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There is an increasing burden of non-AIDS-defining malignancies (NADM) in the antiretroviral therapy (ART) era. The recent literature is reviewed with respect to NADM risk, ART use, and immune function.
Recent studies have increasingly focused on individual ART use, CD4 T-cell counts and the risk of NADMs. Certain NADMs have been shown to have a reduced risk with ART use including liver, breast, colorectal, and lung cancers. NADMs associated with immunosuppression included Hodgkin’s lymphoma, oral/pharynx, lung, anal, and colorectal cancers. Despite the potential protective effect of ART on some NADMs, recent studies evaluating calendar era trends have noted an increased risk of Hodgkin’s lymphoma and anal cancer, and no change in risk for lung cancer in the ART era.
Successful ART use and improvements in immune function for HIV-infected persons may reduce the risk of certain NADMs. However, a continued high risk in the ART era for certain cancers have been observed, including Hodgkin’s lymphoma and anal cancers. Future studies should monitor trends in NADMs in HIV-infected persons in the ART era, as well as changes in the prevalence of risk factors, co-infections, and screening practices in this population.
Effective antiretroviral therapy (ART) use has prolonged the lifespan of HIV-infected patients and resulted in dramatic declines in the risk of AIDS clinical events, including AIDS-defining malignancies (ADM). However, there is a growing concern in the ART era for non-AIDS-defining malignancies (NADM) given the aging population of HIV-infected patients and the high prevalence of tobacco use, alcohol use and viral co-infections in this population . Thus, many prior studies have focused on changes in risk in the ART era for more common NADMs in HIV patients, namely Hodgkin’s lymphoma [2–6], lung [2–4, 7, 8], and anal [2–5, 9] cancers, but with mixed results. More recent studies have evaluated malignancy risk with respect to individual ART use, including the effect of specific antiretroviral agents, ART drug classes, or ART duration. Others have evaluated the association of immune function and NADM risk which may mediate observed relationships of cancer risk and ART use.
We provide here a summary and discussion of the recent published literature regarding malignancy risk, ART use, and immunosuppression. We performed an English-language MEDLINE search for relevant studies during the period January 2007 to July 2008.
The ecologic comparison of cancer incidence before and after the introduction of ART has been the most common method for examining the effect of ART use on cancer risk [2–17]. However, this approach may not accurately reflect the association of ART on cancer incidence since other factors influencing cancer risk may have also changed over time. Furthermore, many patients may not be taking ART in the post-ART era. A few studies earlier in the ART era have examined the effect of individual ART use on cancer risk [2, 17–20], although all classified ART use dichotomously as ever or never, and only Clifford et al.  examined individual NADMs.
There have been substantial declines in the incidence of ADMs in the ART era [5–6, 10–15]. Prior studies focusing on NADMs, however, were mixed. Higher incidence in the ART era relative to the pre-ART era have been previously demonstrated for Hodgkin’s lymphoma [2, 3, 6, 16], non-melanoma skin , lung [3, 7], anal [5, 9], kidney  and for all NADMs combined . Others demonstrated no calendar era changes for Hodgkin’s lymphoma [4, 5], non-melanoma skin [2– 4], anal [2–4] all NADMs combined [2–4, 6, 8, 17], various other individual cancers [2–6], and no change [2, 4, 8] or declines for lung cancer .
More recent studies (Table 1) with extended follow-up in the ART era support the observation of increased rates of Hodgkin’s lymphoma [22**, 23**] and anal cancer [22**, 24*, 26**], and no change in the incidence of lung cancer [22**, 23**, 24*, 27**, 28**]. Other individual cancers elevated in the ART era according to more recent studies were melanoma [22**], colorectal [22**], prostate [22**, 29*], and liver [23**] cancers.
Several of these recent studies determined cancer rates by linking U.S.-based HIV/AIDS and cancer registries [23**, 24*, 27**]. Major strengths of registry match studies are the population-based design and the large sample sizes. However, a limitation of this study design was the inclusion of AIDS cases only, and not HIV-infected persons at earlier stages of disease. The recent cancer registry match study by Engels et. al. [23**] was notable in that both reported HIV and AIDS cases were included. Others have evaluated trends in cancer risk in cohort studies [21*, 22**, 25*, 26**, 28**, 29*, 30, 31], which tend to be smaller in size, but include HIV patients at all stages of disease. Patel et al. [22**] reported the results of cancer risk using two large cohorts, the Adult and Adolescent Spectrum of Disease Project (n=47,832), and the HIV Outpatient Study (n=6,948). The strengths of this analysis were the large sample size, the inclusion of HIV patients with any stage of HIV/AIDS, and the ability to evaluate individual risk factors. They found higher risks of several cancers in the ART era (Table 1), but only anal cancer increased over time compared to general population rates.
Observed changes over time in risks of individual cancers may be due to differences in the prevalence of risk factors over time, or perhaps increased screening for anal, prostate or other cancers in HIV-infected patients in recent years. Few studies have evaluated cancer screening practice changes in HIV patients, although Rimland et al. [29*] noted marked increases in prostate-specific antigen testing in the ART era for HIV-infected U.S. Veterans.
Studies comparing cancer rates in the pre- and post-ART era may not reflect the true effect of ART use. Thus, recent studies have increasingly focused on individual ART use and cancer risk (Table 2). In the largest study to date to evaluate the risk of cancers and individual ART use, Piketty et al. [26**] reported an increased risk for anal cancer with any ART use (hazard ratio [HR]=1.7; 95% CI=1.1–2.8), but this has not been confirmed by others [22**, 24*, 37**]. Hessol et al. [24*] determined that only liver cancer among all cancers studied had a reduced risk with current ART use (HR=0.3; 95% CI=0.1–0.9), again a finding not supported by other studies [22**, 35*]. Patel et al [22**] reported that any ART use was associated with a lower risk of breast (RR=0.4; p=0.013), colorectal (RR=0.5; p=0.027), and lung (RR=0.5; p<0.003) cancers. However, others have not found an association with ART use and these same cancers [24*, 28**, 35*]. Finally, others have reported that ART use is not associated with skin cancer , Hodgkin’s lymphoma [22**, 24*, 35*], oral/pharyngeal cancers [22**, 24*, 35*], melanoma [22**, 24*], prostate cancer [22**, 24*] other various individual cancers [24*], and all NADMs combined [24*, 32**, 33**, 35*]. Two studies by Hessol et al. [24*] and Patel et al. [22**] were unique because they reported both calendar era trends and the effect of individual ART use. Cancers associated with ART use and calendar era trends were not the same within each study, indicating that calendar era trends may reflect changes in the epidemiology of cancers, but not necessarily direct effects of individual ART use.
Individual ART medications or therapeutic classes may also have a more direct effect on cancer risk. Early studies in the ART era reported that among KS cases, lesions tended to regress after initiating a PI-based ART regimen [38–43]. Others, however, demonstrated no difference in progression of KS [44, 45] or NHL  comparing PI-based and PI-sparing regimens. Only one cohort study to date has evaluated individual PIs, namely nelfinavir and indinavir, on any NADM risk and found no association [34**]. Experimentally, a beneficial effect for PIs has been demonstrated for KS [47–49], and for ritonavir , saquinavir [50, 51], indinavir , nelfinavir [52–55] and atazanavir  in human cancer cells. Phase I clinical trials are underway to evaluate nelfinavir as a potential anti-cancer agent . As demonstrated for KS , it is possible that PIs may have an indirect effect through improved immune surveillance for cancer cells or a direct effect on the development of cancer. The proposed mechanism of nelfinavir was the induction of endoplasmic reticulum stress and resulting cell death [52–54].
An additional concern regarding cancer risk and antiretroviral use is the recent introduction and use of newer ART classes such as entry, fusion, and integrase inhibitors. It is biologically feasible, for example, that inhibition of these mechanisms may interfere with tumor surveillance. Early trial results suggested the possibility of a higher risk of malignancies in raltegravir-treated  or vicriviroc-treated  patients versus placebo, while others have shown no increased malignancy risk for maraviroc-treated patients [58, 59]. Ongoing surveillance for malignancies is needed for these therapies given the limited use in HIV-infected populations to date.
As described, the decreased incidence for certain NADMs in the ART era may be a result of better immune surveillance for malignancy. Prior studies have indicated that individual NADMs associated with immunodeficiency include Hodgkin’s lymphoma [2, 60–62], lung , penile , lip , testicular [60, 61], sarcomas [60, 61, 63], myeloma , and brain , but others have not found this association with NADMs [8, 17, 64–66]. Many prior studies relied on proximity to the AIDS diagnosis as a marker for immunodeficiency [60, 61–63, 67], with few examining the association of CD4 T-cell counts and NADM risk [2, 64].
Several recent studies have also reported on the association of a prior AIDS diagnosis [23**, 26**, 27**, 68**] and the risk of NADMs (Table 3). Cancers shown to be elevated following a diagnosis of AIDS include Hodgkin’s lymphoma [23**], oral/pharynx [23**], lung [23**, 27**], and anal [26**] cancers. In addition, in a large cohort of HIV-infected persons with known dates of seroconversion in EUROSIDA, Marin et al. [68**] reported higher rates of fatal NADM for those with a diagnosis of AIDS. However, a diagnosis of AIDS likely provides a poor indication of the current immune status for HIV-infected persons, particularly with the substantial improvements observed under ART, including those with a prior AIDS diagnosis.
Many recent studies have evaluated the relationship of NADM risk and CD4 T-cell counts, a more direct measure of immune function (Table 3). Two recent cancer registry match studies incorporated CD4 T-cell counts [23**, 27**]. Engels et al. [23**] reported no association of CD4 T-cell counts at HIV registration and risk of any individual NADM, and Chaturvedi et al. [27**] reported no association of CD4 T-cell counts at AIDS registration and risk of lung cancers. Cohort studies and RCTs, although generally smaller in size, have evaluated other measures of immune status, including baseline (i.e. study entry) [71**], current [69*, 70*], nadir CD4 T-cell counts [22**, 26**, 28**, 32**, 37**, 68**], and duration of low CD4 T-cell counts [33**]. In a large cohort study among U.S. Veterans, Bedimo et al. [71**] determined that CD4 T-cell counts at baseline were lower for those with anal cancer, Hodgkin’s lymphoma, and any NADM combined compared to those without these cancers. The association of current CD4 T-cell counts and NADM risk was evaluated in FIRST [69*] and D:A:D [70*]. In FIRST [69*], the authors reported an HR for any NADM of 0.82 (95% CI=0.68, 0.98) per 100 cells/uL higher. In D:A:D, the authors reported an RR for fatal NADMs of 0.61 (95% CI=0.57, 0.66) per 2-fold higher CD4+ T-cells/uL. Regarding nadir CD4 T-cell counts, Marin et al. reported an association of low nadir CD4 T-cell counts and any fatal NADM [68**], and Patel et al [22**] reported an association of low nadir CD4 T-cell counts with anal, colorectal, and lung cancers, but not with other cancers studied. Others have reported no association of nadir T-cell counts and any NADM [32**], anal cancer [26**, 37**] and lung cancer [28**]. Finally, Bruyand et al. [33**] observed a higher risk of any NADM per year longer duration of CD4 <200 T-cells/uL (HR per year=1.16; 95% CI=1.03–1.30) and CD4 <500 T-cells/uL (HR per year=1.11; 95% CI=1.01–1.22).
Others have provided additional evidence of an association of NADMs and immune status (Table 3). In the SMART trial [32**], patients enrolled in the CD4-guided episodic use of ART study arm had a similar risk of NADMs compared to control patients on continuous ART with an HR of 1.3 (95% CI: 0.7, 2.1), suggesting CD4 improvements with ART are not strongly associated with NADM risk. A small study in the Women’s Interagency HIV Study evaluated the risk of any malignancy (ADM and NADM) and other markers of immune function, including Natural Killer (NK), NK T-cells and CD8 T-cells. Although baseline markers were not associated with malignancy, current NK T-cells were associated with a lower risk (HR per % higher=0.7; 95% CI=0.5–0.9) [72*].
A large meta-analysis by Grulich et al. [73**] compared cancers elevated in two populations known to have suppressed immune systems (i.e., persons with HIV or AIDS and organ transplant recipients). The authors included results from seven HIV or AIDS cancer match studies (n=444,712), and five cohorts of transplant recipients (n=31,977). Results indicated that NADMs elevated in both populations were largely related to infections including EBV-related cancers (Hodgkin’s lymphoma), HBV/HCV-related cancers (liver), helicobacter pylori-related cancer (stomach), and HPV-related cancers (vulva/vaginal, penis, anal, oral cavity/pharynx, non-melanoma skin, lip, esophagus, larynx, eye). Other malignancies elevated in both populations were lung and kidney cancers, multiple myeloma, and leukemia. A similarly designed but smaller study indicated that only liver cancer and the combined group of any NADM were elevated in persons with HIV or AIDS and transplant recipients [35*].
Several NADMs may have a lower risk with use of ART, including liver, breast, colorectal, and lung cancers. In addition, recent studies have indicated that certain individual NADMs appear to be associated with immunosuppression including Hodgkin’s lymphoma, oral/pharynx, lung, anal, and colorectal cancers. Thus, continued ART use likely reduces the risk of certain NADMs with improved immune surveillance for malignancy. However, recent studies also indicated that rates of Hodgkin’s lymphoma and anal cancer were increased in the ART era, and there has been no change in the risk of lung cancers. Thus, future studies should further characterize the epidemiology of NADMs in HIV-infected persons in the ART era, including changes in the prevalence of risk factors, co-infections, and screening practices in this population.
Dr. Silverberg’s contribution was supported in part by grant number K01AI071725 from the NIAID. Dr. Abrams contribution was supported in part by a grant from NIH to INSIGHT UO1 AI068641.
Funding source: This work was supported in part by Grant Number K01AI071725 from the National Institute of Allergy and Infectious Diseases.
Papers of particular interest, published within the period of review, have been highlighted as:
* of special interest
** of outstanding interest