among HIV-infected women with CIN at time of hysterectomy. Thus, the most apt comparison is to HIV-uninfected women with CIN at hysterectomy. The frequency of cytologic and histologic abnormalities we observed in HIV-infected women after hysterectomy is much higher than that reported from studies of women in the general population. For example, in a study published in 1984 on 810 women who had cervical carcinoma in situ at hysterectomy, 13 (2%) women had recurrence; 10 in the first year, one 4 years into follow-up, and two at 3 and 9 years, respectively (these two women did not have regular follow-up). 22 More recently, Gemmell et al. 23 reported on their retrospective longitudinal review of 219 women who had a hysterectomy in association with CIN III and at least 10 years of follow-up. Eight (4%) developed abnormal vaginal Papanicolaou smears, but only 2 (1%) had VAIN (detected within a year of hysterectomy). In 1992, Wiener et al. 24 reported that 5 (3%) of 195 women who had CIN at hysterectomy had abnormal vaginal Papanicolaou smears during follow-up; 3 of the 5 developed VAIN in the first 2 years after hysterectomy.
The frequency of abnormal vaginal Papanicolaou smears in women who have had a hysterectomy for conditions other than cervical dysplasia has been shown to be around 1%, 25 and the rate of VAIN in these women has been shown to be <1%. 26 Few studies have been conducted on VAIN in HIV-infected women who have had hysterectomies, but several studies have shown an increased incidence of vulvovaginal lesions in HIV-infected women with a cervix still present. A longitudinal study by Conley et al. 13 found that 9% of the HIV-infected women had vulvovaginal or perianal lesions, but the majority of these lesions were condylomata acuminata. The proportion of lower genital tract neoplasia and VAIN reported in these HIV-infected women was much lower than the proportion of VAIN we observed. Only 5 women (1%) had vulvar and perianal intraepithelial neoplasia, and none had VAIN detected.
Although we observed a higher proportion of lower tract intraepithelial neoplasia than previously described, the risk factors for this disease were similar to previously described risk factors for SIL. Low CD4 count and HPV infection have been shown to predict SIL cervical cytology, 4,5 but it is unclear why HAART use was associated with increased risk of abnormal vaginal Papanicolau test in our analysis. This association may have been due to residual confounding by HIV disease severity, because advanced HIV disease is an indication for HAART use. In addition, although several studies have found HAART use to be associated with a decreased prevalence of cervical lesions, 27–29 others have found no significant effect on prevalence. 30–32
Our study had several limitations. First, we were unable to determine whether the abnormal vaginal cytology and the vaginal lesions occurred before the hysterectomy, and we were unable to distinguish early recurrence of cervical disease from new vaginal malignancy. Women did not have vaginal Papanicolaou smears before their hysterectomy, and if a colposcopy was performed only the cervix was routinely examined. Second, because some women were referred to their primary physician for colposcopy, there was incomplete colposcopic follow-up in women with abnormal vaginal Papanicolaou smears. Of the VAIN biopsies that were taken, we were unable to determine the exact location in the vagina from where they originated. Finally, we had limited data on events that occurred before study enrollment, and we were unable to determine whether women who had had a hysterectomy before enrollment had evidence of CIN before or at their hysterectomy.
These limitations not withstanding, this study has several strengths. This is the largest study to examine lower genital tract dysplasia and intraepithelial neoplasia in HIV-infected women after hysterectomy. These women are from a well-described cohort of HIV-infected women who had semiannual cervical Papanicolaou smears before their hysterectomy and vaginal Papanicolaou smears after their hysterectomy. For women who had a hysterectomy during the study, we were also able to ascertain through surgical pathology reports whether cervical dysplasia was present at the time of hysterectomy.
In conclusion, our study found that an SIL vaginal Papanicolau test at some point during follow-up is very common among HIV-infected women. CIN before or at hysterectomy, low CD4 count, and high HIV viral load appear to be predictors of SIL during follow-up. A trend was observed for increased risk of abnormal vaginal Papanicolaou smears among women with detectable HPV. Our study suggests that women with abnormal vaginal cytology are at elevated risk for abnormal histology. The high rate of SIL vaginal Papanicolaou smears as well as the presence of high-grade VAIN underscore the need for continued follow-up for lower genital tract lesions among HIV-infected women after hysterectomy. In the future, larger cohort studies will need to be done with closer surveillance to be able to determine the optimal screening regimen for HIV-infected women who have had a hysterectomy.
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The HER 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, PhD, MPH, Lytt I. Gardner, PhD, Charles M. Heilig, PhD, Scott Holmberg, MD, Denise Jamieson, MD, MPH, Jan Moore, PhD, Ruby Phelps, BS, Dawn Smith, MD, MPH, and Dora Warren, PhD, from the Centers for Disease Control and Prevention; and Katherine Davenny, PhD, from the National Institute of Drug Abuse.