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Original Contribution |

Incidence of Cervical Squamous Intraepithelial Lesions Associated With HIV Serostatus, CD4 Cell Counts, and Human Papillomavirus Test Results FREE

Tiffany G. Harris, PhD; Robert D. Burk, MD; Joel M. Palefsky, MD; L. Stewart Massad, MD; Ji Yon Bang, MS; Kathryn Anastos, MD; Howard Minkoff, MD; Charles B. Hall, PhD; Melanie C. Bacon, RN, MPH; Alexandra M. Levine, MD; D. Heather Watts, MD; Michael J. Silverberg, MPH, PhD; Xiaonan Xue, PhD; Sandra L. Melnick, DrPH; Howard D. Strickler, MD, MPH
[+] Author Affiliations

Author Affiliations: Albert Einstein College of Medicine, Bronx, NY (Drs Harris, Burk, Anastos, Hall, Xue, and Strickler and Ms Bang); University of California, San Francisco (Dr Palefsky); Southern Illinois University School of Medicine, Springfield (Dr Massad); Maimonides Medical Center, Brooklyn, NY (Dr Minkoff); Georgetown University Medical Center, Washington, DC (Ms Bacon); University of Southern California, Los Angeles (Dr Levine); National Institute of Child Health and Human Development, Bethesda, Md (Dr Watts); Johns Hopkins University, Baltimore, Md (Dr Silverberg); and National Cancer Institute, Bethesda, Md (Dr Melnick). Ms Bacon is now with the National Institute of Allergy and Infectious Diseases, Bethesda, Md, Dr Silverberg is now with Kaiser Permanente, Oakland, Calif, and Dr Melnick is now with the Center for Scientific Review, Bethesda, Md.

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JAMA. 2005;293(12):1471-1476. doi:10.1001/jama.293.12.1471.
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Context Recent cervical cancer screening guidelines state that the interval between screenings can be safely extended to 3 years in healthy women 30 years or older who have normal cytology results and have negative test results for oncogenic human papillomavirus (HPV) DNA.

Objective To determine the incidence of squamous intraepithelial lesions (SILs) in HIV-seropositive women with normal cytology results, by baseline HPV DNA results.

Design, Setting, and Patients Participants were HIV-seropositive (n = 855; mean age, 36 years) and HIV-seronegative (n = 343; mean age, 34 years) US women with normal baseline cervical cytology who were enrolled in the Women’s Interagency HIV Study (WIHS), a large, multi-institutional prospective cohort study. Since their recruitment during 1994-1995, WIHS participants have been followed up semi-annually with repeated Pap smears for a median of 7 years.

Main Outcome Measure The cumulative incidence of any SIL and high-grade SIL or cancer (HSIL+) was estimated according to baseline HPV DNA results, stratified by HIV serostatus and CD4 T-cell count.

Results Development of any SIL in women with negative HPV results (both oncogenic and nononcogenic) at 2 years was as follows: in HIV-seropositive women with CD4 counts less than 200/μL, 9% (95% CI, 1%-18%); with CD4 counts between 200/μL and 500/μL, 9% (95% CI, 4%-13%); and with CD4 counts greater than 500/μL, 4% (95% CI, 1%-7%). The CIs for these estimates overlapped with those for HIV-seronegative women with normal baseline cytology who were HPV-negative (3%; 95% CI, 1%-5%), indicating that at 2 years, there were no large absolute differences in the cumulative incidence of any SIL between groups. Furthermore, no HPV-negative participants in any group developed HSIL+ lesions within 3 years. Multivariate Cox models showed that on a relative scale, the incidence of any SIL among HIV-seropositive women with CD4 counts greater than 500/μL (hazard ratio [HR], 1.2; 95% CI, 0.5-3.0), but not those with CD4 counts less than or equal to 500/μL (HR, 2.9; 95% CI, 1.2-7.1), was similar to that in HIV-seronegative women.

Conclusion The similar low cumulative incidence of any SIL among HIV-seronegative and HIV-seropositive women with CD4 counts greater than 500/μL and who had normal cervical cytology and HPV-negative test results suggests that similar cervical cancer screening practices may be applicable to both groups, although this strategy warrants evaluation in an appropriate clinical trial.

Cervical cancer screening recommendations in the United States have been recently updated and now advise using an interval of 3 years between screenings in healthy women 30 years or older who have normal cytology results and who test negative for oncogenic (cancer-associated) human papillomavirus (HPV) DNA.1,2 The recommended interval is 6 to 12 months for women with normal cytology results and detectable oncogenic HPV. If no HPV test is conducted, 3 consecutive normal annual Papanicolaou (Pap) smear results are required before the Pap smear frequency is changed to once every 2 or 3 years. Support for these recommendations comes from several large observational studies.15

However, guidelines for human immunodeficiency virus (HIV)–seropositive women have not been revised since 19951,2,6,7 and state that HIV-seropositive women should obtain 2 Pap smears 6 months apart after the initial HIV diagnosis and, if results of both are normal, should undergo annual cytologic screening. Human papillomavirus test results are not considered,1,2,6 even though economic models have suggested that HPV testing in HIV-seropositive women might be cost-effective.8 In this study, we determined the cumulative incidence of cervical squamous intraepithelial lesions (SILs) among HIV-seropositive and HIV-seronegative women according to baseline HPV results in a large prospective cohort. We sought to determine, in keeping with recommendations for HIV-seronegative women, whether a single initial HPV test result can be used to determine the appropriate cervical cancer screening interval in an HIV-seropositive woman with normal cervical cytology.

Participants were HIV-seropositive (n = 855) and HIV-seronegative (n = 343) women who were enrolled in the Women’s Interagency HIV Study (WIHS) and had normal cervical cytology at baseline. The cohort has been described in detail elsewhere.911 Briefly, 2059 HIV-seropositive women and 569 HIV-seronegative women were enrolled during 1994-1995 from similar clinical and outreach sources in New York City, Chicago, Ill, Los Angeles and San Francisco, Calif, and the District of Columbia. All participants provided written informed consent, and the study protocol was approved by each local institutional review board. The HIV-seropositive cohort has been previously shown to have demographic characteristics and risk behaviors similar to those of US women with AIDS nationwide.9

Participants were not included in the current analysis if (1) their baseline Pap smear was abnormal or missing (834 HIV-seropositive, 106 HIV-seronegative); (2) they were missing information on baseline HPV status (126 HIV-seropositive, 33 HIV-seronegative) or CD4 T-cell count (35 HIV-seropositive); (3) they did not have an intact cervix at baseline (113 HIV-seropositive, 31 HIV-seronegative); (4) follow-up data were unavailable (96 HIV-seropositive, 43 HIV-seronegative); or (5) they HIV-seroconverted during follow-up (13 HIV-seronegative). Race and ethnicity information was obtained via questionnaire. Study participants were asked whether they were Hispanic and to identify their race from the following choices: black, white, Asian/Pacific Islander, Native American/Alaskan Native, or other. We then categorized the women further as Hispanic, black (non-Hispanic), white (non-Hispanic), and other. Race and ethnicity were included in the analysis because they may be related to HIV serostatus and the risk of SIL.

At baseline and semi-annual clinical visits, WIHS participants underwent a pelvic examination with collection of a cervicovaginal lavage for HPV testing, followed by a Pap smear using a wooden Ayres spatula and cytologic brush. All Pap smears were interpreted centrally with the 1991 Bethesda System12 criteria. Two independent cytotechnologists examined each Pap smear, and all smears identified as abnormal by either technologist, as well as 10% of all negative smears, were evaluated by a cytopathologist. The WIHS protocol calls for colposcopy for all women with an abnormal Pap smear result, but compliance with colposcopy has been incomplete (approximately 70%) in this high-risk population, and there is no central review of histologic results. For these reasons, we used cytology to define end points in our analysis. Cytology is primarily subject to false-negative results (ie, it is insensitive),1316 and occasional low-grade SILs are known to contain high-grade lesions when evaluated by biopsy.1720 Therefore, we used “any SIL” as our main end point and high-grade SIL or cancer (HSIL+) as a secondary end point.

HPV DNA testing was conducted using a well-established MY09/MY11 polymerase chain reaction assay.10,11 HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 73 were considered oncogenic. All other HPVs, including types 6, 11, 13, 26, 32, 34, 40, 42, 53, 54, 55, 57, 61, 62, 64, 66, 67, 69, 70, 71 (AE8), 72, 81 (AE7), 82 (W13B and AE2), 83 (PAP291), 84 (PAP155),85 (AE5) 89 (AE6), AE9, and AE10, as well as all those HPVs that hybridized only with the consensus probe, were considered nononcogenic.

Standard life-table methods were used to estimate the cumulative incidence of any SIL and HSIL+ according to baseline HPV DNA test results, stratified by HIV serostatus and CD4 T-cell count.21 Cox models were used to conduct multivariate analyses after demonstration that the proportional hazard assumption applied to this data set (data not shown).22 Participants who had a hysterectomy (n = 14) after their baseline visit were censored at the visit before the procedure. In the analysis of HSIL+, women were additionally censored if they reported cervical treatment. Treatment of low-grade lesions is at the discretion of the physician in the WIHS, but high-grade lesions must be treated. For analytic purposes, we considered as treated any woman who answered affirmatively to the question, “Since your last study visit, were you treated for any cervical or other abnormality?” Although self-report is not entirely reliable, we used this broad definition to be conservative; we could not exclude the possibility that some women who received treatment privately did so without this information being captured by our medical record review. In the footnotes to the tables, we report not only the number censored because of a self-report of treatment but also the number of these women who had an abnormal biopsy result (ie, those most likely to have actually received treatment).

P<.05 was set for significance. Analyses were conducted with SAS version 8.2 (SAS Institute Inc, Cary, NC) and StatXact version 6.0 (Cytel Software, Cambridge, Mass).

Table 1 shows the baseline characteristics of the HIV-seropositive and HIV-seronegative women in the WIHS who had normal cytology at baseline and were included in the current analysis. Mean age was 36 years (range 18-66 years) and 34 years (range 17-55 years) among the HIV-seropositive and HIV-seronegative women, respectively. Approximately 50% of the participants categorized themselves as black and 25% to 30% as Hispanic. HIV-seronegative women were somewhat more likely to be currently sexually active than HIV-seropositive women. Participants in both groups were followed up for a median of 7 years. The main analyses were truncated at 5 years, however, because a longer interval was not thought to be relevant, given the 3-year interval recommended for Pap-smear screening in HIV-seronegative women.

Table Graphic Jump LocationTable 1. Baseline Characteristics of HIV-Seropositive and HIV-Seronegative Participants With Normal Baseline Cytology in the Women’s Interagency HIV Study*

Among the HIV-seropositive women who had normal cytology results and were HPV-negative, 9% (95% confidence interval [CI], 1%-18%) with CD4 counts less than 200/μL, 9% (CI, 4%-13%) with CD4 counts of  200/μL to 500/μL, and 4% (CI, 1%-7%) with CD4 counts greater than 500/μL developed any SIL within 2 years (Table 2). The CIs for these estimates overlapped with that in HIV-seronegative participants who were HPV-negative (3%; CI, 1%-5%), indicating that after 2 years there were no large or significant absolute differences in the cumulative incidence of any SIL between groups (all P>.25).

Table Graphic Jump LocationTable 2. Cumulative Incidence of Any SIL and HSIL+ Among Women With Normal Cytology Results and HPV-Negative at Baseline

At 3 years, however, those with less than 200/μL and 200/μL to 500/μL CD4 T cells at baseline had a cumulative incidence of any SIL of 29% (95% CI, 15%-44%) and 14% (95% CI, 8%-20%), respectively. HIV-seropositive/HPV-negative women with CD4 T cell counts greater than 500/μL continued to have a low rate of any SIL through 3 years of follow-up (6%; 95% CI, 2%-10%), a cumulative incidence comparable to that in HIV-seronegative women (5%; 95% CI, 2%-9%). There were no cases of HSIL or cancer during the first 3 years of follow-up in any HPV-negative subgroup. In fact, there were no cases of cancer through the entire 7-year follow-up period.

The risk of any SIL was greater for participants positive for a nononcogenic HPV type at baseline (Table 3) compared with that for the HPV-negative women. At 2 years of follow-up, HIV-seropositive women with a nononcogenic HPV infection and CD4 counts less than 200/μL had a cumulative incidence rate of 31% (95% CI, 19%-42%) and those with 200/μL to 500/μL had a rate of 24% (95% CI, 17%-32%). The rate was much lower among HIV-seropositive women with greater than 500/μL CD4 T cells (6%; 95% CI, 1%-11%) and in HIV-seronegative women (8%; 95% CI, 1%-15%). Few incident HSILs and no cancers were observed throughout follow-up in the nononcogenic HPV-positive subgroup.

Table Graphic Jump LocationTable 3. Cumulative Incidence of Any SIL and HSIL+ Among Women With Normal Cytology Results and Positive for a Nononcogenic HPV at Baseline

Using the commercially available test for HPV, HPV test results are clinically considered negative if no oncogenic HPV type is detected (ie, women who are HPV DNA negative and those with a nononcogenic HPV type are grouped together). HIV-seropositive women with CD4 counts less than 200/μL and 200/μL to 500/μL who were negative for an oncogenic HPV had a 2-year cumulative incidence of any SIL of 21% (95% CI, 13%-29%) and 15% (95% CI, 11%-20%), respectively. HIV-seropositive women with CD4 counts greater than 500/μL had a 2-year rate (5%; 95% CI, 2%-7%) similar to the low rate in HIV-seronegative women (4%; 95% CI, 2%-7%), and even at 3 years the cumulative incidence of any SIL was similar in HIV-seropositive women with CD4 counts greater than 500/μL (9%; 95% CI, 5%-13%) and HIV-seronegative women (6%; 95% CI, 3%-9%). HIV-seropositive women positive for an oncogenic HPV type at baseline had the highest cumulative incidence of any SIL, and even those with CD4 counts greater than 500/μL had a markedly higher rate than HIV-seronegative women (Table 4).

Table Graphic Jump LocationTable 4. Cumulative Incidence of Any SIL and HSIL+ Among Women With Normal Cytology Results and Positive for an Oncogenic HPV at Baseline

Multivariate Cox models that controlled for age and race/ethnicity largely corroborated the above results: through 3 years of follow-up, the incidence of any SIL was similar in HIV-seronegative and HIV-seropositive women with CD4 counts greater than 500/μL who had negative results for oncogenic HPV (hazard ratio [HR], 1.4; 95% CI, 0.7-2.7) or all HPV (HR, 1.2; 95% CI, 0.5-3.0). HIV-seropositive women with CD4 counts of 500/μL or less, however, had a greater incidence of any SIL relative to HIV-seronegative participants after just 2 years, even among women with negative test results for all HPVs (HR, 2.9; CI, 1.2-7.1). Last, we measured the strength of association of incident SIL with nononcogenic (HR, 1.6; 95% CI, 1.2-2.1) and oncogenic (HR, 2.7; 95% CI, 2.0-3.7) HPV infection at baseline, controlling for HIV serostatus, CD4 T-cell count, age, and race/ethnicity and using all 5 years of data in this study. For HSIL+, the corresponding HRs were 1.7 (95% CI, 0.3-8.9) for nononcogenic and 10.2 (95% CI, 2.3-44.5) for oncogenic HPV.

In this observational cohort study, HIV-seronegative and HIV-seropositive women who had normal cytology results with CD4 counts greater than 500/μL and who had negative test results for HPV at baseline had a similar low cumulative incidence of any SIL for 3 years or more. If these findings are confirmed, comparable risk of cervical lesions would suggest that comparable cancer-screening practices may be applicable to both groups. Current cervical cancer screening recommendations for HIV-seronegative women 30 years of age or older advise using an interval of 3 years between screenings among those who have normal cytology results and negative test results for oncogenic HPV.1,2 Most women in our study were aged 30 years or older. However, only an adequately powered clinical trial can determine whether the cervical cancer screening strategy in HIV-seronegative women can be safely used in HIV-seropositive women with CD4 counts greater than 500/μL.

Among women with negative test results for all HPVs, the absolute difference in the cumulative incidence of any SIL in HIV-seropositive women with CD4 counts of 500/μL or less (9% cumulative incidence) compared with that in HIV-seronegative women (3% cumulative incidence) was only 6%. There were also no cases of HSIL+ in any HPV-negative women for 3 or more years. Whether HPV DNA testing might be useful in determining the appropriate frequency of cervical cancer screening among HIV-seropositive women with normal cytology results and CD4 counts of 500/μL or less may also warrant formal evaluation in a clinical trial.

There has, to our knowledge, been little published about the risk of SIL among HIV-seropositive women with normal cytology results as stratified by HPV test results. Ellerbrock et al23 reported a low cumulative incidence of SIL (approximately 5% at 24 months) among HIV-seropositive women who were HPV negative at baseline, consistent with our results. Conversely, Delmas et al24 reported that at 18 months, 23% of HIV-seropositive women who were HPV negative at baseline had developed a cervical lesion. Younger age (eg, <35 years) is an established risk factor for incident HPV infection and SIL, and the women in the study by Delmas et al24 were younger than those in either the study by Ellerbrock et al23 or our study; the median age in the study by Ellerbrock et al was approximately 35 years, and it was 37 years in our study, whereas only a third of women in the study by Delmas et al were 34 years or older. Nonetheless, given the conflicting reports, it is appropriate to be cautious in interpreting the findings of our study.

Furthermore, our study has important limitations. First, it is possible that we have underestimated the rate of neoplasia in the cohort because our end points of SIL and HSIL+ were determined by using cytology without histologic confirmation, and there was no end-of-study colposcopy or blind biopsy to seek occult lesions. However, in a population in which low-grade SIL is uncommon and there is little or no HSIL detected, we believe that we can be reasonably certain that few cases of high-grade neoplasia have been missed. Given that participants were also evaluated every 6 months for more than 5 years, it would seem unlikely that much significant disease went undetected. A second major concern is that the polymerase chain reaction assay we used, albeit well established and widely used, is not a commercial, clinically approved test.10,11 In fact, in cervical cancer screening, the HPV DNA test currently approved by the US Food and Drug Administration is approved only for the detection of oncogenic HPV types. Therefore, unlike in our study, women who are infected with nononcogenic HPV would be considered as testing negative with the approved test as it is generally used. With reagents available from the manufacturer, however, this HPV DNA test can detect a wide range of oncogenic and nononcogenic HPV types, which is of interest because our data showed that in HIV-seropositive women with CD4 counts of 500/μL or less, only those who were negative for both oncogenic and nononcogenic HPV had low rates of any SIL.

Another possible limitation of our investigation is that we did not consider changes in HPV and immune status over time in our analyses. The similarity, though, in the 3-year cumulative incidence rate of any SIL in HIV-seronegative and HIV-seropositive women with CD4 cell counts greater than 500/μL who were oncogenic HPV-negative at baseline suggests that this was not a major concern, at least among HIV-seropositive women who were fairly immunocompetent at the time of evaluation. In any case, changes in HPV and immune status over time were not highly relevant to our research question, whether a single initial HPV test result can be used to determine the appropriate interval between Pap smears in HIV-seropositive women.

Finally, the most important limitation to our study was its observational design. Consideration will also need to be given to the psychosocial costs of a positive HPV test in HIV-seropositive women, many of whom will not develop SIL. However, according to the results of our study, we believe that the use of HPV testing in HIV-seropositive women warrants evaluation in a formal clinical trial.

Corresponding Author: Tiffany G. Harris, PhD, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave, Belfer 1308A, Bronx, NY 10461 (tharris@aecom.yu.edu).

Author Contributions: Dr Harris 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: Harris, Burk, Palefsky, Strickler.

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

Analysis and interpretation of data: Harris, Burk, Palefsky, Massad, Bang, Hall, Bacon, Watts, Silverberg, Xue, Melnick, Strickler.

Drafting of the manuscript: Harris, Burk, Palefsky, Bang, Xue, Strickler.

Critical revision of the manuscript for important intellectual content: Harris, Burk, Palefsky, Massad, Anastos, Minkoff, Hall, Bacon, Levine, Watts, Silverberg, Xue, Melnick, Strickler.

Statistical analysis: Harris, Burk, Palefsky, Bang, Hall, Silverberg, Xue, Strickler.

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

Administrative, technical, or material support: Burk, Palefsky, Anastos, Bacon, Levine, Watts, Strickler.

Study supervision: Burk, Palefsky, Watts, Strickler.

Financial Disclosures: None reported.

Funding/Support: HPV DNA testing is funded through R01-CA-085178. All specimens and other data in this study were collected by the Women’s Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Kathryn Anastos, MD); Brooklyn, NY (Howard Minkoff, MD); Washington, DC Metropolitan Consortium (Mary Young, MD); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt, MD); Los Angeles County/Southern California Consortium (Alexandra Levine, MD); Chicago Consortium (Mardge Cohen, MD); Data Coordinating Center (Stephen Gange, MD). The WIHS is funded by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute and the National Institute on Drug Abuse (U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, and U01-AI-42590). Funding is also provided by the National Institute of Child Health and Human Development (U01-CH-32632) and the National Center for Research Resources (M01-RR-00071, M01-RR-00079, M01-RR-00083).

Role of the Sponsors: The WIHS is an NIH-funded multicenter cohort study, and the funding sources had a role in the WIHS study design; in the collection, analysis, and interpretation of data; and in the preparation, review, and approval of the manuscript.

Previous Presentation: Presented in part at the 8th International Conference on Malignancies in AIDS and Other Immunodeficiencies (ICMAOI): Basic, Epidemiologic and Clinical Research; April 29-30, 2004; Bethesda, Md.

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Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of HIV-Seropositive and HIV-Seronegative Participants With Normal Baseline Cytology in the Women’s Interagency HIV Study*
Table Graphic Jump LocationTable 2. Cumulative Incidence of Any SIL and HSIL+ Among Women With Normal Cytology Results and HPV-Negative at Baseline
Table Graphic Jump LocationTable 3. Cumulative Incidence of Any SIL and HSIL+ Among Women With Normal Cytology Results and Positive for a Nononcogenic HPV at Baseline
Table Graphic Jump LocationTable 4. Cumulative Incidence of Any SIL and HSIL+ Among Women With Normal Cytology Results and Positive for an Oncogenic HPV at Baseline

References

Wright TC Jr, Schiffman M, Solomon D.  et al.  Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening.  Obstet Gynecol. 2004;103:304-309
PubMed   |  Link to Article
Practice Bulletin ACOG.  Clinical management guidelines for obstetrician-gynecologists: number 45, August 2003: cervical cytology screening (replaces committee opinion 152, March 1995).  Obstet Gynecol. 2003;102:417-427
PubMed   |  Link to Article
Rozendaal L, Westerga J, van der Linden JC.  et al.  PCR based high risk HPV testing is superior to neural network based screening for predicting incident CIN III in women with normal cytology and borderline changes.  J Clin Pathol. 2000;53:606-611
PubMed   |  Link to Article
Sherman ME, Lorincz AT, Scott DR.  et al.  Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis.  J Natl Cancer Inst. 2003;95:46-52
PubMed   |  Link to Article
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