Special Feature

How Should You Manage Cervical Cancer Screening in Women with HIV?

By Rebecca H. Allen, MD, MPH, Assistant Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI, is Associate Editor for OB/GYN Clinical Alert.

Dr. Allen reports no financial relationships relevant to this field of study.

Synopsis: Annual Pap testing is safe for women infected with HIV and longer intervals are appropriate for those with serial negative tests. For women age 30 and older infected with HIV, cotesting with high-risk HPV DNA also could allow for longer intervals between testing.

Sources: Castle PE, et al. Safety against cervical precancer and cancer following negative human papillomavirus and Papanicolaou test results in human immunodeficiency virus-infected women. Arch Intern Med 2012;172:1041-1043.

Keller MJ, et al. Risk of cervical precancer and cancer among HIV-infected women with normal cervical cytology and no evidence of oncogenic HPV infection. JAMA 2012;308:362-369.

Massad LS, et al. Negative predictive value of Pap testing: Implications for screening intervals for women with human immunodeficiency virus. Obstet Gynecol2012;120:791-797.

Women with HIV have a higher incidence of cervical intraepithelial neoplasia (CIN) because of the burden and persistence of HPV in that population.1,2 In our colposcopy clinic, we often see women infected with HIV who struggle with persistent HPV infection and come back year after year for evaluations. Therefore, screening women with HIV for cervical cancer is extremely important. The question of how to handle cervical cancer screening in women infected with HIV has never been explicitly answered by the American Society for Colposcopy and Cervical Pathology (ASCCP) in its guidelines.3 The United States Preventive Services Task Force states that its cervical cancer screening guidelines do not apply to women who are immunocompromised (e.g., with HIV).4 Because women with HIV have a higher chance of developing cervical precancer and cancer compared to the general population, the Centers for Disease Control and Prevention has recommended two Pap tests in the first year after HIV diagnosis followed by annual Pap tests provided the results are normal.5 This recommendation is based on expert opinion because the sensitivity of a single Pap smear was not deemed adequate in this high-risk population. Nevertheless, if the Pap smear result is abnormal, according to ASCCP guidelines, women with HIV are managed the same as women in the general population.6,7

To explore the question of cervical cancer screening in women infected with HIV, I reviewed this trio of studies published in 2012. With the new cervical cancer screening guidelines for the general population including lengthening screening intervals,3 investigators are now looking at screening frequency in the HIV-positive population. Massad et al used data from the Women's Interagency HIV Study, an ongoing U.S. multicenter cohort study of women with and without HIV who are followed to ascertain the development of HIV-related disease. Every 6 months, participants underwent a physical exam including a conventional Pap test. The primary study outcome was cervical precancer defined as a composite of high-grade Pap smears and biopsy results (CIN 2 or worse). The authors excluded women with past abnormal Pap smears, cervical dysplasia, cervical cancer, and hysterectomy. Out of 1225 women with HIV and a baseline Pap test, the authors identified 942 (77%) women with a negative Pap smear. Eight of these women (1%) developed precancer within 15 months and 40 (4%) within 39 months. After three consecutive negative Pap tests, the negative predictive value was 100% at 15 months and 98.1% (95% confidence interval [CI] 97.0-99.3) at 39 months. Additionally, after 10 consecutive negative Pap tests, the negative predictive value was 100% at both 15 and 39 months of follow-up. Therefore, the authors concluded that in HIV-infected women with no history of abnormal Pap cytology or cervical precancer, annual Pap testing is safe and Pap testing every 6 months after diagnosis is unnecessary. Another important finding in this study was that women with HIV with serial negative tests could likely increase their screening interval safely similar to the general population.

In a multivariate analysis during the 15 months of follow-up, Massad et al identified risk factors for precancer in HIV seropositive women were any abnormal cytology (adjusted hazard ratio [HR], 9.9; 95% CI, 7.7-12.6), current smoking (adjusted HR, 1.5; 95% CI, 1.2-2.0), age younger than 31 compared to age older than 45 (adjusted HR 1.5, 95% CI 1.1-2.1), and CD4 count of 200-500 (adjusted HR, 1.8; 95% CI, 1.3-2.3) and < 200 (adjusted HR, 2.2; 95% CI, 1.6-2.9) compared to CD4 > 500, respectively. Use of HAART was not associated with precancer risk. These risk factors make clinical sense and it may be that lengthening screening intervals would be more appropriate for women with normal CD4 counts.

What about incorporating HPV DNA testing for cervical cancer screening in HIV-infected women? Traditionally, HPV DNA testing was not recommended for use in women with HIV because of the higher prevalence of HPV infection and limited evidence for its use in this population.5 However, in 2003, the Kaiser Permanente Northern California system initiated cotesting with Pap and HPV DNA tests in all women, including those HIV positive, who were 30 years or older. In Castle et al, investigators from Kaiser Permanente Northern California reviewed records on these women in their health plan. The primary outcome was the risk of CIN 2 or worse on biopsy and/or HSIL cytology. Between 2003 and 2010, the authors identified 245 women who had a negative baseline HPV and Pap test and underwent a second cotest. The second cotest was performed at a mean of 24.4 months. Second cotest results were available for 241 women (21 [8.7%] with a positive result) and HPV results for 240 women (27 [11.3%] with a positive result). Of the 236 women with complete follow up, there were no cases of CIN 2 or more (0%; 95% CI, 0.0%, 1.6%) and one case of HSIL cytology (0.4%; 95% CI, 0.0%, 2.3%). Therefore, this small retrospective study showed that HPV DNA testing can be used in conjunction with Pap tests for primary screening in women infected with HIV.

These results are further supported by another analysis of the Women's Interagency HIV Study. Keller et al identified 420 HIV-infected women and compared them to 279 HIV-uninfected women who had normal cervical cytology at baseline. Every 6 months, women underwent Pap testing and cervicovaginal lavage for HPV DNA testing. The primary outcome was the 5-year cumulative incidence of cervical precancer and cancer. Women were censored from the analysis if they had undergone cervical treatment or were lost to follow up. At enrollment, 369 (88%) HIV-infected women and 255 (91%) HIV-uninfected women were high-risk HPV negative. The 5-year cumulative incidence of CIN 2+ was 5% (95% CI, 2%, 8%) in women with HIV and 5% (95% CI, 1%, 8%) in women without HIV. One HIV-infected and one HIV-uninfected woman had CIN 3, but none had cancer. The authors concluded that the risk of precancer and cancer at 5 years was similar in HIV negative and positive women who had negative cotesting. It is important to note the limitations of the Women's Interagency HIV Study in that the results are only generalizable to women with HIV who have undergone regular medical care with long-term follow up.

It may be that more observational or randomized controlled trials on this question will be necessary before organizations change their guidelines for women with HIV. Nevertheless, the results are intriguing and suggest that women with HIV with no past history of abnormal cytology or cervical precancer can be screened with cotesting if they are ≤ 30 years of age and that screening intervals could be lengthened with serial negative Pap tests. This would especially apply to women with normal CD4 counts. Of course, women with HIV who have abnormal Pap smear results should undergo colposcopy and be managed appropriately by current guidelines.6,7 In addition, one should not forget to perform a visual inspection of the vagina, vulva, and anus at annual exams in HIV-positive patients given the high rate of concurrent HPV disease.8

References

  1. Strickler HD, et al. Natural history and possible reactivation of HPV in HIV-positive women. J Natl Cancer Inst 2005;97:577-586.
  2. Frisch M, et al. HPV-associated cancers in patients with HIV and AIDS. J Natl Cancer Inst 2000;92:1500-1510.
  3. Saslow D, et al. American Cancer Society, ASCCP, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Ca Cancer J Clin 2012;62:147-172.
  4. United States Preventive Services Task Force. Screening for cervical cancer. Available at: www.uspreventiveservicestaskforce.org/uspstf/uspscerv.htm. Accessed Oct. 23, 2012.
  5. Kaplan JE, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from CDC, the NIH, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR 2009;58:1-207.
  6. Wright TC Jr, et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197:346-355.
  7. Wright TC Jr, et al. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in-situ. Am J Obstet Gynecol2007;197:340-345.
  8. Jamieson DJ, et al. Vulvar, vaginal, and perianal intraepithelial neoplasia in women with or at risk for human immunodeficiency virus. Obstet Gynecol 2006;107:1023-1028.