Massad, L. Stewart MD; D'Souza, Gypsyamber PhD; Tian, Fang MPH; Minkoff, Howard MD; Cohen, Mardge MD; Wright, Rodney L. MD; Colie, Christine MD; Hessol, Nancy A. MSPH
From the Washington University School of Medicine, St. Louis, Missouri; the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Maimonides Medical Center, State University of New York, Downstate, Brooklyn, and the Albert Einstein College of Medicine, Bronx, New York; Rush Medical College and Cook County Bureau of Health Services, Chicago, Illinois; Keck School of Medicine, University of Southern California, Los Angeles, and the University of California, San Francisco, San Francisco, California; the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland; and Georgetown University School of Medicine, Washington, DC.
See related article on page 783.
The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
The authors thank the Women's Interagency HIV Study (WIHS) Collaborative Study Group for data collection. Centers (Principal Investigators) are located at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange).
Corresponding author: L. Stewart Massad, Division of Gynecologic Oncology, Washington University School of Medicine, 4911 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
Women with human immunodeficiency virus (HIV) face a higher risk for cervical cancer than the general population.1 That risk has remained elevated despite the widespread adoption of antiretroviral therapy.2 Nevertheless, most cervical cancers are preventable, even in women with HIV. With frequent Pap test surveillance and treatment of precursors, HIV-infected and HIV-uninfected women have similar cervical cancer risk.3 The Centers for Disease Control and Prevention recommends two Pap tests in the first year after HIV diagnosis, with annual Pap tests thereafter.4 This recommendation is based on expert opinion and has not been validated.
Cervical cancer prevention guidelines for the general U.S. population have been amended recently to recommend longer intervals between Pap tests.5 Under these guidelines, women should be screened only every 3 years. Cotesting with Pap and an assay for human papillomavirus (HPV) allows 5-year screening intervals, but HPV screening may not be suitable for women with HIV, who have a high burden of HPV. More frequent testing is cost-ineffective: because cervical cancer is uncommon in the general population, many positive test results will reflect self-limited infection with HPVs conveying minimal oncogenic risk; shortening screening intervals from 3 years to one leads to cervical cancer in about 3 of 100,000 women screened.6
The cumulative risk of abnormal Pap test results among women who are HIV-seropositive is as high as 77%.7 The 2-year negative predictive value (NPV) of HPV testing for SIL Pap test results ranged from 91% to 96%, depending on CD4 count.8 Pap tests may have a similarly high NPV for cervical precancer.
The aims of this analysis of Pap test results obtained at 6-month intervals in a large cohort of women who are HIV-seropositive were to estimate the 1-year and 3-year NPV of Pap testing, to compare these results with those from HIV-seronegative women, to estimate the accuracy of Pap testing, and to confirm or recommend adjusting Centers for Disease Control and Prevention Pap test–screening recommendations for women who are HIV-seropositive.
PATIENTS AND METHODS
This study was part of the Women's Interagency HIV Study, an ongoing multicenter cohort study of HIV-related disease among women who are HIV-seropositive and at-risk seronegative comparison women.9 Enrollment began October 1, 1994, at six study consortia and over time enrolled 3,766 women, including an expansion during 2001–2002.10 Follow-up continues, but this analysis includes information obtained before October 1, 2010. Written informed consent for study was obtained after local human subjects committees approved protocols.
Every 6 months, participants had a physical examination that included a conventional Pap test. Slides were interpreted centrally according to the 1991 Bethesda system for classification of cervicovaginal cytology and were classified as negative for squamous abnormality, atypical squamous cells of undetermined significance (ASC-US), atypical glandular cells, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ, and cancer11; a later modification included atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions.
Women with Pap test results available from study entry were identified. We excluded those with documented or self-reported prior abnormal Pap test results, cervical cancer, or cervical disease treatments such as cryotherapy or loop excision. We also excluded women with prior hysterectomy.
Because cervical cancer is rare in our cohort,3 the primary study endpoint was cervical precancer, defined for this study as a composite of cervical cytology read as HSIL, atypical glandular cells favor neoplasia or adenocarcinoma in situ, or cancer, as well as cervical biopsies read as grade 2 or 3 cervical intraepithelial neoplasia (CIN), or adenocarcinoma in situ (CIN 2 or worse). Pap test results read as ASC-US or LSIL but not precancer were considered abnormal but not precancer. Colposcopy was prescribed by protocol for women with any cytologic abnormality or visible condylomata, later modified to allow annual colposcopy for women with persistent ASC-US results but negative colposcopy. Decisions about biopsy were made by site colposcopists and study participants, although conization was recommended for most patients with precancer. The proportion of women with precancer diagnosed within 15 and 39 months after 1, 3, or 10 consecutive negative Pap test results was assessed to estimate NPV; these intervals were selected to allow for 12 and 36 months of additional surveillance plus 3 further months for workup of abnormalities. When interval Pap tests were missing, we imputed negative tests for single missing results between two consecutive negatives but left them as missing values when two or more consecutive Pap tests were missing. Negative predictive value was estimated further for subgroups stratified by HIV status and age.
Longitudinal analysis of predictors of precancer was performed using Cox proportional hazards models with time-updated covariates for current Pap test results, age, current tobacco use, current CD4 count, and current use of highly active antiretroviral therapy (HAART), as well as race. Models were run lagging risk factors both 15 and 39 months from the current Pap test or biopsy test. Highly active antiretroviral therapy use was defined as previously described.12 Risk factors for precancer were modeled among all women, as well as when restricted to only women who are HIV-seropositive. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) are reported.
Of 3,729 women in the Women's Interagency HIV Study with at least one satisfactory Pap test result, we excluded 1,736; women with one or more reasons for exclusion included 136 with precancer at the initial visit, 138 with a prior history of cervical disease or treatment, 131 with a self-reported prior history of cervical cancer, 348 with prior hysterectomy, and 1,426 with a self-reported history of prior abnormal Pap test result. We also excluded 182 women with no follow-up, leaving 1,811 women (1,225 HIV-seropositive and 586 HIV-seronegative) with no prior precancer and an available baseline Pap test result for this analysis. Among these, 1,462 women (942 HIV-seropositive, 520 HIV-seronegative) had a negative baseline Pap test result.
The baseline demographic and medical characteristics of the women with negative initial Pap test results are presented in Table 1. For the analysis of outcomes after 15 months among these women with negative baseline Pap test results, we had 1,153 person-years of follow-up among women who are HIV-seropositive and 634 person-years of observation among women who are seronegative. For analysis of outcomes after 39 months, women who are HIV-seropositive contributed 2,818, and women who are seronegative contributed 1,556 person-years of follow-up.
The distribution of cytologic and histologic results is shown in Table 2; most women had precancer identified at a visit when cytology was only ASC or LSIL. Only 14 of the 40 women with Pap test results that proved to be falsely negative during 39 months of observation (ie, women with baseline negative Pap test results who developed precancer) had biopsy-confirmed CIN 3. This represents only 1% of the 942 women at risk. No cancers were found in these women. One woman developed vaginal intraepithelial neoplasia 2 after hysterectomy within the 39-month window but had been censored because of the hysterectomy.
We first assessed the accuracy of a single baseline cytology test among women who are HIV-seropositive. Among the 1,225 such women without a prior history of abnormal Pap test results or cervical disease at study entry, 25 (2%) were diagnosed with precancer during 15 months of follow-up, and 17 of these 25 (68%) had initial abnormal Pap test results. Of 1,200 women without precancer during 15 months of observation, 934 (78%) had negative Pap test results at baseline. Thus, eight (1%) of the women with negative cytology developed precancer within 15 months and 40 (4%) within 39 months. These results yield a sensitivity of Pap testing in women who are HIV-seropositive of 68%, a specificity of 78%, and a positive predictive value of 6%. Table 3 shows how NPV varied by age, HIV serostatus, and number of prior negative Pap test results. Because NPV varies with prevalence, we modeled outcomes using the same sensitivity and specificity values while varying the prevalence of precancer from 1% to 6%; NPV in these models fell only from 99.6% (95% CI 99.2–100%) to 97.4% (95% CI 96.4–98.5%).
We next evaluated precancer risk among these same women with negative baseline Pap test results when monitored longer. Among our 1,225 HIV-seropositive women, precancer developed in 71; 31 (44%) of these had abnormal Pap test results at baseline. Conversely, of 1,154 women who did not develop precancer, 252 (22%) had abnormal Pap test results at baseline and 902 had negative Pap test results. From these data we derived the sensitivity of a single Pap test for precancer within 39 months of 44%, a specificity of 78%, and a positive predictive value of 11%. When we evaluated the effect of varying 39-month precancer prevalence 1% to 6%, the NPV of cytology fell from 99.3% (95% CI 98.7–99.8%) to 95.6% (95% CI 94.3–96.9%).
We also compared precancer risk among women with HIV with that among HIV-uninfected women. Risk was consistently higher for women who are HIV-seropositive in all comparisons, both those at 15 and those at 39 months after one and three negative Pap test results (not shown).
We next attempted to estimate the NPV of serial negative Pap test results. After three consecutive negative Pap test results, including those from baseline and subsequently, none of 539 eligible women who were HIV-seropositive developed precancer during the subsequent 15 months, whereas 10 (2%) developed precancer within 39 months. Among 182 eligible women who are HIV-seropositive with 10 consecutive negative Pap test results, none developed precancer within the next 39 months. These 182 HIV-seropositive women with 10 consecutive negative Pap test results represented 55% of all women who are seropositive with 39 months of follow-up after 10 Pap test results; the remaining 45% of women with adequate follow-up had one or more Pap test result abnormalities among the 10 specimens collected.
We estimated risk factors for precancer longitudinally among all Women's Interagency HIV Study participants with at least one Pap test, including those with Pap test results initially read as ASC-US or LSIL. In multivariate analysis (Table 4), women who are HIV-seropositive had twice the risk of precancer at 15 months compared with seronegative women (adjusted HR 1.9, 95% CI 1.5–2.5, P<.001). Other significant risk factors for precancer at 15 months included younger age (adjusted HR 1.7 for age younger than 31 years compared with older than 45 years, 95% CI 1.3–2.2, P<.001), current tobacco use (adjusted HR 1.5, 95% CI 1.2–1.9, P<.001), and abnormal Pap test result during follow-up (adjusted HR 11.9, 95% CI 9.6–14.8, P<.001). Risk factors for precancer within 39 months of a single negative Pap test result were similar to those observed at 15 months (Table 4). Current oral contraceptive use and the number of male sexual partners in previous 6 months were not associated with precancer risk within 15 or 39 months (data not shown). We also examined the effect of reporting a new sexual partner within the previous 6 months on the subsequent incidence of precancer at 15 and 39 months. Having a new sexual partner was not a significant predictor of precancer in any of these models.
Risk factors for precancer were similar when restricted to women who are HIV-seropositive only (Table 5). In that analysis, precancer during 15 months of follow-up was associated with any abnormal Pap test result (adjusted HR 9.9, 95% CI 7.7–12.6), current smoking (adjusted HR 1.5, 95% CI 1.2–2.0 compared with nonsmokers), younger age (adjusted HR 1.5, 95% CI 1.1–2.1 for age younger than 31 years compared with age older than 45), and lower CD4 count (adjusted HR 1.8, 95% CI 1.3–2.3 for CD4 200–500; adjusted HR 2.2, 95% CI 1.6–2.9 for CD4 less than 200, compared with CD4 more than 500). Use of HAART, age, and ethnicity were not associated with precancer risk within 15 months.
We also examined the effect of reporting a new sexual partner within 6 months of an index Pap test result on the subsequent incidence of precancer at 15 and 39 months. We used separate Cox models adjusting for Pap test results, age, and HIV status among all women; for Pap test result only for women with HIV; and for Pap test result only among HIV-seronegative women. Having a new sexual partner was not a significant predictor of precancer in any of these models.
Current guidelines recommend that women infected with HIV obtain Pap test results at HIV diagnosis and 6 months later, with subsequent lifetime annual testing if both are negative.4 This guideline is based on expert opinion and the observations that the sensitivity of Pap testing is limited and women with HIV are at increased risk for cervical precancer. Harris and colleagues using data from the Women's Interagency HIV Study have shown that 3-year screening intervals are safe for women who are HIV-seropositive after a single combination Pap and high-risk HPV DNA test.8
Our results show that women who are HIV-seropositive with negative Pap test results and no history of Pap test result abnormalities have a low short-term risk for precancer and negligible risk for cancer. After HIV diagnosis, annual rather than semiannual Pap testing is safe for women with newly diagnosed HIV and no history of abnormal Pap test results.
Castle and associates have established guidance for cervical cancer prevention measures based on risk stratification for CIN 3 or worse, the most advanced marker for cancer risk.13 Given the slow rate of development of cervical precancer to cancer, they suggested routine screening intervals for women with a risk for CIN 3 or worse of 2% or less over two to 3 years. Because the rate of progression from CIN to cancer may be accelerated in immunodeficient women, we used a more liberal definition of precancer than Castle and colleagues did, including CIN 2 and unconfirmed HSIL Pap test results. Three-year risk for precancer among women who are HIV-seropositive in the Women's Interagency HIV Study with three consecutive negative Pap test results was only 2%; only 1% developed CIN 3 or worse and none developed cancer within 3 years. These findings suggest that women who are HIV-seropositive with negative Pap test result histories can be screened at longer intervals than currently recommended.
Our finding that women with negative Pap test results are at relatively low risk of precancer and can be screened at intervals similar to those recommended for HIV-seronegative women does not imply that women who are HIV-seropositive are at low risk for precancer. Women with any Pap test result abnormalities require colposcopy to identify precancer and guide treatment that will interrupt oncogenesis, although management of abnormalities can follow current guidelines for HIV-seronegative women.14,15 Women with prior Pap test result abnormalities and those with treated precancer and cancer were not evaluated in this study and are not candidates for longer screening intervals. With intensive screening and follow-up women who are HIV-seropositive are at very low risk for cancer.3
Our study was limited by several factors. First, women in the Women's Interagency HIV Study were recruited from sites where some had received prior care, including Pap tests and treatment for cervical cancer precursors; initial study Pap tests may not be the first Pap tests after HIV diagnosis. However, the incidence of Pap test result abnormalities declined over time in the Women's Interagency HIV Study, suggesting that intake screening identified many women with evolving cervical lesions.7 Further, exploratory analysis of our study group showed that Pap testing had a robustly high NPV for precancer across hypothetical populations with precancer risk as high as 6%. Second, women in the Women's Interagency HIV Study represent a self-selected group of women who are HIV-seropositive. Our recommendations would be strengthened by validation at centers providing care for women who are HIV-seropositive who have received less intensive surveillance. Third, we used 6-month rather than annual Pap-test intervals. However, women who have survived 3 years without a Pap test result abnormality should have lower precancer risk than those monitored only 18 months, so our data on precancer risk should be considered a conservative estimate for women tested annually. Fourth, because this study population was restricted to women with no history of any abnormal Pap test result, including the baseline study visit, clinicians may encounter a lower proportion of women who are HIV-seropositive with three consecutive negative Pap test results. Fifth, many women in our cohort were recruited before the adoption of HAART; precancer risk for women on HAART may be lower. Finally, we used precancer rather than biopsy-confirmed CIN 2 or worse as our endpoint as a conservative assumption because compliance with recommended colposcopy in the Women's Interagency HIV Study is suboptimal. Because some HSIL Pap test results may reflect low-grade disease and some CIN 2 may regress, our results likely underestimate the Pap test's NPV, and longer screening intervals are probably safer than our results would indicate.
In conclusion, we suggest that, after three negative annual Pap test results, women who are HIV-seropositive can be screened at 3-year intervals. Alternatively, 3-year intervals for women with three consecutive negative Pap test results may be restricted to women aged 40 and older because these women had a risk of precancer in our study of less than 1%. Women with 10 or more consecutive Pap tests should defer screening for at least 3 years; further research may allow even longer screening intervals for these women.
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