There were insufficient cases of invasive cervical cancer (n = 1 case among 9806 person-years of follow-up among females with HIV) to allow analysis.
The study cohort for the analysis of all other cancers included 20 232 people (Table 1). There were 80 155 person-years (mean 5.8) during the pre-HAART period and 37 700 person-years (mean 3.3) and 58 462 person-years (mean 4.2) during the early-HAART and late-HAART periods, respectively.
There were 45 cases of Hodgkin lymphoma, of which mixed cellularity was the most commonly specified subtype (n = 15 of 28 cases for which subtype was specified). SIRs were significantly raised across all periods. In multivariate analysis adjusted for categories of age (<35, 35–59, 60+ years), there was no significant change in incidence (Ptrend = 0.804). However, incidence was significantly higher during the early-HAART period than the late-HAART period (Pdiff = 0.014). Results were similar when age was modelled as a continuous variable (data not shown).
There were 41 cases of anal cancer, of which 38 (93%) were squamous cell carcinoma. SIRs were at least 30-fold across all HAART periods, and no trend in incidence was observed in multivariate analysis (Ptrend = 0.451). Almost all cases occurred in males (n = 40); the SIR during the late-HAART period for males was 34.22 (95% CI 20.60–53.44) and was 39.61 (95% CI 23.47–62.60) for those males reporting HIV exposure through homosexual or bisexual contact.
There were 11 cases of liver cancer, all of which occurred in the post-HAART period. SIRs were significantly raised during both the early-HAART and late-HAART periods. Multivariate analyses were not performed as there were no cases during the period prior to HAART.
There were 53 cases of cutaneous melanoma. Most (n = 21 of 28 cases for which morphology was specified) were superficial spreading melanoma, and over half of all cases affected the trunk. SIRs were not significantly raised during the pre-HAART and early-HAART periods, and in the late-HAART period, the SIR was significantly decreased. A significant decline in incidence was observed across periods in multivariate analysis (Ptrend = 0.041).
SIRs for prostate (n = 24) and colorectal (n = 17; 10 colon, seven rectum) cancers were either not raised or were significantly decreased. For prostate cancer, a significant decline in incidence was observed across periods in multivariate analysis (Ptrend = 0.026).
No significant trends in incidence were noted for cancers of the oral cavity and oropharynx, lip, lung, or leukaemia.
Nonuniform trends in the incidence of specific cancer types were observed in people with HIV in Australia since the introduction of HAART. Among those cancers occurring at greatly increased rates in the pre-HAART period, three distinct patterns emerged. First, for Kaposi sarcoma and NHL, incidence declined dramatically and continued to decline in the late-HAART period, though it remained substantially elevated. Second, for Hodgkin lymphoma, incidence increased during the early-HAART period but later declined. Third, for anal cancer, there was no change in incidence over time. For two cancers not increased in the pre-HAART period, melanoma and prostate cancer, incidence declined significantly and by the late-HAART period, was lower than in the general population. For colorectal cancer, incidence was consistently lower than in the general population. There was no significant trend for all other cancer types examined.
A dramatic and continuing reduction in incidence of Kaposi sarcoma and NHL since the introduction of HAART has been well described [2–4,6], though a recent plateau in incidence of Kaposi sarcoma was reported in one study . Incidence of both cancers is rapidly reduced following HAART initiation [19,20] and is strongly inversely correlated with CD4+ T-cell count [3,6,21]. Both are associated with gamma herpesvirus infection: Kaposi sarcoma with human herpesvirus type 8 in all cases and NHL with Epstein–Barr virus (EBV) in more than 50% of HIV-associated cases . Clearly, for both these cancers, current functional immunity is central to pathogenesis. The continuing decline in their incidence raises the question of whether it may be reduced to normal with earlier or more effective HAART.
Among NHL subtypes, a significant decline in incidence was observed for DLBL but not for Burkitt lymphoma. The unchanging incidence of Burkitt lymphoma, noted by others [6,23], likely reflects its less-frequent association with EBV infection and absence of a relationship with the level of immunodeficiency . That incidence of CNS lymphoma did not decline was unexpected. This may be an artefact of underascertainment of histopathologically verified AIDS-associated CNS lymphoma in Australia in the pre-HAART period, in which the majority of cases in earlier years were diagnosed on radiological and clinical grounds alone  and may not have been registered as cancer.
A number of studies have suggested that incidence of Hodgkin lymphoma has remained stable [3,26] or increased in the post-HAART era  or with HAART use . An association between Hodgkin lymphoma incidence and moderate levels of immunodeficiency has been suggested by some  but not all  studies. Our finding of a peak in incidence in the early-HAART period would be consistent with a cohort which passed through a phase of moderate immunodeficiency post-HAART. It is acknowledged that the interpretation of Hodgkin lymphoma incidence trends is complicated by its bimodal age distribution and that the increase in incidence observed post-HAART may reflect cohort ageing . However, appropriate age adjustment, using categories of age reflecting the two age peaks of Hodgkin lymphoma, did not substantially alter our results.
Anal cancer incidence has remained stable in people with HIV in Australia, and, by the late-HAART period, it was the third most common type of cancer in this cohort. In other studies, stable [3,23] or increasing incidence [2,4] has been described. No studies have reported declining incidence. Anal cancer is causally associated with anal infection by high-risk subtypes of human papillomavirus (HPV) . Immunodeficiency is associated with a higher prevalence of anal HPV infection and with precursor anal squamous lesions. However, whether the restoration of cellular immunity post-HAART affects risk of invasive anal cancer is unclear .
A significant decline in melanoma incidence was observed. Melanoma risk is strongly related to immunodeficiency in immunosuppressed transplant recipients . Eruption of dysplastic melanocytic nevi has been documented soon after both HIV infection and solid organ transplantation, and fading of nevi on reduction of immunosuppression has been reported . Curiously, incidence of melanoma was significantly lower than in the general population during the late-HAART period. Although the risk of melanoma is slightly raised overall in people with HIV , most studies reporting data in the post-HAART period have not observed excess risk [5,23].
Prostate cancer incidence was the same, or lower, than for the general population and declined significantly after HAART. For reasons unclear, reduced prostate cancer risk has been repeatedly documented in HIV-infected men [3,23]. Lower rates of prostate cancer screening and complications of HIV infection including lower androgen levels  and diabetes mellitus , each believed to be associated with reduced prostate cancer risk, may be possible explanations. In addition, there has been a single report of an inhibitory effect of protease inhibitors on prostate cancer cell lines . Incidence of colorectal cancer was consistently reduced relative to that in the general population, providing some evidence against an obvious infectious cause.
This study had several strengths, including the use of national, population-based registries of both people with HIV and cancer and the long period of follow-up, an average of 8 years per person. Most prior registry-based studies did not involve nationwide data, and follow-up was commonly truncated after 2–5 years. As comparison of SIRs over time may be confounded by cohort ageing, interpretation of trends in cancer risk before and after HAART was verified through the use of age-adjusted, within-cohort analyses.
Some limitations include the size of the cohort, and therefore, limited statistical power with which to detect significant associations for rare cancers. Cancer ascertainment will have been affected by the accuracy of the data linkage algorithm, though it was based on a previously validated algorithm with 99% sensitivity and 100% specificity in identifying cases of AIDS-related NHL on the New South Wales cancer registry . Bias may have been introduced through heightened medical surveillance for cancer, though the absence of increased risk for screen-detected cancer argues against substantial surveillance bias. The method of adjustment for survival after cancer diagnosis was approximate and could have resulted in either underestimation or overestimation of the expected numbers of cancers. Patient-level data on HAART use were not available, and, therefore, estimation of the effect of HAART was based on calendar-periods.
In an era of improving efficacy and wider availability of HAART, the pattern of cancer occurrence in people with HIV continues to change. For Kaposi sarcoma and NHL, continuing declines in incidence are being observed, though it remains very markedly increased relative to the general population. For Hodgkin lymphoma, this article provides evidence of a possible decline in incidence. Anal cancer has increased in prominence, being the third most common type of cancer in our cohort. Reasons for the declining incidence of prostate cancer, and continually low incidence of colorectal cancer, are largely unclear. The variation in cancer trends likely reflects the different role of immune function and infection in the pathogenesis of individual cancers. Large-scale cohort studies with patient-level data on current CD4+ T-cell count and HAART use have the potential to greatly inform the management of long-term cancer risk in this population.
This publication was funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian government. This work was also supported by the University of New South Wales Faculty of Medicine (Early Career Researcher Award to C.V.); the Cancer Institute New South Wales (07/CDF/1–38 to C.V., 06/RSA/1/28 to M.T.v.L); the National Health and Medical Research Council (ID 510346 to C.V., ID 401131 to M.T.v.L.) and the United States National Cancer Institute (NCI), as part of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) (grant no. U01AI069907).
A.E.G. is on the advisory board for the Gardasil human papillomavirus vaccine for the Commonwealth Serum Laboratories. No other authors reported financial disclosures.
We would like to acknowledge the work of the National BBV and STI Surveillance Committee who coordinate National HIV/AIDS Surveillance. In particular, we would like to thank the following members for collecting HIV/AIDS data: Riemke Kampen, Kate Ward, Jiunn-yih Su, Jo Murray, Tess Davey, David Coleman, Carol El-Hayek and Carolien Giele.
The authors are also grateful to the staff of the state and territory cancer registries for the use of their data. The authors also acknowledge assistance by the Australian Institute of Health and Welfare, and the Cancer Council Victoria, in the conduct of this study.
Author contributions: all authors did the revision and review of final submitted manuscript. Study concept and design were done by M.T.v.L., C.M.V., A.E.G., J.M.K. Data acquisition was done by M.T.v.L., M.G.M., A.M.M. Statistical analysis was done by M.T.v.L., M.L. Interpretation of results were done by M.T.v.L., C.M.V., A.E.G. Drafting of manuscript was done by M.T.v.L., C.M.V., A.E.G.
1. 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.
2. Crum-Cianflone N, Hullsiek KH, Marconi V, Weintrob A, Ganesan A, Barthel RV, et al
. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS 2009; 23:41–50.
3. Engels E, Biggar R, Hall H, Cross H, Crutchfield A, Finch J, et al
. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer 2008; 123:187–194.
4. Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, 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; 148:728–736.
5. Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, Gazzard B, et al
. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol 2009; 27:884–890.
6. Biggar RJ, Chaturvedi AK, Goedert JJ, Engels EA. AIDS-related cancer and severity of immunosuppression in persons with AIDS. J Natl Cancer Inst 2007; 99:962–972.
7. Grulich AE, Li Y, McDonald A, Correll PK, Law MG, Kaldor JM. Rates of non-AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis. AIDS 2002; 16:1155–1161.
8. Falster K, Gelgor L, Shaik A, Zablotska I, Prestage G, Grierson J, et al
. Trends in antiretroviral treatment use and treatment response in three Australian states in the first decade of combination antiretroviral treatment. Sexual Health 2008; 5:141–154.
9. Australian HIV Observational Database (AHOD). AHOD Annual Report
. Sydney, Australia; 2008.
10. Australian Institute of Health and Welfare (AIHW) and Australasian Association of Cancer Registries (AACR). Cancer in Australia: an overview, 2008
. Canberra, Australia: AIHW; 2008. AIHW Cat. No. CAN 42. Cancer Series No. 46.
11. Grulich AE, Wan X, Law MG, Coates M, Kaldor JM. Risk of cancer in people with AIDS. AIDS 1999; 13:839–843.
12. Grulich AE, Li Y, McDonald AM, Correll PK, Law MG, Kaldor JM. Decreasing rates of Kaposi's sarcoma and non-Hodgkin's lymphoma in the era of potent combination antiretroviral therapy. AIDS 2001; 15:629–633.
13. Li Y, Law M, McDonald A, Correll P, Kaldor JM, Grulich AE. Estimation of risk of cancers before occurrence of acquired immunodeficiency syndrome in persons infected with human immunodeficiency virus. Am J Epidemiol 2002; 155:153–158.
14. Australian Institute of Health and Welfare (AIHW) & Australasian Association of Cancer Registries (AACR). Cancer survival in Australia, 2001. Part 2: Statistical tables.
Canberra, Australia: AIHW; 2001. AIHW Cat. No. CAN 14. Cancer Series No. 19.
15. South Australian Cancer Registry. Epidemiology of Cancer in South Australia 1977–1998
. Adelaide, Australia: South Australian Cancer Registry; 2000.
16. Jaffe ES, Harris NL, Stein H, Vardiman J, editors. World Health Organization Classification of Tumours
. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues
. Lyon, France: IARC Press; 2001.
17. Breslow NE, Day NE. Statistical methods in cancer research
. Volume II: The design and analysis of cohort studies. IARC Scientific Publications No. 82
. Lyon, France: Oxford University Press; 1987.
18. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, Ghissassi FE, et al
. A review of human carcinogens: Part B – biological agents. Lancet Oncol 2009; 10:321–322.
19. Franceschi S, Maso LD, Rickenbach M, Polesel J, Hirschel B, Cavassini M, et al
. Kaposi sarcoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. Br J Cancer 2008; 99:800–804.
20. Polesel J, Clifford GM, Rickenbach M, Dal Maso L, Battegay M, Bouchardy C, et al
. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 2008; 22:301–306.
21. Bower M, Fisher M, Hill T, Reeves I, Walsh J, Orkin C, et al
. CD4 counts and the risk of systemic non-Hodgkin's lymphoma in individuals with HIV in the UK. Haematologica 2009; 94:875–880.
22. International Agency for Research on Cancer (IARC). IARC Monographs on the evaluation of carcinogenic risks to humans: Epstein–Barr Virus and Kaposi's Sarcoma herpesvirus/human herpesvirus 8
. Lyon, France: IARC Press; 1997.
23. Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, et al
. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS 2006; 20:1645–1654.
24. Engels EA. Infectious agents as causes of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 2007; 16:401–404.
25. Newell M, Hoy J, Cooper S, DeGraaff B, Grulich AE, Bryant M, et al
. Human immunodeficiency virus-related primary central nervous system lymphoma: factors influencing survival in 111 patients. Cancer 2004; 100:2627–2636.
26. Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA, et al
. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 2006; 108:3786–3791.
27. Clifford GM, Rickenbach M, Lise M, Dal Maso L, Battegay M, Bohlius J, et al
. Hodgkin lymphoma in the Swiss HIV Cohort Study. Blood 2009; 113:5737–5742.
28. International Agency for Research on Cancer (IARC). IARC monographs on the evaluation of carcinogenic risks to humans: human papillomaviruses
. Lyon, France: IARC Press; 2007.
29. Palefsky J. Human papillomavirus-related tumors in HIV. Curr Opin Oncol 2006; 18:463–468.
30. Vajdic CM, van Leeuwen MT, Webster AC, McCredie MRE, Stewart JH, Chapman JR, et al
. Cutaneous melanoma is related to immune suppression in kidney transplant recipients. Cancer Epidemiol Biomarkers Prev 2009; 18:2297–2303.
31. Zattra E, Fortina AB, Bordignon M, Piaserico S, Alaibac M. Immunosuppression and melanocyte proliferation. Melanoma Res 2009; 19:63–68.
32. Crum NF, Furtek KJ, Olson PE, Amling CL, Wallace MR. A review of hypogonadism and erectile dysfunction among HIV-infected men during the pre and post-HAART eras: diagnosis, pathogenesis, and management. AIDS Patient Care STDs 2005; 19:655–671.
33. Grinspoon S. Diabetes mellitus, cardiovascular risk, and HIV disease. Circulation 2009; 119:770–772.
34. Pajonk F, Himmelsbach J, Riess K, Sommer A, McBride WH. The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res 2002; 62:5230–5235.
35. Grulich AE, Wan X, Coates M, Day P, Kaldor JM. Validation of a nonidentifying method of linking cancer and AIDS register data. J Epidemiol Biostat 1996; 1:207–212.
Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
cancer; cohort studies; HAART; HIV; infection