We read with interest the recent article by Crum-Cianflone et al. describing the independent predictors of incident AIDS-defining and non-AIDS-defining cancer in their multicenter, prospective natural history study of 4498 US military beneficiaries diagnosed with HIV between 1984 and 2006. Analyses were adjusted for year of HIV diagnosis and stratified by HIV diagnosis era (<1996 and >1996). Multivariate risk factors for non-AIDS-defining cancer (n = 135; most common cancer, nonmelanoma skin cancer n = 63) included increasing age at HIV diagnosis and white race; there was no association with latest CD4 cell count or HAART use. The authors concluded that the ageing of the HIV population was the primary factor associated with the rising rates of non-AIDS-defining cancer between the pre-HAART and post-HAART eras. Cumulative duration of immunosuppression was not assessed.
The finding of an absence of an association between markers of immune deficiency and non-AIDS-defining cancer risk differs with those from two recently published cohort studies. The D:A:D study examined risk factors for mortality due to AIDS-defining and non-AIDS-defining cancer in 23 437 HIV-positive patients on HAART . The independent risk factors for death from a non-AIDS-defining cancer (n = 193; most common cancer, lung cancer n = 62) were current age, latest CD4 cell count, duration of exposure to HAART, hepatitis B status, and calendar year. Interestingly, cumulative duration of immunosuppression, defined as the total time spent with a CD4 cell count less than 200 cells/μl, was significant in univariate modeling but not after adjustment for latest CD4 cell count.
The Chelsea and Westminster HIV cohort study examined risk factors for incident non-AIDS-defining cancer in 11 112 HIV-positive patients between 1983 and 2007 . Nadir CD4 cell count less than 200 cells/μl and receipt of HAART independently predicted risk of non-AIDS-defining cancer (n = 150; most common cancer, anal cancer, n = 44) after adjustment for age, sex, ethnic group, AIDS-defining condition, and duration of HIV infection more than 5 years. In the multivariate model, HIV infection for more than 5 years was associated with a nonsignificantly increased risk [hazard ratio (HR) 1.44, 95% confidence interval (CI) 0.97–2.14]. Site-specific analyses were also performed, but the risk estimates were very imprecise.
We believe that the findings from these studies suggest that HIV-related immunosuppression does play an important role in the risk of specific cancers in the HAART era. The remarkable similarity in the range of cancers occurring at excess rates in solid organ transplant recipients and people with HIV infection strongly supports an effect of long-term immunosuppression on cancer incidence . Independent risk factors for immune-related cancers such as nonmelanoma skin cancer  and lip cancer  in kidney transplant recipients include a strong positive association with both increasing age and increasing duration of immunosuppression.
We recommend that future, large-scale studies of cohorts in the HAART era examine the independent effects of ageing, the time-dependent severity of immunosuppression, and the cumulative duration of immunosuppression on cancer risk. Furthermore, we suggest that these analyses be performed for individual cancers or perhaps for groups of related cancers, such as those associated with infection by the same virus. Interpretation of risk factor analyses based on all ‘non-AIDS-defining cancers’ is very challenging, given the broad array of cancers included in this classification and the differential effect of immunodeficiency on cancer risk . Findings from site-specific risk factor analyses will assist in the development of strategies to minimize or prevent the occurrence of cancer in patients with long-term immune deficiency.
C.M.V. is supported by a National Health and Medical Research Council Career Development Award (ID 510346) and a Cancer Institute NSW Career Support and Development Fellowship (ID 07-CDF-1/38). M.T.V. is supported by a National Health and Medical Research Council Postgraduate Scholarship Award (ID 401131) and a Cancer Institute NSW Research Scholar Award (06/RSA/1/28).
1. Crum-Cianflone N, Huppler Hullsiek K, Marconi V, Weintrob A, Ganesan A, Vincent Barthel R, 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.
2. The D:A:D Study Group. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies.AIDS
3. 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.
4. 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.
5. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Nicol DL, Harden PN. Factors associated with nonmelanoma skin cancer following renal transplantation in Queensland, Australia. J Am Acad Dermatol 2003; 49:397–406.
6. van Leeuwen MT, Grulich AE, McDonald SP, McCredie MRE, Amin J, Stewart JH, et al
. Immunosuppression and other risk factors for lip cancer after kidney transplantation. Cancer Epid Biomark Prev 2009; 18:561–569.