We appreciate the interest in our paper on trends in the incidence of cancer among HIV-infected persons . In our study, we found that the incidence rates of non-AIDS-defining cancers (NADCs) have risen over the course of the HIV epidemic, and now account for the majority of cancers seen among HIV-infected persons. We also examined the factors associated with the development of NADCs and found increasing age to be significantly associated. White race was also related, but this relationship was confined to the development of non-AIDS-defining skin cancers.
Regarding the relationship between immunosuppression and NADCs, prior studies have shown no consistent relationship between NADCs and CD4 cells counts; however, those studies were often limited by examining only the CD4 cell count at HIV or cancer diagnosis, but not sequentially over time [2–6]. Our study had the advantage of evaluating time-updated CD4 cell counts, which included all measurements from HIV diagnosis to the time of cancer development or censoring, and we found no associations between CD4 cell counts and NADC development. We also examined time-updated highly active antiretroviral therapy use and did not find it protective of NADCs.
Two recent studies have provided additional data on the potential association between levels of immunosuppression and NADCs. In the first study, performed by the D:A:D study group , a lower latest CD4 cell count was associated with an increased risk of NADC mortality. Our study evaluated a different outcome, the development of NADCs, rather than NADC mortality. CD4 cell counts may play a role in NADC mortality beyond their potential role in cancer development by several mechanisms, including their possible influence on the type of treatment offered, the tolerability to chemoradiotherapy, and the risk for events such as opportunistic infections during therapy [8,9]. The D:A:D study also examined the association between NADC mortality and the CD4 nadir count, but this relationship was weaker and not independently associated with death in their multivariate model.
In the second study, which examined the Chelsea and Westminster HIV cohort, a CD4 nadir count of less than 200 cells/μl was associated with the occurrence of NADCs . We reexamined our data for a risk of a NADC event using time-updated CD4 nadir count. From separate univariate models including CD4 nadir count of less than 200, less than 350, and less than 500 cells/μl, there was a nonsignificant increased risk of a NADC event: hazard ratios (HRs) with 95% confidence intervals were 1.20 (0.81–1.77; P = 0.36), 1.32 (0.92–1.90; P = 0.13), and 1.61 (1.01–2.57; P = 0.05), respectively. In multivariate models (adjusted for the same variables as shown in Table 4 of our original study, but using an indicator for time-updated CD4 nadir count rather than time-updated CD4 cell count as a continuous variable), we found that no level of CD4 nadir count predicted NADC events: HR was 0.89 (0.58–1.37; P = 0.60), 1.08 (0.74–1.57; P = 0.71), and 1.40 (0.87–2.25; P = 0.16) for CD4 nadir count of less than 200, less than 350, and less than 500 cells/μl, respectively. We also examined the time-updated CD4 nadir count as a continuous variable in the multivariate model, and found no statistically significant association: HR per 50-cell increase was 0.99 (0.95–1.03; P = 0.57). Finally, we examined only nonskin NADCs and again found no significant relationships in any of our models.
Differing findings between our study and that of Powles et al.  may due to dissimilarities in study populations. For example, our population consisted of early diagnosed HIV patients with open and free access to medical care. As a result, our study cohort had higher CD4 nadir count compared with many other cohorts; our cohort had a median CD4 nadir count prior to the NADC event of 305 cells/μl [interquartile range (IQR) = 148–415], in contrast to Powles et al. , which had a median nadir of 104 cells/μl (IQR = 35–176). Second, the most common NADC in our study was cutaneous malignancies, whereas the Chelsea and Westminster HIV cohort study had a large number of anal cancers, a cancer type that may be more associated with low CD4 nadir count [11,12]. As noted in our study, we were unable to examine individual NADC cancer types due to the limited number of each cancer type available in our dataset; instead, we examined all NADCs and then nonskin NADCs. We agree that the pathogenic mechanisms involved in the development of NADCs are likely diverse and that analyses of individual cancer types would be useful.
In summary, we did not find a relationship between the development of NADCs and immunocompetence as measured by time-updated CD4 cell counts or nadir counts in our study cohort. Perhaps among HIV cohorts with more severe levels of immunosuppression, a potential relationship between long-term immunodeficiency and NADCs may exist. As NADCs are a major cause of morbidity and mortality among HIV-infected persons, we agree that further studies examining the effects of time-dependent severity and duration of immunosuppression on the development of these cancers are needed.
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. Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr 2003; 32:527–533.
3. Kirk GD, Merlo C, O'Driscoll PO, 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; 45:103–110.
4. Frisch M, Biggar RJ, Engels EA, Goedert JJ, AIDS–Cancer Match Registry Group. Association of cancer with AIDS related immunosuppression in adults. JAMA 2001; 248:1736–1745.
5. Clifford G, Polesel J, Rickenbach M, Dal Maso L, Keiser O, Kofler A, et al
. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 2005; 97:425–432.
6. 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; 22:489–496.
7. The D:A:D Study Group. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS
8. Spano JP, Atlan D, Breau JL, Farge D. AIDS and non-AIDS-related malignancies: a new vexing challenge in HIV-positive patients. Part II. Cervical and anal squamous epithelial lesions, lung cancer, testicular germ cell cancers, and skin cancers. Eur J Intern Med 2002; 13:227–232.
9. Hoffman R, Welton ML, Klencke B, Weinberg V, Krieg R. The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys 1999; 44:127–131.
10. 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.
11. Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, et al
, Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. 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.
12. Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, et al
. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS 2008; 22:1203–1211.