Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 Jan 1.
Published in final edited form as: Curr Opin HIV AIDS. 2014 Jan;9(1):34–40. doi: 10.1097/COH.0000000000000025

Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier cART will alter this risk

Álvaro H Borges 1, Robert Dubrow 2, Michael J Silverberg 3
PMCID: PMC3992916  NIHMSID: NIHMS567265  PMID: 24225382

Abstract

Purpose of review

To critically appraise recent published literature about factors associated with cancer risk likely to be influenced by combination antiretroviral therapy (cART) in HIV-infected individuals, and the potential of earlier cART initiation to reduce this risk.

Recent findings

Factors leading to increased risk of non-AIDS defining malignancies (NADM) in particular remain poorly understood. Immunodeficiency appears to be key, whereas evidence is emerging that a direct pro-oncogenic effect of HIV, activated inflammatory and coagulation pathways, and cART toxicity may also contribute. By reducing HIV replication, improving immune function and limiting chronic inflammation, cART initiation at higher CD4+ cell counts may therefore reduce NADM risk. However, cART only partly normalizes enhanced inflammation and coagulation seen during HIV infection and conflicting laboratory and epidemiological data have been reported as to if (and how) cART affects NADM risk. Furthermore, secondary analyses of randomized controlled trials comparing early versus delayed cART initiation were inconclusive.

Summary

Continuous epidemiological surveillance is warranted to monitor trends in cancer incidence among HIV-infected individuals and to better understand the impact of earlier cART on NADM risk. The role of adjuvant anti-inflammatory or anti-thrombotic therapies to reduce cancer risk deserves further investigation.

Keywords: HIV, cancer, antiretroviral therapy, inflammation

Introduction

Cancer and HIV infection have been inextricably intertwined since the beginning of the AIDS pandemic [1,2]. Three cancer types, namely Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), and invasive cervical cancer (ICC), were soon found to have a particularly higher incidence in HIV-infected individuals and, for epidemiological surveillance purposes, have classically been referred to as AIDS-defining-malignancies (ADM) [3]. Including ICC in the list of ADM also served the purpose of emphasizing the importance of integrating gynaecologic care into medical services for HIV-infected women [3].

However, the spectrum of cancer types observed in excess in HIV-infected individuals was subsequently broadened to encompass a number of non-AIDS defining malignancies (NADM). With the advent of combination antiretroviral therapy (cART) resulting in prolonged life expectancy, the incidence of NADM rose more than 3-fold [4] and its burden has now surpassed the burden of ADM [4,5, ••6]. Moreover, when compared to the general population, HIV-infected individuals have been found to be at higher risk of NADM [7–9], with a standardised incidence ratio of approximately 2.0 [10]. Risk estimates differ considerably for individual NADM types. For instance, HIV-infected individuals have been shown to have, in large cohort studies, a 55-fold higher risk of anal cancer, 19-fold higher risk of Hodgkin lymphoma, 2.1-fold higher risk of non-melanoma skin cancer and 1.8-fold higher risk of melanoma and liver cancer [9,••11]. Of interest, the risk seems to be distinctly higher for those cancer types associated with viral infection and smoking [5,10,12,13], factors that are particularly prevalent in those with HIV. As a result, NADM are now a leading cause of death in the setting of HIV infection [•14].

The changing epidemiology of cancer during HIV infection has rendered the categorization of malignancies into ADM and NADM out-of-date. Anal cancer, a human papillomavirus (HPV)-related NADM, is more strongly associated with HIV infection than ICC [15], with incidence rates 80–110 times as high for HIV-infected men who have sex with men compared with the general population [••16,••17]. Moreover, the incidence of anal cancer was found to be 5-fold higher in HIV-positive than HIV-negative men who have sex with men [18]. Hodgkin lymphoma, an Epstein-Barr virus (EBV)-related NADM [19], is about 5 to 20 times more common in HIV-infected than in HIV-uninfected individuals [••11,20]. Hence, an emerging trend in recent studies is to categorize cancer into infection-related and infection-unrelated [5,7,9,10,12,21,••22].

The factors leading to an increased cancer risk among HIV-infected individuals remain poorly understood. Immunodeficiency and high prevalence of traditional cancer risk factors (e.g., smoking, oncogenic virus infection) [23–26] appear to be key, whereas evidence is emerging that a direct pro-oncogenic effects of HIV, activated inflammatory and coagulation pathways, and cART toxicity may also contribute [••6,••22,25,27]. It remains elusive, however, whether these factors act independently or synergistically. By reducing HIV replication, improving immune function and reducing inflammation at earlier stages of HIV infection, cART initiation at higher CD4+ cell counts has been proposed as a potentially effective approach for reducing NADM risk [••6, 9,28,29]. The purpose of this review is to critically appraise recent evidence regarding established and suspected factors associated with cancer risk likely to be influenced by cART, including immunodeficiency, HIV viral load, enhanced inflammation and coagulation, cART toxicity, and the potential of earlier cART initiation to reduce this risk. We focused on Medline-indexed English literature published from June 2012 to June 2013 that evaluated cART effects, including immunodeficiency and viral replication, on NADM risk. In this review, we will not address traditional cancer risk factors.

Immunodeficiency

The strong relationship between lower CD4+ count (i.e., immunodeficiency) and increased ADM risk is well-established [••6]. Furthermore, there is mounting evidence for an inverse relationship between CD4+ count and NADM risk as well [••6]. Although earlier studies that used static (i.e., time-fixed) CD4+ measures were inconsistent regarding this relationship, more recent studies that used time-updated measures of CD4+ count have observed associations between lower recent CD4+ count and increased risk of NADM (grouped) and of a range of specific cancer types. These reports have been reviewed in detail elsewhere [••6]. As mentioned above, HIV-infected individuals have been found to be at a particularly higher risk of infection-related NADM [5,10,12,13]. Moreover, infection-related NADM may be diagnosed at later stages and may be associated with elevated morbidity and mortality in people with HIV infection [30–32]. On the other hand, the augmented risk of infection-unrelated NADM observed among individuals with lower CD4+ cell counts [9,28,29,33–36] is consistent with a possibly impaired surveillance of pre-malignant and malignant cells (or with an unknown viral component to cancer types that are currently considered infection-unrelated). Thus, HIV-associated immunodeficiency appears to exert its cancer-predisposing effects through two main mechanisms: (1) reduced clearance and control of oncogenic virus infection and (2) reduced immune surveillance of malignant cells.

HIV viral load and direct oncogenic effects of HIV

Some studies have reported an association between ongoing viral replication and cancer risk. In one report, both cumulative and current HIV RNA levels >500 copies/mL were independently associated with increased risk of ADM [37]. In another study, a direct relationship was found between current HIV RNA level and risk of KS and NHL, and between duration of time with HIV RNA >100,000 copies/mL and anal cancer risk [28]. Evidence has accrued indicating that HIV itself, via tat and Vpr proteins, may have direct pro-oncogenic effects. The potential mechanisms are multiple and complex, involving synergism with other pro-oncogenic viruses [38], disruption of cell cycle regulation [39], blockage of tumour suppressor gene function [40], promotion of chromosome instability through the inhibition of telomerase activity [41], impairment of DNA repair function [42], induction of tumour angiogenesis [38,43] and enhancement of the effects of exogenous carcinogens [44,45].

Enhanced inflammation and coagulation

More recently, evidence has emerged linking activated inflammatory and coagulation pathways, as demonstrated by higher plasma levels of biomarkers, to cancer risk. In The Strategies for Management of Antiretroviral Therapy (SMART) Study [46], structured cART interruptions were reciprocally associated with higher levels of coagulation and inflammatory biomarkers [47] and increased risk of cancer [48]. In a recent study of ours, we investigated the relationship between plasma levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, C-reactive protein (CRP), an inflammatory marker whose hepatic production is stimulated by IL-6, and D-dimer, a fibrin-degradation product and marker of enhanced coagulation, and the risk of cancer among 5,000 HIV-infected individuals enrolled in the control arms (i.e., standard of care) of three randomized trials [••22]. Increasing baseline biomarker plasma levels were independently associated with higher cancer risk; the hazard ratio (HR) per doubling in biomarker level was 1.38 (P < 0.001) for IL-6, 1.16 (P = 0.001) for CRP, and 1.17 (P = 0.03) for D-dimer. Results were similar for infection-related and infection-unrelated cancers. This association was strongest for IL-6, the only biomarker that remained significantly associated with cancer risk with simultaneous adjustment for all three markers. Although not providing definitive evidence for a causal link between enhanced inflammation/coagulation and cancer risk during HIV infection, these findings do indicate that trials of interventions that reduce inflammatory and coagulation biomarker levels, in particular IL-6, may be warranted.

cART toxicity

With regard to cART toxicity as a risk factor for cancer, a number of studies have failed to detect positive associations between cART use and cancer risk [49–52]. Furthermore, the beneficial effects of cART on HIV replication, immune function, and inflammation suggest that cART use would lead to a reduction in overall cancer risk [••6,9,28,29]. Nevertheless, potential carcinogenic effects of specific cART agents and drug classes may result in increased risk of cancer. This is the case not only for toxic, older drugs, such as zidovudine [53,54], but also for antiretrovirals currently recommended as first-line therapy for treatment-naïve patients. Protease inhibitors have been linked to a higher risk of anal cancer in observational studies after adjustment for important confounders [••55–57] and efavirenz, a non-nucleoside reverse transcriptase inhibitor, was associated with increased risk of Hodgkin lymphoma in one study [58]. In a recent report, raltegravir, an integrase inhibitor, was found to induce host DNA rearrangements, which, from a theoretical point of view, may have unforeseen consequences including an increased risk of cancer [59]. It is also biologically plausible that, by reducing immunological surveillance of malignant cells, CCR5 inhibitors, a drug class increasingly used in treatment-experienced individuals who failed previous cART regimens, may also lead to an increased incidence of NADM [60]. However, in the absence of any epidemiologic evidence, the clinical relevance of the potential carcinogenic effects of integrase and CCR5 inhibitors remains to be determined.

Would earlier ART initiation reduce the risk of NADM?

There is global consensus that the overall risk:benefit ratio of cART initiation at CD4+ cell counts below 350 cells/mm3 is favourable. However, given the lack of randomized trial evidence and inconsistent results from observational studies [61,62], a debate on whether and when to initiate cART at higher CD4+ cell count thresholds is still unfolding [•63, •64]. This has resulted in inconsistencies among treatment guidelines. The US Department of Health and Human Services guidelines [65] recommend cART for all HIV-infected persons, regardless of CD4+ cell count (i.e., no threshold), whereas the British HIV Association guidelines only recommend cART initiation in asymptomatic persons with CD4+ counts below 350 cells/mm3, an exception being serodiscordant couples, where cART can be initiated in asymptomatic HIV-positive individuals with higher CD4+ counts to reduce the risk of transmission to the HIV-negative partner [66]. The World Health Organization (WHO), in its newest guidelines, recommends cART initiation when CD4+ cell counts drop below 500 cells/mm3 [67]. Earlier cART initiation has clear benefits in terms of reduced HIV transmission at the population level [68], but is not without potential drawbacks in individuals with early HIV infection and thus low risk of disease progression, including cART toxicity, risk of drug resistance and required commitment to life-long therapy.

There is evidence that earlier cART initiation, by preventing immune deterioration associated with the decline in CD4+ cell counts, reduces KS and NHL risk [69–71]; indeed, cART initiation results in regression of early stage KS [72]. Furthermore, because cART improves immune function, lowers HIV viral load, and reduces inflammation, earlier cART initiation has been suggested as a potential approach for reducing NADM risk as well, among HIV-infected individuals [••6,9,28,29]. Thus, reduced incidence [•73, •74] and even regression of HPV-related pre-malignant squamous intraepithelial lesions [•75] following cART initiation have been reported. Alongside their potential benefit in terms of cancer prevention through immune reconstitution and reduced inflammation and viral suppression, some drugs used in cART regimens have been found to have a direct anti-neoplasic effect. In in vitro and in vivo experiments, protease inhibitors were shown to block angiogenesis [76,77] and inhibit tumour growth and invasion [77]. Similarly, efavirenz was found to have selective anti-tumour cytoxic effects [78] and to inhibit proliferation and differentiation of neoplasic cells [79]. However, the clinical relevance of these findings is yet to be determined and, as discussed above, conflicting laboratory and epidemiological evidence suggests that some cART agents or classes may be associated with increased NADM risk.

The definitive way to determine the effect of earlier cART initiation on risk of NADM is to conduct a large, cancer endpoint-driven randomized controlled trial. However, such a trial would require a very large sample size with extended follow-up. Currently, additional randomized evidence to inform this debate can be obtained only from secondary analyses of trials in which cancer events were not primary endpoints. For two [80,81] of three contemporary randomized trials comparing immediate versus delayed cART initiation in treatment-naïve patients [68,80,82], data on NADM outcomes have been reported (Table 1), with no difference noted between the two strategies. The number of NADM events was, however, too small and much longer follow-up will be required to demonstrate differences (if any) between early versus deferred cART initiation. The deferred strategy in these trials allowed CD4+ cell counts to drop far below the thresholds currently recommended for cART initiation by the majority of treatment guidelines [65,66,83]. In this respect, data from the ongoing Strategic Timing of AntiRetroviral Treatment (START) study [84], a large (N=4,600) randomized trial, will be of particular interest. This study, with a composite clinical endpoint including NADM, is comparing immediate versus deferred (i.e., when CD4+ counts drop below 350) cART initiation in HIV-positive persons with CD4+ counts higher than 500 cells/mm3.

Table 1.

Impact of immediate vs. deferred initiation of cART on NADM incidence: data from randomized controlled trials involving cART-naïve HIV+ persons

Study Sample size Median follow up time (years) Median baseline CD4+ count (cells/mm3) Deferral Strategy Median CD4+ count (cells/mm3) at cART initiation in the deferred arm NADM in immediate cART initiation arm NADM in deferred cART initiation arm Relative risk (95% CI) for NADM (immediate vs. deferred cART)
SMARTa [80] 249 2.6 437 cART deferred until:

  1. CD4+ declined to < 250 cells/mm3

  2. CD4+ percentage declined to < 15%

  3. Symptoms of HIV disease developed

 245 0/131 0/118 n/a
HPTN 052 [81] 1761 2.1 428 cART deferred until:

  1. CD4+ declined to ≤ 250 cells/mm3

  2. AIDS-defining illness developed

 229 3/886 3/875 0.99 (0.20–4.88)
Pooled data from the two trials 3/1017 3/993 0.98 (0.20–4.83)
Open in a new tab
a

Only includes the sub-set of patients who were treatment-naïve at study entry

Finally, virological suppression induced by cART only partly normalizes the activated inflammatory and coagulation pathways observed in persons with HIV [85,86]: the reduction of T-cell activation as a result of effective therapy does not reach the level of HIV-uninfected controls [87]. Should activated inflammatory or coagulation pathways be demonstrated definitively to play a causal role in carcinogenesis among HIV-infected individuals, adjunctive anti-inflammatory or anti-thrombotic therapies may be required to further reduce cancer risk in this population [••22]. In an AIDS Clinical Trial Group observational study investigating whether statin use is associated with decreased risk of serious non-AIDS-defining events [••88], statin use was found to be associated with a 57% reduction in NADM risk. As no significant benefits were observed for cardiovascular events, it was hypothesized that the reduction in cancer risk was driven by cholesterol-independent, anti-inflammatory properties of statins. On the other hand, the lack of an inverse association between statin use and cardiovascular events may also be explained by unknown biases (as such an association would be expected) or by low statistical power for cardiovascular events (adjusted and weighted HR = 0.89; 95% confidence interval = 0.32–2.44). However, the report findings are consistent with a case-control study nested within an HIV cohort in which statin exposure, but not use of other lipid lowering drugs, was found to be associated with a significantly decreased risk of NHL [89], a cancer type whose development was shown be preceded by chronic immune activation [90,91].

Conclusion

Cancer, in particular NADM, imposes a growing burden on the aging population of HIV-infected individuals. Immunodeficiency and high prevalence of traditional cancer risk factors (e.g., smoking, oncogenic virus infection) appear to be key to the increased cancer risk observed in this population, whereas evidence is emerging that a direct pro-oncogenic effect of HIV, activated inflammatory pathways, and cART toxicity may also contribute to the higher risk. Because cART improves immune function, lowers HIV viral load, and reduces inflammation, cART initiation at higher CD4+ cell counts has been proposed as a potentially effective approach to reducing NADM risk. cART is, however, not without risks and there is no conclusive laboratory or epidemiological evidence regarding the association of cART and NADM risk. Therefore, continuous epidemiological surveillance is warranted to monitor trends in cancer incidence among HIV-infected individuals and to better understand the impact of earlier cART on NADM risk. Since cART alone only partly normalizes the enhanced inflammation and coagulation associated with HIV infection, the role of adjuvant anti-inflammatory or anti-thrombotic therapies to reduce NADM risk deserves further investigation.

Key Points.

  • Cancer, in particular non-AIDS defining malignancies (NADM), imposes a growing burden on HIV-infected individuals. Immunodeficiency appears to be key to the increased cancer risk observed in this population, whereas evidence is emerging that a direct pro-oncogenic effect of HIV, activated inflammatory and coagulation pathways, and combination antiretroviral therapy (cART) toxicity may also contribute.

  • Because cART improves immune function, lowers HIV viral load, and reduces inflammation, cART initiation at higher CD4+ cell counts has been proposed as a potentially effective approach to reducing NADM risk.

  • Nevertheless, cART only partly normalizes the enhanced inflammation associated with HIV infection and conflicting laboratory and epidemiological data have been reported as to if (and how) cART affects cancer risk.

  • Continuous epidemiological surveillance is warranted to better understand the impact of earlier cART on NADM risk. The role of adjuvant anti-inflammatory or anti-thrombotic therapies to reduce cancer risk deserves further investigation.

Acknowledgments

We are grateful to Jacqueline Neuhaus, University of Minnesota, for checking the cancer figures in the subset of treatment-naïve participants of the SMART study and to Prof Jens Lundgren, Department of Infectious Disease at Rigshospitalet, for critically reading the manuscript. This work was supported in part by the National Cancer Institute of the National Institutes of Health (NIH) under Award Number R01CA165937. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Abbreviations

ADM

AIDS defining malignancies

cART

combination antiretroviral therapy

CCR

C-C chemokine receptor type 5

CRP

C-reactive protein

DNA

Deoxyribonucleic acid

EBV

Epstein-Barr virus

HIV

human immunodeficiency virus

HPV

human papillomavirus

HR

Hazard ratio

ICC

invasive cervical cancer

IL-

interleukin-6

KS

Kaposi sarcoma

NADM

non-AIDS defining malignancies

NHL

non-Hodgkin lymphoma

RNA

Ribonucleic acid

SMART

The Strategies for Management of Antiretroviral Therapy Study

START

Strategic Timing of AntiRetroviral Treatment Study

WHO

World Health Organization

Footnotes

Conflicts of Interest:

Álvaro H Borges: none to declare

Robert Dubrow: none to declare

Michael J Silverberg: none to declare

Contributor Information

Álvaro H Borges, Department of Infectious Diseases, Rigshospitalet & Copenhagen HIV Programme, University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark.

Robert Dubrow, Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale School of Medicine, New Haven, Connecticut, USA.

Michael J Silverberg, Division of Research, Kaiser Permanente, Oakland, California, USA.

References

• of special interest

•• of outstanding interest

  • 1.Centers for Disease Control (CDC) Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California. MMWR Morb Mortal Wkly Rep. 1981;30:305–308. [PubMed] [Google Scholar]
  • 2.Hymes KB, Cheung T, Greene JB, et al. Kaposi’s sarcoma in homosexual men-a report of eight cases. Lancet. 1981;2:598–600. doi: 10.1016/s0140-6736(81)92740-9. [DOI] [PubMed] [Google Scholar]
  • 3.Centers for Disease Control (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41:1–19. [PubMed] [Google Scholar]
  • 4.Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103:753–762. doi: 10.1093/jnci/djr076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Silverberg MJ, Chao C, Leyden WA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009;23:2337–2345. doi: 10.1097/QAD.0b013e3283319184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.••Dubrow R, Silverberg MJ, Park LS, et al. HIV infection, aging, and immune function: implications for cancer risk and prevention. Curr Opin Oncol. 2012;24:506–516. doi: 10.1097/CCO.0b013e328355e131. In depth review of the mechanisms postulated to lead to cancer risk in the setting of HIV infection. A detailed summary of available data on the association between CD4+ cell counts, as a proxy marker of immunodeficiency, and cancer risk is also provided. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.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. doi: 10.1016/S0140-6736(07)61050-2. [DOI] [PubMed] [Google Scholar]
  • 8.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. doi: 10.7326/0003-4819-148-10-200805200-00005. [DOI] [PubMed] [Google Scholar]
  • 9.Silverberg MJ, Chao C, Leyden WA, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev. 2011;20:2551–2559. doi: 10.1158/1055-9965.EPI-11-0777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52:611–622. doi: 10.1097/QAI.0b013e3181b327ca. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.••Silverberg MJ, Leyden W, Warton EM, et al. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst. 2013;105:350–360. doi: 10.1093/jnci/djs529. The incidence of both squamous cell and basal cell carcinoma of the skin was elevated in HIV-infected persons. However, squamous, but not basal cell carcinoma, was associated with immunodeficiency, suggesting that the pathogenesis of squamous cell carcinoma may involve an infectious agent, such as human papillomavirus. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Franzetti M, Adorni F, Parravicini C, et al. Trends and predictors of non AIDS-defining cancers in men and women with HIV infection. A single-institution retrospective study before and after the introduction of HAART. J Acquir Immune Defic Syndr. 2013;62:414–420. doi: 10.1097/QAI.0b013e318282a189. [DOI] [PubMed] [Google Scholar]
  • 13.Calabresi A, Ferraresi A, Festa A, et al. Incidence of AIDS-defining cancers and virus-related and non-virus-related non-AIDS-defining cancers among HIV-infected patients compared with the general population in a large health district of northern Italy, 1999–2009. HIV Med. 2013;14:481–490. doi: 10.1111/hiv.12034. [DOI] [PubMed] [Google Scholar]
  • 14.•Rodger AJ, Lodwick R, Schechter M, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27:973–979. doi: 10.1097/QAD.0b013e32835cae9c. NADM was the second leading cause of death in this study among virologically-suppressed individuals with high CD4+ cell counts. [DOI] [PubMed] [Google Scholar]
  • 15.Chaturvedi AK, Madeleine MM, Biggar RJ, Engels EA. Risk of human papillomavirus-associated cancers among persons with AIDS. J Natl Cancer Inst. 2009;101:1120–1130. doi: 10.1093/jnci/djp205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.••Silverberg MJ, Lau B, Justice AC, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis. 2012;54:1026–1034. doi: 10.1093/cid/cir1012. This large study, which combined data from 13 cohorts from North America, noted substantially elevated anal cancer incidence rates for HIV-infected patients, especially men who have sex with men. The study also noted initially increasing anal cancer rates in the cART era, which have since plateaued. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.••Piketty C, Selinger-Leneman H, Bouvier AM, et al. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the French hospital database on HIV. J Clin Oncol. 2012;30:4360–4366. doi: 10.1200/JCO.2012.44.5486. This study compared anal cancer incidence rates in the French Hospital Database on HIV with rates in the French Network of Population-Based Cancer Registries. A large excess risk of anal cancer was reported in HIV-infected patients, particularly men who have sex with men, compared with the general population. [DOI] [PubMed] [Google Scholar]
  • 18.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. doi: 10.1097/QAI.0b013e31817aebfe. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Thompson LD, Fisher SI, Chu WS, et al. HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am J Clin Pathol. 2004;121:727–738. doi: 10.1309/PNVQ-0PQG-XHVY-6L7G. [DOI] [PubMed] [Google Scholar]
  • 20.Goedert JJ, Bower M. Impact of highly effective antiretroviral therapy on the risk for Hodgkin lymphoma among people with human immunodeficiency virus infection. Curr Opin Oncol. 2012;24:531–536. doi: 10.1097/CCO.0b013e3283560697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Albini L, Calabresi A, Gotti D, et al. Burden of Non-AIDS-Defining and Non-Virus-Related Cancers Among HIV-Infected Patients in the Combined Antiretroviral Therapy Era. AIDS Res Hum Retroviruses. 2013;29:1097–1104. doi: 10.1089/aid.2012.0321. [DOI] [PubMed] [Google Scholar]
  • 22.••Borges AH, Silverberg MJ, Wentworth D, et al. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS. 2013;27:1433–1441. doi: 10.1097/QAD.0b013e32835f6b0c. This is the largest prospective study to investigate, in the setting of HIV infection, the relationship between plasma levels of coagulation (D-dimer) and inflammatory biomarkers (CRP and IL-6) and cancer risk. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lifson AR, Neuhaus J, Arribas JR, et al. Smoking-related health risks among persons with HIV in the Strategies for Management of Antiretroviral Therapy clinical trial. Am J Public Health. 2010;100:1896–1903. doi: 10.2105/AJPH.2009.188664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Lifson AR, Lando HA. Smoking and HIV: prevalence, health risks, and cessation strategies. Curr HIV/AIDS Rep. 2012;9:223–230. doi: 10.1007/s11904-012-0121-0. [DOI] [PubMed] [Google Scholar]
  • 25.Grulich AE, Jin F, Poynten IM, Vajdic CM. HIV, cancer, and aging. Sex Health. 2011;8:521–525. doi: 10.1071/SH11048. [DOI] [PubMed] [Google Scholar]
  • 26.Engels EA. Non-AIDS-defining malignancies in HIV-infected persons: etiologic puzzles, epidemiologic perils, prevention opportunities. AIDS. 2009;23:875–885. doi: 10.1097/QAD.0b013e328329216a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011;62:141–155. doi: 10.1146/annurev-med-042909-093756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Guiguet M, Boué F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol. 2009 Dec;10(12):1152–9. doi: 10.1016/S1470-2045(09)70282-7. [DOI] [PubMed] [Google Scholar]
  • 29.Reekie J, Kosa C, Engsig F, et al. Relationship between current level of immunodeficiency and non-acquired immunodeficiency syndrome-defining malignancies. Cancer. 2010;116:5306–5315. doi: 10.1002/cncr.25311. [DOI] [PubMed] [Google Scholar]
  • 30.Bräu N, Fox RK, Xiao P, et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S-Canadian multicenter study. J Hepatol. 2007;47:527–537. doi: 10.1016/j.jhep.2007.06.010. [DOI] [PubMed] [Google Scholar]
  • 31.Achenbach CJ, Cole SR, Kitahata MM, et al. Mortality after cancer diagnosis in HIV-infected individuals treated with antiretroviral therapy. AIDS. 2011;25:691–700. doi: 10.1097/QAD.0b013e3283437f77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Riedel DJ, Mwangi EI, Fantry LE, et al. High cancer-related mortality in an urban, predominantly African-American, HIV-infected population. AIDS. 2013;27:1109–1117. doi: 10.1097/QAD.0b013e32835dc068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Monforte Ad, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. 2008;22:2143–2153. doi: 10.1097/QAD.0b013e3283112b77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Bedimo RJ, McGinnis KA, Dunlap M, et al. Incidence of non-AIDS-defining malignancies in HIV-infected versus noninfected patients in the HAART era: impact of immunosuppression. J Acquir Immune Defic Syndr. 2009;52:203–208. doi: 10.1097/QAI.0b013e3181b033ab. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kesselring A, Gras L, Smit C, et al. Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis. 2011;52:1458–1465. doi: 10.1093/cid/cir207. [DOI] [PubMed] [Google Scholar]
  • 36.Helleberg M, Kronborg G, Larsen CS, et al. CD4 Decline Is Associated With Increased Risk of Cardiovascular Disease, Cancer, and Death in Virally Suppressed Patients With HIV. Clin Infect Dis. 2013;57:314–321. doi: 10.1093/cid/cit232. [DOI] [PubMed] [Google Scholar]
  • 37.Bruyand M, Thiébaut R, Lawson-Ayayi S, et al. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis. 2009;49:1109–1116. doi: 10.1086/605594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Zhou F, Xue M, Qin D, et al. HIV-1 Tat promotes Kaposi’s sarcoma-associated herpesvirus (KSHV) vIL-6-induced angiogenesis and tumorigenesis by regulating PI3K/PTEN/AKT/GSK-3β signaling pathway. PLoS One. 2013;8:e53145. doi: 10.1371/journal.pone.0053145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Amini S, Khalili K, Sawaya BE. Effect of HIV–1 Vpr on cell cycle regulators. DNA Cell Biol. 2004;23:249–260. doi: 10.1089/104454904773819833. [DOI] [PubMed] [Google Scholar]
  • 40.Harrod R, Nacsa J, Van Lint C, et al. Human immunodeficiency virus type-1 Tat/co-activator acetyltransferase interactions inhibit p53Lys-320 acetylation and p53-responsive transcription. J Biol Chem. 2003;278:12310–12318. doi: 10.1074/jbc.M211167200. [DOI] [PubMed] [Google Scholar]
  • 41.Wang X, Singh S, Jung HY, et al. HIV-1 Vpr protein inhibits telomerase activity via the EDD-DDB1-VPRBP E3 ligase complex. J Biol Chem. 2013;288:15474–15480. doi: 10.1074/jbc.M112.416735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Nunnari G, Smith JA, Daniel R. HIV-1 Tat and AIDS-associated cancer: targeting the cellular anti-cancer barrier? J Exp Clin Cancer Res. 2008;27:3. doi: 10.1186/1756-9966-27-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Corallini A, Campioni D, Rossi C, et al. Promotion of tumour metastases and induction of angiogenesis by native HIV-1 Tat protein from BK virus/tat transgenic mice. AIDS. 1996;10:701–710. doi: 10.1097/00002030-199606001-00003. [DOI] [PubMed] [Google Scholar]
  • 44.Vogel J, Cepeda M, Enk A, et al. The hiv tat gene is a promoter of epidermal skin tumors. Int J Oncol. 1995;7:727–733. doi: 10.3892/ijo.7.4.727. [DOI] [PubMed] [Google Scholar]
  • 45.Altavilla G, Caputo A, Lanfredi M, et al. Enhancement of chemical hepatocarcinogenesis by the HIV-1 tat gene. Am J Pathol. 2000;157:1081–1089. doi: 10.1016/S0002-9440(10)64622-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–2296. doi: 10.1056/NEJMoa062360. [DOI] [PubMed] [Google Scholar]
  • 47.Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:e203. doi: 10.1371/journal.pmed.0050203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Silverberg MJ, Neuhaus J, Bower M, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS. 2007;21:1957–1963. doi: 10.1097/QAD.0b013e3282ed6338. [DOI] [PubMed] [Google Scholar]
  • 49.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. doi: 10.1002/cncr.21334. [DOI] [PubMed] [Google Scholar]
  • 50.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. doi: 10.1093/aje/kwm017. [DOI] [PubMed] [Google Scholar]
  • 51.Crum-Cianflone NF, Hullsiek KH, Marconi V, et al. The impact of nelfinavir exposure on cancer development among a large cohort of HIV-infected patients. J Acquir Immune Defic Syndr. 2009;51:305–309. doi: 10.1097/QAI.0b013e3181aa13c7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Krishnan S, Schouten JT, Jacobson DL, et al. Incidence of non-AIDS-defining cancer in antiretroviral treatment-naïve subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis. Oncology. 2011;80:42–49. doi: 10.1159/000328032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Olivero OA, Anderson LM, Diwan BA, et al. Transplacental effects of 3′-azido-2′,3′-dideoxythymidine (AZT): tumorigenicity in mice and genotoxicity in mice and monkeys. J Natl Cancer Inst. 1997;89:1602–1608. doi: 10.1093/jnci/89.21.1602. [DOI] [PubMed] [Google Scholar]
  • 54.National Toxicology Program. Toxicology and carcinogenesis studies of mixtures of 3′-azido-3′-deoxythymidine (AZT), lamivudine (3TC), nevirapine (NVP), and nelfinavir mesylate (NFV) (Cas Nos 30516-87-1, 134678-17-4, 129618-40-2, 159989-65-8) in B6C3F1 Mice (transplacental exposure studies) Natl Toxicol Program. Tech Rep Ser. 2013;569:1–212. [PubMed] [Google Scholar]
  • 55.••Chao C, Leyden WA, Xu L, et al. Exposure to antiretroviral therapy and risk of cancer in HIV-infected persons. AIDS. 2012;26:2223–2231. doi: 10.1097/QAD.0b013e32835935b3. In this large study investigating the relationship between cART and cancer risk, the overall NADM incidence decreased with increased cART duration, but a higher anal cancer risk was observed among participants receiving PI-based cART regimens. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Bruyand M, Ryom L, Shepherd L, et al. Cancer Risk and Use of PI or NNRTI-based Combination Antiretroviral Therapy (cART): The D:A:D Study. Program and abstracts of the XX Conference on Retroviruses and Opportunistic Infections; 2-6 March 2013; Atlanta , USA. p. Abstract Q-1002. [Google Scholar]
  • 57.Mbang P, Kowalkowski M, Chiao E. The effect of protease inhibitors on the incidence of HIV-associated squamous cell carcinoma of the anus. Program and abstracts of the XX Conference on Retroviruses and Opportunistic Infections; 2–6 March 2013; Atlanta , USA. p. Abstract Q-1002. [Google Scholar]
  • 58.Powles T, Robinson D, Stebbing J, 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. doi: 10.1200/JCO.2008.19.6626. [DOI] [PubMed] [Google Scholar]
  • 59.Varadarajan J, McWilliams MJ, Hughes SH. Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations. Proc Natl Acad Sci U S A. 2013;110:14747–14752. doi: 10.1073/pnas.1305066110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.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. doi: 10.1086/518797. [DOI] [PubMed] [Google Scholar]
  • 61.Sabin CA, Cooper DA, Collins S, Schechter M. Rating evidence in treatment guidelines: a case example of when to initiate combination antiretroviral therapy (cART) in HIV-positive asymptomatic persons. AIDS. 2013;27:1839–1846. doi: 10.1097/qad.0b013e328360d546. [DOI] [PubMed] [Google Scholar]
  • 62.de Cock KM, El-Sadr WM. When to start ART in Africa–an urgent research priority. N Engl J Med. 2013;11:886–889. doi: 10.1056/NEJMp1300458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.•Lundgren JD, Babiker AG, Gordin FM, et al. When to start antiretroviral therapy: the need for an evidence base during early HIV infection. BMC Med. 2013;11:148. doi: 10.1186/1741-7015-11-148. This opinion article highlights the need for randomized data to better define the individual risk:benefit ratio of cART initiation at higher CD4+ counts. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.•Franco RA, Saag MS. When to start antiretroviral therapy: as soon as possible. BMC Med. 2013;11:147. doi: 10.1186/1741-7015-11-147. This opinion article advocates initiating cART as soon as possible. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Washington DC: 2013. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. [Google Scholar]
  • 66.Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. HIV Med. 2012;13:1–85. doi: 10.1111/j.1468-1293.2012.01029.x. [DOI] [PubMed] [Google Scholar]
  • 67.World Health Organization. Recommendations for a public health approach. Geneva: 2013. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. [PubMed] [Google Scholar]
  • 68.Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493–505. doi: 10.1056/NEJMoa1105243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Biggar RJ, Chaturvedi AK, Goedert JJ, et al. AIDS-related cancer and severity of immunosuppression in persons with AIDS. J Natl Cancer Inst. 2007;99:962–972. doi: 10.1093/jnci/djm010. [DOI] [PubMed] [Google Scholar]
  • 70.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. doi: 10.1097/QAD.0b013e3282f2705d. [DOI] [PubMed] [Google Scholar]
  • 71.Clifford GM, Franceschi S. Cancer risk in HIV-infected persons: influence of CD4(+) count. Future Oncol. 2009;5:669–678. doi: 10.2217/fon.09.28. [DOI] [PubMed] [Google Scholar]
  • 72.Bower M, Weir J, Francis N, et al. The effect of HAART in 254 consecutive patients with AIDS-related Kaposi’s sarcoma. AIDS. 2009;23:1701–1706. doi: 10.1097/QAD.0b013e32832d080d. [DOI] [PubMed] [Google Scholar]
  • 73.van der Snoek EM, van der Ende ME, den Hollander JC, et al. Use of highly active antiretroviral therapy is associated with lower prevalence of anal intraepithelial neoplastic lesions and lower prevalence of human papillomavirus in HIV-infected men who have sex with men. Sex Transm Dis. 2012;39:495–500. doi: 10.1097/OLQ.0b013e31825aa764. In this cross sectional study among Dutch HIV-positive men who have sex with men, cART use was independently associated with reduced prevalence of anal intraepithelial neoplastic lesions and anal HPV infection. [DOI] [PubMed] [Google Scholar]
  • 74.•Firnhaber C, Westreich D, Schulze D, et al. Highly active antiretroviral therapy and cervical dysplasia in HIV-positive women in South Africa. J Int AIDS Soc. 2012;15:17382. doi: 10.7448/IAS.15.2.17382. In this cohort study among HIV-positive South-African women, cART use was associated with a reduction in the incidence and progression of cervical intraepithelial lesions. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.•Blitz S, Baxter J, Raboud J, et al. Evaluation of HIV and highly active antiretroviral therapy on the natural history of human papillomavirus infection and cervical cytopathologic findings in HIV-positive and high-risk HIV-negative women. J Infect Dis. 2013;208:454–462. doi: 10.1093/infdis/jit181. In this cohort study reporting data from the Canadian Women’s HIV Study, cART use was associated with increased clearance of oncogenic HPV and regression of cervical intraepithelial lesions. [DOI] [PubMed] [Google Scholar]
  • 76.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. doi: 10.1038/nm0302-225. [DOI] [PubMed] [Google Scholar]
  • 77.Toschi E, Sgadari C, Malavasi L, et al. Human immunodeficiency virus protease inhibitors reduce the growth of human tumors via a proteasome-independent block of angiogenesis and matrix metalloproteinases. Int J Cancer. 2011;128:82–93. doi: 10.1002/ijc.25550. [DOI] [PubMed] [Google Scholar]
  • 78.Hecht M, Harrer T, Büttner M, et al. Cytotoxic effect of Efavirenz is selective against cancer cells and associated with the cannabinoid system. AIDS. 2013;27:2031–2040. doi: 10.1097/QAD.0b013e3283625444. [DOI] [PubMed] [Google Scholar]
  • 79.Sciamanna I, Landriscina M, Pittoggi C, et al. Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Oncogene. 2005;24:3923–3931. doi: 10.1038/sj.onc.1208562. [DOI] [PubMed] [Google Scholar]
  • 80.Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197:1133–1144. doi: 10.1086/586713. [DOI] [PubMed] [Google Scholar]
  • 81.Grinsztejn B, Hosseinipour M, Swindells S, et al. Effect of early versus delayed initiation of antiretroviral therapy (ART) on clinical outcomes in the HPTN 052 randomized clinical trial. Program and abstracts of the XIX International AIDS Conference; 22–27 July 2012; Washington DC. Abstract THLBB05. [Google Scholar]
  • 82.Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010;363:257–265. doi: 10.1056/NEJMoa0910370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.European AIDS Clinical Society. European Guidelines for treatment of HIV infected adults in Europe. Paris: 2012. http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. [Google Scholar]
  • 84.Babiker AG, Emery S, Fätkenheuer G, et al. Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study. Clin Trials. 2013;10:S5–S36. doi: 10.1177/1740774512440342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Neuhaus J, Jacobs DR, Jr, Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010;201:1788–1795. doi: 10.1086/652749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Rönsholt FF, Ullum H, Katzenstein TL, et al. Persistent inflammation and endothelial activation in HIV-1 infected patients after 12 years of antiretroviral therapy. PLoS One. 2013;8:e65182. doi: 10.1371/journal.pone.0065182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187:1534–1543. doi: 10.1086/374786. [DOI] [PubMed] [Google Scholar]
  • 88.••Overton ET, Kitch D, Benson CA, et al. Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death. Clin Infect Dis. 2013;56:1471–1479. doi: 10.1093/cid/cit053. In this AIDS Clinical Trials Group observational study that investigated the association between statin use and the risk of non-AIDS-defining events, risk of NADM, but not other clinical events, was significantly lower in those receiving statins. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Chao C, Xu L, Abrams DI, et al. HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons. AIDS. 2011;25:1771–1777. doi: 10.1097/QAD.0b013e328349c67a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Breen EC, van der Meijden M, Cumberland W, et al. The development of AIDS-associated Burkitt’s/small noncleaved cell lymphoma is preceded by elevated serum levels of interleukin 6. Clin Immunol. 1999;92:293–2999. doi: 10.1006/clim.1999.4760. [DOI] [PubMed] [Google Scholar]
  • 91.Breen EC, Hussain SK, Magpantay L, et al. B-cell stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B-cell lymphoma. Cancer Epidemiol Biomarkers Prev. 2011;20:1303–1314. doi: 10.1158/1055-9965.EPI-11-0037. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES