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Overview of cancer incidence and mortality among people living with HIV/AIDS in British Columbia, Canada:… Chiu, Connie G; Smith, Danielle; Salters, Kate A; Zhang, Wendy; Kanters, Steve; Milan, David; Montaner, Julio S; Coldman, Andy; Hogg, Robert S; Wiseman, Sam M Apr 14, 2017

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RESEARCH ARTICLE Open AccessOverview of cancer incidence and mortalityamong people living with HIV/AIDS inBritish Columbia, Canada: Implications forHAART use and NADM developmentConnie G. Chiu1, Danielle Smith2,3, Kate A. Salters2,3, Wendy Zhang3, Steve Kanters3, David Milan3,Julio S.G. Montaner3,4, Andy Coldman5, Robert S. Hogg2,3 and Sam M. Wiseman1*AbstractBackground: The objective of this study is to evaluate the incidence of non-AIDS defining malignancies (NADMs)among people living with HIV/AIDS (PLWHA) in British Columbia, focusing on clinical correlates, highly activeantiretroviral therapy (HAART) use, and survival, in order to elucidate mechanisms for NADM development.Methods: A retrospective population based analysis was carried out for individuals with HIV/AIDS that began theirtreatment between 1996 and 2008.Results: There were 145 (2.95%) NADMs and 123 (2.50%) AIDS defining malignancies (ADMs) identified in 4918PLWHA in the study population. NADMs were represented by a range of cancer types including, most commonly,lung cancer, followed by anal, breast, head/neck, prostate, liver, rectal, and renal cancers. PLWHA had a SIR of 2.05(CI:1.73, 2.41) for the development of NADMs compared to individuals without an HIV/AIDS diagnosis in the generalpopulation. Independent factors significantly associated with a NADM were: male gender, older age, lower CD4 cellcounts, previous NADM, absence of HAART (non-HAART versus HAART) and treatment during the early-HAART era(before 2000 versus after 2000).Conclusions: NADMs represent an important source of morbidity for PLWHA. Use of HAART with its associatedimprovement in immune-restoration, and tailored targeted cancer screening interventions, may be beneficial andimprove outcomes in this unique patient population.Keywords: Cancer, HIV, Aids, Epidemiology, HAART, MalignancyBackgroundThe advent of combination triple antiretroviral therapy(ART), later referred to as highly active ART (HAART),was found to result in superior patient outcomes andsustained HIV suppression [1, 2]. Reports of remarkableimprovements in patient survival and morbidity with theexpanded use of the HAART regimen soon followed,ushering in a new era in which HIV/AIDS becameviewed as a chronic manageable disease [3–6]. The lon-gevity experienced by people living with HIV/AIDS(PLWHA) in the modern HAART era has resulted in in-creasing vulnerability to age-related diseases and newhealth challenges [7, 8]. The decline in the incidence ofAIDS defining malignancies (ADMs) (Kaposi’s sarcoma,non-Hodgkin lymphoma, and invasive cervical cancer)has been accompanied by a dramatic increase in the inci-dence of non-AIDS defining malignancies (NADMs) [9–11]. However, the incidence of NADMs amongst PLWHAdoes not appear to be attributable to age alone, asPLWHA have an increased risk of malignancy comparedto age-matched cohorts in the general population. Whilebehavioural differences between HIV-positive and HIV-negative populations must be noted, studies controllingfor smoking status found PLWHA to remain at increased* Correspondence: smwiseman@providencehealth.bc.ca1Department of Surgery, St. Paul’s Hospital, & University of British Columbia,C303 – 1081 Burrard Street, Vancouver, BC V6Z 1Y6, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Chiu et al. BMC Cancer  (2017) 17:270 DOI 10.1186/s12885-017-3229-1risk for lung cancer development when compared to thegeneral population [12, 13]. Furthermore, as well as an in-creased risk of viral co-infection (such as Hepatitis viruses,Human Papillomaviruses, and the Epstein-Barr virus)[14–18] and incidence of cancers attributable to thesetumor-associated oncogenic viruses, PLWHA also have ahigher incidence of cancer types that have no known viraletiology, notably lung cancer [19]. Finally, cancer-relatedoutcomes may vary by HIV serostatus as NADM relatedmortality is observably higher compared to the generalpopulation [20]. Thus, fundamental characteristics reflect-ive of the immune and health status of PLWHA representimportant factors that may mediate the differential cancerrisk observed in the HIV/AIDS population.This is amongst the first Canadian studies reportingon NADMs in PLWHA. It also represents one of only afew contemporary reports evaluating cancer risk duringthe late-HAART era. Our study is uniquely poisedbecause antiretroviral medications are centrally adminis-tered and are free of charge in British Columbia,Canada, resulting in a comprehensive population baseddatabase of all individuals receiving antiretroviral ther-apy in the province. Thus, our study captured detaileddrug information and reduces confounding bias relatedto access to care. The objective of this study was to de-termine the incidence, clinical correlates, and survivaloutcomes of NADMs amongst PLWHA in BritishColumbia, Canada, during the HAART era.MethodsStudy design and data sourcesThis retrospective study utilized a linkage of health ad-ministrative data from two comprehensive populationhealth databases in Bristish Columbia, Canada. TheBritish Columbia Cancer Registry (BCCR) is a province-wide mandatory reporting database that records all newcancer diagnoses in British Columbia. The BCCRcatalogues individual demographic, cancer specific andmortality data for all cancer patients in the province.The HIV/AIDS Drug Treatment Program (DTP) Regis-try was established by the British Columbia Centre forExcellence in HIV/AIDS (BC-CfE). All antiretroviralmedications are distributed at no cost to all individualswith an HIV/AIDS diagnosis living in British Columbiathrough a centralized single-payer system and are re-corded in the program registry. The registry was cre-ated to monitor trends and regional differences inaccess to antiretroviral therapy and to evaluate thesuccess of treatment on reducing HIV-related morbid-ity and mortality in British Columbia. The DTPRegistry contains individual administrative records ofpatient antiretroviral drug regimens as well as demo-graphic, clinical, and laboratory data. The BCCR andthe DTP Registry are expected to provide acomprehensive listing of all individuals with a cancerdiagnosis and all individuals with an HIV/AIDS diag-nosis undergoing antiretroviral therapy, respectively,in British Columbia. This study was approved by ourinstitutional research ethics board.Data linkageA probabilistic-match procedure based on PersonalHealth Numbers (PHNs), names, and dates of birthcontained in the BCCR and DTP registries was carriedout to generate a province-wide listing of all individualswith an HIV/AIDS diagnosis that had or had not beendiagnosed with cancer. This cohort was then enrichedby the DTP database with antiretroviral related treat-ment information. All individual names and identifyinginformation were removed from the resulting datasetsbefore being provided to the study data analysts at theBC-CfE. Analyses were then carried out on the aggregateindividual level anonymized dataset.Study criteriaIndividuals in the DTP registry were included in thestudy if their antiretroviral therapy was initiated betweenAugust 1st, 1996 and March 31st, 2008. The study startdate was chosen to reflect the beginning of widespreaduse of HAART in British Columbia. Furthermore, thestudy also separates individuals into the early-HAART(1996–2000) and late-HAART (2000 and later) eras,distinguished by the introduction of a more effectiveHAART regimen in 2000. Patients were excluded if theywere aged 18 years or younger at initiation of antiretro-viral therapy. All cases of cutaneous squamous cellcarcinoma and basal cell carcinoma were excluded dueto suspected non-uniform reporting for these cancers ascases may be topically treated without pathologic con-firmation or registry reporting. Follow-up time was untilDecember 31st, 2008. Both NADMs and ADMsdiagnosed after 1996, regardless of HAART status, wereevaluated, as were predictors of NADM while receivingtreatment. While a few individuals in the study cohortwere diagnosed with multiple cancer types, only the firstNADM and ADM that was diagnosed prior to, and after,the initiation of HAART therapy was entered into thestudy database.Statistical analysesTo calculate the standardized incidence ratios (SIR), in-direct method of adjustment for age and sex was used.We applied BC population (as our standard populationvia the BCCR) cancer rates to our study sample to deter-mine expected counts, then we used ‘observed count/ex-pected count’ to determine the standardized incidencerate (SIR). Yearly population incidence rates were avail-able from 1996 to 2003 and for 2007. Expected cases forChiu et al. BMC Cancer  (2017) 17:270 Page 2 of 92004 and 2005 were based upon incidence rates for2003, and expected cases for 2006 through 2008 wereobtained from the 2007 incidence rates.The study cohort was used to evaluate the determinantsof NADM incidence. The variables evaluated in theseanalyses included: gender, age at enrollment in DTP, nadirCD4 level, baseline viral load, history of intravenous druguse, presence of ADM, presence of Hepatitis C infection,use of HAART (non-HAART versus HAART), andHAART era at start of antiretroviral therapy (early-HAART versus late-HAART, i.e. prior to 2000 versus 2000and later). HAART was defined as use of combinationtriple-antiretroviral therapy, and non-HAART was definedas use of mono- or dual-antiretroviral therapy. Contin-gency tables were constructed utilizing Fisher’s exact testfor evaluation of association between variables andcancer incidence. Logistic regression was then utilizedto determine the variables that were independent ofthe development of NADMs. As these were explana-tory models, the model selection was performed byminimizing the Akaike information criterion (AIC)while limiting the type III p-values to less than 0.20.Kaplan-Meier product limit estimates of cumulativeoverall survival were obtained for NADM cases in thestudy cohort. Patients contributed to time at risk (inperson-years) from start of therapy to either date ofNADM diagnosis or date of censoring. Patients werecensored because they had: no NADM by the end of thestudy period, moved out of province, or were lost tofollow-up. All individuals in the DTP cohort, includingthose individuals diagnosed with an ADM, contributedto the person-time calculation.ResultsThe demographic and clinical characteristics of HIV/AIDS patients in the study population are summarizedin Table 1. The cohort consisted of 4918 men andwomen. The median follow-up time was 64 months(Interquartile range (IQR): 32 to 112 months). Studyparticipants were more likely to be men, youngerthan 50 years, and have a nadir CD4 level lower than200 cells/mm3. The majority of the study HIV/AIDSpopulation did not have an ADM at the start of thestudy period upon initiation of antiretroviral therapy.All patients in the study cohort received antiretroviraldrug therapy, with the majority of these individualsreceiving HAART (combination triple-therapy), andonly a few patients receiving non-HAART therapy(mono- or dual-antiretroviral therapy).Incidence of non-AIDS defining malignancies in studyHIV/AIDS populationDuring the study period, 145 cases (2.95%) of NADMsand 123 cases (2.50%) of ADMs were diagnosed in 4918PLWHA. These cases represent individuals that were allreceiving antiretroviral therapy at the time of their can-cer diagnosis. The NADMs there were diagnosed repre-sented a range of cancer types and included cancers ofthe head and neck, breast, lung, gastrointestinal tract,genitourinary system and skin (Table 2). Of the NADMsdiagnosed during the study period, the most commoncancer sites were lung (20.7%) and anus (20.0%),Table 1 Clinical characteristics of PLWHA in the study population(n = 4918)Clinical characteristic Number (Percent)of IndividualsGenderMale 4016 (81.7%)Female 902 (18.3%)Age (years) at Start of Anti-retroviral TherapyUnder 30 697 (14.1%)30–39 1932 (39.3%)40–49 1519 (30.9%)50 or more 770 (15.7%)Nadir CD4 LevelLess than 50 1402 (28.5%)50–99 686 (13.9%)100–199 1430 (29.1%)200 or more 1400 (28.5%)Baseline Viral Load(Log base 10)a 4.95 (4.40–5.00)Intravenous Drug UseYes 1766 (35.9%)No 3152 (64.1%)ADM StatusYes 251 (5.1%)No 4667 (94.9%)Hepatitis C StatusPositive 2014 (41.0%)Negative 2110 (42.9%)Unknown 794 (16.1%)Use of HAARTbYes 4275 (86.9%)No 643 (13.1%)Start of Antiretroviral TherapycEarly-HAART era (before 2000) 2093 (42.6%)Late-HAART era (2000 and after) 2825 (57.4%)aMedian and Interquartile Range (IQR)bAll individuals were treated with antiretroviral therapy (monotherapy, dualtherapy or triple therapy); selected individuals were treated with HAART(triple therapy) according to guidelines at time of treatmentcThe year cut-point was utilized to represent use of more efficient HAARTstarting in the year 2000Chiu et al. BMC Cancer  (2017) 17:270 Page 3 of 9followed by head and neck, liver, rectum, prostate, kid-ney and lymphatic system (>5% each). However, lungand anal cancers combined represented less than half ofall NADMs, and PLWHA were at increased risk for avariety of other NADM types.The incidence of NADMs in our PLWHA studycohort was compared to their expected incidence inthe general population (Table 3). Individuals with anHIV/AIDS diagnosis had a SIR of 2.05 (95% confi-dence interval [CI]: 1.73 to 2.41) for the developmentof NADMs compared to individuals not diagnosedwith HIV/AIDS in the general population. A particu-larly large effect size was observed in younger menwith HIV/AIDS (age 20 to 39), who had a SIR of 5.42(CI: 3.31 to 8.38) for NADMs. A sub-group SIR analysiswas carried out for the most frequently diagnosed NADMcancer types (Table 3). Cancers of the lung and anal canalhad a significantly higher incidence in PLWHA comparedto the general population.Clinical characteristics associated with a NADM inindividuals with HIV/AIDSAmongst PLWHA receiving antiretroviral therapy, therewere significant differences in the demographic andclinical characteristics of individuals diagnosed with anNADM when compared to individuals not diagnosedwith NADM (Table 4). To further evaluate this effectsize, univariate analysis identified six variables signifi-cantly associated with the development of a NADMamongst PLWHA receiving antiretroviral therapy: malegender, older age at start of antiretroviral therapy, lowernadir CD4 cell counts, presence of another NADM priorto the initiation of antiretroviral therapy, absence ofHAART, and start of antiretroviral therapy in the early-HAART era (i.e. prior to 2000) (Table 5). In multivariatemodeling, the use of HAART (i.e. triple antiretroviraltherapy) was protective against development of a NADMcompared to mono−/dual- antiretroviral drug therapy(aOR: 0.64, CI: 0.43 to 0.95). A higher nadir CD4 countTable 2 NADMs identified in PLWHA receiving antiretroviraltherapy by cancer type (n = 145)Cancer type Number of cases(% of NADMs)Incidence rate (per100,000 person-years)Breast 5 (3.4) 100.03Lung 30 (20.7) 104.97GastrointestinalLiver 8 (5.5) 27.99Gastric 2 (1.4) 6.99Colon 3 (2.1) 10.50Rectum 8 (5.5) 27.99Anal 29 (20.0) 101.47GenitalVulva 3 (2.1) 60.02Testicle, scrotum 3 (2.1) 12.72Prostate 9 (6.2) 38.17UrinaryBladder 2 (1.4) 6.99Kidney 8 (5.5) 27.99SkinMelanoma 2 (1.4) 6.99OtherUnknown primary 5 (3.4) 17.50Soft tissue 2 (1.4) 6.99Brain, spinal cord 2 (1.4) 6.99Hematologic 5 (3.4) 17.50Lymphatic system 10 (6.9) 34.99Total: 145 cases, 28,579.05 person-yearsFemale: 4998.45 person-yearsMale: 23,580.60 person-yearsTable 3 Standardized incidence ratio of NADMs in PLWHA onantiretroviral therapyAge/Sex group Number of NADM StandardizedIncidence ratios(95% CI)Actual ExpectedaAll NADMs20–39/Male 20 3.69 5.42 (3.31,8.38)20–39/Female 3 1.88 1.60 (0.33, 4.66)40–59/Male 80 37.58 2.13 (1.69,2.65)40–59/Female 11 6.92 1.59 (0.79, 2.85)60–79/Male 29 19.40 1.49 (1.00,2.15)60–79/Female 2 1.31 1.53 (0.18, 5.52)Total 145 70.78 2.05 (1.73, 2.41)Lung Cancer20–39/Male 1 0.06 16.55 (0.42, 92.21)20–39/Female 0 0.03 0 (0, 118.43)40–59/Male 14 4.16 3.37 (1.84, 5.65)40–59/Female 4 0.63 6.37 (1.74, 16.31)60–79/Male 11 2.90 3.80 (1.90, 6.79)60–79/Female 0 0.24 0 (0, 15.55)Total 30 8.02 3.74 (2.52, 5.34)Anal Cancer20–39/Male 5 0.08 64.55 (20.98, 150.66)20–39/Female 0 0.005 0 (0, 749.71)40–59/Male 21 2.50 8.39 (5.19, 12.82)40–59/Female 1 0.26 3.82 (0.10, 21.29)60–79/Male 2 0.99 2.02 (0.24, 7.30)60–79/Female 0 0.05 0 (0, 69.03)Total 29 3.89 7.46 (4.99, 10.70)aExpected number of NADMs are based on population incidence for that NADMChiu et al. BMC Cancer  (2017) 17:270 Page 4 of 9was also found to be an independent protective factor forthe development of a NADM (aOR: 0.61, CI: 0.41 to 0.93for a CD4 of 200 cells/mm3 or greater). Being over the ageof 50 (aOR: 4.03, CI: 3.05–6.06) and having history ofNADM before initiating ART (aOR: 3.42, CI: 1.50–7.83)were both associated with the development of NADMamong the sample of PLWHA in our study.Survival of PLWHA diagnosed with a NADMKaplan-Meier product limit estimates of cumulativeoverall survival were constructed for PLWHA in thestudy cohort (Fig. 1). Five patients were diagnosed withboth a NADM and an ADM during the study period (i.e.during antiretroviral therapy) and were excluded fromthe categorical survival analysis. There was no significantTable 4 Clinical characteristics of PLWHA on antiretroviraltherapy by NADM statusClinical characteristic Individualswith NADMIndividualswithout NADMap-value(N = 145) (N = 4773)GenderMale 129 (88.97%) 3887 (81.44%) 0.021*Female 16 (11.03%) 886 (18.56%)Age (years) at Start of Antiretroviral TherapyUnder 30 8 (11.8%) 689 (14.44%) <0.001*30–39 41 (27.7%) 1891 (39.62%)40–49 41 (28.7%) 1478 (30.97%)50 or more 55 (31.8%) 715 (14.98%)History of Intravenous Drug UseYes 42 (28.97%) 1724 (36.12%) 0.077No 103 (71.03%) 3049 (63.88%)Nadir CD4 (cells/mm3)200 or more 28 (19.31%) 1372 (28.75%) 0.040*100–199 48 (33.10%) 1382 (28.95%)50–99 28 (19.31%) 658 (13.79%)less than 50 41 (28.28%) 1361 (28.51%)DM StatusYes 7 (4.83%) 244 (5.11%) 0.878No 138 (95.17%) 4529 (94.89%)Hepatitis C StatusPositive 52 (35.86%) 1962 (41.11%) 0.085Negative 75 (51.72%) 2035 (42.64%)Unknown 18 (12.41%) 776 (16.26%)NADM Prior to Start of Antiretroviral TherapybYes 6 (4.14%) 54 (1.13%) 0.008*No 139 (95.86%) 4719 (98.87%)Use of HAARTcYes 112 (77.24%) 4163 (87.22%) <0.001*No 33 (22.76%) 610 (12.78%)Start of Antiretroviral TherapydEarly-HAART era(before 2000)91 (62.76%) 2002 (41.94%) <0.001*Late-HAART era(2000 and after)54 (37.24%) 2771 (58.06%)aIndividuals with no NADM were represented by patients with either nocancer diagnosis (no ADM or NADM) or with an ADM only (but no NADM)bComparison groups were defined by individuals with diagnosis of NADM afterinitiation of antiretroviral therapy. There were 6 patients in the group “Individualswith NADM” that had a NADM prior to start of antiretroviral therapy anddeveloped a second NADM during antiretroviral therapy. There were 54 patients inthe group “Individuals without NADM” that had a NADM prior to antiretroviraltreatment and did not develop an NADM during antiretroviral therapycAll individuals were treated with antiretroviral therapy (monotherapy, dualtherapy, or triple therapy); selected individuals were treated with HAART(triple therapy) according to guidelines at time of treatmentdThe year cut-point was utilized to represent use of more efficient HAARTstarting in the year 2000bolding and * indicates statistical significance at alpha 0.05Table 5 Association of clinical characteristics with developmentof NADM in PLWHA receiving antiretroviral therapya (n = 4918)Clinical characteristic UnadjustedOdds ratioAdjustedOdds ratiob(95% ConfidenceIntervals)(95% ConfidenceIntervals)GenderMale 1.00 (−-) —Female 0.59 (0.35–0.98)Age (years) at Start of Antiretroviral therapyUnder 50 1.00 (−-) 1.00 (–)50 or more 4.32 (3.08–6.06) 4.03 (3.05–6.06)Nadir CD4 (cells/mm3)Less than 200 1.00 (−-) 1.00 (–)200 or more 0.63 (0.42–0.95) 0.61 (0.41–0.93)NADM Prior to Start of Antiretroviral TherapycNo 1.00 (−-) 1.00 (–)Yes 4.87 (2.15–11.02) 3.42 (1.50–7.83)Use of HAARTdNo 1.00 (−-) 1.00 (–)Yes 0.76 (0.51–1.13) 0.64 (0.43–0.95)Start of Antiretroviral TherapyeEarly-HAART era (before 2000) 1.00 (−-) —Late-HAART era (2000 and after) 0.93 (0.31–1.34)aAmongst individuals with a NADM diagnosis compared to individuals withouta NADM (represented by patients with either no cancer diagnosis [no ADM orNADM] or with an ADM only [but no NADM])bAdjusted odds ratio includes all variables listed under ‘Clinical Characteristic’column. C-statistic = 0.689; multi-collinearity was verified and all varianceinflation factors were less than 2cOnly individuals with diagnosis of NADM after initiation of antiretroviraltherapy were included in the comparison groups. There were 6 patients in thegroup “Individuals with NADM” that had a NADM prior to antiretroviraltreatment and developed a second NADM during anti-retroviral therapydAll individuals were treated with antiretroviral therapy (monotherapy, dualtherapy, or triple therapy); selected individuals were treated with HAART(triple therapy) according to guidelines at time of treatmenteThe year cut-point was utilized to represent use of more efficient HAARTstarting in the year 2000Chiu et al. BMC Cancer  (2017) 17:270 Page 5 of 9difference in survival when comparing individualsdiagnosed with an NADM compared to individuals diag-nosed with an ADM prior to their cancer diagnosis(p = 0·073). Although a trend for improved early survivalwas observed in PLWHA diagnosed with an NADMcompared to patients with an ADM, the survival prob-ability of these two groups normalized at longer termfollow-up. Amongst PLWHA receiving antiretroviraltherapy, individuals with a NADM had a significantlylower survival compared to individuals without a cancerdiagnosis (p < 0.001).DiscussionThis is amongst the first study to report on NADM inci-dence in a Canadian PLWHA population. The studyspecifically focused on PLWHA that were receivingtreatment during the current HAART era. Outcomeswere based on linked, single-payer administrative datafrom the Bristish Columbia Cancer Registry (BCCR)and the Drug Treatment Program (DTP), whichprovides a comprehensive analysis of province-wideantiretroviral use and cancer incidence in BritishColumbia, Canada.Within our study, 2.95% (145 of 4918) of patients de-veloped a NADM, which represents a significantlyhigher risk when compared to individuals without HIV/AIDS in the general population (SIR 2.05, CI: 1.73 to2.41). The types of NADMs most commonly diagnosedin our study population were generally consistent withother reports of HIV/AIDS populations [21–24]. The in-creased incidence of lung cancer that we observed inour study population has also been reported by othergroups in PLWHA during both the pre-HAART andpost-HAART eras [25–28]. Our study also found a sig-nificantly increased incidence of anal cancer in PLWHAwhen compared to the general population, particularlyfor males aged 20 to 39 years (SIR 64.55, C.I. 20.98 to150.66) and aged 40 to 59 years (SIR 8.39, C.I. 5.19 to12.82). This is a higher incidence than observationsmade by other groups in which the SIR for developmentof anal cancer ranged from 6.8 to 10.3 [29, 30]. Anincrease in lung and anal cancer incidence is known tobe associated with shared risk factors, such as increasedincidence of smoking in PLWHA [27, 31].Along with the increased incidence in lung and analcancers, we also observed that the majority of NADMswere represented by other cancer types, including cancersof the head and neck, liver, rectum, prostate, kidney andlymphatic system. These observations have importantimplications on screening and treatment protocols forPLWHA. Screening interventions for a variety of cancertypes have been proven to be beneficial in the generalpopulation, and studies have been encouraging for adop-tion of specific cancer screening practices for PLWHA[28]. The increased incidence of other cancer types, notjust lung and anal cancers, suggests that physicianawareness and cancer screening are especially importantfor PLWHA.To further address the observed increase in NADMs di-agnosed in PLWHA, our study analyzed the associationbetween NADM development, HAART utilization, andhost clinical characteristics. Previous studies have hypoth-esized that HAART utilization is indirectly associated withdecreased cancer incidence due to improvement of hostimmune surveillance and clearance of tumor cells [32].HAART utilization is also associated with increasedsurvival, which results in a more prolonged time intervalfor the development of NADMs. Furthermore, in recentyears, cancer incidence may also be influenced byFig. 1 Overall survival of PLWHA receiving anti-retroviral therapyby cancer status from time of a cancer diagnosis and b start ofantiretroviral therapyChiu et al. BMC Cancer  (2017) 17:270 Page 6 of 9intensified screening practices and greater physicianawareness of the HIV/AIDS population.Our current study found that individuals undergoingtreatment in the late-HAART era (2000 and later) didnot have a significantly decreased incidence of NADMwhen compared to individuals that began therapyduring the early-HAART era (prior to 2000). How-ever, this may be due to the fact that many individ-uals would have changed treatment regimens duringthe later HAART era and as such, cannot be simplycategorized by the date of initiation. However ourwork does suggest that although NADM incidence isincreased when compared with the general popula-tion, the use of more effective and efficient HAARTtherapy is protective against the development ofNADMs in PLWHA through immune reconstitution,and this is also supported by previous research [33–37].This observation underscores the importance of early ini-tiation of effective antiretroviral treatment, and impliesthat NADM incidence may be associated with immuno-logical correlates in the HIV/AIDS population.To further understand the mechanism by whichHAART protects against NADM development, ourpresent study found that a nadir CD4 level > 200 cells/mm3 was also protective against NADM development.Previous research has suggested that a higher percentagetime with undetectable HIV RNA was protective againstthe development of NADMs, highlighting the importanceof the host immune system in HIV clearance and NADMdevelopment [38]. Therefore, our observed associationbetween CD4 levels and NADM development furthersupports the concept that HAART utilization may be pro-tective due to its immune-restorative properties. Thesefindings support early initiation of effective HAARTtherapy in order to maintain high CD4 levels. Further-more, although the mechanisms that underlie the effectsof HAART on the development of NADM in PLWHA arecurrently poorly understood, our observations suggest theimportance of host immunological factors.Previous studies have also suggested an associationbetween HAART utilization and NADM incidence. In astudy by Burgi et al. reporting on a cohort of 4144 HIV-positive individuals treated at military clinics in theUnited States between 1988 and 2003, the use ofHAART was significantly associated with lower rates ofNADMs [39]. Furthermore, studies from Australia andEurope have also reported higher CD4 levels andHAART utilization as being protective against NADMdevelopment [40, 41]. These reports are consistent withour observation and further suggest that the on-goingimmune-restorative effects of HAART may be beneficialin reducing the risk of NADM in PLWHA.In our current study, we also observed that thedevelopment of a NADM not only resulted in asignificantly reduced survival in PLWHA when comparedto PLWHA without a cancer diagnosis, but also a post-cancer survival probability similar to individuals diagnosedwith ADMs. The similarity in these survival outcomessuggests similarities in host reactions to all types of malig-nancies, which could be due to the specific immune fac-tors required to clear the cancer cells. This would suggestthat regardless of whether a cancer diagnosed in PLWHAis an ADM or NADM, protection against its developmentis impacted by adequate immune function, and thereforeimportantly mediated by HAART therapy.The current study had several limitations, many ofwhich are a consequence of its retrospective design.Evaluation of the number of NADMs and ADMs ishighly dependent upon the accurate reporting of cancerin the provincial database. Furthermore, attempts toevaluate the impact of HAART on NADM diagnosis,represented by the absence or presence of HAART aswell as the start date of antiretroviral treatment, are alsopotentially confounded by the changes that occurred intreatments over time. Moreover, there is considerableheterogeneity across NADM, and over time, and it canbe difficult to infer direct clinical benefits of HAARTuptake from epidemiological trends, although we suggestthat overall we see a positive association between higherCD4 cell counts and cancer incidence. Conversely, thereare notable differences between individuals receivingHAART therapy compared to individuals receivingmono−/dual- antiretroviral treatment, as we have con-trolled for duration of HIV infection but are unable tocontrol for varying effects of therapeutic changes overtime. Furthermore, age and CD4 level were included inthe multivariate modeling as an objective measure of thehealth status of the study population.ConclusionsThe current study provides a contemporary overview ofcancer risk in a large population of PLWHA during theHAART era. Currently, NADMs are an important causeof morbidity in PLWHA. Utilization of HAART and itsassociated improved immune-restoration may be benefi-cial for these individuals. Unquestionably, the develop-ment of more effective cancer screening and preventionpractices, that are not limited to anal and lung cancers,will be important in the future. Further study of cancerepidemiology in PLWHA is important and will lead tothe development of strategies that improve outcomes forthis unique population.AbbreviationsADM: AIDS-defining malignancy; AIC: Akaike information criterion;ART: Antiretroviral Therapy; BC-CfE: British Columbia Centre for Excellence inHIV/AIDS; BCCR: British Columbia Cancer Registry; DTP: HIV/AIDS DrugTreatment Program; HAART: Highly active antiretroviral therapy; NADM: non-AIDS defining malignancy; PHN: Personal Health Number; PLWHA: Peopleliving with HIV/AIDS; SIR: Standardized incidence ratiosChiu et al. BMC Cancer  (2017) 17:270 Page 7 of 9FundingThis research study has not received any funding support from any source.Availability of data and materialsThe datasets supporting the conclusions of this article are included withinthe article.Authors’ contributionsCG carried out the literature search, drafted the figures, designed thestudy, collected data, carried out the data analysis, interpreted data,drafted the manuscript, and was involved in the critical review and editof the manuscript. DS carried out the literature search, interpreted data,and was involved in the critical review and edit of the manuscript. SKdrafted the figures, analyzed data, interpreted data, and was involved inthe critical review and edit of the manuscript. DM drafted the figures,analyzed data, interpreted data, and was involved in the critical reviewand edit of the manuscript. WZ drafted the figures, analyzed data,interpreted data, and was involved in the critical review and edit of themanuscript. KS assisted with the data analysis, revisions and criticalre-writes of the manuscript. JM collected data, interpreted data, and wasinvolved in the critical review and edit of the manuscript. AC collecteddata, analyzed data, and was involved in the critical review and edit ofthe manuscript. RH designed the study, collected data, analyzed data,interpreted data, and was involved in the critical review and edit of themanuscript. SW carried out the literature search, drafted the figures,designed the study, carried out the data analysis, interpreted data,drafted the manuscript, and was involved in the critical review and editof the manuscript. All authors read and approved the final manuscript.Competing interestsNo funding was received for this research study and there is no conflict ofinterest that could be perceived as prejudicing the impartiality of theresearch reported.Consent to publicationAs no details/images/videos that would allow for identification of studyparticipants are presented in this work Consent for Publication is notapplicable.Ethics approval and consent to participateThis study was approved and consent to participate was obtained by theethics committee of Providence Health Care Research Ethics Board of St.Paul’s Hospital and University of British Columbia. The reference number isH08–01389. Informed consent was obtained from all the participants.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Surgery, St. Paul’s Hospital, & University of British Columbia,C303 – 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada. 2Faculty оfHealth Sciences, Simon Fraser University, Burnaby, BC, Canada. 3BritishColumbia Centre For Excellence In HIV/AIDS, Providence Health Care, St.Paul’s Hospital, Vancouver, BC, Canada. 4Faculty of Medicine, University ofBritish Columbia, Vancouver, Canada. 5Population and Preventive Oncology,British Columbia Cancer Agency, Vancouver, BC, Canada.Received: 8 March 2016 Accepted: 24 March 2017References1. Montaner JS, Reiss P, Cooper D, Vella S, Harris M, Conway B, Wainberg MA,Smith D, Robinson P, Hall D. A randomized, double-blind trial comparingcombinations of nevirapine, didanosine, and zidovudine for HIV-infectedpatients: the INCAS trial. 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Eur J Med Res. 2011;16(3):101–7.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Chiu et al. BMC Cancer  (2017) 17:270 Page 9 of 9


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