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Longitudinal Study of Cervical Squamous Intraepithelial Lesions in Human Immunodeficiency Virus (HIV)-Seropositive and At-Risk HIV-Seronegative Women

  1. Paula Schuman1,
  2. Suzanne E. Ohmit1,a,
  3. Robert S. Klein2,
  4. Ann Duerr3,
  5. Susan Cu-Uvin4,
  6. Denise J. Jamieson3,
  7. Jean Anderson5 and
  8. Keerti V. Shah5
  1. 1 Wayne State University School of Medicine, Detroit, Michigan
  2. 2 Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York
  3. 3 Centers for Disease Control and Prevention, Atlanta, Georgia
  4. 4 Miriam Hospital and Brown University School of Medicine, Providence, Rhode Island
  5. 5 Johns Hopkins University School of Medicine, Baltimore, Maryland
  1. Reprints or correspondence: Dr. Suzanne E. Ohmit, University of Michigan School of Public Health, Dept. of Epidemiology, 109 Observatory, Ann Arbor, MI 48109 (sohmit{at}umich.edu).

  • ↵Present affiliation: Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor.

 
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Abstract

We examined incidence and correlates of progression and regression of abnormal cervical cytologic test results, defined as at least low-grade squamous intraepithelial lesions (SILs), in 774 human immunodeficiency virus (HIV)-seropositive and 391 HIV-seronegative women monitored semiannually for up to 5.5 years. During follow-up, 224 (35%) HIV-seropositive women and 34 (9%) HIV-seronegative women had incident SILs detected by Pap test; 47 (7%) HIV-seropositive women developed high-grade lesions. The incidence of SILs was 11.5 cases among HIV-seropositive and 2.6 cases among HIV-seronegative women per 100 person-years of observation (rate ratio, 4.5; 95% confidence interval, 3.1–6.4; P<.001). Risk of incident SILs and likelihood of Pap test progression were increased among HIV-seropositive women with CD4+ lymphocyte counts <500 cells/mm3 and among women with human papillomavirus (HPV) infection, with risk-ordering from low-to high-risk HPV type. SIL regression was less likely among HIV-seropositive women with higher HIV loads. No beneficial effect of highly active antiretroviral therapy was demonstrated.

Squamous intraepithelial lesions (SILs) of the uterine cervix, which are precursors to invasive cervical cancer, are among the most prevalent gynecologic manifestations of human immunodeficiency virus (HIV) infection [1–4]. The etiologic association of human papillomavirus (HPV) infection with cervical SILs has been established elsewhere [5, 6]. HIV-associated, cell-mediated immunocompromise may increase risk for HPV infection, promote reactivation of latent infection, or permit HPV persistence, resulting in increased risk of cervical dysplasia [7–9]. HIV load may also influence the natural history of dysplasia and invasive cancer [2, 10, 11]. Although standard therapy for cervical dysplasia in immunocompetent women is highly successful with minimal morbidity, in the context of HIV infection, cervical dysplasia may progress more rapidly to invasive disease and respond less well to standard therapy [3, 4, 12–14]. Theoretically, highly active antiretroviral therapy (HAART) could reduce the risk of cervical dysplasia and progression to invasive disease by controlling HIV replication and reversing immunodeficiency, but that possibility has not yet been established.

We report findings from the HIV Epidemiology Research Study (HERS), a multicenter, longitudinal cohort study of women living with or at-risk of HIV infection. HERS was designed to study the biological, behavioral, and social determinants of HIV disease progression among US women [15]. Our objectives in the present study were to determine the incidence of cervical SILs detected by Pap test among HIV-seropositive and -seronegative women monitored prospectively from 1993 through 1999, and to describe the natural history of cervical SILs in these 2 groups by estimating the associations of various factors with progression and regression of these lesions.

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Subjects and Methods

From April 1993 through January 1995, 871 HIV-seropositive women and 439 demographically and behaviorally similar HIV-seronegative women were enrolled at HERS sites in Bronx, New York; Detroit, Michigan; Baltimore, Maryland; and Providence, Rhode Island. Institutional review boards at participating centers and the Centers for Disease Control and Prevention reviewed and approved this study for protection of human subjects. All participants provided written informed consent. Details of the HERS design and selection of participants have been published elsewhere [15]. Women 16–55 years old were eligible for participation if they reported injection drug use (since 1985) or high-risk sexual behavior (>4 partners during the last 5 years, sex for money or drugs, sex with male injection drug users, or sex with partners known or suspected to have HIV or AIDS), agreed to HIV counseling and testing, and, if they were HIV seropositive, reported no history of clinical AIDS-defining conditions. By design, each study site contributed equal numbers of participants, and enrollment risk behaviors were equally distributed by HIV serostatus; HIV-seropositive and -seronegative women were enrolled at a 2:1 ratio. Women were interviewed and received targeted physical examinations at baseline and at each semiannual follow-up visit. Data collected during interviews included information on sociodemographics; medical, gynecologic, and obstetric history; health care utilization; and behavioral characteristics. Retrospective abstraction of medical records was initiated by participants' reports of hospitalizations or medical/surgical procedures.

At each visit, pelvic examinations were performed by study clinicians trained in the diagnosis of genital tract conditions. Specimens were collected for Pap tests and HPV detection and typing. Cervical Pap tests were performed using an Ayres spatula and cytobrush and were shipped to a single commercial cytology laboratory (Kyto Diagnostics) for interpretation according to predefined criteria [16]. Cytopathologists were blinded to participants' serostatus; a senior pathologist, also blinded, read all tests originally classified as abnormal and 10% of those classified as normal. For analysis, Pap test reports were categorized as normal, atypical squamous cells of uncertain significance (ASCUS), lowgrade SILs (LSILs), or high-grade SILs (HSILs). The HSIL category included Pap tests interpreted as squamous cell carcinoma, because it was not possible to analyze that small group separately. Women with LSILs or HSILs were categorized as having cervical SILs.

At each visit, cervical and vaginal secretions and exfoliated cells were collected by cervicovaginal lavage; specimens were tested for HPV by polymerase chain reaction using consensus L1 primers [17] with amplification of cellular β-globin as a control for sample adequacy. HPV type in the amplified product was identified by hybridization with a generic probe designed to recognize most HPV types and with multiple type-specific probes [18]. Specimens positive by the generic probe but negative by all type-specific probes were considered to be “untyped” HPV. At least 25 different HPV types were detected [19]. For analysis, HPV types were grouped by risk categories defined on the basis of their prevalence in cervical cancers in an international study [6]. High-risk types included 16, 18, 31, and 45; intermediate-risk types included 33, 35, 39, 51, 52, 56, 58, 59, 68, 73, and 82; low-risk types included 6, 11, 26, 40, 53, 54, 55, 66, 83, and 84; and a fourth risk category included “untyped” HPV [19–21]. Specimens with multiple HPV types were classified by the highest risk-type identified [19–21]. A longitudinal examination of type-specific prevalence, incidence and persistence of HPV infection in the HERS population has been published elsewhere [19].

At each visit, blood was collected for immunophenotyping by flow cytometry and determination of plasma HIV-1 RNA levels. CD4+ lymphocyte counts were categorized as <200, 200–500, and >500 cells/mm3. HIV loads were determined using a branched-DNA signal amplification assay (lower limit of quantification, <50 HIV-1 RNA copies/mL; Chiron). Virus load values were log-transformed for improved symmetry and considered in models as continuous values [22].

At baseline, 112 women reported having had a hysterectomy (76 were HIV seropositive). During follow-up, 37 additional women (27 were HIV seropositive) were identified by review of medical records as having had hysterectomies. Data obtained from women who reported hysterectomy at baseline and subsequent data from those who had hysterectomy during followup were excluded from the longitudinal analyses presented here. An additional 33 women (21 were HIV seropositive) were excluded from all analyses because they did not contribute any Pap test data.

Women with abnormal cervical cytologic test results from study visit Pap tests were referred for follow-up care; however, no uniform treatment protocol existed across study sites. Data from medical record abstractions were reviewed for reports of excisional or ablative cervical procedures, including those identified as cervical cone biopsy, loop excision of transformation zone, and cryotherapy, but excluding endocervical curettage and punch biopsies. Documented procedures for treating dysplasia were coded as affirmative at the study visit following the procedure date.

Demographic variables considered in analyses included age, race/ethnicity, and education. At each visit, women were asked whether in the last 6 months they were sexually active with ⩾1 partners or used tobacco, and, if HIV-seropositive, whether they currently used antiretroviral therapy, including highly active antiretroviral therapy (HAART), as defined by Department of Health and Human Services guidelines [23]. Reported antiretroviral therapy was categorized as either HAART or sub-HAART (non-HAART combination therapy or monotherapy), compared with no antiretroviral therapy.

Statistical analyses were performed using SAS statistical software (version 6.12; SAS Institute). Baseline population characteristics, including prevalence of cervical SILs by HIV serostatus, were examined using the χ2 test for categorical variables and Wilcoxon rank sum test for continuous values [21]. Hazard rates (incidence of SILs during follow-up expressed as cases per 100 person-years observation) and rate ratios (RRs) for seropositive versus seronegative women were estimated using exponential survival models. SIL incidence during follow-up, stratified by HIV serostatus and CD4+ lymphocyte count at baseline, was evaluated by the Kaplan-Meier method, with comparison of survival curves (time to event), using the log-rank test.

Risk of SILs during follow-up and factors associated with risk were evaluated using discrete time survival analysis with the complementary log-log model link; this model permitted a relative risk interpretation of the coefficients. Odds of Pap test status progression (moving from normal or ASCUS to LSILs or HSILs, or from LSILs to HSILs) or regression (moving from LSILs or HSILs to a lower category) between consecutive visits and factors associated with these outcomes were estimated using repeated-measures multivariate logistic regression models. These models used appropriate correlation structures to account for within-subject correlation across multiple observations on individual participants [24] and were adjusted for Pap test status at the first visit of consecutive visits.

Covariates considered in all models were permitted to have different values at each visit and were modeled as status at time of visit or at previous visit (lag variables). Multivariate models were adjusted for study site and considered the associations of HIV serostatus plus CD4+ lymphocyte count, demographic characteristics, risk behaviors, and HPV risk category with the outcomes. In separate models that considered only HIVseropositive participants, the associations of CD4+ lymphocyte count, HIV load, and categories of antiretroviral therapy with the outcomes were evaluated.

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Results

Pap test data considered here were available from up to 12 semiannual study visits (5.5 years of observation) and included results from 8852 tests. Data from 774 HIV-seropositive and 391 HIV-seronegative women (n = 1165) with intact cervices at baseline were available. Median follow-up time of 4 years did not differ by serostatus. Baseline characteristics of participants, by HIV serostatus, are presented in table 1.

Figure 1.
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Figure 1.

Follow-up time to incident squamous intraepitheliallesions(SILs), by baseline human immunodeficincy virus (HIV) serostatus (infected [+] or uninfected [−]) and CD4+ lymphocyte count (cells/mm3).

Table 1.
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Table 1.

Baseline characteristics of participants in the HIV Epidemiology Research Study who contributed Pap test data, by human immunodeficiency virus (HIV) serostatus.

Among participants with baseline Pap test data (n = 1048), 134 HIV-seropositive and 18 HIV-seronegative women had SILs identified at baseline [21]. An additional 11 HIV-seropositive women without baseline Pap test results had SILs detected at their first follow-up visit for which Pap test data were available; thus, 19% (145/774) of HIV-seropositive women and 5% (18/391) of HIV-seronegative women (P<.001) had prevalent SILs detected on the first available Pap test. During follow-up (excluding those with baseline SILs), 224 (35%) HIV-seropositive women and 34 (9%) HIV-seronegative women had incident SILs detected by Pap test. The incidence rate for SILs among HIV-seropositive women was 11.5 cases/100 person-years of observation, compared with 2.6 cases/100 person-years of observation among HIV-seronegative women (RR, 4.5; 95% confidence interval [CI], 3.1–6.4; P<.001). Eleven women included in these analyses became HIV seropositive during follow-up. Two of these women had SILs identified, both after seroconversion; these 2 cases were included with incident values for HIV-seropositive women.

Follow-up time to incident SILs, stratified by baseline HIV serostatus and CD4+ lymphocyte count category, is presented in figure 1. Risk of SIL during follow-up varied significantly by HIV serostatus, and, among HIV-seropositive women, risk significantly varied by baseline CD4+ lymphocyte count category (P<.001 , log-rank test) (women who seroconverted during follow-up were excluded from this presentation). Fifty-six percent (144/258) of women with incident SILs by study visit Pap test had colposcopy or cervical biopsy studies performed within 6 months before and 12 months after the Pap test. Colposcopy or biopsy results confirmed Pap tests diagnoses for 76% (109/144) of those with incident SILs and additional studies. In addition, 98% of women with incident SILs by study visit Pap test had concurrent HPV test results; 93% of those with incident SILs were also HPV positive. Among those who were not HPV positive at the time of their SIL diagnoses, 71% tested positive for HPV at ⩾1 prior visit.

Of the 163 prevalent cases of SILs detected at baseline, 30 (18%) were classified as HSILs, including one Pap test read as squamous cell carcinoma; 24 (3%) of these cases occurred among HIV-seropositive women (including the Pap test read as squamous cell carcinoma), and 6 (2%) occurred among HIVseronegative women. During follow-up, 47 HIV-seropositive women (7%) and 4 HIV-seronegative women (1%) had incident HSILs (including a second Pap test read as squamous cell carcinoma in an HIV-seropositive women). The incidence rate of HSILs among HIV-seropositive women was 1.6 cases/100 person-years of observation, compared with 0.3 cases/100 person-years of observation among HIV-seronegative women (RR, 5.1; 95% CI, 1.9–14.2; P = .002).

Multivariate analyses of factors associated with risk of incident SILs are presented in table 2. HIV-seropositive women with CD4+ lymphocyte counts <200 or 200–500 cells/mm3 had at least twice the risk of developing SILs as did HIV-seronegative women; those with CD4+ lymphocyte counts >500 cells/mm3 were not at increased risk. Detection of HPV infection was significantly associated with incident SILs, with risk-ordering for SILs from low-to high-risk HPV types. Age, race/ethnicity, education, sexual activity, and tobacco use were not significantly associated with risk of developing SILs. In separate analyses among HIV-seropositive women only, those with CD4+ lymphocyte counts <500 cells/mm3 were approximately twice as likely to develop SIL during follow-up as were HIV-seropositive women with CD4+ lymphocyte counts >500 cells/mm3.HIV load values were not related to risk of incident SIL, and reported use of HAART was not associated with reduced risk. The associations of demographic and HPV risk category with SIL outcome were similar to those demonstrated in the model that included all participants and are not shown in table 2.

Table 2.
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Table 2.

Discrete time survival analysis of factors associated with risk for cervical squamous intraepithelial lesions during follow-up.

Table 3 presents results from analyses of factors associated with odds ratios of Pap test status progression (moving from normal or ASCUS to LSILs or HSILs, or from LSILs to HSILs) between consecutive visits for all women, and in separate analysis for HIV-seropositive women alone. HIV-seropositive women with CD4+ lymphocyte counts ⩾500 cells/mm3 were more likely to progress than were HIV-seronegative women, as were HPV-positive women, compared with HPV-negative women. Pap test status at the first visit of consecutive visits was considered in this model, and results indicated that women with ASCUS were more likely to progress and that women with LSILs were less likely to progress, compared with women with normal initial Pap tests. This model was adjusted for dysplasia treatment procedures documented in the medical record. In the model that considered HIV-seropositive women only, women with CD4+ lymphocyte counts <200 cells/mm3 were more likely to progress than were those with CD4+ lymphocyte counts >500/mm3; neither HIV load value nor use of HAART was significantly associated with likelihood of progression.

Table 3.
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Table 3.

Multivariate logistic regression analysis of factors associated with Pap test status progression.

Table 4 presents results from analyses of factors associated with odds ratios of Pap test status regression (moving from LSILs or HSILs to a lower category) between consecutive visits for all women and in separate analysis for HIV-seropositive women alone. HIV-seropositive women with CD4+ lymphocyte counts ⩽500 cells/mm 3 were less likely to regress than were HIV-seronegative women, as were HPV-positive women, compared with HPV-negative women. Women with initial visit Pap tests indicating the presence of HSILs were more likely than those with LSILs to regress. This model was adjusted for dysplasia treatment procedures documented in the medical record. In the model that considered HIV-seropositive women only, likelihood of regression was decreased 22% for every log10 increase in HIV load (i.e., HIV load values of 1000 vs. 10,000 copies/mL). No effect of immunodeficiency (i.e., CD4+ lymphocyte count ⩽500 cells/mm3) on likelihood of regression was seen after adjustment for the effects of HIV load. Women who received HAART were not more likely to regress, compared with women who received either sub-HAART or no antiretroviral therapy.

Table 4.
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Table 4.

Multivariate logistic regression analysis of factors associated with Pap test status regression.

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Discussion

Our study presents analyses of the incidence and natural history of cervical SILs among a large cohort of demographically and behaviorally similar HIV-seropositive and -seronegative women observed prospectively for a median of 4 years. HIV-seropositive women had higher risk of cervical SILs, including incident high-grade SILs, than did HIV-seronegative women, with more than one-third of HIV-seropositive participants developing SILs during follow-up. Incidence rates were slightly higher than those estimated in the New York Cervical Disease Study [1], but, in that study, only biopsy-confirmed SILs were included. Risk estimates of cervical SILs were determined from results of Pap tests performed at scheduled study visits; rates might have been different if outcomes were based on routine colposcopy or confirmed by biopsy. Published estimates of the sensitivity and specificity of Pap tests in HIV-seropositive women [4, 25] are comparable to those seen in the general population [26].

In our study, cervical HPV infection at the time of Pap test was the single most important factor in predicting increased risk of incident SILs and increased likelihood of progression to SILs; this finding is consistent with results of multiple previous studies [1, 8, 27]. All HPV risk categories increased the risk of incident SILs, with risk-ordering from low- to high-risk types. We did not model persistent HPV infection, per se, but rather any current positive status, which could have represented incident, intermittent, or persistent infection [8]. A longitudinal analysis of HPV infection in the HERS population has been published elsewhere [19]; that analysis indicated that typespecific incident and persistent HPV infection occurred more frequently in the HIV-seropositive cohort, compared with that in the HIV-seronegative cohort, and, among HIV-seropositive women, these outcomes were inversely associated with CD4+ lymphocyte count.

HIV-associated cell-mediated immunodeficiency (CD4+ lymphocyte count ⩽500 cells/mm3) was also a factor in predicting incident SILs and in influencing the likelihood of progression of Pap test status between consecutive visits [28]. Immunodeficiency may increase the risk of SILs by permitting HPV persistence [7, 8, 19] or by accelerating the transit time to SILs [29]. Higher HIV loads were significantly associated with reduced likelihood of SIL regression. The direct impact of HIV load on risk of cervical dysplasia has been examined only recently [2] and may involve interactions between HIV and HPV at the molecular level [10, 11].

Limited data are available on the natural history of HPV infection and dysplasia in patients treated with HAART, and results are inconsistent across available studies. Two studies describe regression of cervical lesions in women treated with HAART [30, 31]. A study of anal SILs in HIV-seropositive men found that 75% of high-grade lesions in those treated with HAART failed to regress [9]. Lillio et al. [32] reported that persistence of high-risk HPV infection and progression of SILs were similar among HIV-seropositive women treated with HAART, non-HAART, or no antiretroviral therapy. Our study found no beneficial effect of HAART in reducing the risk of progression or increasing the likelihood of regression. Antiretroviral therapy status at the visit before SIL outcome (lag therapy) was used in analytic models to measure the influence of therapy on the outcomes. Because the analyses as presented were organized around visit data, it was not possible to model duration of therapy; instead, reported medication status at each visit was considered. These measures could have represented new, intermittent, or prolonged treatment with ⩾1 antiretroviral medications. In some models, antiretroviral therapy was associated with increased likelihood of outcomes, which suggests that therapy was acting as a marker for more severe immunocompromise because of the increased likelihood of antiretroviral therapy among participants with later-stage disease. Timing and duration of therapy in relation to SIL outcomes, antiretroviral resistance complications, and adherence issues could all have affected our ability to measure a significant benefit for therapy if one exists. We should also emphasize that the observational design of our study is not ideal for evaluating the impact of HAART on the natural history of cervical dysplasia.

We found that the likelihood of Pap test progression between consecutive visits was greater for those tests read as ASCUS, compared with those read as LSILs. This result suggests that rapid progression to HSILs is relatively rare, compared with progression to LSILs, regardless of HIV serostatus. ASCUS is the most common abnormal Pap test result currently reported by US cytology laboratories and represents a clinical challenge, regardless of the population involved. Adding HPV DNA testing to cytologic testing may help to identify those with underlying SILs [33].

We found that the likelihood of Pap test regression between consecutive visits was greater for those tests read as HSILs, compared with those read as LSILs, even after adjustment for treatment procedures. It is possible that we have incomplete information from medical record abstraction of treatment procedures or that women with Pap tests read as HSILs were deemed not to require treatment on the basis of colposcopic findings. Highgrade lesions also could have appeared to be more likely to regress than low-grade lesions, because of one more level that could be scored as improvement. Diagnostic reproducibility of cervical cytologic and histologic studies was examined in a recent trial, and results suggested low levels of agreement of diagnostic interpretations [34, 35].

Five HIV-seropositive women, but no HIV-seronegative women, were identified in our study as having invasive cervical cancer. There were 2 cases detected by Pap test, and 3 diagnosed during hospitalization, with identification based on medical record abstractions. Four of the women had SILs on a Pap test at a study visit before the cancer diagnosis. These cases have been reported in detail elsewhere [36].

Age, race/ethnicity, education, and sexual activity were not significantly associated with risk of SILs, confirming that sociodemographic and behavioral risk factors for dysplasia are likely predictors of HPV infection but are not associated with SIL outcomes after adjustment for HPV status [4, 28, 29, 37]. Failure to find that age was related to SILs suggests that many of the HPV infections we observed in the present study were reactivated, rather than newly acquired, infections.

Our results highlight the importance of increasing the capacity of cervical cancer screening programs and the availability of treatment in this population. Nearly half (48%) of the HIV-seropositive women in our cohort had SILs at baseline Pap test or developed SILs, as shown by Pap test results obtained during follow-up. Seven percent had HSILs diagnosed, and 5 developed invasive cervical cancer, an outcome that is preventable by appropriate screening and therapy. These findings suggest that some of the substantial gains in women's health over the past decade may be threatened. At this time, we should give high priority to the development of innovative and cost-effective methods of screening for and treating SILs in the growing numbers of HIVinfected women living longer lives.

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HIV Epidemiology Research Study (HERS) Study Group Members

HERS study group members include Robert S. Klein, Ellie Schoenbaum, Julia Arnsten, Robert D. Burk, Chee Jen Chang, Penelope Demas, and Andrea Howard (Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY); Paula Schuman, Jack D. Sobel, and Suzanne E. Ohmit (Wayne State University School of Medicine, Detroit, MI); Anne Rompalo, David Vlahov, Keerti Shaw, and David Celentano (Johns Hopkins University School of Medicine, Baltimore, MD); Charles Carpenter, Kenneth Mayer, Susan Cu-Uvin, Timothy Flanigan, Joseph Hogan, Valerie Stone, Karen Tashima, and Josiah Rich (Brown University School of Medicine, Providence, RI); and Ann Duerr, Lytt I. Gardner, Chad Heilig, Scott D. Holmberg, Denise J. Jamieson, Janet S. Moore, Ruby M. Phelps, Dawn K. Smith, and Dora Warren (Centers for Disease Control and Prevention, Atlanta, GA).

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Acknowledgments

We thank the study staff at each site and all the women who participated in the study.

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Footnotes

  • ↵Study group members are listed after the text.

  • Financial support: Centers for Disease Control and Prevention (cooperative agreements U64/CCU106795, U64/CCU200714, U64/CCU306802, and U64/CCU506831).

  • Received November 8, 2002.
  • Accepted February 5, 2003.
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  1. J Infect Dis. (2003) 188 (1): 128-136. doi: 10.1086/375783
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