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Research Letters |

Safety Against Cervical Precancer and Cancer Following Negative Human Papillomavirus and Papanicolaou Test Results in Human Immunodeficiency Virus–Infected Women FREE

Philip E. Castle, PhD, MPH; Barbara Fetterman, SCT(ASCP); Nancy Poitras, PMP; Thomas Lorey, MD; Walter Kinney, MD
[+] Author Affiliations

Author Affiliations: American Society for Clinical Pathology Institute, Washington, DC (Dr Castle); Regional Laboratory, Kaiser Permanente Northern California, Berkeley (Mss Fetterman and Poitras and Dr Lorey); and Division of Gynecologic Oncology and Department of Women's Health, The Permanente Medical Group, Oakland, California (Dr Kinney).


Arch Intern Med. 2012;172(13):1041-1043. doi:10.1001/archinternmed.2012.1744.
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The American Cancer Society (ACS) first recommended cotesting (cervical cytologic and human papillomavirus [HPV] DNA testing) as an acceptable alternative to routine cervical cytologic testing alone for cervical cancer screening in 2002.1 The ACS recommendations included extending the screening interval to not less than 3 years for those women who tested negative for both tests (“negative cotest”).

Human immunodeficiency virus (HIV) infection, and its clinical manifestation of AIDS, is a known risk factor for cervical precancer2 and cancer,3 and cervical cancer is considered an AIDS-defining malignancy. Current guidelines4 for cervical cancer screening recommend Papanicolaou (Pap) testing twice during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. It is unknown whether a negative cotest result might provide similar safety for HIV-infected women as it does for HIV-negative women. Thus, the objective of this analysis was to assess the risk of cervical precancer and cancer following a negative cotest result in HIV-seropositive women 30 years and older.

In January 2003, Kaiser Permanente Northern California (KPNC) introduced cotesting using Hybrid Capture 2 (Qiagen) and conventional Pap testing, with a screening interval extension to 3 years after a negative cotest result. Papanicolaou test results were interpreted according to the 2001 Bethesda System.5 Annual Pap tests continued to be available as an option. By early 2007, 95% of KPNC screening participants 30 years and older elected cotesting at 3-year intervals in preference to annual Pap testing. For women who tested positive for HPV and had negative Pap test results (HPV+/Pap−), management evolved from annual follow-up with retesting, to recommending colposcopy after 2 HPV+/Pap− screening results in 2006, to mandatory colposcopy after 2 HPV+/Pap− screening results in 2008, according to interim guidance.6

There were no special recommendations for cervical cancer screening of HIV-infected women at KPNC, so those 30 years and older underwent routine cotesting. We used electronic medical records to identify HIV-infected women who had a negative cotest result to examine the safety it conveys.

We calculated the risk of histologically confirmed cervical (CIN2) or more severe (CIN2+) intraepithelial neoplasia and high-grade squamous intraepithelial lesion (HSIL) cytology and/or CIN2+ histology (HSIL+) with binomial exact 95% confidence intervals.

The KPNC Institutional Review Board and Western Institutional Review Board (for Dr Castle) approved the use of these data. The KPNC HIV Steering Committee also approved the use of these data.

We identified 245 women 30 years and older who had negative HPV and Pap test (“negative cotest”) results and underwent a second cotest between 2003 and 2010. The second cotest was done at 24.4 months (mean), 23 months (median), 15 to 35 months (interquartile range [IQR]), and 5 to 42 months (range) after the first cotest; 32% of women had a cotest 30 months or later. CD4 cell counts were 519.7/μL (mean), 475/μL (median), 338/μL to 681/μL (IQR), and 4/μL to 1380/μL (range); the distribution of CD4 cell counts was 9% with lower than 200/μL, 44% with 200/μL to 499/μL, and 47% with 500/μL or higher. The CD4 cell measurements were conducted a mean of 3.1 months after and a median of 0.2 months before the first cotest. Of the 92 women whose HIV viral load data we were able to retrieve, measurements were 20 274.5/mL (mean), 7552.5/mL (median), 766/mL to 32 363.5/mL (IQR), and 75/mL to 352 531/mL (range). The HIV viral load measurement was conducted a mean 8.2 and a median of 0.2 months after the first cotest.

We found Pap test results for 241 women (21 [8.7%] with a positive result) and HPV results for 240 women (27 [11.3%] with a positive result). The combined HPV and Pap test results for the second cotest and the third cotest results for those women who underwent a 12-month follow-up per current guidelines (HPV+/Pap− and HPV−/atypical squamous cells of undetermined significance) are given in the Table. For 236 women with a complete follow-up, we found no cases of histologically confirmed CIN2+, for a CIN2+ risk of 0.0% (95% CI, 0.0%-1.6%), and 1 case of HSIL cytology (on the third cotest as a follow-up of HPV+/Pap− result on the second cotest), for a risk of HSIL cytology of 0.4% (95% CI, 0.0%-2.3%). Among the 78 women with a complete follow-up of 30 months or more after the first cotest, there was 0% (95% CI, 0.0%-4.6%) risk for CIN2+.

Table Graphic Jump LocationTable. Results for HPV and Papanicolaou Cotesting for 245 HIV-Infected Women 30 Years and Older Who Had a Preceding Negative Cotest Result (Concurrent HPV− and Pap− Test Results)a

In this population of HIV-infected women 30 years and older, we found that a negative cotest result conferred excellent safety against cervical precancer and cancer, which is akin to the safety cotesting provides HIV-negative populations.7 These findings are consistent with our understanding of the natural history of HPV and cervical cancer,8 in which CIN2+ only develops several years after a newly detected HPV infection. While more data are needed, these results suggest that it may be acceptable and safe to extend cervical cancer screening intervals by including HPV testing, thereby minimizing the harms of screening.

Correspondence: Dr Castle, American Society for Clinical Pathology Institute, 1225 New York Ave NW, Ste 350, Washington, DC 20005 (philip.castle@ascp.org).

Published Online: May 28, 2012. doi:10.1001/archinternmed.2012.1744

Author Contributions: Ms Fetterman and Dr Kinney had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Castle and Fetterman. Acquisition of data: Fetterman, Poitras, Lorey, and Kinney. Analysis and interpretation of data: Castle. Drafting of the manuscript: Castle and Kinney. Critical revision of the manuscript for important intellectual content: Castle, Fetterman, Poitras, and Lorey. Statistical analysis: Castle and Fetterman. Administrative, technical, and material support: Fetterman and Lorey.

Financial Disclosure: Dr Castle serves on a data and safety monitoring board for Merck. Dr Castle has received HPV tests and testing for research at reduced or no cost from Qiagen and Roche.

Funding/Support: The American Cancer Society provided financial support to Dr Kinney.

Role of the Sponsor: The funder played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Additional Contributions: Michael Allerton, MS, Jane Hrynkow, and Leo Hurley, MPH (KPNC), assisted in acquiring the data for this report.

Saslow D, Runowicz CD, Solomon D,  et al; American Cancer Society.  American Cancer Society guideline for the early detection of cervical neoplasia and cancer.  CA Cancer J Clin. 2002;52(6):342-362
PubMed   |  Link to Article
Hawes SE, Critchlow CW, Faye Niang MA,  et al.  Increased risk of high-grade cervical squamous intraepithelial lesions and invasive cervical cancer among African women with human immunodeficiency virus type 1 and 2 infections.  J Infect Dis. 2003;188(4):555-563
PubMed   |  Link to Article
Shiels MS, Pfeiffer RM, Hall HI,  et al.  Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980-2007.  JAMA. 2011;305(14):1450-1459
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
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
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(2):304-309
PubMed   |  Link to Article
Katki HA, Kinney WK, Fetterman B,  et al.  Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice.  Lancet Oncol. 2011;12(7):663-672
PubMed   |  Link to Article
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer.  Lancet. 2007;370(9590):890-907
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable. Results for HPV and Papanicolaou Cotesting for 245 HIV-Infected Women 30 Years and Older Who Had a Preceding Negative Cotest Result (Concurrent HPV− and Pap− Test Results)a

References

Saslow D, Runowicz CD, Solomon D,  et al; American Cancer Society.  American Cancer Society guideline for the early detection of cervical neoplasia and cancer.  CA Cancer J Clin. 2002;52(6):342-362
PubMed   |  Link to Article
Hawes SE, Critchlow CW, Faye Niang MA,  et al.  Increased risk of high-grade cervical squamous intraepithelial lesions and invasive cervical cancer among African women with human immunodeficiency virus type 1 and 2 infections.  J Infect Dis. 2003;188(4):555-563
PubMed   |  Link to Article
Shiels MS, Pfeiffer RM, Hall HI,  et al.  Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980-2007.  JAMA. 2011;305(14):1450-1459
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
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
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(2):304-309
PubMed   |  Link to Article
Katki HA, Kinney WK, Fetterman B,  et al.  Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice.  Lancet Oncol. 2011;12(7):663-672
PubMed   |  Link to Article
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer.  Lancet. 2007;370(9590):890-907
PubMed   |  Link to Article

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