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Changes in mortality rates and causes of death in a population-based cohort of persons living with and… Eyawo, Oghenowede; Franco-Villalobos, Conrado; Hull, Mark W; Nohpal, Adriana; Samji, Hasina; Sereda, Paul; Lima, Viviane D.; Shoveller, Jeannie; Moore, David; Montaner, Julio S G; Hogg, Robert S Feb 27, 2017

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RESEARCH ARTICLE Open AccessChanges in mortality rates and causes ofdeath in a population-based cohort ofpersons living with and without HIV from1996 to 2012Oghenowede Eyawo1,2 , Conrado Franco-Villalobos1, Mark W. Hull1, Adriana Nohpal3, Hasina Samji4, Paul Sereda1,Viviane D. Lima1, Jeannie Shoveller1,5, David Moore1, Julio S. G. Montaner1,6, Robert S. Hogg1,2* and for theComparative Outcomes And Service Utilization Trends (COAST) studyAbstractBackground: Non-HIV/AIDS-related diseases are gaining prominence as important causes of morbidity andmortality among people living with HIV. The purpose of this study was to characterize and compare changes overtime in mortality rates and causes of death among a population-based cohort of persons living with and withoutHIV in British Columbia (BC), Canada.Methods: We analysed data from the Comparative Outcomes And Service Utilization Trends (COAST) study; aretrospective population-based study created via linkage between the BC Centre for Excellence in HIV/AIDS andPopulation Data BC, and containing data for HIV-infected individuals and the general population of BC, respectively.Our analysis included all known HIV-infected adults (≥ 20 years) in BC and a random 10% sample of uninfected BCadults followed from 1996 to 2012. Deaths were identified through Population Data BC – which containsinformation on all registered deaths in BC (BC Vital Statistics Agency dataset) and classified into cause of deathcategories using International Classification of Diseases (ICD) 9/10 codes. Age-standardized mortality rates (ASMR)and mortality rate ratios were calculated. Trend test were performed.Results: 3401 (25%), and 47,647 (9%) individuals died during the 5,620,150 person-years of follow-up among 13,729HIV-infected and 510,313 uninfected individuals, respectively. All-cause and cause-specific mortality rates wereconsistently higher among HIV-infected compared to HIV-negative individuals, except for neurological disorders. All-cause ASMR decreased from 126.75 (95% CI: 84.92-168.57) per 1000 population in 1996 to 21.29 (95% CI: 17.79-24.79) in 2011-2012 (83% decline; p < 0.001 for trend), compared to a change from 7.97 (95% CI: 7.61-8.33) to 6.87(95% CI: 6.70-7.04) among uninfected individuals (14% decline; p < 0.001). Mortality rates from HIV/AIDS-relatedcauses decreased by 94% from 103.85 per 1000 population in 1996 to 6.72 by the 2011–2012 era (p < 0.001).Significant ASMR reductions were also observed for hepatic/liver disease and drug abuse/overdose deaths. ASMRsfor neurological disorders increased significantly over time. Non-AIDS-defining cancers are currently the leadingnon-HIV/AIDS-related cause of death in both HIV-infected and uninfected individuals.(Continued on next page)* Correspondence: rhogg@sfu.ca1British Columbia Centre for Excellence in HIV/AIDS, St. Paul’s Hospital,608-1081 Burrard Street, Vancouver, BC, Canada2Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, 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.Eyawo et al. BMC Infectious Diseases  (2017) 17:174 DOI 10.1186/s12879-017-2254-7(Continued from previous page)Conclusions: Despite the significant mortality rate reductions observed among HIV-infected individuals from 1996to 2012, they still have excess mortality risk compared to uninfected individuals. Additional efforts are needed topromote effective risk factor management and appropriate screening measures among people living with HIV.Keywords: Mortality, HIV infection, Age-standardized mortality rate, Mortality rate ratio, Cause of deathBackgroundThe widespread uptake of combination antiretroviraltherapy (cART) has led to substantial reductions inmorbidity and mortality associated with HIV/AIDS[1–3]. Over the last 20 years, cART regimens havebecome, not only more effective and less toxic, butalso simpler in terms of pill burden and frequency,thus enhancing adherence [4, 5]. This has translatedinto improvement in survival among cART-treatedpersons living with HIV [6]. Today in many regions,HIV/AIDS is widely viewed as a manageable chroniccondition [7], with the life expectancy of HIV-infectedindividuals receiving cART approaching that of thegeneral population in some settings [8–10].Improved survival rates now observed among HIV-infected individuals treated with cART have been ac-companied by a gradual shift in their morbidity andmortality patterns in some studies [11, 12]. Non-HIV-specific diseases, including non-AIDS-defining cancers,cardiovascular diseases (CVD), renal and liver diseases,are becoming more prevalent with many HIV-infectedindividuals now experiencing one or more of these co-morbid conditions [11–16]. As a result, causes of deathamong people living with HIV have shifted in severalimportant ways. In particular, deaths from thesechronic diseases and other complications typically asso-ciated with natural aging have gained prominence as in-dividuals are living longer on cART. It is thusimportant to monitor changes in the causes of death asthis information will be useful in projecting future mor-bidity and mortality trends. Ultimately, such knowledgewill provide guidance that may inform how risk factorsfor such increasingly common adverse health outcomesare addressed in this population.Although decreases in all-cause mortality rates havebeen well documented among HIV-infected individualsin British Columbia (BC), Canada [1, 6, 17–21],changes in cause-specific deaths in this population fol-lowing cART introduction in this setting is less wellcharacterized. Furthermore, it is unclear how the trendsand causes of death among HIV-infected individuals inthis setting compare to that of the general uninfectedpopulation. Given the changing pattern of causes ofdeath reported among HIV-infected individuals in othersettings after cART introduction [11–14], we hypothe-sized that similar patterns may be observed amongHIV-infected BC residents. Our objective was, there-fore, to characterize the changes in mortality rates andcauses of death over time following cART introductionamong a population-based cohort of HIV-infected indi-viduals in BC. Secondly, we compared these patterns ofdeath to that observed in a population-based sample ofuninfected individuals drawn from the BC generalpopulation over the same time period.MethodsStudy population and settingWe used data from the Comparative Outcomes AndService Utilization Trends (COAST) study. COAST isa large population-based retrospective cohort studyincluding longitudinal data of HIV-infected adults (≥19 years) and a control group from the general popu-lation of BC residents meeting the age criterion andrecruited into the cohort in the period between April1, 1996 and March 31, 2013. Briefly, the COAST co-hort was designed to characterize health outcomesand healthcare utilization of persons living with HIVinfection since the introduction of cART and toevaluate differences in these parameters from thoseobserved in the general population. COAST containsde-identified health-related data arising from a uniquedata linkage between the BC Centre for Excellence inHIV/AIDS (BCCfE) Drug Treatment Program [22]and Population Data BC [23]. The Drug TreatmentProgram manages the province-wide antiretroviraltherapy dispensation program. It prospectively collectsdemographic, immunologic, virologic, ART-use andother clinical data on all known HIV-infected individ-uals who have ever accessed ART, which is accessibleat no cost through the BCCfE. Population Data BC isBC’s repository of individual-level longitudinal datafrom health administrative databases [24–31]; datathat are collected by public bodies for all four millionBC residents.The follow-up for this analysis started at cohort entryand ended in December 31, 2012. The current analysis islimited to COAST study participants aged 20 years orolder with at least one day of follow-up since enteringthe cohort. This age criterion was necessary to facilitateage groupings by five-year categories and thus permitage standardization of mortality rates. The study popula-tion comprised of two distinct cohorts distinguished byEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 2 of 15their HIV status. The HIV-infected cohort is comprisedof all age-eligible individuals known to be HIV-positiveduring the follow-up period. HIV diagnosis was basedon the presence of at least one detectable HIV plasmaviral load, and/or an initiation of ART as indicated in theBCCfE Drug Treatment Program registry. The HIV caseidentification was supplemented through administrativehealth records review of International Classification ofDiseases (ICD) – 9 and 10 codes for records with at leastone documentation of having received care for an HIV/AIDS-related medical condition or death. The followingHIV-related ICD 9/10 codes were used: (i) ICD-9 codes042–44, V08, 795.71, 795.8; (ii) ICD-10 codes B20-24,R75, Z21; and (iii) ICD-10-CA codes B20-24, R75, Z21.To avoid potential misclassification, we applied a vali-dated HIV case-finding algorithm – an additional criteriaof ≥ 1 inpatient and/or ≥ 3 outpatient ICD-9/10 codes topotential cases identified within administrative health re-cords [32]. The uninfected cohort was created based ona ten percent randomly generated sample of adult indi-viduals from the general population of BC over the sametime frame and excludes any known HIV-infected indi-vidual. The random sample in COAST was created byexecuting a computer-generated simple random sam-pling technique to draw a ten percent sample from acombined pool of all distinct individuals with a PersonalHealth Number (PHN) in the general population of BCand meeting the age eligibility criterion (≥ 19 years) be-tween April 1, 1996 and March 31, 2013. The PHN is aunique identifier that tracks health care system encoun-ters for all BC residents.Outcome and definitionsOur primary outcome was death from any cause.Deaths were identified through the BC Vital StatisticsAgency mortality dataset [31], which contains infor-mation on all registered deaths in BC and wasaccessed through a data linkage conducted by Popula-tion Data BC. As part of the death registration in BCas well as elsewhere in Canada, a medical certificateof cause of death is completed by a medical examiner,coroner or other certifier, and elicits relevant informa-tion on the nature of the death. We classified deathsbased on the underlying cause of death informationinto categories by causes using ICD-9 codes fordeaths through 1999, and ICD-10 codes for deathsfrom 2000 onwards. The causes of death weregrouped into the following categories: HIV/AIDS-re-lated, cancers, CVD, chronic respiratory diseases, drugabuse and overdose, hepatic and liver diseases, neuro-logic disorders, renal diseases, suicides, unintentionalinjuries (including accidents), other infectious andparasitic diseases (excluding HIV and viral hepatitis),and ‘other causes’, which includes all causes of deathnot listed in the aforementioned categories. Sincedeaths from cancers such as Kaposi sarcoma, cervicalcancer and Non-Hodgkin’s lymphoma are typicallyregarded as AIDS-defining; we grouped codes forsuch deaths occurring within the HIV-infected cohortunder the ‘HIV/AIDS-related’ cause of death categoryand excluded them from the ‘cancer’ category. Table 1lists the ICD-9/10 codes associated with the causes ofdeath categories.Table 1 Causes of death categories and the applicable ICD 9 and 10 codesCause of death ICD 9 code ICD 10 codeHIV/AIDS-related 042-044 B20-B24Cancera 140-239 C00-D48Cardiovascular diseases 410-414, 428, 430-438, 362.3 I00-I99Chronic respiratory diseases 491, 492, 496, 493 J40-J46Drug abuse and overdose 304, 305, E850-E858 F10-F19, F55, X40-X45, T40Hepatic and liver diseases 070, 570-572, 275, 456, 155, 782.4 B15-B19, K70-K77Neurologic disorders 320-327, 330-359 F03, G00-G99Renal diseases 250.4, 403-404, 580-590, 593, 792.5, V45.1, V42.0 N00-N07, N17-N19, N25-N27Suicides E950-E959 X60-X84, Y87.0Unintentional injuries (including accidents)b 800-999, E800-E999 V01-Y89Other infectious and parasitic diseasesc 001-139, 480-487 A00-B99, J10-J18Other causes All codes not previously listed All codes not previously listedLegend: ICD International Classification of DiseasesaSince deaths from cancers such as Kaposi sarcoma, cervical cancer and Non-Hodgkin’s lymphoma are typically regarded as AIDS-defining; we grouped codes forsuch deaths occurring within the HIV-infected cohort under the ‘HIV-related’ cause of death category and excluded them from the ‘cancer’ category. The applicablecodes are: 176, 180, 200, 202 (ICD 9) and C46, C53, C82 C83 (ICD 10)bExcludes suicides, drug abuse and overdose codescExcludes HIV and viral hepatitis codesEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 3 of 15Statistical analysisCrude all-cause and cause-specific mortality rate per1000 person-years (PY) were calculated from theobserved number of deaths and PYs of observation.To account for differences in the age structure andto permit comparability between the HIV-infectedand uninfected cohorts, we computed the age-standardized mortality rates (ASMR) using the directstandardization method with the 1991 Canadian cen-sual population as the reference standard population.The 1991 Canadian population is typically used forthe standardization of age-specific disease rates inCanada. Additionally, we compared the ASMRs inthe cohorts per calendar interval. We divided theobservation period into 11 calendar intervals: 1996,1997–1998, 1999–2000, 2001–2002, 2003–2004,2005–2006, 2007–2008, 2009–2010, and 2011–2012).Although shorter than the other calendar periods,we elected to include 1996 (available data from Aprilto December) to enable us capture mortality aroundthe period of cART introduction. The remaining 10calendar intervals were 2-year periods each. In sensi-tivity analyses, we investigated trends over time inASMR among HIV-infected individuals according toantiretroviral drug uptake (ever vs. never), use oftriple-drug cART at treatment initiation (yes vs.never), both compared to uninfected individuals. Wecalculated the mortality rate ratio as an estimate ofthe relative risk comparing HIV-infected and unin-fected individuals by dividing the ASMRs of HIV-infected individuals by that of uninfected individuals.The 95% confidence intervals (CI) for the mortality ratesand rate ratios were calculated by Normal approximationassuming a Poisson distribution [33, 34]. Population figuresfor the Canadian standard population were obtained fromStatistics Canada [35]. As a sensitivity analysis for com-parison purposes only, we repeated the standardization ofthe mortality rates using the latest available Canadian cen-sual population (2011) [35].Comparisons between groups were performed usingChi-square test or Fisher exact test for categorical vari-ables and Kruskall-Wallis test for continuous variables.Test of trend over time were performed using Kendallrank correlation. Statistical significance is defined at a0.05 level. All data manipulation and statistical analyseswere performed using SAS 9.4 (Cary NC, USA) and RStatistical Program, version 3.2.2 (Vienna, Austria).ResultsParticipant characteristicsFrom April 1996 to December 2012, 13,729 HIV-infected and 510,313 uninfected individuals – a com-bined 524,042 persons – contributed a follow-up of108,990 PYs (median: 7.22 [25th, 75th percentile: 2.96,12.97] years per person) and 5,511,160 PYs (median:12.70 [4.76, 16.75] years per person) of observation, re-spectively to the analysis. The baseline characteristics ofthe study participants are described in Table 2. Com-pared to uninfected individuals, HIV-infected individualswere more likely to be older at cohort entry (medianage: 38 vs 36 years, p < 0.001) and more likely to be male(80% vs. 50%, p < 0.001). Roughly one-quarter of HIV-infected individuals had no record of HIV treatment ini-tiation. Among those who have ever received ART, ap-proximately 37% initiated therapy with an AIDS-defining CD4 count (< 200 cells/mm3).Mortality during follow-upDuring the approximately 17 years of observation, atotal of 3401 HIV-infected (25%) and 47,647 unin-fected individuals (9%) died. Compared to uninfectedindividuals, HIV-infected individuals were more likelyto die young (median age: 46 vs 80 years, p < 0.001),with approximately 75% of the deaths occurringTable 2 Characteristics of study participantsCharacteristics Entire sample, n (%) Dead, n (%)HIV+(N = 13729)HIV-(N = 510313)p-value HIV+(N = 3401)HIV-(N = 47647)p-valueAge at study entry, median (Q1, Q3) years 38 (32, 46) 36 (24, 50) <0.001 41 (34, 49) 71 (59, 78) <0.001Age at death, median (Q1, Q3) years 46 (39, 55) 80 (69, 87) <0.001SexMale 11017 (80.25) 256440 (50.25) <0.001 2716 (79.86) 24394 (51.20) <0.001Female 2712 (19.75) 253873 (49.75) 685 (20.14) 23253 (48.80)Follow-up time, median (Q1, Q3) years 7.22 (2.96, 12.97) 12.70 (4.76,16.75) <0.001 3.91 (1.16, 7.60) 8.42 (4.25, 12.58) <0.001Antiretroviral therapy ever?Yes 10165 (74.04) 2377 (69.89)No 3564 (25.96) – 1024 (30.11) –Legend: Q1, 25th percentile; Q3, 75th percentileEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 4 of 15before or at 55 years of age compared to 87 yearsamong uninfected individuals (Table 2). Table 3 showsthe number of deaths and crude mortality rates byage, sex and cause of death. The proportion of deathsamong HIV-infected women (25.3%) was not signifi-cantly different from that for infected men (24.7%) (p= 0.529). Conversely, the proportion of deaths amonguninfected women was lower compared to uninfectedmen (9.2% vs. 9.5%, p < 0.001).Causes of deathFigures 1 and 2 show the distribution and annualchanges in the proportion of deaths across causes amongthe study participants during the observation period. Al-though HIV/AIDS-related deaths accounted for 50% ofthe total deaths among HIV-infected individuals duringfollow-up (Fig. 1), the proportion of deaths from HIV/AIDS-related causes dropped from 79% in 1996 to 27%by 2012 (p < 0.001) (Fig. 2). Overall, the top non-HIV/AIDS-related causes of death during the study follow-upin decreasing order are: drug abuse and overdose(11.2%), cancers (8.5%), CVD (7.0%), and hepatic andliver diseases (4.4%). The majority of deaths classifiedunder ‘other causes’ included deaths from unknowncauses and a myriad of other conditions. This cause ofdeath category accounted for 7.9% and 13.1% of mortal-ity among HIV-infected and uninfected individualsrespectively.Among HIV-infected individuals, the proportion ofdeaths due to HIV/AIDS decreased significantly overtime since 1996 (p < 0.001), while those from non-HIV/AIDS-related causes either remained stable or increasedover time (Fig. 2). In 1996, CVD and non-AIDS-definingcancer accounted for a combined < 2% of deaths amongHIV-infected individuals compared to 29% in 2012 (p <0.05). Non-AIDS-defining cancers which accounted for< 1.0% of the deaths in 1996 have recently emerged tobecome the leading non-HIV/AIDS-related cause ofdeath, accounting for 17% of all deaths among infectedindividuals by 2012 (p < 0.001). Among deaths attribut-able to non-AIDS defining cancers, lung cancer was themost commonly observed cancer type in both HIV-infected and uninfected individuals. In decreasing order,this was followed by cancer of the liver, colon, pancreas,anus, rectum, stomach and prostate among HIV-infectedindividuals; and colon, breast, prostate, pancreas, blad-der, esophagus, stomach and ovarian cancer among un-infected individuals.Among uninfected individuals, CVD (32%) and can-cers (29%) were the most common accounting for over60% of the deaths during follow-up. In terms of trend,the proportion of deaths from CVD decreased over time(p < 0.001), while deaths due to cancer have increased (p= 0.02), overtaking CVD as the leading cause of death inmore recent years (Fig. 2). Consequently, in both HIV-infected and uninfected individuals, our results demon-strate that cancers are now the leading non-HIV/AIDS-related cause of death. Compared to HIV-infected indi-viduals where deaths due to drug abuse and overdosewas among the leading cause of death, this categoryaccounted for the least proportion of deaths among un-infected individuals during follow-up.Changes in age-standardized mortality rateFigures 3 and 4 describes the changes over time in theage-standardized all-cause and cause-specific mortalityrates, by HIV status. Among HIV-infected individuals,the all-cause ASMR decreased from 126.75 (95% CI:84.92-168.57) per 1000 population in 1996, to 21.29(95% CI: 17.79-24.79) in 2011-2012 (p < 0.001 fortrend). In the uninfected population, the all-causeASMR changed over similar time period, from 7.97(95% CI: 7.61-8.33) per 1000 population to 6.87 (95%CI: 6.70-7.04), respectively (p < 0.001 for trend) (Fig. 3a).This represents an 83% drop in all-cause mortality ratefrom 1996 to 2011-2012 era among HIV-infected indi-viduals compared to a 14% drop among uninfected in-dividuals. The age-adjusted relative risk of death inHIV-infected compared to uninfected individuals de-creased from 15.90 (95% CI: 11.40-22.19) in 1996 to3.10 (95% CI: 2.63-3.66) in the 2011–2012 era, repre-senting a 81% reduction in the relative risk of mortalityover time. When stratified by sex, the relative risk ofdeath comparing infected to uninfected individuals wassimilar in males and females as of 1996 (13.70 vs13.72). By the 2011–2012 era, the relative risk of deathcomparing HIV-infected and uninfected men was 2.33(95% CI: 1.94-2.80), whereas it was 4.65 (95% CI: 3.35-6.45) among HIV-infected compared to uninfectedwomen (Fig. 3b, 3c).The ASMR from HIV/AIDS-related deaths decreasedsignificantly from 103.85 in 1996 to 6.72 per 1000 popu-lation in the 2011–2012 eras (p < 0.001 for trend), repre-senting a 94% reduction in death rate from HIV/AIDS-related causes (Fig. 4a). Over the study’s observationperiod, significant reductions in mortality rates amongHIV-infected individuals were also observed for mortal-ity from hepatic and liver disease, as well as from drugabuse and overdose. Although the proportion of deathsattributable to CVD and non-AIDS-defining cancers sig-nificantly increased over time (p < 0.05) among HIV-infected individuals (Fig. 2a), the mortality rates fromCVD and cancer decreased over time (Fig. 4b, 4f ), albeitnot significantly (p > 0.05). There was a statistically sig-nificant increase over time in mortality rates and propor-tion of deaths attributable to neurological disorders(Figs. 2a and 4j; p < 0.05). For chronic respiratory dis-eases, renal diseases, other infectious and parasiticEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 5 of 15Table3Frequencyofdeathsandcrudemortalityratesbyage,sexandcausesofdeath(1996-2012)HIV-infectedHIV-uninfectedDeaths(%)p-valuePY(per1,000)CMRper1,000PY(95%CI)Deaths(%)p-valuePY(per1,000)CMRper1,000PY(95%CI)Ageatcohortentry(years)20–34873(17.44)<0.00143.3120.16(18.82–21.50)1,929(0.78)<0.0012,321.610.83(0.79–0.87)35–491,723(25.92)52.7532.66(31.12–34.21)4,733(3.50)1,716.512.76(2.68–2.84)50–64582(34.13)11.2451.78(47.58–55.99)9,639(13.52)916.2610.52(10.31–10.73)65+223(60.43)1.7131.37(114.13–148.62)31,346(56.48)556.7756.30(55.68–56.92)Sex Male2,716(24.65)0.52988.7630.60(29.45–31.75)24,394(9.51)<0.0012,704.309.02(8.91–9.13)Female685(25.26)20.2333.85(31.32–36.39)23,253(9.16)2,806.868.28(8.18–8.39)ARVever?Yes2,377(23.38)<0.00190.9526.14(25.08–27.19)No1,024(28.73)18.0456.75(53.28–60.23)CauseofdeathAll-cause3,401(24.77)108.9931.20(30.16–32.25)47,647(9.34)5,511.168.65(8.57–8.72)HIV/AIDS-related1,698(12.37)108.9915.58(14.84–16.32)0(0.00)5,511.160.00(0.00–0.00)Cancers297(2.16)108.992.72(2.42–3.03)13,950(2.73)5,511.162.53(2.49–2.57)Cardiovasculardiseases238(1.73)108.992.18(1.91–2.46)15,295(3.00)5,511.162.78(2.73–2.82)Chronicrespiratorydiseases52(0.38)108.990.48(0.35–0.61)2,179(0.43)5,511.160.40(0.38–0.41)Drugabuseandoverdose380(2.77)108.993.49(3.14–3.84)696(0.14)5,511.160.13(0.12–0.14)Hepaticandliverdiseases150(1.09)108.991.38(1.16–1.60)755(0.15)5,511.160.14(0.13–0.15)Neurologicdisorders19(0.14)108.990.17(0.10–0.25)3,273(0.64)5,511.160.59(0.57–0.61)Renaldiseases21(0.15)108.990.19(0.11–0.28)746(0.15)5,511.160.14(0.13–0.15)Suicides88(0.64)108.990.81(0.64–0.98)712(0.14)5,511.160.13(0.12–0.14)Unintentionalinjuries87(0.63)108.990.80(0.63–0.97)1,792(0.35)5,511.160.33(0.31–0.34)Otherinfectiousandparasiticdiseases101(0.74)108.990.93(0.75–1.11)1,998(0.39)5,511.160.36(0.35–0.38)Othercauses270(1.97)108.992.48(2.18–2.77)6,251(1.22)5,511.161.13(1.11–1.16)Legend:ARVAntiretroviral(drug),CIConfidenceIntervals,CMRCrudemortalityrate,PYPerson-yearsEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 6 of 15Fig. 1 (See legend on next page.)Eyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 7 of 15(See figure on previous page.)Fig. 1 Overall distribution of the proportion of deaths by causes and by HIV status in British Columbia, during 1996-2012. Legend: *, Values are inthe format ‘median age (25th percentile-75th percentile)’ years; Note: The ‘cancer’ category in Fig. 1a excludes deaths attributable to Kaposisarcoma, cervical cancer and Non-Hodgkin’s lymphoma, as these have been accounted for within HIV/AIDS-related deaths. a HIV-infected,b HIV-uninfectedFig. 2 Annual changes in the proportion of deaths by causes and by HIV status in British Columbia, during 1996–2012. Legend: CVD, Cardiovasculardiseases; *, Each bar in the figure represents a one-year period beginning in 1996 (except for the first bar – 1996 –, which is nine months long); Note:The ‘cancer’ category in Fig. 2a excludes deaths attributable to Kaposi sarcoma, cervical cancer and Non-Hodgkin’s lymphoma, as these have beenaccounted for within HIV/AIDS-related deaths. a HIV-infrcted, b HIV-uninfectedEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 8 of 15Fig. 3 Changes over time in all-cause age-standardized mortality rates, overall and by HIV status and sex in British Columbia, during 1996–2012.Legend: CI, Confidence interval; MRR, Mortality rate ratio. a Overall, b Male-only, c Female onlyEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 9 of 15Fig. 4 (See legend on next page.)Eyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 10 of 15diseases deaths, mortality rate increases were observedbut this was not significant.Among uninfected individuals, statistically significantmortality rate reductions were observed over time fordeaths attributable to CVD, cancers, chronic respiratorydiseases, suicides, unintentional injuries and other infec-tious and parasitic diseases; however mortality rates at-tributable to neurologic disorders increased significantlyover time.Sensitivity analysesAlthough we observed slightly higher ASMRs (datanot shown) when we standardized rates using a 2011Canadian censual population compared to the mainanalyses that used a 1991 censual population, theoverall trends remained unchanged. The slight in-crease in mortality rates is likely because the 2011censual population has a higher proportion of individ-uals in older age groups than the 1991 population. Inseparate analyses stratified by antiretroviral therapyuptake (ever vs. never) and initiation of therapy withtriple-drug cART (yes vs. never on therapy), we ob-served significant mortality rate reductions over timeacross all groups (Figs. 5 and 6). During the analyticperiod, individuals who were never on ART had mor-tality rates ranging from 1.4 to almost 5 times higherthan among those ever on ART or those initiatingtreatment with triple-drug cART. Of note, 92% of in-dividuals ever on ART in this study initiated therapyon a triple-drug cART.DiscussionSince cART introduction in 1996, this is the firstpopulation-based study in Canada to characterizechanges in mortality and causes of death among personsliving with HIV infection as compared to uninfected in-dividuals from the same geographical and health caresetting. Compared to uninfected individuals, our resultdemonstrates that the causes of death among HIV-infected individuals in BC have changed dramaticallyover time. We observed significant mortality rate reduc-tions in all-cause, HIV/AIDS-related, drug abuse andoverdose, and liver disease mortality among people livingwith HIV in the period from 1996 to 2012. Despite theremarkable decline in mortality from HIV-relatedcauses, HIV/AIDS is still the leading cause of deathFig. 5 Trend in age-standardized mortality rate, by HIV and antiretroviral therapy uptake status (ever vs. never) in British Columbia, during 1996–2012.Legend: ARV, Antiretroviral (drug); CI, Confidence interval(See figure on previous page.)Fig. 4 Changes over time in cause-specific age-standardized mortality rates, by HIV status in British Columbia, during 1996–2012. Legend: The‘cancer’ mortality line graph for HIV-infected individuals (Fig. 4f, red line) excludes deaths attributable to Kaposi sarcoma, cervical cancer andNon-Hodgkin’s lymphoma, as these have been accounted for within HIV/AIDS-related deaths. a HIV/AIDS related, b cardiovascular diseases,c Hepatic and liver diseases, d Renal diseases, e Chronic respiratory diseases, f Cancers, g Suicides, h Drug abuse and overdose, i unintentional injuries,j Neurologic disorders, k Other infectious and parasitic diseases, l Other causesEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 11 of 15among HIV-infected individuals and the relative risk ofdeath remains in excess of that for uninfected individ-uals. Relative to other causes of death, the proportion oftotal mortality attributable to non-AIDS-defining cancerand CVD has increased among HIV-infected individualssince cART introduction, however, this did not necessar-ily translate into a trend of increasing mortality ratesfrom these causes; a finding that may be likely due tothe overall increased survival in the population. In bothHIV-infected and uninfected individuals, we observedsignificant increases over time in mortality rates fromneurologic disorders.The overall proportion of deaths due to HIV/AIDS-re-lated causes in our study (50.2%) was comparable tothose reported from Spain (40.4%) [36], Italy (41.4%)[16], Denmark (44.4%) [37], England and Wales (46.0%)[38], France (47.3%) [39], USA (51.4%) [15] and frommultinational cohort collaborations such as Antiretro-viral Therapy Cohort Collaboration (49.6%) [14], buthigher than that reported in the Data collection on Ad-verse events of Anti-HIV Drugs [D:A:D] study (28.7%)[40]. While our overall findings are broadly consistentwith the mortality declines and cause of death trendspresented in previous studies of HIV-infected individualsfrom other settings [13–16, 38, 40, 41]; variations in therange of such estimates may exist across studies and arelikely due to heterogeneity in the population (e.g., byage, sex, CD4 levels, cART history, underlying clinicalcharacteristics, ethnicity), differences in the observationperiod, or the coding scheme for causes of deathcategories. In sensitivity analysis stratified by ART up-take (ever vs. never), we observed a better mortalityprognosis among those who had ever been treated withART, thus demonstrating the benefit associated withART. This is supported by a recent BC study amongHIV-infected individuals receiving cART since 2001which demonstrated that cART initiation was independ-ently associated with reduced mortality [21].The current study reflects major changes since theintroduction of cART in terms of non-HIV/AIDS-relatedcauses; in 1996, only 21% of the deaths among HIV-infected individuals were attributable, as compared to73% by 2012. Our results confirm two recent reportssuggesting that non-AIDS-defining cancers are currentlythe leading non-HIV/AIDS-related cause of deathamong HIV-infected individuals [40, 42]. Similarly, weobserved that cancers have also recently overtaken CVDto become the principal cause of death among the unin-fected population. Like the D:A:D study [40] but unlikea report from the HIV Outpatient Study [15], we ob-served a statistically significant mortality rate decreasefrom hepatic and liver disease deaths. Contrary to a find-ing among HIV-infected hemophiliacs in Canada [43],liver disease is an important cause of death especiallyamong individuals co-infected with HIV and hepatitis Cvirus [44], although not the main non-HIV/AIDS-relatedcause of death in the current study. The observed in-crease in mortality rates attributable to neurologic disor-ders is likely a reflection of the increased longevity inboth populations.Fig. 6 Trend in age-standardized mortality rate, by HIV and highly active antiretroviral therapy (HAART) status at treatment initiation (yes vs. never)in British Columbia, during 1996-2012. Legend: ARV, Antiretroviral (drug); CI, Confidence interval; HAART, Highly active antiretroviral therapyEyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 12 of 15Our results indicating that HIV-infected individualscontinue to have a mortality risk ratio that is decreasingas time passes but remains approximately three timesmore than in uninfected individuals as of 2011-2012 issupported by comparable findings from other studiesthat have compared mortality rates among persons withand without HIV infection [37, 45]. We suspect the con-tinuing high relative risk of death among HIV-infected,compared to uninfected individuals may in part be ex-plained by the higher prevalence of behavioral risk fac-tors such as smoking, alcohol abuse and other lifestylefactors that are more common among HIV-infected in-dividuals and predisposes them to higher mortality riskcompared to uninfected individuals.Readers should interpret our findings in light of thepotential strengths and limitations of the study. TheHIV-infected cohort includes the vast majority of allknown HIV-infected adults in BC, irrespective ofwhether they had ever received cART. Despite universalaccess to HIV treatment in BC, approximately 25% ofHIV-infected individuals had no record of HIV treat-ment initiation during this study (1996 to 2012). Re-assuringly, the rates have declined substantially with theimplementation of the Treatment as Prevention strategyin BC [46–48], as in a 2008 study we found that 40% ofthose who died from HIV did not access treatment [49].Our uninfected cohort includes randomly sampled BCresidents who accessed the same universal health caresystem as the HIV-infected participants, thus minimizingpotential selection bias that may arise from using an ex-ternal comparison group. Unlike most clinic-based co-horts [11, 13, 16, 36, 39, 40, 50], the relatively large,linked and population-based nature of the COAST studyis unique to BC and has allowed us to ascertain mortal-ity and cause of death information for all study partici-pants through the same source – the BC Vital StatisticsAgency -[31], which is the provincial office that collectsvital statistic records in BC. However, since this datasetdoes not capture deaths to BC residents that occur out-of-province, such deaths were unaccounted for in ouranalyses. While we suspect this number is likely small, italso will have affected the HIV-infected and uninfectedcohorts equally. Finally, our cause of death assessment islimited by the accuracy of the ICD-9/10 coding used forattribution of the underlying cause of death; and thestudy as a whole, by unmeasured confounding due to itsobservational nature.ConclusionTo sum up, our results suggest that significant improve-ments have been made in reducing mortality over timefrom HIV/AIDS-related and several non-HIV/AIDS-re-lated causes of death among people living with HIV.Despite this progress, HIV-infected individuals still haveexcess mortality risk compared to their uninfectedcounterparts. Additional efforts are needed to promoteeffective risk factor management and appropriate screen-ing measures among people living with HIV. Ongoingmonitoring of mortality trends by causes will be import-ant and will provide the necessary data to enable us opti-mally target our efforts at the conditions that influencemorbidity and mortality outcomes. Ultimately, in bothHIV-infected and uninfected populations, the manage-ment of cancers and CVD as well as their known riskfactors will be key in improving overall survivaloutcomes.AbbreviationsART: Antiretroviral therapy; ARV: Antiretroviral (drug); ASMR: Age-standardizedmortality rate; BC: British Columbia; BCCfE: BC Centre for Excellence in HIV/AIDS; cART: Combination antiretroviral therapy; CI: Confidence interval;COAST: Comparative Outcomes And Service Utilization Trends study;CVD: Cardiovascular disease; D:A:D: Data collection on Adverse events ofAnti-HIV Drugs study; ICD: International Classification of Diseases;MRR: Mortality rate ratio; PY: Person-yearsAcknowledgementsThe authors would like to thank the BCCfE, BC Ministry of Health, BC VitalStatistics Agency, and the institutional data stewards for granting access tothe data, and Population Data BC, for facilitating the data linkage process.The COAST steering committee includes: Julio Montaner, Robert Hogg,Oghenowede Eyawo, Mark Hull, Jeannie Shoveller, David Moore, Paul Seredaand Viviane Lima.FundingCOAST is funded by the Canadian Institutes of Health Research, through anOperating Grant (#130419), a Foundation Award to RSH (#143342) andsupport from the BCCfE. The funders had no role in the study design,analysis, interpretation of the data, drafting of the manuscript or in thedecision to submit for publication.Availability of data and materialThe data used for this study is not publicly available. For further informationon the data and materials used in this study, please contact thecorresponding author.Authors’ contributionsStudy concept and design: OE; acquisition of data: OE, MWH, HS, JSGM, RSH;analysis and interpretation of data: OE, CF, AN, MWH, PS, VL, RSH; drafting ofthe manuscript: OE; critical revision of the manuscript for importantintellectual content and for final approval: OE, CF, MWH, AN, HS, PS, VL, JS,DM, JSGM, RSH; acquisition of funding: OE, VL, JSGM, RSH. All authors haveread and approved the final version.Competing interestsOE is supported by a Canadian Institutes of Health Research doctoral award.MWH has received grant support from the National Institute on Drug Abuse(NIDA R01DA031043-01) and has received honoraria for speaking engage-ments and/or consultancy meetings from the following: Bristol Myers Squibb,Gilead, Merck, Ortho-Janssen, Pfizer, Sunovion, Vertex Pharmaceuticals andViiv. JSGM is supported with grants paid to his institution by the BritishColumbia Ministry of Health and by the US National Institutes of Health(R01DA036307). He has also received limited unrestricted funding, paid to hisinstitution, from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen,Merck, and ViiV Healthcare. RSH has held grant funding in the last 10 yearsfrom the National Institutes of Health, Canadian Institutes of Health Research,Health Canada, Merck, and the Social Sciences and Humanities ResearchCouncil of Canada. The remaining authors have no disclosures to declare.Consent for publicationNot applicable.Eyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 13 of 15Ethics approval and consent to participateThe COAST study has received approval from the University of BritishColumbia/Providence Health Care Research Ethics Board (#H09-02905) andSimon Fraser University Office of Research Ethics (#2013 s0566). The studycomplies with the BC Freedom of Information and Protection of Privacy Act(FIPPA) and did not require informed consent as it is conducted retrospectivelyfor research and statistical purposes only using anonymized data.DisclaimerAll inferences, opinions, and conclusions drawn in this manuscript are thoseof the authors, and do not reflect the opinions or policies of the datastewards or the funders.Author details1British Columbia Centre for Excellence in HIV/AIDS, St. Paul’s Hospital,608-1081 Burrard Street, Vancouver, BC, Canada. 2Faculty of Health Sciences,Simon Fraser University, Burnaby, BC, Canada. 3DataClever Consulting Inc.,Vancouver, BC, Canada. 4British Columbia Centre for Disease Control,Vancouver, BC, Canada. 5School of Population and Public Health, Universityof British Columbia, Vancouver, BC, Canada. 6Department of Medicine,University of British Columbia, Vancouver, BC, Canada.Received: 30 August 2016 Accepted: 8 February 2017References1. 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All-cause mortality intreated HIV-infected adults with CD4 ≥ 500/mm3 compared with thegeneral population: evidence from a large European observational cohortcollaboration. Int J Epidemiol. 2012;41(2):433–45.•  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:Eyawo et al. BMC Infectious Diseases  (2017) 17:174 Page 15 of 15

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