After excluding 22 HIV seroconverters, 418 (11%, 95% C.I. 10%, 12%) of 3744 women in WIHS had reported prior hysterectomy (343 HIV seropositive, 75 seronegative), including 241 with hysterectomy before enrollment and 177 during follow-up. Of these, 410 (335 HIV seropositive, 75 seronegative) contributed up to 28 vaginal Pap tests over a median of 5.6 years of follow-up after enrollment or hysterectomy, for a total of 4463 vaginal Pap test results (3,700 among HIV seropositive and 763 from seronegative women). presents the demographic and medical characteristics of these women; except for a higher rate of smoking in women without HIV, HIV seropositive and seronegative women with hysterectomy were similar.
Demographic and Medical Characteristics of 410 Women With Vaginal Pap Test Results After Hysterectomy
Pap tests were abnormal at 1076/3700 (29%, 95% C.I. 25%, 33%) visits among HIV seropositive women, but only 31/763 (4%, 95% C.I. 2%, 8%) visits among HIV seronegative women (P < 0.001), in analyses using GEE logistic regression. The distribution of Pap test results by HIV serostatus is shown in ; women with HIV had more Pap test abnormalities, although most were ASCUS and LSIL, suggesting poorly controlled HPV infection rather than precancer. While HSIL Pap results were uncommon, they were more frequent in HIV seropositive (10/3700, 0.3%, 95% C.I. 0.1%, 0.6%) than in seronegative women (0/763, 95% C.I. 0%, 0%, P = 0.0007). The frequency of vaginal Pap test abnormality was similar for HIV seropositive women with hysterectomy before (698/2418 (29%, 95% C.I. 27%, 31%) smears) and after (378/1282 (29%, 95% C.I. 27%, 32%) smears) after study entry.
Distribution of Posthysterectomy Vaginal Pap Test Results from 3,700 Person-Visits Among HIV Seropositive and 763 Visits Among HIV Seronegative Women
We have previously shown that visit-specific prevalence of cervical Pap test abnormality among all WIHS participants fell across time, presumably as treatments decreased the burden of cervical disease (8
). In contrast, shows no time trend in the prevalence of vaginal Pap test abnormality in either HIV seropositive or seronegative women (P = 0.11 for HIV seropositive women and 0.50 for seronegative women).
Prevalence of Pap abnormality across time among women with and without human immunodeficiency virus (HIV) infection after hysterectomy.
As shown in , multivariable analyses found that prevalent detection of any abnormal vaginal Pap test was more common in HIV seropositive women with increasing immunosuppression and current smokers but less likely among women with multiple sexual partners. CD4 count was also significantly associated with HSIL Pap test (P for trend < 0.001). As shown in , when analysis was repeated among only HIV seropositive women, CD4 lymphocyte count, HIV RNA level, use of HAART, and smoking were independently associated with vaginal Pap abnormality; age, ethnicity, number of sexual partners in the prior six months, and prevalent vs incident hysterectomy were not linked to a finding of abnormal Pap in these women. Similar results were obtained if analysis was restricted to any SIL (excluding ASC-US) and to prevalent Pap abnormalities (not shown).
Factors Associated With Finding Any Abnormal Vaginal Pap Result After Hysterectomy
Correlates of Any Vaginal Pap Abnormality Among HIV Seropositive Women
We also analyzed the incidence of abnormal vaginal Pap tests. Among the 410 hysterectomized women, 136 (121 HIV seropositive, 15 seronegative) were excluded because of abnormal Pap tests at the time of hysterectomy (n = 108) or lack of follow-up (n = 28). Among the remaining 274 hysterectomized women, 114 (42%, 95% C.I. 38%, 46%) developed incident abnormal vaginal Pap tests while 160 (58%, 95% C.I. 52%, 64%) did not. The incidence of abnormal vaginal Pap tests after hysterectomy was 14/100 person-years among HIV seropositive and 2/100 person-years among seronegative women (P < 0.001).
The cumulative risk of an abnormal Pap test, including baseline and follow-up, was high in both groups: after 12 years of observation, the risk of ever having abnormal vaginal cytology was 75%(95% C.I. 64%, 83%) in HIV seropositive and 42% (95% C.I. 2%, 66%) in seronegative women (P = 0.13). The risk of ever having a Pap read as HSIL or worse over 12 years of observation was 6.4% (95% C.I. 0.3%, 12.2%) for HIV seropositive women and 0.0% (95% C.I. 0%, 0%) for HIV seronegative women (P = 0.03).
Clearance of Pap abnormality was evaluated among all 193 women (177 HIV seropositive, 16 seronegative) with prevalent or incident Pap abnormalities. After excluding 25 women without follow-up and 4 women who were treated (all excluded women were seropositive), the 193 women included 91 (84 HIV seropositive and 7 seronegative) women with prevalent Pap abnormalities and 102 (93 HIV seropositive, 9 seronegative) with incident abnormalities. Of these, 113 (64%, 95% C.I. 57%, 71%) of HIV seropositive and 13 (81%, 95% C.I. 57%, 93%) of seronegative women cleared their abnormality without treatment (P = 0.16) across all visits. The 5-year clearance rate was 34 cases/100 person-years for HIV seropositive women and 116/100 person-years for HIV seronegative women (P < 0.001). Clearance rates were higher for women with ASC-US (98, 72%, 95% C.I. 63%, 78%) than LSIL (28 (50%, 95% C.I. 37%, 63%, P = 0.004). In multivariable Cox analysis, clearance of any Pap abnormality was less likely among HIV seropositive women with lower CD4 counts (HR 0.79, 95% C.I. 0.37, 1.66 for CD4 >500/μl, 0.53, 95% C.I. 0.26, 1.1 for CD4 200–500/μl, and 0.36, 95% C.I. 0.16, 0.80, for CD4 <200/μl; P for trend = 0.002, compared to HIV seronegative women), or with LSIL vs ASC-US cytology (H.R. 0.52, 95% C.I. 0.32, 0.87, P = 0.01). Those with more than one sexual partner in the six months before abnormal Pap were more likely to clear Pap abnormalities (H.R. 2.34, 95% C.I. 1.19, 4.59, P = 0.01 vs no sexual partner). Age, ethnicity, smoking, parity, and incident vs prevalent hysterectomy were not linked to clearance of cytologic abnormality. In a separate model limited to HIV seropositive women, after adjusting for CD4 count, plasma HIV RNA level and HAART use were not associated with clearance.
We next assessed vaginal biopsy results, including women with and without prior hysterectomy. Biopsies were obtained from 269 women, including 255/2791 (9%, 95% C.I. 8%, 10%) HIV seropositive women and 14/953 (1%, 95% C.I. 1%, 2%) seronegative women (P < 0.001). shows the highest grade VAIN for each woman, including results from women with multiple biopsies; although only HIV seropositive women had VAIN3, differences in the distribution of biopsy grade did not reach significance. Prevalent VAIN of any grade was found within six months of intake in 21/2791 (1%, 95% C.I. 0.7%, 1.4%) HIV seropositive women and no seronegative women (P = 0.01). Incident VAIN was found in 151 HIV seropositive and 7 seronegative women, and the incidence rate of VAIN was 0.8 per 100 person-years for HIV seropositive and 0.1 per 100 person-years for seronegative women (P < 0.001).
Highest Grade Vaginal Biopsy Result Among 269 HIV Seropositive and Seronegative Women Undergoing Biopsy
We found no prevalent cases of VAIN2+ in HIV seropositive or seronegative women, while incident VAIN2+ developed in 36 HIV seropositive women and one seronegative woman. The incidence of VAIN2+ was 0.2 per 100 person-years for HIV seropositive women and 0.01 per 100 person-years for HIV seronegative women (P = 0.001). Associations between VAIN and various risk factors are shown in . In multivariable Cox models, incident VAIN was associated with lower CD4 count, current smoking, and higher parity but not age, ethnicity, or number of recent sexual partners. In a separate model limited to HIV seropositive women, HIV RNA level in blood was not associated with incident VAIN after controlling for CD4 count. In another model incorporating HIV seropositive women that adjusted for multiple additional risk factors in addition to CD4 count and HIV RNA level, incident VAIN was linked to HAART use in the prior six months (HR 1.94, 95% CI 1.23, 3.05, P = 0.004) and current smoking (HR 2.04, 95% CI 1.19, 3.51, P = 0.01).
Factors Associated With Incident Vaginal Intraepithelial Neoplasia in Multivariable Analysis
The incidence of VAIN remained higher among HIV seropositive women when only the 418 women with hysterectomy were evaluated. VAIN was found within six months of enrollment in 13 women, all HIV seropositive (4% of all seropositive women with hysterectomy, 95% C.I. 2%, 6%). In all, incident VAIN was found in 56 women (54 HIV seropositive, two seronegative). The incidence of VAIN was 2.9/100 person-years for HIV seropositive women and 0.4/100 person-years for seronegative women (P = 0.002). However, the incidence of VAIN2+ in women after hysterectomy was only 0.8/100 person-years for HIV seropositive and 0/100 person-years in HIV seronegative women (P = 0.05). Treatment for VAIN was undertaken for 41 women (38 HIV seropositive, three seronegative). Only 12 women (11 HIV seropositive, one seronegative) required treatment for VAIN detected after hysterectomy, but Paps remained abnormal after treatment in 10 (9 HIV seropositive, one seronegative).
Two women, both HIV seropositive, developed vaginal cancer after prior hysterectomy. The first was diagnosed with stage II squamous cell carcinoma in 2000 and was treated with radiotherapy; she died 10 months later from substance abuse complications but with persistent vaginal cancer. Prior Paps tests had shown ASCUS or LSIL, but three vaginal biopsies prior to diagnosis showed only condyloma. The second patient had undergone hysterectomy in 1997 for cervical carcinoma in situ and a Pap test read as atypical glandular cells. No cancer was found then and no subsequent vaginal biopsies were done. She was diagnosed with a stage II adenosquamous carcinoma of the vagina in 2004 and was treated with excision and radiotherapy and was free of disease seven years after initial treatment.