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Original Contribution |

Risk of Cervical Precancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection FREE

Marla J. Keller, MD; Robert D. Burk, MD; Xianhong Xie, PhD; Kathryn Anastos, MD; L. Stewart Massad, MD; Howard Minkoff, MD; Xiaonan Xue, PhD; Gypsyamber D’Souza, PhD; D. Heather Watts, MD; Alexandra M. Levine, MD; Philip E. Castle, PhD; Christine Colie, MD; Joel M. Palefsky, MD; Howard D. Strickler, MD, MPH
[+] Author Affiliations

Author Affiliations: Albert Einstein College of Medicine, Bronx, New York (Drs Keller, Burk, Xie, Anastos, Xue, and Strickler); Washington University School of Medicine, St. Louis, Missouri (Dr Massad); Maimonides Medical Center, Brooklyn, New York (Dr Minkoff); Johns Hopkins School of Public Health, Baltimore, Maryland (Dr D’Souza); National Institute of Child Health and Human Development, Bethesda, Maryland (Dr Watts); City of Hope National Medical Center, Duarte, California (Dr Levine); American Society for Clinical Pathology, Washington, DC (Dr Castle); Georgetown University Medical Center, Washington, DC (Dr Colie); and University of California, San Francisco (Dr Palefsky).


JAMA. 2012;308(4):362-369. doi:10.1001/jama.2012.5664.
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Published online

Context US cervical cancer screening guidelines for human immunodeficiency virus (HIV)–uninfected women 30 years or older have recently been revised, increasing the suggested interval between Papanicolaou (Pap) tests from 3 years to 5 years among those with normal cervical cytology (Pap test) results who test negative for oncogenic human papillomavirus (HPV). Whether a 3-year or 5-year screening interval could be used in HIV-infected women who are cytologically normal and oncogenic HPV–negative is unknown.

Objective To determine the risk of cervical precancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as 2 separate end points, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test result and were negative for oncogenic HPV.

Design, Setting, and Participants Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional US cohort of the Women's Interagency HIV Study, between October 1, 2001, and September 30, 2002, with follow-up through April 30, 2011. Semiannual visits at 6 clinical sites included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using polymerase chain reaction. The primary analysis was truncated at 5 years of follow-up.

Main Outcome Measure Five-year cumulative incidence of cervical precancer and cancer.

Results No oncogenic HPV was detected in 369 (88% [95% CI, 84%-91%]) HIV-infected women and 255 (91% [95% CI, 88%-94%]) HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV–negative women, 2 cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500 cells/μL or greater. Histologic data were obtained from 4 of the 6 clinical sites. There were 6 cases of CIN-2+ in 145 HIV-uninfected women (cumulative incidence, 5% [95% CI, 1%-8%]) and 9 cases in 219 HIV-infected women (cumulative incidence, 5% [95% CI, 2%-8%]). This included 1 case of CIN-2+ in 44 oncogenic HPV–negative HIV-infected women with CD4 cell count less than 350 cells/μL (cumulative incidence, 2% [95% CI, 0%-7%]), 1 case in 47 women with CD4 cell count of 350 to 499 cells/μL (cumulative incidence, 2% [95% CI, 0%-7%]), and 7 cases in 128 women with CD4 cell count of 500 cells/μL or greater (cumulative incidence, 6% [95% CI, 2%-10%]). One HIV-infected and 1 HIV-uninfected woman had CIN-3, but none had cancer.

Conclusion The 5-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV–negative at enrollment.

Figures in this Article

In an approach termed human papillomavirus (HPV) co-testing, cervical cancer screening guidelines in the United States endorse the use of oncogenic HPV DNA testing concurrent with cervical cytology in human immunodeficiency virus (HIV)–uninfected women 30 years or older.1,2 According to these guidelines, women with a normal Papanicolaou (Pap) test result who test positive for oncogenic HPV should be rescreened in 1 year, whereas the recommended interval for rescreening in those who are oncogenic HPV–negative was recently increased from 3 years3 to 5 years.1,2 These recommendations reflect the low risk of cervical precancer and cancer observed in cytologically normal, oncogenic HPV–negative women during long-term follow-up studies (as recently reviewed by Whitlock et al,4 2011) and modeling studies that found that HPV co-testing at 3- and 5-year intervals provided outcomes similar to those provided by annual conventional Pap tests.5

However, HPV co-testing is not currently recommended as part of cervical cancer screening in HIV-infected women,6 nor was this issue addressed in the updated screening guidelines.1,2 Current recommendations are for HIV-infected women who have initiated sexual intercourse to have 2 Pap tests at 6-month intervals in the first year following diagnosis of HIV infection and, if results of the Pap tests are normal, then on an annual basis.6 To our knowledge, only 1 study in HIV-infected women prospectively examined the risk of incident cervical precancer and cancer following a normal Pap test result and a negative oncogenic HPV DNA test result. That study in the Women's Interagency HIV Study (WIHS), a large prospective cohort of HIV-infected women and HIV-uninfected women, measured the cumulative incidence of any squamous intraepithelial lesion (SIL) and of high-grade SIL or greater (HSIL+), according to baseline HPV DNA results. No cases of HSIL+ were observed through 3 years of follow-up, and no cancers were diagnosed for up to 7 years among 412 cytologically normal, HPV-negative, HIV-infected women.7

Women in this earlier study, however, were enrolled during 1994-1995, prior to the widespread use of highly active antiretroviral therapy (HAART), which began in late 1996, and most remained naive to HAART for the first several years of the study. Approximately 20% had a CD4 cell count less than 200 cells/μL. Further, that study was limited by the absence of histologic results, the major clinical criteria used to determine the need for cervical treatment. Therefore, the current investigation examined the 3-year and 5-year risk of cervical precancer and cancer defined by cytology (ie, HSIL+) and histology (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), each as its own end point, in a separate cohort of HIV-infected women and HIV-uninfected women enrolled in the WIHS during 2001-2002. The HIV-infected women in the 2001-2002 cohort were shown to be representative of US women with HIV/AIDS.8

Participants and Specimens

The WIHS is an ongoing, geographically and ethnically diverse prospective cohort study of HIV-infected women and HIV-uninfected women enrolled through similar clinical and outreach sources at each of 6 clinical consortia located in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC.9 The initial enrollment was conducted between October 1, 1994, and November 15, 1995 (n = 2059 HIV-infected women and n = 569 HIV-uninfected women), and a second enrollment was separately conducted between October 1, 2001, and September 30, 2002 (n = 737 HIV-infected women and n = 406 HIV-uninfected women).8,9

Interviewer-administered questionnaires are completed at each semiannual visit and include information regarding age, race/ethnicity (ie, black, white, Hispanic, other), additional demographic variables, medical history, and risk behaviors. The HIV-infected women in the 2001-2002 cohort were shown to be similar to women with AIDS among US women nationwide reported by the Centers for Disease Control and Prevention (CDC) in 2001, in terms of their racial distribution, other demographic factors, and CDC-defined HIV exposure category.8

At all semiannual visits participants received a Pap test and a cervicovaginal lavage for HPV DNA testing. Pap tests were interpreted centrally according to the 2001 Bethesda System.10 Colposcopy is recommended for a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC-US) or greater. Cytologic data for the current study were obtained from all WIHS sites, whereas colposcopic and histologic data were obtained from 4 designated WIHS sites (Brooklyn, Chicago, Los Angeles, San Francisco), chosen based on their facilities and clinician training. Written informed consent was obtained from all participants, and the study was approved by each local institutional review board. Data were available through April 30, 2011.

Laboratory Testing

Human papillomavirus DNA was detected with L1 consensus primer MY09/MY11/HMB01 polymerase chain reaction assays. Primer set PC04/GH20, which amplifies a 268–base-pair cellular β-globin DNA fragment, was included in each assay as an internal control to assess the adequacy of amplification. Details of these methods have been previously reported,11,12 and the results were shown to have high sensitivity and specificity.1315 Within the WIHS, these assays have been shown to have high interlaboratory reproducibility.13 Briefly, after proteinase K digestion, 2 to 10 μL of each cell digest was used in reaction mixtures containing 10mM Tris-HCl, 50mM KCl, 4mM MgCl2, all 4 deoxyribonucleotide triphosphates (each at 200μM), 2.5 U of AmpliTaq DNA polymerase, and 0.5μM solutions of each primer. There were 35 amplification cycles (95°C for 20 seconds, 55°C for 30 seconds, and 72°C for 30 seconds), with a 5-minute extension period at 72°C on the last cycle. Amplification products were probed for the presence of any HPV DNA with a generic probe mixture and probed for HPV DNA with filters individually hybridized with type-specific biotinylated oligonucleotide probes for more than 40 individual HPV types.11,12 The HPV types defined as oncogenic were 16/18/31/33/35/39/45/51/52/56/58/59/68/73, and other HPV types were considered nononcogenic.16,17

Statistical Methods

Initial descriptive analyses contrasted the characteristics of the HIV-infected women and HIV-uninfected women in this study, using the t test (means), Wilcoxon test (medians), or Pearson χ2 test (proportions). For the oncogenic HPV-negative women, standard life-table methods were used to estimate the cumulative incidence of SIL and CIN of any grade, with 95% confidence intervals (a measure of the precision of each estimate) calculated based on the life-table estimator under a normal approximation assumption. The CD4 cell count was used to stratify HIV-infected participants in preference to HIV viral load, because CD4 cell count but not HIV viral load has been associated with risk of incident invasive cervical cancer.18,19

In keeping with cervical cancer screening guidelines, our main analyses examined both 3-year and 5-year cumulative incidence. Participants who had had a hysterectomy or who reported cervical treatment were censored at the visit before their procedure. In life-table analysis, censoring is assumed to occur uniformly throughout each interval.20 Therefore, to determine the overall follow-up rate in HPV-negative women at 5 years of observation, the effective sample size (the numerator) was calculated based on the number of women entering year 5 (which reflects all attrition that came before that final year) minus half of those who during that last year were censored. Cases were not considered censored and were included in the numerator. The overall follow-up rate was then this numerator divided by the number of women at the start of the study.20 Given the low event rate, the main analyses used all available data and assumed that disease status did not change during intervals of missing data. To assess this assumption, however, in additional analyses, participants who for any reason had missing data for more than 1 year were censored at the time of the last visit at which they had complete data. Because this affected less than an average of 1.6% of participants annually and did not alter the findings, we elected to report herein the life-table results calculated without this additional censoring. The results censored for missing data are reported in eTable 1 and eTable 2. The extent of missing data is shown in the footnotes of the life tables. Statistical significance was defined as P < .05, determined using 2-sided tests. All analyses were conducted using SAS version 9.1.3 (SAS Institute Inc), except where indicated.

Study Participants

There were 505 HIV-infected women and 345 HIV-uninfected women with normal cervical cytology at enrollment. Women were excluded from analysis if (1) their baseline HPV or CD4 cell count data were missing (n = 52 HIV-infected women and n = 31 HIV-uninfected women); (2) the cervix had been removed prior to enrollment (n = 15 and n = 7); (3) follow-up data were unavailable (n = 18 and n = 27); or (4) HIV seroconversion occurred during follow-up (n = 1).

In total, 420 HIV-infected women and 279 HIV-uninfected women were included in the current analysis. Table 1 shows selected baseline characteristics of these women. The HIV-infected women were modestly older and more likely to be Hispanic than the HIV-uninfected women. Nearly half (47%) of the HIV-infected women were receiving HAART, and 56% had a CD4 cell count of 500 cells/μL or greater. Although HIV-infected women reported less recent sexual activity, they were more likely than HIV-uninfected women to test positive for any HPV DNA (32% vs 22%; P = .02). Among HIV-infected women, the prevalence of any HPV DNA and of oncogenic HPV DNA increased with decreasing CD4 cell count (P ≤ .004 for trend for both); ie, the prevalence was 25% for any HPV and 8% for oncogenic HPV in HIV-infected women with CD4 cell count of 500 cells/μL or greater; 34% and 17%, respectively, for those with CD4 cell count of 350 to 499 cells/μL; and 47% and 18%, respectively, for those with CD4 cell count less than 350 cells/μL.

Table Graphic Jump LocationTable 1. Baseline Characteristics of HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology at Enrollment During 2001-2002 in the Women's Interagency HIV Study (WIHS)

Overall, no oncogenic HPV was detected in 369 (88% [95% CI, 84%-91%]) of the HIV-infected women and 255 (91% [95% CI, 88%-94%]) of the HIV-uninfected women with normal cervical cytology at enrollment. We measured the cumulative incidence of cervical precancer and cancer in oncogenic HPV–negative women using cytology (HSIL+) and histology (CIN-2+) as separate end points.

Through the first 5 years of observation there were a total of 3281 person-visits of observation in HIV-infected women and 2242 person-visits in HIV-uninfected women, with a median follow-up time of 4.9 years. Figure 1 shows censoring because of treatment or loss to follow-up in these women, by year and HIV status. Six women who had undergone hysterectomy and 115 women who reported other cervical treatment (n = 69 HIV-infected women and n = 46 HIV-uninfected women) during follow-up were censored at the visit before their procedure. Loss to follow-up averaged 3.6% per year in HIV-infected women and 3.1% in HIV-uninfected women. In life-table analysis, all censoring is assumed to occur uniformly throughout each interval (see “Statistical Methods”). Overall, in the analysis of HSIL+, 70% (effective sample size, 177 noncases + 1 case) of the 255 HIV-uninfected women and 67% (effective sample size, 245 noncases + 1 case) of the 369 HIV-infected women contributed 5 years of observation. The corresponding rates of follow-up at 3 years of observation were 86% and 81%, respectively.

Place holder to copy figure label and caption
Figure 1. Loss to Follow-up and Censoring for Cervical Treatment (Including Hysterectomy) Among Cytologically Normal, Oncogenic Human Papillomavirus–Negative Women in the Life-Table Analysis of HSIL+, by Year of Follow-up and HIV Status
Graphic Jump Location

In life-table analysis, all censoring is assumed to occur uniformly throughout each interval (see “Statistical Methods”). Therefore, to determine the follow-up rate, the effective sample size was calculated based on the number of women entering each year (which reflects all attrition that came before that year) minus half of those who during the previous year were censored plus the number of women who had events up to and including that year. For example, the effective sample size at year 5 for the analysis of high-grade squamous intraepithelial lesions or greater (HSIL+) in human immunodeficiency virus (HIV)–uninfected women is 182 − (5 + 5) ÷ 2 + 1 = 177 + 1. Thus, in the analysis of HSIL+, 70% (effective sample size, 177 noncases + 1 case) of the 255 HIV-uninfected women and 67% (effective sample size, 245 noncases + 1 case) of the 369 HIV-infected women contributed 5 years of observation. The corresponding rates of follow-up at 3 years of observation were 86% and 81%, respectively.

Four of the 6 sites provided colposcopic and histologic data for the analysis of CIN-2+. The baseline characteristics of these women were similar to those of all cytologically normal participants in this study (eTable 3). Colposcopy results were obtained in 87% of HIV-infected women (85% ASC-US, 93% low-grade SIL, 100% HSIL) and 82% of HIV-uninfected women (83% ASC-US, 80% LSIL, 100% HSIL) with a subsequent abnormal Pap test result. Loss to follow-up, 2.9% per year in HIV-infected women and 2.9% in HIV-uninfected women, was similar to that reported above for all participants (Figure 2). In total, 83% (114 noncases + 6 cases) of 145 HIV-uninfected women and 78% (162 noncases + 9 cases) of 219 HIV-infected women contributed 5 years of observation to the analysis of CIN-2+. The corresponding rates of follow-up at 3 years of observation were 92% and 88%, respectively.

Place holder to copy figure label and caption
Figure 2. Loss to Follow-up and Censoring for Cervical Treatment (Including Hysterectomy) Among Cytologically Normal, Oncogenic Human Papillomavirus–Negative Women in the Life-Table Analysis of CIN-2+, by Year of Follow-up and HIV Status
Graphic Jump Location

In life-table analysis, all censoring is assumed to occur uniformly throughout each interval (see “Statistical Methods”). Therefore, to determine the follow-up rate, the effective sample size was calculated based on the number of women entering each year (which reflects all attrition that came before that year) minus half of those who during the previous year were censored plus the number of women who had events up to and including that year. For example, the effective sample size at year 5 for the analysis of cervical intraepithelial neoplasia 2 or greater (CIN-2+) in human immunodeficiency virus (HIV)–uninfected women is 116 − (2 + 3) ÷ 2 + 6 = 114 + 6. Thus, in the analysis of CIN-2+, 83% (114 noncases + 6 cases) of 145 HIV-uninfected women and 78% (162 noncases + 9 cases) of 219 HIV-infected women contributed 5 years of observation. The corresponding rates of follow-up at 3 years of observation were 92% and 88%, respectively.

Cumulative Incidence of Precancer

Table 2 and Table 3 show the data for cytology and histology, respectively. Two cases of HSIL+ were observed during the 5 years of observation (Table 2), 1 among the HIV-uninfected women and 1 among the HIV-infected women with a CD4 cell count of 500 cells/μL or greater. Overall, the cumulative incidence of HSIL+ was 0.3% (95% CI, 0%-0.9%) in HIV-infected women and 0.4% (95% CI, 0%-1.3%) in HIV-uninfected women. Similarly, there were few cases of CIN-2+ (Table 3). Based on a total of 15 cases, the cumulative incidence of CIN-2+ over 5 years of follow-up was 2% (95% CI, 0%-7%) in HIV-infected women with CD4 cell count less than 350 cells/μL, 2% (95% CI, 0%-7%) in those with CD4 cell count of 350 to 499 cells/μL, 6% (95% CI, 2%-10%) in those women with CD4 cell count of 500 cells/μL or greater, and 5% (95% CI, 1%-8%) in HIV-uninfected women. Given the concordance of the findings across CD4 cell count strata, we combined the data among HIV-infected women. The overall 5-year cumulative incidence of CIN-2+ in HIV-infected women was 5% (95% CI, 2%-8%). Of the CIN-2+ cases, 2 were CIN-3 (an HIV-infected woman with a baseline CD4 cell count of 350-499 cells/μL, and an HIV-uninfected woman). The overall 5-year cumulative incidence of CIN-3+ was 0.5% (95% CI, 0%-2%) in HIV-infected women and 0.7% (95% CI, 0%-2%) in HIV-uninfected women. No cancers were observed.

Table Graphic Jump LocationTable 2. Cumulative Incidence of Any SIL and High-Grade SIL or Greater (HSIL+) in HIV-Infected Women and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollmenta
Table Graphic Jump LocationTable 3. Cumulative Incidence of Any CIN and CIN-2+ in HIV-Infected Women and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollmenta

Although the 5-year cumulative incidence rate of CIN-2+ was estimated to be 5% in HIV-infected women as well as HIV-uninfected women, we examined to what extent their true values could be different. Specifically, we calculated the upper and lower confidence limits for these data (estimated difference, 0% [95% CI, −4% to 5%]). A similar analysis was conducted for HSIL+. As reported above, the cumulative incidence of HSIL+ in HIV-infected women and HIV-uninfected women was 0.3% and 0.4%, respectively, and the calculated difference was −0.1% (95% CI, −0.9% to 0.9%). Interestingly, unlike with HSIL+, the cumulative incidence of any SIL differed by host immune status (Table 2). HIV-infected women with CD4 cell count less than 350 cells/μL had a 5-year cumulative incidence of any SIL of 25% (95% CI, 13%-34%), compared with 11% in each of the other 2 HIV-infected groups and 6% in HIV-uninfected women. The cumulative incidence of any CIN did not vary substantially by HIV serostatus or CD4 cell count (Table 3).

Data from follow-up visits beyond 5 years of observation are also of interest but need to be addressed conservatively, because there was continued incremental loss to follow-up—an average of 4.0% and 3.4% per year, respectively, for HSIL+ and CIN-2+ (eTables 4–7). Most notably, no cases of invasive cancer were detected during all 9 years of observation. There was 1 case of CIN-3 in an HIV-infected woman with a CD4 cell count of 500 cells/μL or greater, which occurred between 8 and 9 years of follow-up, and 1 case of HSIL involving an HIV-uninfected woman diagnosed between 6 and 7 years of follow-up. Of the 5 cases of CIN-2 observed after 5 years of follow-up, 3 occurred among HIV-infected women with CD4 cell count of 500 cells/μL or greater, 1 among those with CD4 cell count of 350 to 499 cells/μL, and 1 in an HIV-uninfected woman. Overall, the 7-year cumulative incidence of CIN-2+ was 6% (95% CI, 2%-9%) in HIV-infected women and 5% (95% CI, 1%-9%) in HIV-uninfected women, whereas it was 8% (95% CI, 3%-12%) and 5% (95% CI, 1%-9%), respectively, after 9 years of observation. For CIN-3+, the cumulative incidence rates were 2% (95% CI, 0%-4%) and 0.7% (95% CI, 0%-2%), respectively, after 9 years of observation.

This study found similar risk of cervical precancer and cancer in HIV-infected women and HIV-uninfected women with normal cervical cytology and a negative test result for oncogenic HPV DNA at enrollment. Specifically, through 5 years of follow-up, we observed no meaningful differences in the cumulative incidence of HSIL+ or CIN-2+ between HIV-uninfected women and HIV-infected women, regardless of CD4 cell count in this cohort. Based on our analyses, few cases of cervical precancer would have gone undiagnosed had the HIV-infected women we studied not had any additional Pap tests for 5 years following enrollment and no more than in the HIV-uninfected women. The estimated cumulative incidence of CIN-2+ in HIV-infected women was 5% across the 5 years of observation, with an upper 95% confidence limit of 8%. Two HIV-infected women had CIN-3, representing a 5-year cumulative incidence of 0.5%. None had cancer through 9 years of follow-up.

These results are consistent with those of a prior study conducted by our research group in a separate cohort of women enrolled in the WIHS.7 That study involved a much larger number of HIV-infected women with low CD4 cell count, consistent with the fact that the prior cohort was enrolled in 1994-1995, before the widespread use of HAART. Nonetheless, no cases of HSIL+ were detected in HIV-infected women within 3 years of their normal Pap test and negative HPV DNA results at study entry. Although differences in the 2 cohorts and the absence of histologic data from the earlier study make it inappropriate to combine their data, it is reassuring that both cohort investigations conducted to date found that HIV-infected women who were cytologically normal and oncogenic HPV–negative had similar risk of cervical precancer and cancer as those who were HIV-uninfected.

There are, however, limitations to the current study. Most importantly, the current findings are generalizable only to women who are similar to those in the WIHS—mainly HIV-infected women undergoing long-term follow-up. Second, testing of cervicovaginal lavage specimens may have lower sensitivity for detection of oncogenic HPV than does testing of cervical swabs or cytobrushes.21,22 Our results are therefore likely conservative, because a small improvement in assay sensitivity would likely result in an improvement in the negative predictive value of HPV testing for CIN-2+ in cytologically normal HIV-infected women. The study used life-table analysis, which has unavoidable limitations. In particular, life-table methods assume noninformative censoring (ie, that the rate of disease in censored participants is similar to that in those not censored), and no statistical methods have been developed to estimate exact confidence intervals for cumulative incidence rates when events are rare, although for sample sizes and event rates in the range we studied, the normal approximation has been shown to provide accurate results.23 It also must be noted that some women with an abnormal Pap test result did not follow investigators' recommendations to have colposcopy, and there was no centralized review of histologic specimens. Reassuringly, though, a recent review by an expert pathologist confirmed 25 of 27 cases of CIN-2+ diagnosed in other WIHS women by their local pathologists (personal communication, Teresa Darragh, MD, Professor of Clinical Pathology, University of California, San Francisco, written communication, October 21, 2011).

In summary, the results of this prospective study suggest that HIV-infected women undergoing long-term clinical follow-up who are cytologically normal and oncogenic HPV–negative have a risk of cervical precancer similar to that in HIV-uninfected women through 5 years of follow-up. Additional observational studies or a randomized clinical trial may be necessary before clinical guideline committees consider whether to expand current recommendations regarding HPV co-testing to HIV-infected women. More broadly, the current investigation highlights the potential for a new era of molecular testing, including HPV as well as other biomarkers, to improve cervical cancer screening in HIV-infected women.

Corresponding Author: Marla J. Keller, MD, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Mazer Bldg, Room 512, Bronx, NY 10461 (marla.keller@einstein.yu.edu).

Author Contributions: Dr Strickler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Keller, Burk, Massad, Palefsky, Strickler.

Acquisition of data: Burk, Anastos, Massad, Minkoff, Levine, Strickler.

Analysis and interpretation of data: Keller, Burk, Xie, Massad, Xue, D’Souza, Watts, Castle, Colie, Strickler.

Drafting of the manuscript: Keller, Xie, Massad, Xue, Palefsky, Strickler.

Critical revision of the manuscript for important intellectual content: Keller, Burk, Xie, Anastos, Massad, Minkoff, Xue, D’Souza, Watts, Levine, Castle, Colie, Palefsky, Strickler.

Statistical analysis: Keller, Xie, Xue, D’Souza, Strickler.

Obtained funding: Burk, Anastos, Minkoff, Levine, Palefsky, Strickler.

Administrative, technical, or material support: Burk, Watts, Castle, Colie, Strickler.

Study supervision: Burk, Anastos, Minkoff, Levine, Strickler.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Castle reported receiving fees from Merck Sharp & Dohme for serving as a member of a data and safety monitoring board. Dr Palefsky reported receiving grant support, as well as travel support and fees for review activities, through his institution from Merck Sharp & Dohme; receiving fees through his institution for serving as a board member and consultant and providing expert testimony for Merck Sharp & Dohme; and serving as a member of the scientific advisory board of Pharmajet. No other authors reported disclosures.

Funding/Support: Support for this study, including HPV DNA testing, was provided through R01-CA-085178. Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Dr Anastos); Brooklyn, New York (Dr Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Dr Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, and U01-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) (U01-HD-32632). The study is cofunded 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 UL1 RR024131). Additional support was provided by R33-AI079763, the Einstein-Montefiore Center for AIDS Research (P30-AI-51519), and the Institute for Clinical and Translational Research (UL1 RR025750).

Role of the Sponsor: The WIHS is a National Institutes of Health (NIH)–funded multicenter cohort study. Thus, the funding sources had a role in the overall WIHS study design but not the design of the current ancillary study; one coauthor, Dr Watts, is an employee of NICHD/NIH, and as an author had a role in the interpretation of the current data, and she reviewed and approved the submitted manuscript.

Disclaimer: 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.

Previous Presentation: Presented in part at the 2011 International Papillomavirus Conference; September 17-22, 2011; Berlin, Germany.

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Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks.  Arch Intern Med. 2008;168(17):1881-1889
PubMed   |  Link to Article
Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H.Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America.  Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.  MMWR Recomm Rep. 2009;58(RR-4):1-207
PubMed
Harris TG, Burk RD, Palefsky JM,  et al.  Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results.  JAMA. 2005;293(12):1471-1476
PubMed   |  Link to Article
Bacon MC, von Wyl V, Alden C,  et al.  The Women's Interagency HIV Study: an observational cohort brings clinical sciences to the bench.  Clin Diagn Lab Immunol. 2005;12(9):1013-1019
PubMed
Barkan SE, Melnick SL, Preston-Martin S,  et al; WIHS Collaborative Study Group.  The Women's Interagency HIV Study.  Epidemiology. 1998;9(2):117-125
PubMed   |  Link to Article
Solomon D, Davey D, Kurman R,  et al; Forum Group Members; Bethesda 2001 Workshop.  The 2001 Bethesda System: terminology for reporting results of cervical cytology.  JAMA. 2002;287(16):2114-2119
PubMed   |  Link to Article
Burk RD, Ho GY, Beardsley L, Lempa M, Peters M, Bierman R. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women.  J Infect Dis. 1996;174(4):679-689
PubMed   |  Link to Article
Strickler HD, Burk RD, Fazzari M,  et al.  Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus–positive women.  J Natl Cancer Inst. 2005;97(8):577-586
PubMed   |  Link to Article
Palefsky JM, Minkoff H, Kalish LA,  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(3):226-236
PubMed   |  Link to Article
Qu W, Jiang G, Cruz Y,  et al.  PCR detection of human papillomavirus: comparison between MY09/MY11 and GP5+/GP6+ primer systems.  J Clin Microbiol. 1997;35(6):1304-1310
PubMed
Jiang G, Qu W, Ruan H, Burk RD. Elimination of false-positive signals in enhanced chemiluminescence (ECL) detection of amplified HPV DNA from clinical samples.  Biotechniques. 1995;19(4):566-568
PubMed
Muñoz N, Bosch FX, de Sanjosé S,  et al; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group.  Epidemiologic classification of human papillomavirus types associated with cervical cancer.  N Engl J Med. 2003;348(6):518-527
PubMed   |  Link to Article
Bouvard V, Baan R, Straif K,  et al; WHO International Agency for Research on Cancer Monograph Working Group.  A review of human carcinogens, part B: biological agents.  Lancet Oncol. 2009;10(4):321-322
PubMed   |  Link to Article
Guiguet M, Boué F, Cadranel J, Lang JM, Rosenthal E, Costagliola D.Clinical Epidemiology Group of the FHDH-ANRS CO4 cohort.  Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study.  Lancet Oncol. 2009;10(12):1152-1159
PubMed   |  Link to Article
Chaturvedi AK, Madeleine MM, Biggar RJ, Engels EA. Risk of human papillomavirus–associated cancers among persons with AIDS.  J Natl Cancer Inst. 2009;101(16):1120-1130
PubMed   |  Link to Article
Leung KM, Elashoff RM, Afifi AA. Censoring issues in survival analysis.  Annu Rev Public Health. 1997;18:83-104
PubMed   |  Link to Article
Vermund SH, Schiffman MH, Goldberg GL, Ritter DB, Weltman A, Burk RD. Molecular diagnosis of genital human papillomavirus infection: comparison of two methods used to collect exfoliated cervical cells.  Am J Obstet Gynecol. 1989;160(2):304-308
PubMed   |  Link to Article
Wheeler CM, Greer CE, Becker TM, Hunt WC, Anderson SM, Manos MM. Short-term fluctuations in the detection of cervical human papillomavirus DNA.  Obstet Gynecol. 1996;88(2):261-268
PubMed   |  Link to Article
Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion.  Stat Sci. 2001;16(2):101-133

Figures

Place holder to copy figure label and caption
Figure 1. Loss to Follow-up and Censoring for Cervical Treatment (Including Hysterectomy) Among Cytologically Normal, Oncogenic Human Papillomavirus–Negative Women in the Life-Table Analysis of HSIL+, by Year of Follow-up and HIV Status
Graphic Jump Location

In life-table analysis, all censoring is assumed to occur uniformly throughout each interval (see “Statistical Methods”). Therefore, to determine the follow-up rate, the effective sample size was calculated based on the number of women entering each year (which reflects all attrition that came before that year) minus half of those who during the previous year were censored plus the number of women who had events up to and including that year. For example, the effective sample size at year 5 for the analysis of high-grade squamous intraepithelial lesions or greater (HSIL+) in human immunodeficiency virus (HIV)–uninfected women is 182 − (5 + 5) ÷ 2 + 1 = 177 + 1. Thus, in the analysis of HSIL+, 70% (effective sample size, 177 noncases + 1 case) of the 255 HIV-uninfected women and 67% (effective sample size, 245 noncases + 1 case) of the 369 HIV-infected women contributed 5 years of observation. The corresponding rates of follow-up at 3 years of observation were 86% and 81%, respectively.

Place holder to copy figure label and caption
Figure 2. Loss to Follow-up and Censoring for Cervical Treatment (Including Hysterectomy) Among Cytologically Normal, Oncogenic Human Papillomavirus–Negative Women in the Life-Table Analysis of CIN-2+, by Year of Follow-up and HIV Status
Graphic Jump Location

In life-table analysis, all censoring is assumed to occur uniformly throughout each interval (see “Statistical Methods”). Therefore, to determine the follow-up rate, the effective sample size was calculated based on the number of women entering each year (which reflects all attrition that came before that year) minus half of those who during the previous year were censored plus the number of women who had events up to and including that year. For example, the effective sample size at year 5 for the analysis of cervical intraepithelial neoplasia 2 or greater (CIN-2+) in human immunodeficiency virus (HIV)–uninfected women is 116 − (2 + 3) ÷ 2 + 6 = 114 + 6. Thus, in the analysis of CIN-2+, 83% (114 noncases + 6 cases) of 145 HIV-uninfected women and 78% (162 noncases + 9 cases) of 219 HIV-infected women contributed 5 years of observation. The corresponding rates of follow-up at 3 years of observation were 92% and 88%, respectively.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology at Enrollment During 2001-2002 in the Women's Interagency HIV Study (WIHS)
Table Graphic Jump LocationTable 2. Cumulative Incidence of Any SIL and High-Grade SIL or Greater (HSIL+) in HIV-Infected Women and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollmenta
Table Graphic Jump LocationTable 3. Cumulative Incidence of Any CIN and CIN-2+ in HIV-Infected Women and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollmenta

References

Saslow D, Solomon D, Lawson HW,  et al.  American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer [published online ahead of print March 13, 2012].  J Low Genit Tract DisLink to Article
Moyer VA. Screening for Cervical Cancer: U.S. Preventive Services Task Force Recommendation Statement.  Ann Intern Med. 2012;156(12):880-891
PubMed   |  Link to Article
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D.2006 ASCCP-Sponsored Consensus Conference.  2006 consensus guidelines for the management of women with abnormal cervical screening tests.  J Low Genit Tract Dis. 2007;11(4):201-222
PubMed   |  Link to Article
Whitlock EP, Vesco KK, Eder M, Lin JS, Senger CA, Burda BU. Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force.  Ann Intern Med. 2011;155(10):687-697
PubMed   |  Link to Article
Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks.  Arch Intern Med. 2008;168(17):1881-1889
PubMed   |  Link to Article
Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H.Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America.  Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.  MMWR Recomm Rep. 2009;58(RR-4):1-207
PubMed
Harris TG, Burk RD, Palefsky JM,  et al.  Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results.  JAMA. 2005;293(12):1471-1476
PubMed   |  Link to Article
Bacon MC, von Wyl V, Alden C,  et al.  The Women's Interagency HIV Study: an observational cohort brings clinical sciences to the bench.  Clin Diagn Lab Immunol. 2005;12(9):1013-1019
PubMed
Barkan SE, Melnick SL, Preston-Martin S,  et al; WIHS Collaborative Study Group.  The Women's Interagency HIV Study.  Epidemiology. 1998;9(2):117-125
PubMed   |  Link to Article
Solomon D, Davey D, Kurman R,  et al; Forum Group Members; Bethesda 2001 Workshop.  The 2001 Bethesda System: terminology for reporting results of cervical cytology.  JAMA. 2002;287(16):2114-2119
PubMed   |  Link to Article
Burk RD, Ho GY, Beardsley L, Lempa M, Peters M, Bierman R. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women.  J Infect Dis. 1996;174(4):679-689
PubMed   |  Link to Article
Strickler HD, Burk RD, Fazzari M,  et al.  Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus–positive women.  J Natl Cancer Inst. 2005;97(8):577-586
PubMed   |  Link to Article
Palefsky JM, Minkoff H, Kalish LA,  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(3):226-236
PubMed   |  Link to Article
Qu W, Jiang G, Cruz Y,  et al.  PCR detection of human papillomavirus: comparison between MY09/MY11 and GP5+/GP6+ primer systems.  J Clin Microbiol. 1997;35(6):1304-1310
PubMed
Jiang G, Qu W, Ruan H, Burk RD. Elimination of false-positive signals in enhanced chemiluminescence (ECL) detection of amplified HPV DNA from clinical samples.  Biotechniques. 1995;19(4):566-568
PubMed
Muñoz N, Bosch FX, de Sanjosé S,  et al; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group.  Epidemiologic classification of human papillomavirus types associated with cervical cancer.  N Engl J Med. 2003;348(6):518-527
PubMed   |  Link to Article
Bouvard V, Baan R, Straif K,  et al; WHO International Agency for Research on Cancer Monograph Working Group.  A review of human carcinogens, part B: biological agents.  Lancet Oncol. 2009;10(4):321-322
PubMed   |  Link to Article
Guiguet M, Boué F, Cadranel J, Lang JM, Rosenthal E, Costagliola D.Clinical Epidemiology Group of the FHDH-ANRS CO4 cohort.  Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study.  Lancet Oncol. 2009;10(12):1152-1159
PubMed   |  Link to Article
Chaturvedi AK, Madeleine MM, Biggar RJ, Engels EA. Risk of human papillomavirus–associated cancers among persons with AIDS.  J Natl Cancer Inst. 2009;101(16):1120-1130
PubMed   |  Link to Article
Leung KM, Elashoff RM, Afifi AA. Censoring issues in survival analysis.  Annu Rev Public Health. 1997;18:83-104
PubMed   |  Link to Article
Vermund SH, Schiffman MH, Goldberg GL, Ritter DB, Weltman A, Burk RD. Molecular diagnosis of genital human papillomavirus infection: comparison of two methods used to collect exfoliated cervical cells.  Am J Obstet Gynecol. 1989;160(2):304-308
PubMed   |  Link to Article
Wheeler CM, Greer CE, Becker TM, Hunt WC, Anderson SM, Manos MM. Short-term fluctuations in the detection of cervical human papillomavirus DNA.  Obstet Gynecol. 1996;88(2):261-268
PubMed   |  Link to Article
Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion.  Stat Sci. 2001;16(2):101-133

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Supplemental Content

Keller MJ, Burk RD, Xie X, et al. Risk of cervical precancer and cancer among HIV-infected women with normal cervical cytology and no evidence of oncogenic HPV infection. JAMA. doi:10.1001/jama.2012.5664.

eTable 1. Cumulative Incidence of Any SIL and HSIL+ in HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollment (With Censoring for Missing Data)

eTable 2. Cumulative Incidence of Any CIN and CIN-2+ in HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollment (With Censoring for Missing Data)

eTable 3. Baseline Characteristics of HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology at Enrollment in the Women’s Interagency HIV Study (WIHS) at the Four Clinical Sites That Provided Colposcopy and Histologic Data for the Analysis of Cervical Intraepithelial Neoplasia (CIN)

eTable 4. Cumulative Incidence of Any SIL and HSIL+ in HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollment (With Follow-up Across all Available, Nine Years, of Observation)

eTable 5. Cumulative Incidence of any CIN and CIN-2+ in HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollment (With Follow-up Across all Available, Nine Years, of Observation)

eTable 6. Cumulative Incidence of Any SIL and HSIL+ in HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollment (With Follow-up Across All Available, Nine Years, of Observation, and Censoring for Missing Data)

eTable 7. Cumulative Incidence of Any CIN and CIN-2+ in HIV-Infected and HIV-Uninfected Women Who Had Normal Cervical Cytology and Tested Negative for Oncogenic HPV DNA at Enrollment (With Follow-up Across all Available, Nine Years, of Observation, and Censoring for Missing Data)

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