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Curr Opin HIV AIDS. Author manuscript; available in PMC 2010 January 1.
Published in final edited form as:
PMCID: PMC2698664
NIHMSID: NIHMS94539
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DO ANTIRETROVIRALS REDUCE THE RISK OF NON-AIDS DEFINING MALIGNANCIES?
Michael J. Silverberg1 and Donald I. Abrams2
1Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
2Hematology-Oncology Division, San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA
Request for reprints to: Michael J. Silverberg, Ph.D., M.P.H., Kaiser Permanente, Division of Research, 2000 Broadway, Oakland, CA 94612, phone: 510-891-3801; fax: 510-891-3761, Michael.J.Silverberg/at/kp.org
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Abstract
Purpose of review
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 findings
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.
Summary
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.
Keywords: HIV, antiretroviral therapy, immunodeficiency, malignancy
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 [1]. 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. [2] examined individual NADMs.
Calendar-era trends
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 [5], lung [3, 7], anal [5, 9], kidney [6] and for all NADMs combined [5]. 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 [6].
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.
Table 1
Table 1
Recent literature evaluating calendar era changes in the risk of non-AIDS-defining malignancies
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.
Individual ART use
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 [30], 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.
Table 2
Table 2
Recent literature evaluating antiretroviral therapy use and risk of non-AIDS-defining malignancies
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 [46] 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 [50], saquinavir [50, 51], indinavir [50], nelfinavir [52–55] and atazanavir [54] in human cancer cells. Phase I clinical trials are underway to evaluate nelfinavir as a potential anti-cancer agent [56]. As demonstrated for KS [49], 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 [36] or vicriviroc-treated [57] 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 [60], penile [60], lip [60], testicular [60, 61], sarcomas [60, 61, 63], myeloma [61], and brain [61], 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].
AIDS diagnosis
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.
Table 3
Table 3
Recent literature evaluating immune suppression and risk of non-AIDS-defining malignancies
CD4 T-cell counts
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).
Other measures of immune function
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.
ACKNOWLEDGEMENTS
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.
REFERENCES
Papers of particular interest, published within the period of review, have been highlighted as:
* of special interest
** of outstanding interest
1. Silverberg MJ, Abrams DI. AIDS-defining and non-AIDS-defining malignancies: cancer occurrence in the antiretroviral therapy era. Curr Opin Oncol. 2007;19:446–451. [PubMed]
2. 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;97:425–432. [PubMed]
3. Herida M, Mary-Krause M, Kaphan R, et al. Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol. 2003;21:3447–3453. [PubMed]
4. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst. 2000;92:1823–1830. [PubMed]
5. Bedimo R, Chen RY, Accortt NA, et al. Trends in AIDS-defining and non-AIDS-defining malignancies among HIV-infected patients: 1989–2002. Clin Infect Dis. 2004;39:1380–1384. [PubMed]
6. Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS. 2006;20:1645–1654. [PubMed]
7. Bower M, Powles T, Nelson M, et al. HIV-related lung cancer in the era of highly active antiretroviral therapy. AIDS. 2003;17:371–375. [PubMed]
8. Hessol NA, Seaberg EC, Preston-Martin S, et al. Cancer risk among participants in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr. 2004;36:978–985. [PubMed]
9. Diamond C, Taylor TH, Aboumrad T, et al. Increased incidence of squamous cell anal cancer among men with AIDS in the era of highly active antiretroviral therapy. Sex Transm Dis. 2005;32:314–320. [PubMed]
10. Bahl S, Theis B, Nishri D, Marrett LD. Changing incidence of AIDS-related Kaposi sarcoma and non-Hodgkin lymphoma in Ontario, Canada. Cancer Causes Control. 2008 [PubMed]
11. 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. [PubMed]
12. Franceschi S, Maso LD, Rickenbach M, et al. Kaposi sarcoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. Br J Cancer. 2008 [PMC free article] [PubMed]
13. Mocroft A, Kirk O, Clumeck N, et al. The changing pattern of Kaposi sarcoma in patients with HIV, 1994–2003: the EuroSIDA Study. Cancer. 2004;100:2644–2654. [PubMed]
14. Polesel J, Clifford GM, Rickenbach M, et al. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS. 2008;22:301–306. [PubMed]
15. Shiels MS, Cole SR, Wegner S, et al. Effect of HAART on Incident Cancer and Noncancer AIDS Events Among Male HIV Seroconverters. J Acquir Immune Defic Syndr. 2008;48:485–490. [PMC free article] [PubMed]
16. Biggar RJ, Jaffe ES, Goedert JJ, et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006;108:3786–3791. [PubMed]
17. Burgi A, Brodine S, Wegner S, et al. Incidence and risk factors for the occurrence of non-AIDS-defining cancers among human immunodeficiency virus-infected individuals. Cancer. 2005;104:1505–1511. [PubMed]
18. Kirk O, Pedersen C, Cozzi-Lepri A, et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood. 2001;98:3406–3412. [PubMed]
19. Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA. 1999;282:2220–2226. [PubMed]
20. Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994–98: the EuroSIDA study. Lancet. 2000;356:291–296. [PubMed]
21. Ferreros I, Lumbreras B, Hurtado I, et al. The shifting pattern of cause-specific mortality in a cohort of human immunodeficiency virus-infected and non-infected injecting drug users. Addiction. 2008;103:651–659. [PubMed] * Unique in that cause-specific mortality rates were compared in HIV-infected and HIV-uninfected injection drug users
22. 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;148:728–736. [PubMed] ** Large cohort study evaluating risk factors and trends in cancer among HIV-infected patients. One of few studies to evaluate NADM risk with respect to both calendar year and individual ART use.
23. 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;123:187–194. [PubMed] ** One of few cancer registry match studies to include both reported HIV and AIDS cases. Also evaluated association of NADMs with AIDS diagnosis and CD4 T-cell counts
24. Hessol NA, Pipkin S, Schwarcz S, et al. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol. 2007;165:1143–1153. [PubMed] * One of few studies to evaluate NADM risk with respect to both calendar year and individual ART use. Also unique in that few other AIDS Cancer registry match studies include data on individual ART use.
25. 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. [PubMed] * Provides interesting analysis of NADM trends, clinical characteristics and survival compared to patients with ADM
26. Piketty C, Selinger-Leneman H, Grabar S, 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. [PubMed] ** Largest recent study to focus exclusively on anal cancer
27. Chaturvedi AK, Pfeiffer RM, Chang L, et al. Elevated risk of lung cancer among people with AIDS. AIDS. 2007;21:207–213. [PubMed] ** Large and well-designed U.S.-based AIDS and cancer registry match study of lung cancer. Indirect adjustment used to control for smoking.
28. Kirk GD, Merlo C, P OD, et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Infect Dis. 2007;45:103–110. [PubMed] ** Despite small numbers, provided comparison to HIV-uninfected injection drug users and had more complete adjustment for smoking compared to other studies.
29. Rimland D, Guest JL Increasing incidence of prostate cancer in the Atlanta VA cohort study (HAVACS) [abstract]. 14th Conference on Retroviruses and Opportunistic Infections; 25–28 February; Los Angeles, CA. 2007. Abstract 874. * Evaluated both prostate cancer and prostate-specific antigen testing rates over time.
30. Crum-Cianflone N, Marconi V, Weintrob A, et al. Increased incidence of skin cancers among HIV-infected persons [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 22–25 July; Sydney, Australia. 2007. Abstract MOPEB086.
31. Crum-Cianflone N, Marconi V, Weintrob A, et al. A Trends in AIDS-defining and non-AIDS-defining cancers among HIV-infected patients: a 20-year study [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 22–25 July; Sydney, Australia. 2007. Abstract MOPEB084.
32. Silverberg MJ, Neuhaus J, Bower M, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS. 2007;21:1957–1963. [PubMed] ** Broad generalizability given many countries involved, and one of few randomized clinical trials to focus on incidence and risk factors for malignancies
33. Bruyand M, Thiebaut R, Lawson-Ayayi S, et al. Immunodeficiency and Risk of AIDS-defining and Non-AIDS-defining Cancers: ANRSCO3 Aquitaine Cohort, 1998 to 2006 [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; 3–6 February; Boston, MA. 2008. Abstract 15. ** Novel evaluation of duration exposed to low CD4+ T-cell counts
34. Crum-Cianflone N, Huppler Hullsiek K, Ganesan A, et al. The impact of nelfinavir on cancer development among HIV-infected persons [abstract]. 17th International AIDS Conference; 3–8 August; Mexico City, Mexico. 2008. Abstract THPE0232. ** One of few studies to evaluate individual antiretrovirals on cancer risk
35. Serraino D, Piselli P, Busnach G, et al. Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe. Eur J Cancer. 2007;43:2117–2123. [PubMed] * Although much smaller in size compared to the Grulich et al. meta-analysis on same topic, this article provides a novel comparison of NADM risk in two immunosuppressed populations: patients with HIV and transplant recipients.
36. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339–354. [PubMed]
37. D'Souza G, Wiley DJ, Li X, et al. Incidence and Epidemiology of Anal Cancer in the Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 2008;48:491–499. [PubMed] ** Small numbers but one of few studies to include HIV-uninfected controls for study of anal cancer and provided comprehensive evaluation of risk factors including sexual behaviors and smoking
38. Blum L, Pellet C, Agbalika F, et al. Complete remission of AIDS-related Kaposi's sarcoma associated with undetectable human herpesvirus-8 sequences during anti-HIV protease therapy. AIDS. 1997;11:1653–1655. [PubMed]
39. Cattelan AM, Calabro ML, Aversa SM, et al. Regression of AIDS-related Kaposi's sarcoma following antiretroviral therapy with protease inhibitors: biological correlates of clinical outcome. Eur J Cancer. 1999;35:1809–1815. [PubMed]
40. Cattelan AM, Calabro ML, Gasperini P, et al. Acquired immunodeficiency syndrome-related Kaposi's sarcoma regression after highly active antiretroviral therapy: biologic correlates of clinical outcome. J Natl Cancer Inst Monogr. 2001:44–49. [PubMed]
41. Conant MA, Opp KM, Poretz D, Mills RG. Reduction of Kaposi's sarcoma lesions following treatment of AIDS with ritonovir. AIDS. 1997;11:1300–1301. [PubMed]
42. Lebbe C, Blum L, Pellet C, et al. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma. AIDS. 1998;12:F45–F49. [PubMed]
43. Murphy M, Armstrong D, Sepkowitz KA, et al. Regression of AIDS-related Kaposi's sarcoma following treatment with an HIV-1 protease inhibitor. AIDS. 1997;11:261–262. [PubMed]
44. Bower M, Fox P, Fife K, et al. Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi's sarcoma. AIDS. 1999;13:2105–2111. [PubMed]
45. Gill J, Bourboulia D, Wilkinson J, et al. Prospective study of the effects of antiretroviral therapy on Kaposi sarcoma--associated herpesvirus infection in patients with and without Kaposi sarcoma. J Acquir Immune Defic Syndr. 2002;31:384–390. [PubMed]
46. Wolf T, Brodt HR, Fichtlscherer S, et al. Changing incidence and prognostic factors of survival in AIDS-related non-Hodgkin's lymphoma in the era of highly active antiretroviral therapy (HAART) Leuk Lymphoma. 2005;46:207–215. [PubMed]
47. Pati S, Pelser CB, Dufraine J, et al. Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood. 2002;99:3771–3779. [PubMed]
48. Sgadari C, Barillari G, Toschi E, et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med. 2002;8:225–232. [PubMed]
49. Sgadari C, Monini P, Barillari G, Ensoli B. Use of HIV protease inhibitors to block Kaposi's sarcoma and tumour growth. Lancet Oncol. 2003;4:537–547. [PubMed]
50. Ikezoe T, Hisatake Y, Takeuchi T, et al. HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res. 2004;64:7426–7431. [PubMed]
51. Pajonk F, Himmelsbach J, Riess K, et al. 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. [PubMed]
52. Gills JJ, Lopiccolo J, Tsurutani J, et al. Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin Cancer Res. 2007;13:5183–5194. [PubMed]
53. Gupta AK, Li B, Cerniglia GJ, et al. The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Neoplasia. 2007;9:271–278. [PMC free article] [PubMed]
54. Pyrko P, Kardosh A, Wang W, et al. HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer Res. 2007;67:10920–10928. [PubMed]
55. Valdes F, Chow WA. The HIV protease inhibitor Nelfinavir inhibits human SW872 liposarcoma clonogenicity by inducing apoptosis and is associated with an increase in levels of SREBP-1 [abstract]. 95th Annual Meeting of the American Association for Cancer Research; 27–31 March; Orlando, FL. 2004. Abstract 535.
56. Brunner TB, Geiger M, Grabenbauer GG, et al. Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer. J Clin Oncol. 2008;26:2699–2706. [PubMed]
57. Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis. 2007;196:304–312. [PubMed]
58. Gulick R, Su Z, Flexner C, et al. ACTG 5211: phase II study of the safety and efficacy of vicriviroc (VCV) in HIV-infected treatment experienced subjects: 48 week results [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 22–25 July; Sydney, Australia. 2007. Abstract TUAB102.
59. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: Week 48 results of the MERIT study [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 22–25 July; Sydney, Australia. 2007. Abstract WESS104.
60. Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA. 2001;285:1736–1745. [PubMed]
61. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. Lancet. 1998;351:1833–1839. [PubMed]
62. Grulich AE, Wan X, Law MG, et al. Risk of cancer in people with AIDS. AIDS. 1999;13:839–843. [PubMed]
63. Grulich AE, Li Y, McDonald A, et al. Rates of non-AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis. AIDS. 2002;16:1155–1161. [PubMed]
64. Engels EA, Brock MV, Chen J, et al. Elevated incidence of lung cancer among HIV-infected individuals. J Clin Oncol. 2006;24:1383–1388. [PubMed]
65. 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. [PubMed]
66. Phelps RM, Smith DK, Heilig CM, et al. Cancer incidence in women with or at risk for HIV. Int J Cancer. 2001;94:753–757. [PubMed]
67. Biggar RJ, Kirby KA, Atkinson J, et al. Cancer risk in elderly persons with HIV/AIDS. J Acquir Immune Defic Syndr. 2004;36:861–868. [PubMed]
68. Marin B, Thiébaut R, Rondeau V, et al. Association between CD4 and HIV RNA with non AIDS-related causes of death in the era of combination antiretroviral therapy (cART) [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 22–25 July; Sydney, Australia. 2007. Abstract WEPEB019. ** Using data from CASCADE, this is the largest study to date on topic among patients with known duration of HIV infection
69. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22:841–848. [PubMed] * One of few randomized clinical trials to focus on malignancies. Provides a comprehensive overview of association between immunodeficiency and fatal malignancies and other fatal non-AIDS conditions
70. Monforte AD, Abrams D, Pradier C, et al. HIV-induced Immunodeficiency and Risk of Fatal AIDS-defining and Non-AIDS-defining Malignancies: Results from the D:A:D Study [abstract]. 14th Conference on Retroviruses and Opportunistic Infections; 25–28 February; Los Angeles, CA. 2007. Abstract 84. * Excellent description of association of immunodeficiency and risk of fatal malignancies and risk factors for ADMs and NADMs
71. Bedimo R, Dunlap M, McGinnis K, et al. Trends in incidence of non-AIDS-defining malignancies in HIV-infected vs. non-infected veterans in the HAART era: impact of immunosuppression [abstract]. 17th International AIDS Conference; 3–8 August; Mexico City, Mexico. 2008. Abstract MOPE0243. ** Large cohort study and one of few studies to include HIV-uninfected persons from same population (i.e., U.S. Veterans).
72. Nowicki MJ, Vigen C, Mack WJ, et al. Association of cells with natural killer (NK) and NKT immunophenotype with incident cancers in HIV-infected women. AIDS Res Hum Retroviruses. 2008;24:163–168. [PubMed] * Only recent study to evaluate innate immunity in relation to cancer risk in HIV patients.
73. 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. [PubMed] ** Large meta-analysis providing novel comparison of NADM risk in two immunosuppressed populations: patients with HIV or AIDS and transplant recipients.