Human Papillomavirus in the HIV-Infected Host: Epidemiology and Pathogenesis in the Antiretroviral Era
Human papillomavirus (HPV) infection is associated with essentially all cervical cancers, 80–90 % of anal cancers, and a high proportion of oropharyngeal, vaginal, penile, and vulvar cancers. Malignancy is preceded by the development of precancerous lesions termed high-grade squamous intraepithelial lesions (HSIL). Men and women with human immunodeficiency virus (HIV) infection are at high risk of HPV-related malignancies. The incidence of anal cancer in particular has markedly risen during the antiretroviral era due to the increased longevity of patients with HIV and the absence of anal malignancy screening programs. HIV infection may facilitate initial HPV infection by disrupting epithelial cell tight junctions. Once infection is established, HIV may promote HSIL development via the up-regulation of HPV oncogene expression and impairment of the immune response needed to clear the lesion. HIV-infected women should be screened for cervical HSIL and cancer, and HIV-infected men and women should be considered for anal screening programs.
KeywordsHuman papillomavirus Human immunodeficiency virus Cervical cancer Anal cancer Antiretroviral therapy Anal squamous intraepithelial lesions Cervical squamous intraepithelial lesions
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Conflict of Interest
Cristina Brickman declares that she has no conflict of interest.
Joel Palefsky reports grants, travel support, and board membership from Merck & Co., Inc.; grants from Hologic; and stocks from Aura Biosciences, and he is a consultant for Qiagen.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Stanley M, Lowy DR, Frazer I. Chapter 12: prophylactic HPV vaccines: underlying mechanisms. Vaccine. 2006;24 Suppl 3:S3/106–13.Google Scholar
- 3.Centers for Disease, C. and Prevention. Human papillomavirus-associated cancers—United States, 2004–2008. MMWR Morb Mortal Wkly Rep. 2012;61:258–61.Google Scholar
- 9.Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No.11 [Internet]. 2012; Available from: http://globocan.iarc.fr, accessed on 11/28/2014.
- 11.International Collaboration of Epidemiological Studies of Cervical, C. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer. 2007;120(4):885–91.CrossRefGoogle Scholar
- 12.Castro KG et al. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17):1–19.Google Scholar
- 15.••Hleyhel M et al. Risk of AIDS-defining cancers among HIV-1-infected patients in France between 1992 and 2009: results from the FHDH-ANRS CO4 cohort. Clin Infect Dis. 2013;57(11):1638–47. Data from large French HIV cohort that summarizes the most recent incidence trends of AIDS-defining malignancies. CrossRefPubMedGoogle Scholar
- 25.••Steinau M et al. Human papillomavirus prevalence in invasive anal cancers in the United States before vaccine introduction. J Low Genit Tract Dis. 2013;17(4):397–403. Used SEER registry to identify and perform HPV testing on anal cancer specimens. 90% of anal cancers are associated with HPV-infection, primarily HPV-16. CrossRefPubMedCentralPubMedGoogle Scholar
- 26.Darragh T, et al. The anal canal and perianus: HPV-related disease, in modern colposcopy: textbook and atlas E.J. Mayeaux and J. Thomas Cox, Editors. 2012, Lippincott, Williams, & Wilkins: Baltimore.Google Scholar
- 36.••Piketty C et al. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the French hospital database on HIV. J Clin Oncol. 2012;30(35):4360–6. Data from large French HIV cohort that summarizes recent incidence trends for anal cancer in HIV-infected patients. CrossRefPubMedGoogle Scholar
- 41.Prevention, C.f.D.C.a. HIV surveillance report, 2011. 2013 November 28 2013]; Available from: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/.
- 58.•Strickler HD et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst. 2005;97(8):577–86. First study to show that newly detected HPV infection occurs in celibate women, suggesting the reactivation of previously latent HPV infection. CrossRefPubMedGoogle Scholar
- 62.•Konopnicki D et al. Sustained viral suppression and higher CD4+ T-cell count reduces the risk of persistent cervical high-risk human papillomavirus infection in HIV-positive women. J Infect Dis. 2013;207(11):1723–9. Large cohort study of HIV-infected women with extended follow-up time. Shows very limited effect of ART in decreasing the risk of persistent cervical hr-HPV infection.CrossRefPubMedGoogle Scholar
- 63.•Blitz S et al. Evaluation of HIV and highly active antiretroviral therapy on the natural history of human papillomavirus infection and cervical cytopathologic findings in HIV-positive and high-risk HIV-negative women. J Infect Dis. 2013;208(3):454–62. Additional recent large cohort of HIV-infected women with extended follow-up time. Shows limited effect of ART in promoting regression of SIL. CrossRefPubMedGoogle Scholar
- 66.The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA, 1989. 262(7): p. 931–4.Google Scholar
- 67.••Darragh TM et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;16(3):205–42. Describes the Lower Anogenital Terminology Standardization (LAST) project and new proposed terminology to classify HPV lesion. CrossRefPubMedGoogle Scholar
- 68.Wright TC, Kurman RJ, and Ferenczy A. Precancerous lesions of the cervix, in Blaustein’s pathology of the female genital tract, Kurman RJ, Editor. 2002, Springer-Verlag: New York City. p. 277.Google Scholar
- 70.Committee on Practice, B.-G. ACOG practice bulletin number 131: screening for cervical cancer. Obstet Gynecol. 2012;120(5):1222–38.Google Scholar
- 81.•McCredie MR et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9(5):425–34. Describes New Zealand study that quantified risk of cervical HSIL progression in HIV-uninfected women. CrossRefPubMedGoogle Scholar
- 83.••Machalek DA et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012;13(5):487–500. Uses data from meta-analysis to estimate yearly risk of developing anal cancer among HIV-infected and HIV-uninfected MSM with HSIL. CrossRefPubMedGoogle Scholar
- 92.••Tugizov SM et al. HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus. Virology. 2013;446(1–2):378–88. In vitro study that shows how HIV-derived tat and gp120 disrupt epithelial tight-cell junctions which allow HPV pseudovirion infection of the basal cell l epithelium. CrossRefPubMedGoogle Scholar
- 95.•Nowak RG et al. Increases in human papillomavirus detection during early HIV infection among women in Zimbabwe. J Infect Dis. 2011;203(8):1182–91. Cohort study showing a rapid rise in cervical HPV infection soon after HIV infection. Argues that immune dysregulation associated with acute HIV leads to the reactivation of previously latent HPV. CrossRefPubMedCentralPubMedGoogle Scholar
- 96.•Wang C et al. Rapid rise in detection of human papillomavirus (HPV) infection soon after incident HIV infection among South African women. J Infect Dis. 2011;203(4):479–86. Cohort study showing a rapid rise in cervical HPV infection soon after HIV infection. Argues that immune dysregulation associated with acute HIV leads to the reactivation of previously latent HPV. CrossRefPubMedCentralPubMedGoogle Scholar