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Life expectancy of HIV-positive individuals on combination antiretroviral therapy in Canada Patterson, Sophie; Cescon, Angela; Samji, Hasina; Chan, Keith; Zhang, Wendy; Raboud, Janet; Burchell, Ann N; Cooper, Curtis; Klein, Marina B; Rourke, Sean B; Loutfy, Mona R; Machouf, Nima; Montaner, Julio S G; Tsoukas, Chris; Hogg, Robert S Jul 17, 2015

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RESEARCH ARTICLE Open AccessLife expectancy of HIV-positive individualson combination antiretroviral therapy inConclusions: Life expectancy and mortality for HIV-positive individuals receiving ART differ by calendar periodPatterson et al. BMC Infectious Diseases  (2015) 15:274 DOI 10.1186/s12879-015-0969-x1British Columbia Centre for Excellence in HIV/AIDS, Vancouver, CanadaFull list of author information is available at the end of the article* Correspondence: sophie_patterson@sfu.ca; robert_hogg@sfu.caand patient characteristics at treatment initiation. Failure to consider LTFU may result in underestimation of mortalityrates and overestimation of life expectancy.Keywords: Life expectancy, Mortality, HIV, Antiretroviral therapy, CANOC, Canadaperiods 2004–2007 and 2008–2012 in the LTFU-adjustedSophie Patterson1,2*, Angela Cescon1,14, Hasina Samji1, Keith Chan1, Wendy Zhang1, Janet Raboud3,4, Ann N. Burchell5,Curtis Cooper6, Marina B. Klein7,8, Sean B. Rourke5, Mona R. Loutfy9,10,11, Nima Machouf12, Julio S. G. Montaner1,13,Chris Tsoukas7, Robert S. Hogg1,2* and CANOC collaborationAbstractBackground: We sought to evaluate life expectancy and mortality of HIV-positive individuals initiating combinationantiretroviral therapy (ART) across Canada, and to consider the potential error introduced by participant loss tofollow-up (LTFU).Methods: Our study used data from the Canadian Observational Cohort (CANOC) collaboration, including HIV-positiveindividuals aged ≥18 years who initiated ART on or after January 1, 2000. The CANOC collaboration collates data fromeight sites in British Columbia, Ontario, and Quebec. We computed abridged life-tables and remaining life expectanciesat age 20 and compared outcomes by calendar period and patient characteristics at treatment initiation. To correct forpotential underreporting of mortality due to participant LTFU, we conservatively estimated 30 % mortality amongparticipants lost to follow-up.Results: 9997 individuals contributed 49,589 person-years and 830 deaths for a crude mortality rate of 16.7 [standarderror (SE) 0.6] per 1000 person-years. When assigning death to 30 % of participants lost to follow-up, we estimated1170 deaths and a mortality rate of 23.6 [SE 0.7] per 1000 person-years. The crude overall life expectancy at age 20 was45.2 [SE 0.7] and 37.5 [SE 0.6] years after adjusting for LTFU. In the LTFU-adjusted analysis, lower life expectancy at age20 was observed for women compared to men (32.4 [SE 1.1] vs. 39.2 [SE 0.7] years), for participants with injection druguse (IDU) history compared to those without IDU history (23.9 [SE 1.0] vs. 52.3 [SE 0.8] years), for participants reportingAboriginal ancestry compared to those with no Aboriginal ancestry (17.7 [SE 1.5] vs. 51.2 [SE 1.0] years), and forparticipants with CD4 count <350 cells/μL compared to CD4 count ≥350 cells/μL at treatment initiation (36.3[SE 0.7] vs. 43.5 [SE 1.3] years). Life expectancy at age 20 in the calendar period 2000–2003 was lower than inanalyses (30.8 [SE 0.9] vs. 38.6 [SE 1.0] and 54.2 [SE 1.4]).Canada© 2015 Patterson et al. This is an Open Access article distributed under the terms of the Creative Commons AttributionLicense (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly credited. 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.Columbia, Ontario and Quebec. Each cohort site performsAntiretroviral Therapy Cohort (IRB/REBs approve thePatterson et al. BMC Infectious Diseases  (2015) 15:274 Page 2 of 10BackgroundTwenty-five years since the World Health Organizationannounced the Global Program on AIDS to respond tothe HIV/AIDS pandemic, an HIV cure remains elusive[1]. Recent reports estimate that 35 million people livewith HIV globally, and this figure continues to increase[2]. That being said, treatment options available to indi-viduals living with HIV have significantly improved inefficacy, safety and tolerability over the last decade.There is global consensus that combination antiretro-viral therapy (ART) decreases mortality and morbidityamong the HIV-positive population [3–5]; and new ap-proaches in ART delivery, such as PI boosting andfixed-dose combinations, are thought to improve treat-ment outcomes [6]. The improving efficacy of ART reg-imens has resulted in the recognition of HIV as achronic, manageable condition.At the end of 2011 there were approximately 71,300people living with HIV/AIDS in Canada [7]. Antiretroviralregimens have been available to Canadian residentseligible for treatment since the mid-1980s. Treatmentprovision and coverage vary across Canada, dependingon the provincial and territorial programs imple-mented. With improvements in treatment regimen ac-cess, uptake and efficacy, the mortality and morbidityof HIV-positive persons have significantly decreasedover time [8, 9]. However, despite widespread availabil-ity of more efficacious ART regimens, life expectancy(an important population health indicator) remainslower for HIV-positive individuals compared with the gen-eral population [8]. Additionally, other non-AIDS definingcomorbidities are of increasing concern for HIV-positiveindividuals accessing ART; including malignancy, cardio-vascular disease, pulmonary disease, liver disease, andrenal disease [10, 11]. These comorbidities are hypothe-sized to occur at a higher rate among people living withHIV due to immunodeficiency [10], inflammation [12], ahigher prevalence of behavioural risk factors [10], viral co-infections and the toxicity of antiretroviral regimens [13].The effect of HIV on life expectancy in the era ofART is not well explored in the Canadian context.Similarly, the effect of baseline characteristics, such assex and HIV transmission risk group, on life expect-ancy and mortality among treatment-experiencedindividuals has not yet been defined for our region.This analysis sought to evaluate life expectancy andmortality rates of HIV-positive individuals accessingantiretroviral regimens across three Canadian prov-inces, comparing outcomes in the modern treatmentera by calendar year and by subgroups defined by pa-tient characteristics at treatment initiation. In addition,we sought to consider the potential error introduced inmortality analyses due to loss to follow-up (LTFU) ofcohort participants.anonymous use of data retrospectively extracted fromclinical care databases without requiring consent; pa-tients sign a general waiver on opening a medical chartat the hospital but no specific study related consent).Inclusion criteriaCANOC includes individuals with documented HIVinfection, aged at least 18 years, and currently residentin Canada. Participation is restricted to formerly ART-naive HIV-positive individuals initiating combinationART on or after 1 January 2000. All participants hadbaseline CD4 cell count and viral load measurements(within six months prior to ART initiation). This ana-data extraction of demographic, laboratory and clinicalvariables of interest and annually submits these data to thecoordinating centre in Vancouver, British Columbia. A de-tailed CANOC profile was published in 2011 [14].Ethics statementEthics board approval of the CANOC collaboration wasgranted by the Simon Fraser University Research EthicsBoard (REB) and the University of British Columbia REB.Additionally, approval from local institutional reviewboards (IRBs) was granted at each participating cohortsite, including: Providence Health Care Research InstituteOffice of Research Services, the Ottawa Hospital REB,University Health Network (UHN) REB, Véritas IRB,Biomedical C REB of the McGill University Heath Centre(MUHC), University of Toronto HIV REB, and Women’sCollege Hospital REB.Written consent for study participation has beenobtained from all study cohorts except: HAART Obser-vational Medical Evaluation and Research Cohort (IRBapproves the retrospective use of anonymous adminis-trative data without requiring consent; an informationsheet is provided in lieu of a consent form); OttawaHospital Cohort, UHN and Maple Leaf Medical Clinic(IRB/REBs approve the anonymous use of data retro-spectively extracted from clinical care databases with-out requiring consent); and MUHC and the ElectronicMethodsData sourceThe Canadian Observational Cohort (CANOC) collab-oration is a pan-provincial cohort of HIV-positive indi-viduals initiating ART naively, established to evaluatepatterns of treatment uptake and response, and healthservice provision and outcomes across Canada. CANOCconsists of eight cohorts from the provinces of Britishlysis included individuals enrolled in CANOC from2000–2012.Patterson et al. BMC Infectious Diseases  (2015) 15:274 Page 3 of 10Outcomes and statistical methodsThe primary outcome of interest was date of death fromall-causes, used to assess mortality rates and life expect-ancy. Demographic and clinical characteristics of interestincluded sex, Aboriginal ancestry, baseline CD4 cellcount and HIV transmission group (injection drug use(IDU) history vs. no IDU history).This analysis compared life expectancy among HIV-positive individuals on ART in Canada over three calendarperiods, based on year of ART initiation (2000–2003,2004–2007 and 2008–2012). We also considered differ-ences in mortality rates and life expectancy in subgroupsdefined by patient characteristics at initiation of treatment.Crude and age-specific mortality rates were calculated.Mortality rates (per 1000 person-years) were calculated bydividing the total number of deaths by the total number ofperson-years of follow-up; we report these results withstandard errors, calculated using Poisson distribution.Mortality rates were stratified by sex (male vs. female),Aboriginal ancestry (Aboriginal vs. non-Aboriginal), HIVtransmission risk group (IDU history vs. no IDU history),and baseline CD4 count (<350 and ≥350 cells/μL). Wherethe data set was incomplete, analyses were restricted tocohort participants with non-missing information.Abridged life tables were constructed from age-specificmortality rates to compare life expectancy at the age of20 years in the three designated calendar periods understudy. Life expectancy at age 20 refers to the number ofremaining years a participant would be expected to live.Abridged life tables constructed for this analysis werebased on widely used and standardized methods [15]. Wepartitioned each individual’s total person-time contribu-tion and deaths into five-year age categories to computeabridged life tables and life expectancies with correspond-ing standard errors [SE]. Due to the relatively smallproportion of participants within older age categories, thefinal age category constructed within the life tables was 55+ years. Life expectancy values at the exact age of 20 yearswere reported for the whole cohort as well as stratified bysex, transmission group, Aboriginal ancestry and CD4 cellcount at treatment initiation.Estimation of potential error due to LTFUFor the purposes of this analysis, LTFU was defined as thelast recorded known contact date being more than18 months before the end of the study period. To correctfor potential misclassification of death among personsrecorded as lost to follow-up (and differences in ascertain-ment rates between individual cohorts/provinces), we con-servatively estimated that 30 % of participants who werelost to follow-up had died. This estimate was recently usedin a mortality analysis conducted within the AntiretroviralTherapy Cohort Collaboration (ART-CC) [16], chosen toreflect the findings of a survey evaluating mortality amongLoss to follow-upThe median follow-up time within the cohort was52 months (IQR: 24–89). Overall, 11 % of all participantswere lost to follow-up during the study period. Table 2compares the clinical and sociodemographic characteris-tics at treatment initiation for participants retained withinthe cohort and participants lost to follow-up. Participantslost to follow-up were more likely to be female, report noIDU history, report no Aboriginal ancestry and have aCD4 count <350 cells/μL at treatment initiation, as com-pared to participants retained in the cohort (all p <0.05).Table 3 compares the clinical and sociodemographic char-acteristics at treatment initiation for participants lost tofollow-up who were assigned and not assigned the out-come death. Participants assigned the outcome death weremore likely to report IDU history and Aboriginal ancestry,and have a CD4 count <350 cells/μL at treatment initi-ation (all p < 0.001). In all analyses, adjusting for mor-tality among cohort participants lost to follow-upResultsBaseline characteristics of the 9997 participants withinthe analytic sample are presented in Table 1. The cohortwas predominantly male (82 %), with a history of IDUreported by 27 % of participants. The median baselineage was 40 (interquartile range (IQR): 33–47), with 10 %of participants reporting Aboriginal ancestry. Of the9350 participants with available data on hepatitis Cstatus, 26 % were hepatitis C positive. Notably, amongparticipants with a history of IDU the prevalence ofhepatitis C infection was 82 %, compared to 7 % amongparticipants with no IDU history (p < 0.001).those lost to follow-up within the French hospital data-base on HIV infection (FHDH) [16, 17]. Our 30% esti-mate is consistent with published literature describingmortality rates among HIV-positive participants lost tofollow-up in a Ugandan setting, ranging from 28–29 %[18–20], and Canadian estimates of mortality ratesamong HIV-hepatitis C co-infected participants lost tofollow-up, reported at 40 % [21].Among participants not lost to follow-up, a multivari-able logistic regression model (containing demographicand clinical characteristics) was created, with death asthe outcome variable. The resulting parameter estimateswere then applied to those lost to follow-up, whichgenerated estimated probabilities of death for these lostpatients, of which the highest 30 % were categorized asdeaths. Date of death was recorded as the last contactdate for participants lost to follow-up who were assignedthe outcome.decreased the estimated life expectancy and increasedthe estimated mortality rate, as expected.Table 2 Clinical and sociodemographic characteristics attreatment initiation for participants retained within the cohort andparticipants lost to follow-up (n = 9997)Characteristic Total (n) Not lost tofollow-up (%)Lost tofollow-up (%)P-valueAll Participants 9997 8865 (88.7) 1132 (11.3)Sex 0.044Female 1831 1599 (87.3) 232 (12.7)Male 8166 7266 (89.0) 900 (11.0)History of IDUa <0.001Yes 2141 1964 (91.7) 177 (8.3)No 5702 5051 (88.6) 651 (11.4)Aboriginalancestryb0.001Yes 467 437 (93.6) 30 (6.4)No 4275 3788 (88.6) 487 (11.4)CD4 cell count 0.002Patterson et al. BMC Infectious Diseases  (2015) 15:274 Page 4 of 10Table 1 Demographic and clinical characteristics of participants,overall and by calendar year of ART initiation (n = 9997)Period 1 Period 2 Period 3 Overall(2000–2003) (2004–2007) (2008–2012) (2000–2012)n = 2381 n = 3058 n = 4558 n = 9997(%) (%) (%) (%)Baselineage18–34 693 (29.1) 791 (25.9) 1459 (32.0) 2943 (29.4)35–44 1034 (43.4) 1297 (42.4) 1518 (33.3) 3849 (38.5)45–54 481 (20.2) 718 (23.5) 1145 (25.1) 2344 (23.4)55+ 173 (7.3) 252 (8.2) 436 (9.6) 861 (8.6)SexFemale 480 (20.2) 591 (19.3) 760 (16.7) 1831 (18.3)Male 1901 (79.8) 2467 (80.7) 3798 (8303) 8166 (81.7)Historyof IDUaMortality9997 individuals contributed 49,589 person-years and830 deaths for an overall crude mortality rate of 16.74[SE 0.58] per 1000 person-years (Table 4). After esti-mating 30 % mortality among participants lost tofollow-up, there were 1170 deaths, with a mortality rateof 23.59 [SE 0.69] per 1000 person-years. Unadjustedand adjusted mortality rates, overall and by select char-acteristics, are presented in Table 4. In both unadjustedand LTFU adjusted analyses, female sex, IDU history,Aboriginal ancestry and CD4 count of <350 cells/μL attreatment initiation were significantly associated withincreased mortality.Life expectancyUnadjusted life expectancy at age 20 was 45.2 [SE0.66], and 37.5 [SE 0.61] years after estimating 30 %mortality among those lost to follow-up (Table 5). Inboth unadjusted and LTFU adjusted analyses, femalesex, IDU history, Aboriginal ancestry and CD4 count(cells/μL)<350 7689 6777 (88.1) 912 (11.9)≥350 2308 2088 (90.5) 220 (9.5)IDU injection drug usean = 7843bn = 4742Yes 592 (31.0) 719 (29.5) 830 (23.7) 2141 (27.3)No 1315 (69.0) 1721 (70.5) 2666 (76.3) 5702 (72.7)AboriginalancestrybYes 150 (10.6) 151 (9.7) 166 (9.4) 467 (9.8)No 1266 (89.4) 1410 (90.3) 1599 (90.6) 4275 (90.2)CD4 cell count(cells/μL)<350 2024 (85.0) 2679 (87.6) 2986 (65.5) 7689 (76.9)≥350 357 (15.0) 379 (12.4) 1572 (34.5) 2308 (23.1)Analyses restricted to those with non-missing dataIDU injection drug usean = 7843bn = 4742Table 3 Clinical and sociodemographic characteristics attreatment initiation for participants assigned to the outcomedeath and not assigned to death among those lost to follow-up(n = 1132)Characteristic Total (n) Not assigneddeath (%)Assigneddeath (%)P-valueParticipants lostto follow-up1132 792 (70.0) 340 (30.0)Sex 0.787Female 232 164 (70.7) 68 (29.3)Male 900 628 (69.8) 272 (30.2)History of IDUa <0.001Yes 177 53 (29.9) 124 (70.1)No 651 538 (82.6) 113 (17.4)Aboriginalancestryb<0.001Yes 30 13 (43.3) 17 (56.7)No 487 379 (77.8) 108 (22.2)CD4 cell count(cells/μL)<0.001<350 912 604 (66.2) 308 (33.8)≥350 220 188 (85.5) 32 (14.5)IDU injection drug usean = 828bn = 517Patterson et al. BMC Infectious Diseases  (2015) 15:274 Page 5 of 10Table 4 Population size, deaths, and unadjusted and adjustedmortality rate per 1000 person-years (PY), overall and by selectcharacteristicsPopulationa Deaths PersonYears(PY)Unadjustedmortalityrate per1000PY (SE)Adjustedbmortalityrate per1000PY(SE)Overall 9997 830 49588.88 16.74 (0.58) 23.59 (0.69)SexFemale 1831 184 9303.73 19.78 (1.46) 27.09 (1.71)Male 8166 646 40285.14 16.04 (0.63) 22.79 (0.75)History ofIDUYes 2141 377 11082.71 34.02 (1.75) 45.21 (2.02)No 5702 257 28875.05 8.90 (0.56) 12.81 (0.67)AboriginalancestryYes 467 123 2398.97 51.27 (4.62) 58.36 (4.93)No 4275 255 24627.65 10.35 (0.65) 14.74 (0.77)of <350 cells/μL at treatment initiation were signifi-cantly associated with decreased life expectancy at age20 (Table 5, Fig. 1).Temporal trendsBoth life expectancy and mortality rates improved overtime (Tables 4 and 5, Fig. 1). Mortality rates decreasedwithin more recent time periods, both before and afteradjusting for mortality among participants lost to follow-up (Table 4). Life expectancy at age 20 increased withinmore recent time periods in both the unadjusted andadjusted analyses, reaching a maximum life expectancy of54.2 [SE 1.37] years in the period 2008–2012, after adjust-ing for mortality among participants lost to follow-up(Table 5).Sensitivity analysisGiven that only 8.6 % (n = 861) of our analytic sample wasaged 55+ years (contributing a total of 3903.8 person-years of follow-up) we were concerned that mortality ratesamong participants within this age category, especiallyat the oldest ages, may be underestimated, potentiallyBaseline CD4(cells/μL)<350 7689 740 41016.06 18.04 (0.66) 25.55 (0.79)≥350 2308 90 8572.82 10.50 (1.12) 14.23 (1.29)Year of ARTinitiation2000–2003 2381 399 20389.75 19.57 (0.98) 31.29 (1.24)2004–2007 3058 287 17928.23 16.01 (0.95) 21.03 (1.08)2008–2012 4558 144 11270.90 12.78 (1.07) 13.75 (1.11)SE standard error, IDU injection drug use, ART antiretroviral therapyaAnalyses restricted to those with non-missing databIncluding assumed 30 % mortality in participants lost to follow-upTable 5 Life expectancy estimates at age 20 years, showingunadjusted and adjusted values (assuming 30 % mortality amongthose lost to follow-up), n = 9997Unadjusted AdjustedeOx (SE) eOx (SE)Overall 45.2 (0.66) 37.5 (0.61)SexFemale 40.1 (1.34) 32.4 (1.12)Male 47.0 (0.75) 39.2 (0.72)History of IDUYes 28.2 (1.07) 23.9 (0.96)No 63.9 (0.92) 52.3 (0.84)Aboriginal ancestryYes 19.1 (1.60) 17.7 (1.49)No 62.7 (1.12) 51.2 (0.97)Baseline CD4 (cells/μL)<350 44.1 (0.77) 36.3 (0.70)≥350 50.8 (1.35) 43.5 (1.25)Year of ART initiation2000–2003 40.8 (1.05) 30.8 (0.90)2004–2007 44.4 (1.04) 38.6 (0.96)inflating the life expectancy estimates generated. Toexplore this issue, we conducted a sensitivity analysis using2006 mortality data for the general Canadian population toobtain revised life expectancy estimates [22]. We assumedthat the rise in the mortality rate between participants aged50–54 and participants aged 55+ years in our analytic sam-ple would increase by the same ratio as that demonstratedwithin the general Canadian population of correspondingage categories. Based on this assumption, we extrapolatedthe mortality rates observed among study participants aged50–54 to produce new mortality estimates for participantsaged 55+ years. After performing this adjustment, the over-all life expectancy at age 20 decreased from 45.2 [SE 0.7]years to 31.7 [SE 0.4] years (Additional file 1).DiscussionThe largest of its kind conducted in Canada to date,our study contributes a number of important findingson life expectancy among HIV-positive persons in thisregion. Specifically, we observed that life expectancyand mortality for HIV-positive individuals accessingART differ by sex, IDU history, Aboriginal ancestry,baseline CD4 cell count prior to ART initiation, andcalendar period of ART initiation. Additionally, thismanuscript employs a novel methodological approachto life expectancy analyses; questioning the validity of2008–2012 56.7 (1.43) 54.2 (1.37)eox life expectancy estimate (years), SE standard error, IDU injection drug use,ART antiretroviral therapyadPatterson et al. BMC Infectious Diseases  (2015) 15:274 Page 6 of 10cohort studies that fail to account for mortality among par-ticipants lost to follow-up and those that lack sufficientFig. 1 Life expectancy estimates at age 20 years, showing unadjusted andfollow-up data among older individuals accessing treatment.Life expectancy within this cohort improved with morerecent calendar periods. This finding has been previouslyreported in the literature, and likely reflects improvedcoverage and quality of ART regimes and HIV care [4, 5,23, 24]. Recent reports estimate the average remaining lifeexpectancy for Canadians at age 20 to be 59.7 and63.9 years for men and women, respectively [25]. Whencompared with the findings of our study, it is clear thatdespite advances in the health care services and antiretro-viral therapies available to people living with HIV inCanada, the life expectancy of HIV-positive Canadians re-mains lower than that of the general population.Men demonstrated longer life expectancy and lowermortality rates compared to women in this cohort. This isin contrast to population-level surveillance data publishedby Statistics Canada, reporting increased life expectancyamong women compared with men in the general popula-tion in all Canadian provinces [26]. A recent publicationevaluating regional and sex specific patterns of HIV/AIDSmortality in Canada from 1987-2008 found that age-specific death rates among women in most age categorieswere lower than those observed among men [27]. How-ever, this study observed that the decline in HIV-relatedmortality rates since the mid-1990s was much more pro-nounced among men than women. North American pub-lications evaluating mortality in HIV-positive cohortsaccessing ART have demonstrated comparable sex-relateddifferences to those shown in our study [9, 28, 29].justed values, by clinical and sociodemographic characteristics at baselineHowever, mortality analyses conducted in Europeanand trans-continental settings have observed contrastingsex differences among HIV-positive cohorts, depicting alonger life expectancy among women than men [8, 30, 31].Other studies have found no sex-related differences [32].These inconsistencies may be due to inherent differencesin cohort demographics, treatment access and healthcareutilization. A recent publication commented on the validityof cross-cohort comparisons of mortality rates, suggestingthat cohort characteristics in different settings can signifi-cantly alter HIV outcomes, including mortality [16]. In re-cent years, Canadian studies have reported disparities inretention within key stages of the HIV treatment cascade,including access and adherence to treatment and achieve-ment of viral suppression, according to region of care [33],sex and IDU history [33, 34]. In these studies, women andindividuals with a history of IDU demonstrated decreasedretention within the HIV treatment cascade in Canada[33, 34]. In CANOC, a disproportionate number of HIV-positive individuals reporting IDU history are women,which reflects the composition of the Canadian HIV epi-demic, especially in British Columbia.Individuals with a history of IDU demonstrated poormortality and life expectancy outcomes in this analysis.This finding has been consistently reported in the pub-lished literature [8, 9, 23, 29, 35]. Previous studies haveshown that the increased mortality rates amongAnother potential limitation of this study was that wePatterson et al. BMC Infectious Diseases  (2015) 15:274 Page 7 of 10persons with IDU history primarily reflect higher ratesof all-cause mortality, rather than HIV-related mortality[35, 36]. Indeed this demographic group experiences ahigh prevalence of comorbidities, augmented by poten-tial active drug use, socioeconomic disadvantage andpoor access to health care services [36]. In our studycohort, a significantly higher prevalence of hepatitis Cinfection was identified among participants with a his-tory of IDU compared to individuals with no IDU his-tory. Infection with hepatitis C is an importantcontributor to mortality and morbidity among peopleliving with HIV, primarily due to an increased risk ofliver disease [37, 38]. A recent Canadian cohort studyreported notably higher mortality rates among individ-uals co-infected with HIV and hepatitis C compared topreviously published mortality rates among mono-infected HIV-positive individuals [39].CD4 cell count at treatment initiation was another sig-nificant predictor of mortality and life expectancy in ourcohort. Participants with CD4 cell counts <350 cells/μL attreatment initiation demonstrated increased mortality ratesand decreased life expectancy. This finding is consistentwith previous mortality studies [8, 9], and reinforces thelong-term health benefits of ART initiation earlier in thecourse of HIV infection. Earlier ART initiation is supportedby the 2014 International Antiviral Society-USA guidelines,recommending the initiation of antiretroviral therapy re-gardless of CD4 cell count for most patients [40].In our analysis, we found Aboriginal ancestry to be pre-dictive of decreased life expectancy. This is consistent witha Canadian retrospective cohort study published in 2011,which reported that individuals of Aboriginal descent re-ceiving ART demonstrate increased all-cause and HIV-related mortality rates compared with non-Aboriginalpeople living with HIV in Canada [35]. This observationmay be due to competing life circumstances and social-structural factors that influence access and adherence toART among Aboriginal persons [35]. A report by StatisticsCanada similarly identified this difference in lifeexpectancy between Canadians of Aboriginal ancestry andthe non-Aboriginal population [41]. This observation isconcerning, and initiatives to improve treatment outcomesof Aboriginal Canadians should be made a priority. Tonote, this finding may be influenced by underlying charac-teristics of our cohort, as a disproportionate number ofHIV-positive individuals reporting IDU history in CANOCalso report Aboriginal ancestry.Large-scale longitudinal cohort studies often face asignificant limitation in the form of incomplete data dueto participant LTFU. LTFU affects most cohort studiesand can result in bias, affecting study validity [42]. Inconducting this study we sought to account for the im-pact of LTFU on life expectancy estimates to reduce po-tential bias and improve the validity of our findings.did not allow for censoring in LTFU data. This isparticularly relevant for those who initiated ART in themost recent time period; in some cases not enoughtime had passed to be declared lost to follow-up giventhe 18-month definition. Unfortunately, data describingcauses of death are not currently collected across par-ticipating cohorts in the CANOC collaboration; as suchwe were unable to present the distribution of causes ofdeath within this manuscript.After conservatively estimating 30 % mortality amongparticipants lost to follow-up, unsurprisingly we observedthat mortality rates increased and life expectancy esti-mates decreased. This suggests that failure to account forparticipant lost to follow-up in mortality analyses resultsin the potential for significant underestimation of mortal-ity rates and overestimation of life expectancy data, affect-ing data validity.LimitationsSeveral limitations of this study should be acknowledged.CANOC includes data from only three Canadian prov-inces, and participants included are already linked tospecific health care facilities, therefore the analytic sampleis not be fully representative of the overall HIV-positivepopulation across Canada, including those most at risk ofadverse clinical outcomes. Data from British Columbiainclude all CANOC-eligible HIV-positive individuals inthe province accessing ART, whereas data from Ontarioand Quebec are collected from a selection of clinics,which may introduce a clinic-selection bias. This studyconsiders the Canadian HIV-positive population, thereforeobservations described may not be generalizable to otherglobal settings.We conducted an adjusted analysis to account formisclassification of mortality among participants lost tofollow-up, conservatively estimating the death of 30 %of those lost to follow-up. As published data concern-ing mortality among participants lost to follow-up inCanadian cohorts are limited, this estimate was based onprevious European [17] and Ugandan studies among HIV-positive cohorts [18–20] and findings from a Canadiancohort of HIV-hepatitis C co-infected individuals [21].Therefore, this estimate may not be entirely generalisableto all HIV-positive individuals in Canada. Further studiesmay seek to evaluate how accurate our assumption wasregarding mortality among HIV-positive participants lostto follow-up in this setting. Differences in mortailty ascer-tainment by site also exist, and thus our estimation ofmortality may be more problemetic at sites that do notlink to vital statistics registries.Given that only a small proportion of our analyticsample was aged ≥55 years, we conducted a sensitivity1Patterson et al. BMC Infectious Diseases  (2015) 15:274 Page 8 of 10analysis based on mortality rates within the generalCanadian population to explore whether possibleunderestimation of mortality rates among participantswithin this age category affected the life expectancyvalues generated. The results suggested that our life ex-pectancy estimates may be overestimated due to impre-cise representation of mortality rates within older agecategories. As the Canadian population living with HIVages, the reliability of results generated by life expect-ancy analyses such as this will continue to improve.ConclusionIn conclusion, this study found that while both mortalityrates and life expectancy for HIV-positive Canadiansaccessing ART are improving over time, they remainbelow that of the general Canadian population. Lifeexpectancy and mortality are influenced by baselinecharacteristics at treatment initiation, including Aboriginalancestry, sex, CD4 cell count and IDU history. Thesefindings suggest the need for targeted interventions forpatient subgroups at increased risk of adverse outcomes.Future studies examining patterns of life expectancy andmortality among HIV-positive populations should take intoaccount mortality among participants lost to follow-up toensure validity of estimates.Additional fileAdditional file 1: Life expectancy estimates at age 20 years,showing unadjusted values, estimates adjusted for mortality amongparticipants lost to follow-up, and estimates adjusted to account forlow proportion of participants aged ≥55 years, based on 2006Canadian mortality data (n = 9997).Competing interestCANOC is funded by the Canadian Institutes of Health Research (CIHR)through a Centres Grant (Centres for HIV/AIDS Population Health and HealthServices Research [CIHR 711314]), two Operating Grants (HIV/AIDS PriorityAnnouncement [CIHR 711310]; Population and Public Health [CIHR 711319]),and is also supported by the CIHR Canadian HIV Trials Network (CTN 242).ANB is supported by a CIHR New Investigator Award. AC is supportedthrough a CANOC Centre Scholar Award. CC is supported through anApplied HIV Research Chair from the OHTN. RSH is supported by a UniversityProfessorship at Simon Fraser University. MBK is supported by a Chercheur-Boursier Clinicien Senior Career Award from the Fonds de recherche en santédu Québec (FRSQ). MRL receives salary support from CIHR. JSGM is sup-ported by an Avant-Garde Award from the National Institute on Drug Abuse,National Institutes of Health. SP is supported by a Study Abroad Studentshipfrom the Leverhulme Trust. JR is supported through an OHTN Chair inBiostatistics.Authors’ contributionsAll authors contributed to this study, as required by the InternationalCommittee of Medical Journal Editors. RSH, SP, AC, KC, and HS wereinvolved in the conception and design of the study. RSH, JR, AB, CC, MBK,SBR, MRL, NM, JSG and CT were involved in data acquisition, KC, WZ andRSH conducted the data analysis, and KC, AC, HS, SP, WZ and RSH wereresponsible for data interpretation. SP, AC and HS drafted the initialmanuscript, and all authors revised the document critically and gave finalapproval prior to completion. All authors take responsibility for theaccuracy and integrity of this work.Authors’ informationThe CANOC Collaborative Research Centre includes: Principal Investigator:Robert Hogg (British Columbia Centre for Excellence in HIV/AIDS, Simon FraserUniversity) Site Principal Investigators: Ann N. Burchell (Ontario HIV TreatmentNetwork, University of Toronto, OHTN Cohort Study [OCS]), Curtis Cooper(University of Ottawa, OCS), Deborah Kelly (Memorial University ofNewfoundland), Marina Klein (Montreal Chest Institute ImmunodeficiencyService Cohort, McGill University), Mona Loutfy (University of Toronto, MapleLeaf Medical Clinic, OCS), Nima Machouf (Clinique Medicale l’Actuel, Universitéde Montréal), Julio Montaner (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Janet Raboud (University of Toronto,University Health Network, OCS), Chris Tsoukas (McGill University), StephenSanche (University of Saskatchewan), Alexander Wong (University ofSaskatchewan) Co-Principal Investigators: Tony Antoniou (St. Michael’s Hospital,University of Toronto, Institute for Clinical Evaluative Sciences), Ahmed Bayoumi(St. Michael’s Hospital, University of Toronto), Mark Hull (British Columbia Centrefor Excellence in HIV/AIDS), Bohdan Nosyk (British Columbia Centre forExcellence in HIV/AIDS, Simon Fraser University) Co-Investigators: AngelaCescon (Northern Ontario School of Medicine), Michelle Cotterchio (CancerCare Ontario, University of Toronto), Charlie Goldsmith (Simon FraserUniversity), Silvia Guillemi (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), P. Richard Harrigan (British ColumbiaCentre for Excellence in HIV/AIDS, University of British Columbia), MarianneHarris (St. Paul’s Hospital), Sean Hosein (CATIE), Sharon Johnston (BruyèreResearch Institute, University of Ottawa), Claire Kendall (Bruyère ResearchInstitute, University of Ottawa), Clare Liddy (Bruyère Research Institute,University of Ottawa), Viviane Lima (British Columbia Centre for Excellencein HIV/AIDS, University of British Columbia), David Moore (British ColumbiaCentre for Excellence in HIV/AIDS, University of British Columbia), AlexisPalmer (British Columbia Centre for Excellence in HIV/AIDS, Simon FraserUniversity), Sophie Patterson (British Columbia Centre for Excellence inHIV/AIDS, Simon Fraser University), Peter Phillips (British Columbia Centrefor Excellence in HIV/AIDS, University of British Columbia), Anita Rachlis(University of Toronto, OCS), Sean B. Rourke (University of Toronto, OCS),Hasina Samji (British Columbia Centre for Excellence in HIV/AIDS), MarekSmieja (McMaster University), Benoit Trottier (Clinique Medicale l’Actuel,Université de Montréal), Mark Wainberg (McGill University, Lady DavisInstitute for Medical Research), Sharon Walmsley (University HealthNetwork, University of Toronto) Collaborators: Chris Archibald (PublicHealth Agency of Canada Centre for Communicable Diseases and InfectionControl), Ken Clement (Canadian Aboriginal AIDS Network), MoniqueDoolittle-Romas (Canadian AIDS Society), Laurie Edmiston (CanadianTreatment Action Council), Sandra Gardner (OHTN, University of Toronto,OCS), Brian Huskins (Canadian Treatment Action Council), Jerry Lawless(University of Waterloo), Douglas Lee (University Health Network, Universityof Toronto, ICES), Renee Masching (Canadian Aboriginal AIDS Network),Stephen Tattle (Canadian Working Group on HIV & Rehabilitation), AlirezaZahirieh (Sunnybrook Health Sciences Centre) Analysts and Staff: ClaireAllen (Regina General Hospital), Stryker Calvez (SHARE), Guillaume Colley(British Columbia Centre for Excellence in HIV/AIDS), Jason Chia (BritishColumbia Centre for Excellence in HIV/AIDS), Daniel Corsi (The OttawaHospital Immunodeficiency Clinic, Ottawa Hospital Research Institute),Louise Gilbert (Immune Deficiency Treatment Centre), Nada Gataric (BritishColumbia Centre for Excellence in HIV/AIDS), Alia Leslie (British ColumbiaCentre for Excellence in HIV/AIDS), Luciana Light (OHTN), David Mackie(The Ottawa Hospital), Costa Pexos (McGill University), Susan Shurgold (BritishColumbia Centre for Excellence in HIV/AIDS), Leah Szadkowski (University ofToronto, University Health Network), Chrissi Galanakis (Clinique MédicaleL’Actuel), Benita Yip (British Columbia Centre for Excellence in HIV/AIDS), JamieYounger (University of Toronto, University Health Network), and Julia Zhu(British Columbia Centre for Excellence in HIV/AIDS).AcknowledgementsWe would like to thank all of the participants for allowing their informationto be a part of the CANOC collaboration. We would also like to thank JamesNakagawa for his work on Figure 1.Author detailsBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.2Faculty of Health Sciences, BLU 9512, Simon Fraser University, 8888University Drive, Burnaby, BC V5A 1S6, Canada. 3Dalla Lana School of PublicPatterson et al. BMC Infectious Diseases  (2015) 15:274 Page 9 of 10Health, University of Toronto, Toronto, Canada. 4Division of InfectiousDiseases, University Health Network, Toronto, Canada. 5Ontario HIVTreatment Network, Toronto, Canada. 6The Ottawa Hospital Division ofInfectious Diseases, University of Ottawa, Ottawa, Canada. 7Faculty ofMedicine, McGill University, Montreal, Canada. 8The Montreal Chest Institute,McGill University Health Centre, Montreal, Canada. 9Faculty of Medicine,University of Toronto, Toronto, Canada. 10Maple Leaf Medical Clinic, Toronto,Canada. 11Women’s College Research Institute, Toronto, Canada. 12CliniqueMedicale l’Actuel, Montreal, Canada. 13Faculty of Medicine, University ofBritish Columbia, Vancouver, Canada. 14Northern Ontario School of Medicine,Sudbury, Ontario, Canada.Received: 27 August 2014 Accepted: 29 May 2015References1. Merson MH. The HIV–AIDS Pandemic at 25—The Global Response. N EnglJ Med. 2006;354:2414–7.2. 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Epidemiology.2002;13(3):347–55.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionPatterson et al. BMC Infectious Diseases  (2015) 15:274 Page 10 of 10Submit your manuscript at www.biomedcentral.com/submit


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