Non-AIDS-Defining Malignancies in the HIV-Infected Population

  • Chia-ching J. WangEmail author
  • Michael J. Silverberg
  • Donald I. Abrams
HIV/AIDS (R MacArthur, Section Editor)
Part of the following topical collections:
  1. Topical Collection on HIV/AIDS


With the advent of effective combination antiretroviral therapy, HIV infection has been transformed from a fatal disease to a chronic condition. There is renewed clinical interest in long-term morbidities, including malignancies that occur disproportionately within this population. Non-AIDS-defining cancers (NADCs) are a significant source of morbidity and mortality in the aging HIV-infected population. There are data to suggest that incidence rates are elevated among HIV-infected individuals for many cancer sites, particularly those with a confirmed or suspected infectious etiology. The complex interplay between behavioral risk factors, coexistence of viral infections, immunodeficiency and antiretroviral therapy makes it difficult to analyze why certain cancers develop more frequently in HIV-infected individuals. The challenge to clinicians caring for HIV-infected patients is to develop and implement effective means to screen, treat, and prevent NADCs in the future. This review presents data on whether NADCs are increased in the HIV-Infected population, as well as ongoing research on epidemiology, prevention and pathogenesis of this evolving aspect of the HIV epidemic.


HIV/AIDS Cancer Epidemiology Lung cancer 


Compliance with Ethics Guidelines

Conflict of Interest

Chia-Ching Wang received travel expense reimbursement from Prime Oncology. Michael Silverberg received grants from Merck and Pfizer. Donald Abrams declares no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Castro KG, Ward JW, Slutsker L, et al. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41:1–19.Google Scholar
  2. 2.
    Engels EA, Pfeiffer RM, Goedert JJ, et al. for the HIV/AIDS Cancer Match Study. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS. 2006;20:1645–54.PubMedCrossRefGoogle Scholar
  3. 3.
    Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123:187–94.PubMedCrossRefGoogle Scholar
  4. 4.
    Long JL, Engels EA, Moore RD, Gebo KA. Incidence and outcomes of malignancy in the HAART era in an urban cohort of HIV-infected individuals. AIDS. 2008;22:489–96.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. 2008;148:728–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52:611–22.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Detels R, Muñoz A, McFarlane G, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA. 1998;280:1497–503.PubMedCrossRefGoogle Scholar
  8. 8.
    Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Silverberg MJ, Wegner SA, Milazzo MJ, et al. Effectiveness of highly-active antiretroviral therapy by race/ethnicity. AIDS. 2006;20:1531–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Bhavan KP, Kampalath VN, Overton ET. The aging of the HIV epidemic. Curr HIV/AIDS Rep. 2008;5:150–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Effros RB, Fletcher CV, Gebo K, et al. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis. 2008;47:542–53.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Silverberg MJ, Chao C, Leyden WA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009;23:2337–45.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370:59–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Clifford GM, Polesel J, Rickenbach M, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst. 2005;97:425–32.PubMedCrossRefGoogle Scholar
  15. 15.••
    Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103:753–62. Used data from the HIV/AIDS Cancer Match Study, which links 15 US population-based HIV and cancer registries, and from the Centers for Disease Control and Prevention.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    CDC. HIV surveillance report, 2011, vol. 23. Atlanta: Centers for Disease Control and Prevention; 2013. Accessed 28 March 2014.
  17. 17.
    Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS ONE. 2013;8:e81355.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med. 2007;146:87–95.PubMedCrossRefGoogle Scholar
  19. 19.
    Losina E, Schackman BR, Sadownik SN, et al. Racial and sex disparities in life expectancy losses among HIV-infected persons in the United States: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy. Clin Infect Dis. 2009;49:1570–8.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Deeks SG. HIV infection, inflammation, immunosenescence and aging. Ann Rev Med. 2011;62:141–55.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Yanik EL, Napravnik S, Cole SR, et al. Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy. Clin Infect Dis. 2013;57:756–64.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Bedimo RJ, McGinnis KA, Dunlap M, et al. Incidence of non-AIDS-defining malignancies in HIV-infected versus non-infected patients in the HAART era: impact of immunosuppression. J Acquir Immune Defic Syndr. 2009;52:203–8.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Guiguet M, Boué F, Cadranel J, et al. 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;10:1152–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Alshafie MT, Donaldson B, Oluwole SF. Human immunodeficiency virus and lung cancer. Br J Surg. 1997;84:1068–71.PubMedCrossRefGoogle Scholar
  25. 25.
    Brock MV, Hooker CM, Engels EA, et al. Delayed diagnosis and elevated mortality in an urban population with HIV and lung cancer: implications for patient care. J Acquir Immune Defic Syndr. 2006;43:47–55.PubMedCrossRefGoogle Scholar
  26. 26.
    Demopoulos BP, Vamvakas E, Ehrlich JE, Demopoulos R. Non-acquired immunodeficiency syndrome-defining malignancies in patients infected with human immunodeficiency virus. Arch Pathol Lab Med. 2003;127:589–92.PubMedGoogle Scholar
  27. 27.
    Bräu N, Fox RK, Xiao P, et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol. 2007;47:527–37.PubMedCrossRefGoogle Scholar
  28. 28.
    Puoti M, Bruno R, Soriano V, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS. 2004;18:2285–93.PubMedCrossRefGoogle Scholar
  29. 29.
    Crum-Cianflone NF, Hullsiek KH, Marconi VC, et al. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence. AIDS. 2010;24:535–43.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Chapman C, Aboulafia DM, Dezube BJ, Pantanowitz L. Human immunodeficiency virus-associated adenocarcinoma of the colon: clinicopathologic findings and outcome. Clin Colorectal Cancer. 2009;8:215–9.PubMedCrossRefGoogle Scholar
  31. 31.
    US Census Bureau. Annual Estimates of the Resident Population by Sex and Five-Year Age Groups for the United States: April 1, 2000 to July 1, 2010. Washington, DC: US Census Bureau; 2010.Google Scholar
  32. 32.
    Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2010. Bethesda, MD: National Cancer Institute. Accessed 28 March 2014.
  33. 33.
    Shiels MS, Pfeiffer RM, Engels EA. Age at cancer diagnosis among persons with AIDS in the United States. Ann Intern Med. 2010;153:452–60.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Palefsky JM, Rubin M. The epidemiology of anal human papillomavirus and related neoplasia. Obstet Gynecol Clin N Am. 2009;36:187–200.CrossRefGoogle Scholar
  35. 35.
    Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44:S6–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Melbye M, Rabkin C, Frisch M, Biggar RJ. Changing patterns of anal cancer incidence in the United States. Am J Epidemiol. 1994;139:772–80.PubMedGoogle Scholar
  37. 37.
    Palefsky J. Human papillomavirus and anal neoplasia. Curr HIV/AIDS Rep. 2008;5:78–85.PubMedCrossRefGoogle Scholar
  38. 38.
    Silverberg MJ, Lau B, Justice AC, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis. 2012;54:1026–34.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.•
    Kesselring A, Gras L, Smit C, et al. Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis. 2011;52:1458–65. Patients starting combination antiretroviral therapy (cART) as of 1 January 1996 were selected from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. Cumulative exposure to CD4+ cell counts <200 cells/mm3 during cART was associated with an increased risk of infection-related non-AIDS-defining malignancies.PubMedCrossRefGoogle Scholar
  40. 40.•
    Silverberg MJ, Chao C, Leyden WA, Xu L, Horberg MA, Klein D, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev. 2011;20:2551–9. Compared cancer risk between HIV-infected individuals and a demographically similar HIV-uninfected internal comparison group, adjusting for cancer risk factors.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Cogliano V, Bann R, Straif K, et al. WHO. IARC Monographs on the evaluation of carcinogenic risks to humans, vol. 90. Human papillomaviruses. Lyon: International Agency for Research on Cancer; 2007. p. 1–670.Google Scholar
  42. 42.
    Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467–75.PubMedCrossRefGoogle Scholar
  43. 43.
    Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst. 2000;92:1500–10.PubMedCrossRefGoogle Scholar
  44. 44.
    Powles T, Robinson D, Stebbing J, et al. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol. 2009;27:884–90.PubMedCrossRefGoogle Scholar
  45. 45.
    Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA. 2001;285:1736–45.PubMedCrossRefGoogle Scholar
  46. 46.
    McGinnis KA, Fultz SL, Skanderson M, et al. Hepatocellular carcinoma and non-Hodgkin’s lymphoma: the roles of HIV, hepatitis C infection, and alcohol abuse. J Clin Oncol. 2006;24:5005–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Kramer JR, Giordano TP, Souchek J, et al. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in U.S. veterans with hepatitis C. Am J Gastroenterol. 2005;100:56–63.PubMedCrossRefGoogle Scholar
  48. 48.
    Di Benedetto N, Peralta M, Alvarez E, et al. Incidence of hepatocellular carcinoma in hepatitis C cirrhotic patients with and without HIV infection: a cohort study, 1999-2011. Ann Hepatol. 2013;13:38–44.PubMedGoogle Scholar
  49. 49.
    Sulkowski M. Hepatocellular carcinoma in HIV-infected patients comes of age: the convergence of epidemiology and treatment effectiveness. J Hepatol. 2009;50:655–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Pineda JA, García-García JA, Aguilar-Guisado M, et al. Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy. Hepatology. 2007;46:622–30.PubMedCrossRefGoogle Scholar
  51. 51.
    Bräu N, Salvatore M, Ríos-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006;44:47–55.PubMedCrossRefGoogle Scholar
  52. 52.
    Montes Ramírez ML, Miró JM, Quereda C, et al. Incidence of hepatocellular carcinoma in HIV-infected patients with cirrhosis: a prospective study. J Acquir Immune Defic Syndr. 2014;65:82–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306–10.PubMedCrossRefGoogle Scholar
  54. 54.
    Puoti M, Spinetti A, Ghezzi A, Donato F, Zaltron S, Putzolu V, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr. 2000;24:211–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Thio CL, Seaberg EC, Skolasky Jr R, Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Clifford GM, Rickenbach M, Polesel J, Dal Maso L, Steffen I, Ledergerber B, et al. Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma. AIDS. 2008;22:2135–41.PubMedCrossRefGoogle Scholar
  57. 57.
    Simard EP, Engels EA. Cancer as a cause of death among people with AIDS in the United States. Clin Infect Dis. 2010;51:957–62.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Chaturvedi AK, Pfeiffer RM, Chang L, Goedert JJ, Biggar RJ, Engels EA. Elevated risk of lung cancer among people with AIDS. AIDS. 2007;21:207–13.PubMedCrossRefGoogle Scholar
  59. 59.
    Hakimian R, Fang H, Thomas L, Edelman MJ. Lung cancer in HIV-infected patients in the era of highly active antiretroviral therapy. J Thorac Oncol. 2007;2:268–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Engels EA, Brock MV, Chen J, et al. Elevated incidence of lung cancer among HIV-infected individuals. J Clin Oncol. 2006;24:1383–8.PubMedCrossRefGoogle Scholar
  61. 61.•
    Shiels MS, Cole SR, Mehta SH, Kirk GD. Lung cancer incidence and mortality among HIV-infected and HIV-uninfected injection drug users. J Acquir Immune Defic Syndr. 2010;55:510–5. Prospective study of 2,495 HIV-infected and HIV-uninfected injection drug users in Baltimore with cancer data from Cancer Registry.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Levine AM, Seaberg EC, Hessol NA, Preston-Martin S, Silver S, Cohen MH, et al. HIV as a risk factor for lung cancer in women: data from the Women’s Interagency HIV Study. J Clin Oncol. 2010;28:1514–9.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Kirk GD, Merlo C, O’Driscoll P, Mehta SH, Galai N, Vlahov D, et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Infect Dis. 2007;45:103–10.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Sigel K, Wisnivesky J, Gordon K, Dubrow R, Justice A, Brown ST, et al. HIV as an independent risk factor for incident lung cancer. AIDS. 2012;26:1017–25.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Prosperi MCF, Cozzi-Lepri A, Castagna A, Mussini C, Murri R, Giacometti A, et al. Incidence of malignancies in HIV-infected patients and prognostic role of current CD4 cell count: evidence from a large Italian cohort study. Clin Infect Dis. 2010;50:1316–21.PubMedCrossRefGoogle Scholar
  66. 66.
    Glaser SL, Clarke CA, Gley ML, Craig FE, DiGiuseppe JA, Dorfman RF, et al. Population-based patterns of human immunodeficiency virus-related Hodgkin lymphoma in the Greater San Francisco Bay Area, 1988-1998. Cancer. 2003;98:300–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Mueller N. Hodgkin’s disease. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer epidemiology and prevention. New York: Oxford University Press; 1996. p. 893–919.Google Scholar
  68. 68.
    Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006;108:3786–91.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Stein H, Hummel M. Hodgkin’s disease: biology and origins of Hodgkin and Reed-Sternberg cells. Cancer Treat Rev. 1999;25:161–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Chan WC. The Reed-Sternberg cells in classical Hodgkin’s disease. Hematol Oncol. 2001;19:1–17.PubMedCrossRefGoogle Scholar
  71. 71.
    van den Berg AL, Visser L, Poppema S. High expression of the CC chemokine TARC in Reed-Sternberg cells: a possible explanation for the characteristic T-cell infiltrate in Hodgkin’s lymphoma. Am J Pathol. 1999;154:1685–91.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood. 2003;101:4283–97.Google Scholar
  73. 73.
    Poppema S, Potters M, Visser L, van den Berg AM. Immune escape mechanisms in Hodgkin’s disease. Ann Oncol. 1998;9:S21–4.PubMedCrossRefGoogle Scholar
  74. 74.
    Rosenwald AG, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198:851–62.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Rowlings PA, Curtis RE, Passweg JR, et al. Increased incidence of Hodgkin’s disease after allogeneic bone marrow transplantation. J Clin Oncol. 1999;17:3122–7.PubMedGoogle Scholar
  76. 76.
    Muller N. Overview of the epidemiology of malignancy in immune deficiency. J Acquir Immune Defic Syndr. 1999;21:S5–10.Google Scholar
  77. 77.
    Brauninger A, Hansmann ML, Strickler JG, et al. Identification of common germinal-center B-cell precursors in two patients with both Hodgkin’s disease and non-Hodgkin’s lymphoma. N Engl J Med. 1999;340:1239–47.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Chia-ching J. Wang
    • 1
    Email author
  • Michael J. Silverberg
    • 2
  • Donald I. Abrams
    • 3
  1. 1.Division of Hematology/Oncology, Helen Diller Comprehensive Cancer CenterUniversity of CaliforniaSan FranciscoUSA
  2. 2.Division of ResearchKaiser Permanente Northern CaliforniaOaklandUSA
  3. 3.Division of Hematology/OncologySan Francisco General Hospital, University of California San FranciscoSan FranciscoUSA

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