CE:;QAD/202675;TotalnosofPages:13; QAD 202675 Risk of cerebrovascular events in persons with and without HIV: A Danish nationwide population-based cohort study a b c Line D. Rasmussen , Frederik N. Engsig , Hanne Christensen , b d a b Jan Gerstoft , Gitte Kronborg , Court Pedersen and Niels Obel Objective: Toassesstheriskofcerebrovascularevents(CVE)inHIV-infectedindividuals and evaluate the impact of proven risk factors, injection drug abuse (IDU), immunodeficiency, highly active antiretroviral therapy (HAART) and family-related risk factors. Design: Nationwide, population-based cohort study Methods: ThestudypopulationincludedallDanishHIV-infectedindividuals,apopu- lationbasedcomparisoncohortandparentsofbothcohorts–allwithnopriorcerebral comorbidity.Wecomputedincidencerateratios(IRR)ofoverallCVEandCVEwithand without proven risk factors, stratifying the analyses on IDU. Impact of immunodeficiency, HAART, protease-inhibitors, indinavir, didanosin, tenofovir and abacavir on risk of CVE was analyzed using time-dependent Cox regression analyses. Results: HIV-infected individuals had an increased risk of CVE compared with the comparisoncohorts{(non-IDUHIVadjustedIRR1.60;95%CI:1.32–1.94),(IDUHIV adjusted IRR 3.94; 95% CI: 2.16–7.16)}. The risk was increased with and without provenriskfactors.ACD4count<¼200cells/mlbeforestartofHAARTandexposureto abacavir increased the risk of CVE {(adjusted IRR 2.26; 95% CI: 1.05–4.86) and (adjusted IRR 1.66; 95% CI: 1.03–2.68)}. Protease-inhibitors, indinavir, didanosin, tenofovirandHAARTingeneralhadnoimpact.RiskofCVEwasonlyincreasedinthe parents of IDU HIV-infected individuals. Conclusion: HIV-infectedindividualshaveanincreasedriskofCVEwithandwithout proven risk factors. The risk is associated with IDU, low CD4 count and exposure to abacavir, but not with HAART. An association with family-related risk factors seems vague except for parents of IDUs. (cid:1)2011WoltersKluwerHealth|LippincottWilliams&Wilkins AIDS 2011, 25:000–000 Keywords: abacavir, AIDS, Cerebrovascular disease, HAART, HIV, immunodeficiency, stroke Introduction disease. Recent studies have shown an increased risk of myocardial infarction associated with HIV infection, Duringthelastdecade,severalstudieshaveestablishedan highly active antiretroviral therapy (HAART) and association between HIV infection and cardiovascular abacavir [1–4]. aDepartmentof InfectiousDiseases, OdenseUniversity Hospital,Odense, Denmark, bDepartment ofInfectious Diseases, CopenhagenUniversity Hospital, Rigshospitalet, Denmark,cDepartmentof Neurology,CopenhagenUniversityHospital, Bispebjerg,Copenhagen, Denmark,and dDepartment ofInfectious Diseases,CopenhagenUniversity Hospital, Hvidovre Hospital,Denmark. CorrespondencetoLineDahlerupRasmussen,MD,PhD-student,DepartmentofInfectiousDiseases,OdenseUniversityHospital Sdr.Boulevard29, 5000OdenseC,Denmark. Tel:+4565411321; fax: +4566117418;e-mail: linedahlerup@hotmail.com Received:10December 2010;revised: 23May2011;accepted: 27May2011. DOI:10.1097/QAD.0b013e3283493fb0 ISSN 0269-9370 Q 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 1 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE:;QAD/202675;TotalnosofPages:13; QAD 202675 2 AIDS 2011, Vol 00 No 00 Lessattentionhasbeenpaidtothepossiblyincreasedrisk classified according to the International Classification of of cerebrovascular disease. Previous studies, which are Diseases[8threvision(ICD-8)untilDec311993and10th primarilyfromthepre-HAARTera,areinconclusivebut revision (ICD-10) thereafter] [28]. favour an increased risk of stroke in HIV-infected individuals [4–23]. The danish cancer register (DCR) DCR, established in 1942, records all cancer diagnoses We conducted a Danish nationwide, population-based according to a modified edition of the International cohortstudytoexaminetheriskofcerebrovascularevents Classification of Diseases [7th revision (ICD-7) since 1943 (CVE) in HIV-infected individuals compared to the andaccordingtothe10threvision(ICD-10)andICD-O general population. As the underlying mechanism for a (for oncology) since 1994 (The cancer diagnoses from possibly increased risk of cerebrovascular disease is 1978–1994waslaterconvertedtoICD-10andICD-O)] unclear, we further examined the impact of 1) proven [29]. risk factors, 2) risk factors often associated with HIV infection (e.g. injection drug abuse (IDU)), 3) immu- Study populations nodeficiency, 4) use of antiretroviral drugs, and 5) the HIV cohort HIV infection per se on risk of CVE. We further We identified all Danish HIV-infected individuals older examined the risk of CVE in parents of HIV-infected than16yearsatdateofHIVdiagnosisfromDHCS.The individuals to evaluate the impact of family-related indexdatewasdefinedasthedateofHIVdiagnosis,date risk factors. of arrival to Denmarkor January 1 1995 whichever was more recent. Individuals diagnosed with cerebrovascular diseaseorcerebralcomorbidity(definedasCNStumour, cancer, lymphoma, metastasis, non-HIV-associated Methode cerebralinfections,HIV-associatedcerebralopportunistic infectionsandAIDSdementia)priortoindexdate,were Setting excluded (Appendix I, Figure 1). As of 1 January 2010 Denmark had a population of 5.5 million [24], with an estimated HIV prevalence General population comparison cohort of 0.1% among adults. Medical care, including A comparison cohort consisting of 9 age- and gender antiretroviral treatment, is tax-supported and provided matched population controls, whowere alive and living free-of-charge to all HIV-infected residents of in Denmark on index date and not diagnosed with Denmark. Treatment of HIV infection is restricted to cerebrovascular disease or cerebral comorbidity prior to eight specialized medical centres, where patients indexdateoftheHIV-infectedindividual,wereidentified are seen on an outpatient basis at intended intervals fromDCRS.Indexdatewasdefinedasdateofindexdate of 12 weeks. During our study’s follow-up period, of the matched HIV-infected individual. national criteria for initiating HAART were HIV- related disease, acute HIV infection, pregnancy, CD4 Parent cohorts cellcount<300cells/ml,and,until2001,plasmaHIV- From DCRS we identified parents of all Danish HIV- RNA >100,000copies/ml. infected individuals and their matched comparison cohort in whom the offspring was born after 1952 and Data sources for whom at least the mother was identifiable. Parents We used the unique 10-digit civil registration number diagnosed with cerebrovascular disease and cerebral assigned to all individuals in Denmark to link data from comorbidity prior to index date were excluded. Index the following registers: dateoftheparentswasdefinedasthestart oftheDanish National Hospital Registry (January 1 1977), date of The danish hiv cohort study (DHCS) arrivaltoDenmarkordateofbirthoftheoffspringwhich DHCS,whichhasbeendescribedindetailelsewhere,isa ever was more recent. nationwide, prospective, population-based cohort study of all Danish HIV-infected individuals treated at Danish Outcome measures hospitals since 1 January 1995 [25,26]. TheprimaryoutcomewastimetofirsteverCVEdefined as the first date an individual was registered with a The danish civil registration system (DCRS) diagnosis of non-traumatic subarachnoid haemorrhage, DCRS, established in 1968, stores information on vital intracerebral haemorrhage cerebral infarction, unspeci- status, residency, and immigration/emigration for all fied stroke or transient ischemic attack in DNHR. Danish residents [27]. Diagnoses obtained from emergency rooms but not confirmed subsequently were not included. The diag- The danish national hospital registry (DNHR) nosis stroke sequels were included as CVE if no prior DNHR, established in 1977, records data on all CVE diagnosis was registered and categorized as admissions to non-psychiatric hospitals in Denmark, unspecified stroke. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE:;QAD/202675;TotalnosofPages:13; QAD 202675 HIV and risk of cerebrovascular events Rasmussen et al. 3 (The diagnoses and ICD8/ICD10 codes are provided in whoinitiatedaspecificantiretroviraldrugwasconsidered appendix I) on this drug for the rest of the observation period independent of cessation or changes in antiretroviral Outcomes (CVE) were classified as ‘‘CVE with proven therapy. Finally, we performed an analysis in which the risk factor’’ if at least one risk factor, as defined in date of first abacavir cessation was included. The appendix I, was registered in DNHR, DCR or DHCS estimated IRRs in the time-dependent analysis on the priortoorwithin30daysafteranevent(forcancerupto non-IDUHIV-infectedindividualswereadjustedforage 90daysafteranevent)[30–41].Theremainingoutcomes at index date (categorized in four age intervals: 16–30, were classified as ‘‘CVE with no proven risk factors’’. 31–45, 46–60, and 61 þ years), gender, calendar year (categorized in five time intervals (index date: 1995– Statistical analysis 1997, 1998–2000, 2001–2003, 2004–2006 and 2007– TimewascomputedfromindexdateuntildateofCVE, 2010) and place of birth. date of other cerebrovascular disease than CVE, 30 days prior to date of cerebral comorbidity, date of death, Statistical analyses were performed using SPSS version emigration, lost to follow up or 1 August 2010, 17.0andRversion2.11.1.Thestudywasapprovedbythe whichever came first. To illustrate the probability of DanishDataProtectionAgency(jr.no2008–41–1781). overall CVE we used cumulative incidence function to illustrate time to first CVE recognizing other cerebro- vasculardiseaseaswellascerebralcomorbidityanddeath as a competing risk. We used Cox regression analyses to Results calculate incidence rate ratios (IRR) as estimates of the relative risk and 95% confidence intervals (CI) for total We identified 5,031 HIV-infected individuals of whom CVEaswellasforCVEsubgroups.Inthecomparisonsof 536 (10.7%) were IDUs and 45,279 comparison cohort HIV-infected individuals and their matched comparison individuals. The median age at index date was almost cohortstheanalyseswerestratifiedaccordingtotheinitial identical in the non-IDU and IDU HIV-infected matchcriteria(ageandgender)andadjustedforcountry individuals (36.9 years vs. 35.6 years), but more non- of birth (Denmark vs. outside Denmark). The estimated IDU HIV-infected individuals than IDU HIV-infected IRRsfor theparentswere adjustedforage atindex date individualswereolderthan50yearsatindexdate(15.3%/ (categorized in five age intervals: 0–30, 31–45, 45–60, 1.9%). Additional characteristics of HIV-infected indi- 60–75and75þyears),calendaryear(categorizedinfive viduals and the two matched comparison cohorts are time intervals (index date: 1977–1985, 1986–1990, provided in Table 1. The registered risk factors are 1991–1995, 1996–2000 and 2001–2010)) and country provided in appendix II, Table 1. of birth. Overall CVE was diagnosed in 123 (2.7%) non-IDU Due to the different characteristics and risk profiles of HIV-infected individuals (43.9% with no proven risk individuals with and without IDU (IDU/non-IDU) all factors) and in 17 (3.2%) IDU HIV-infected individuals. analysis were stratified on the basis of IDU. In the comparison cohorts CVE was observed in 998 (2.5%)individualsfromthenon-IDUcomparisongroup Because the accuracy of coding may differ in the (40.7%withnoprovenriskfactors)and84(1.7%)ofthe discharge diagnoses, we performed a robustness analysis IDU comparison group (39.3% with no proven risk excluding1) individualsregistered with stroke sequels as factors). Additional information on CVE subtypes is first Aofovir and abacavir on the risk of CVE, time- provided in Table 1. dependentCoxregressionanalyseswereusedtocompute IRRsinthenon-IDUHIV-infectedpopulation.Inthese The cumulated incidences of CVE for the four groups calculations, time was divided into four time periods: 1) including5and10yearsriskofCVEafter indexdateare timefromindexdateuntilfirstCD4count<¼200cells/ shown in Fig. 1. ml occurring before initiation of HAART, 2) time from first CD4 count <¼ 200cells/ml until initiation of As illustrated in Table 2, we found a higher risk of total HAART, 3) time from initiation of HAARTuntil first CVE in the HIV-infected population compared to the occurrenceofaCD4count>200cells/mland4)timeon comparisoncohorts.Theriskwassubstantiallyhigher in HAARTwith a CD4 count > 200cells/ml until end of the IDU than the non-IDU HIV-infected population observation. To specifically estimate the impact of (adjusted IRR 3.94; 95% CI: 2.16–7.16 versus adjusted treatment with specific antiretroviral drugs, we per- IRR1.60;95%CI:1.30–1.95).Theincreasedriskinthe formed analyses in which only HIV-infected individuals non-IDU HIV-infected individuals was due to a higher who initiated HAARTwere included, and handled first risk of CVE with (adjusted IRR 1.55; 95% CI: 1.19– initiationofthedrugasatime-updatedvariable(firstdate 2.03)andwithoutprovenriskfactors(adjustedIRR1.65; ofCD4>200cells/mlafterstartofHAARTwasincluded 95% CI: 1.21–2.26). Furthermore, the increased risk of for confounder control). In these analyses an individual CVE was mainly due to a statistically significant higher Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE:;QAD/202675;TotalnosofPages:13; QAD 202675 4 AIDS 2011, Vol 00 No 00 Table1. CharacteristicsofHIV-infectedindividualsandcomparisoncohortindividuals. Non-IDUHIV-infected Comparisoncohort IDUHIV-infected Comparisoncohort individuals(N¼4,495) individuals(N¼40,455) individuals(N¼536) individuals(N¼4,824) Ageatindexdate,medianyears(IQR) 36.9(30.6–45.1) 36.9(30.6–45.1) 35.6(31.0–40.7) 35.6(31.0–40.7) Ageabove50years,N(%) 687(15.3) 6,183(15.3) 10(1.9) 90(1.9) Malegender,N(%) 3,475(77.3) 31,275(77.3) 346(64.6) 3,114(64.6) Caucasianrace,N(%) 3,519(78.3) – 511(95.3) – BorninDenmark,N(%) 3,140(69.9) 39,810(98.4) 464(86.6) 4,746(98.4) Infectionmode: MSM,N(%) 2,278(50.7) – – – Heterosexualcontact,N(%) 1,831(40.7) – – – IDU,N(%) – – 536(100) – Other/unknown,N(%) 386(8.6) – – – HepatitisCpositive,N(%) 340(7.6) – 471(87.9) – NoofpatientsdiagnosedwithHIV-infection 1,569(34.9) – 305(56.9) – priorto1995,N(%) NoofpatientswithAIDSdiagnosedprior 375(8.3) – 36(6.7) – toindexdate,N(%) MedianCD4cellcountatindexdate, 286(117–480) – 341(184–550) – cells/mL(IQR) MedianVLatindexdate,copies/ml(IQR) 45,246(5,863–190,140) – 34,300(8,720–86,300) – No.ofpatientsinitiatingHAARTpriorto 3,463(77.0) – 364(67.9) – orintheobservationperiod,N(%) No.ofpatientsinitiatingAbacavirpriorto 2,075(46.2) 190(35.4) orintheobservationperiod,N(%) Durationoffollow-up,person-years 36,161 410,666 4,225 59,582 Durationoffollow-up,median-years(IQR) 7.6(3.1–13.4) 10.8(5.7–15.6) 7.6(3.1–12.6) 15.6(9.1–15.6) Deathduringfollow-up,N(%) 681(15.2) 1,692(4.2) 239(44.6) 141(2.9) Emigrationduringfollow-up,N(%) 184(4.1) 525(1.3) 14(2.6) 77(1.6) Losttofollow-up,N(%) 19(0.4) 11(0.0) 1(0.2) 2(0.0) Firsthospitalisationforcerebrovascular events(CVE)afterindexdate: Totalno.ofCVE,N(%) 123(2.7) 998(2.5) 17(3.2) 84(1.7) Subarachnoidhaemorrhage,N(%) 9(0.2) 54(0.1) 2(0.4) 8(0.2) Intracerebralhaemorrhage,N(%) 8(0.2) 80(0.2) 5(0.9) 2(0.0) Cerebralinfarction,N(%) 35(0.8) 263(0.7) 3(0.6) 27(0.6) Unspecifiedstoke,N(%) 40(0.9) 354(0.9) 6(1.1) 28(0.6) Transientischemicattack,N(%) 31(0.7) 247(0.6) 1(0.2) 19(0.4) CVEwithprovenriskfactors,N(%) 69(56.1) 592(59.3) 17(100) 51(60.7) CVEwithoutprovenriskfactors,N(%) 54(43.9) 406(40.7) – 33(39.3) AgeatCVE,medianage(IQR) 55.3(43.2–62.0) 56.0(48.4–63.4) 43.6(40.8–48.8) 51.8(46.4–56.0) InitiatedHAARTpriortoCVEdiagnosis,N(%) 88(71.5) – 12(70.6) – InitiatedAbacavirpriortoCVEdiagnosis,N(%) 54(43.9) – 7(41.2) – MedianCD4cellcountwhendiagnosed 442(260–666) – 269(91–473) – withCVE,cells/mL(IQR) MedianVLwhendiagnosedwithCVE,copies/ml(IQR) 40(39–7,375) – 752(29–42,685) – Indexdate:DateofdiagnosisofHIV-infection(ifdiagnosedbefore1995,indexdatewasJanuary11995;ifdiagnosedbeforearrivaltoDenmark, indexdatewasdateofarrivaltoDenmark).IDU,Intravenousdruguser;IQR,Interquartilerange;MSM,Menwhohavesexwithmen. riskofcerebralinfarction,unspecifiedstrokeandtransient nificant (Table 3). In individuals who had initiated ischemicattack.IntheIDUHIV-infectedpopulationrisk HAART,riskofCVEwasincreasedafterfirstexposureto of subarachnoid haemorrhage, intracerebral haemor- abacavir (adjusted IRR 1.66; 95% CI: 1.03–2.68). The rhage, cerebral infarction andunspecified strokewere all risk,however,stayedhighafterfirstcessationof abacavir substantially increased compared to the comparison (asafractionofpatientsre-initiatedabacavir,only70.2% cohort, however only intracerebral haemorrhage and of the remaining observation time was time without unspecified stroke were statistically significant. The abacavirtreatment).ThiswasalsoseenforCVEwithand increased risk of CVE was seen in both genders and a withoutprovenriskfactorsalthoughthelattertworesults trend towards a higher risk in patients reporting HIV were statistically insignificant. Initiating PI, indinavir, transmissionbyheterosexualcontactwasobserved(Table didanosin or tenofovirdidnot change theestimated risk 2). of CVE (Table 3). We found a significantly increased risk of total CVE in The performed robustness analysis, in which 1) non-IDU HIV-infected individuals with a CD4 count individualsregisteredwithstrokesequelsasfirstdiagnosis <¼200cells/mlwhohadnotinitiatedHAART(adjusted of CVE and 2) individuals registered with hepatitis C IRR2.26;95%CI:1.05–4.86)(Table3).Afterinitiation infection were excluded, showed no major changes in of HAART the risk was identical to that of the pre- CVE risk estimates. HAARTperiodwithaCD4count>200cells/ml.Inthe periodwithlowCD4countbeforestartofHAART,we We identified 2,509 mothers and 2,289 fathers of HIV- also observed a higher risk of CVE with and without infectedindividualsaswellas21,982mothersand21,009 proven risk factors although this was statistically insig- fathers of comparison cohort individuals (Appendix II, Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE:;QAD/202675;TotalnosofPages:13; QAD 202675 HIV and risk of cerebrovascular events Rasmussen et al. 5 Fig. 1. Cumulative incidence for first cerebrovascular event (CVE) in non-IDU and IDU HIV-infected individuals and comparison cohort individuals. (cid:1) [Non-IDU HIV-infected individuals: 5 years risk: 1.28 (95%CI: 0.96–1.67); 10 years risk: 2.68 (95%CI: 2.16–3.30). Comparison cohort individuals: 5 years risk: 0.79 (95%CI: 0.71–0.89); 10 years risk: 2.07 (95%CI: 1.92–2.24). IDU HIV-infected individuals: 5 years risk: 1.43 (95%CI: 0.64–2.82); 10 years risk: 3.08 (95%CI: 1.76–4.98). Comparison cohort individuals: 5 years risk: 0.26 (95%CI: 0.14–0.44); 10 years risk: 1.00 (95%CI: 0.73–1.35)]. 95% CI: ConfidenceInterval. Table2).Theparentswerecomparablewithrespecttoage increased risk of CVE, which was almost exclusively andplaceofbirthandthemediantimeoffollow-upwas drivenbyasubstantiallyincreasedriskseenintheparents almost30yearsforallgroups(AppendixII,Table2).The ofoffspring reportingIDUasrouteofHIVtransmission parents of the HIV-infected individuals had a slightly (Table 4). Table2. Relativeriskofcerebrovascularevents(CVE)inHIV-infectedindividuals. IRR(95%CI) Non-IDUHIV-infectedindividualsversus IDUHIV-infectedindividualsversus Comparisoncohortindividuals Comparisoncohortindividuals Outcome: Unadjusted Adjusteda Unadjusted Adjusteda Totalcerebrovascularevents(CVE) 1.60(1.32–1.94) 1.60(1.30–1.95) 3.70(2.10–6.52) 3.94(2.16–7.16) Subarachnoidhaemorrhage 1.85(0.90–3.81) 1.72(0.80–3.69) 4.41(0.81–24.09) 4.41(0.81–24.09) Intracerebralhaemorrhage 1.43(0.68–3.03) 1.47(0.67–3.20) 22.13(4.29–114.11) 35.62(4.04–314.17) Cerebralinfarction 1.76(1.22–2.53) 1.63(1.10–2.41) 2.11(0.60–7.48) 1.90(0.50–7.19) Unspecifiedstroke 1.48(1.06–2.07) 1.54(1.08–2.18) 4.02(1.53–10.58) 4.62(1.63–13.11) Transientischemicattack 1.58(1.08–2.33) 1.64(1.10–2.44) 0.99(0.13–7.80) 1.19(0.15–9.67) CVEwithprovenriskfactors 1.54(1.19–1.99) 1.55(1.19–2.03) – – CVEwithoutprovenriskfactors 1.68(1.25–2.25) 1.65(1.21–2.26) – – Stratifiedongender Male 1.63(1.33–2.00) 1.59(1.29–1.97) 3.61(1.89–6.90) 3.83(1.89–7.77) Female 1.37(0.76–2.46) 1.69(0.89–3.23) 4.00(1.23–12.99) 3.82(1.18–12.41) StratifiedonrouteofHIVtransmission – – MSM 1.31(1.00–1.73) 1.31(0.99–1.74) – – Heterosexual 1.90(1.41–2.56) 1.95(1.40–2.70) – – IRR,Incidencerateratio.95%CI:ConfidenceInterval aAdjustedforcountryofbirth(DenmarkversusoutsideDenmark)andstratifiedaccordingtotheinitialmatchcriteria(ageandgender). MSM:menwhohavesexwithmen. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE:;QAD/202675;TotalnosofPages:13; QAD 202675 6 AIDS 2011, Vol 00 No 00 Table3. ImpactofCD4cellcount,HAARTandabacavironriskofcerebrovascularevents(CVE)inHIV-infectedindividualswithnointravenous drugabuse(Non-IDUHIV). IRR(95%CI) Non-IDUHIV-infectedindividuals Time-updatedvariables: Unadjusted Adjusteda TotalCVE CD4>200cells/mlandnon-HAART 1(ref)’’ 1(ref)’’ Cd4<200cells/mlandnon-HAART 2.28(1.09–4.76) 2.26(1.05–4.86) Cd4<200cells/mlandHAART 1.51(0.65–3.55) 1.17(0.50–2.75) CD4>200cells/mlandHAART 1.00(0.59–1.69) 0.80(0.47–1.36) OnHAARTbeforefirstexposuretoproteaseinhibitors 1(ref.)’’ 1(ref.)’’ OnHAARTafterfirstexposuretoproteaseinhibitors 0.93(0.53–1.62) 0.88(0.46–1.68) OnHAARTbeforefirstexposuretoindinavir 1(ref)’’ 1(ref)’’ OnHAARTafterfirstexposuretoindinavir 1.08(0.70–1.68) 0.98(0.61–1.58) OnHAARTbeforefirstexposuretotenofovir 1(ref.)’’ 1(ref.)’’ OnHAARTafterfirstexposuretotenofovir 0.94(0.55–1.60) 1.01(0.58–1.76) OnHAARTbeforefirstexposuretodidanosin 1(ref.)’’ 1(ref)’’ OnHAARTafterfirstexposuretodidanosin 0.89(0.55–1.44) 0.75(0.45–1.24) OnHAARTbeforefirstexposuretoabacavir 1(ref.)’’ 1(ref.)’’ OnHAARTafterfirstexposuretoabacavir 1.69(1.07–2.68) 1.66(1.03–2.68) OnHAARTafterfirstexposureuntilfirstcessationofabacavir 1.61(0.98–2.66) 1.58(0.94–2.65) OnHAARTafterfirstcessationofabacavir 1.87(1.04–3.37) 1.83(1.00–3.34) CVEwithprovenriskfactors CD4>200cells/mlandnon-HAART 1(ref)’’ 1(ref)’’ CD4<200cells/mlandnon-HAART 2.37(0.78–7.21) 2.26(0.72–7.14) CD4<200cells/mlandHAART 0.54(0.07–4.26) 0.39(0.05–3.09) CD4>200cells/mlandHAART 1.77(0.81–3.88) 1.34(0.61–2.94) OnHAARTbeforefirstexposuretoabacavir 1(ref.)’’ 1(ref.)’’ OnHAARTafterfirstexposuretoabacavir 1.88(1.03–3.44) 1.78(0.95–3.34) OnHAARTafterfirstexposureuntilfirstcessationofabacavir 1.85(0.97–3.52) 1.72(0.88–3.36) OnHAARTafterfirstcessationofabacavir 1.96(0.90–4.24) 1.93(0.87–4.25) CVEwithnoprovenriskfactors CD4>200cells/mlandnon-HAART 1(ref)’’ 1(ref)’’ CD4<200cells/mlandnon-HAART 2.22(0.83–5.97) 2.29(0.82–6.39) CD4<200cells/mlandHAART 2.16(0.82–5.71) 1.79(0.67–4.76) CD4>200cells/mlandHAART 0.55(0.26–1.13) 0.46(0.22–0.96) OnHAARTbeforefirstexposuretoabacavir 1(ref.)’’ 1(ref.)’’ OnHAARTafterfirstexposuretoabacavir 1.45(0.71–2.98) 1.47(0.70–3.10) OnHAARTafterfirstexposureuntilfirstcessationofabacavir 1.31(0.59–2.91) 1.38(0.61–3.14) OnHAARTafterfirstcessationofabacavir 1.76(0.71–4.40) 1.64(0.65–4.17) IRR,Incidencerateratio95%CI:ConfidenceInterval‘‘Ref:Referencetime aAdjustedforage,gender,calendaryearandcountryofbirth.Analysesonproteaseinhibitors,tenofovirandabacavirwerealsoadjustedforCD4 cellcount. Discussion withabacaviralmostdoubledtheriskofCVE,whilePI, indinavir, didanosine, tenofovir or HAART in general We found a higher risk of CVE in HIV-infected had no impact on the risk of CVE. Finally, the risk of individuals than in the general population comparison CVE was only increased in the parents of HIV-infected cohorts. The risk was higher for both CVE with individuals who reported IDU as route of transmission. and without proven risk factors. In the non-IDU HIV- infected population immunodeficiency (CD4 count Amainstrengthofourstudyisitsnationwidepopulation- <¼ 200cells/ml) before start of HAARTand treatment based design with long and complete follow-up. The Table4. Relativeriskofcerebrovascularevents(CVE)inparentsofHIV-infectedindividuals. IRR(95%CI) Mothers Fathers Outcome: Unadjusted Adjusted Unadjusted Adjusted Totalcerebrovascularevents(CVE) 1.16(1.02–1.33) 1.15(1.01–1.32) 1.09(0.97–1.23) 1.05(0.93–1.18) CVEwithprovenriskfactors 1.19(1.00–1.42) 1.10(0.92–1.31) 1.18(1.03–1.37) 1.13(0.98–1.30) CVEwithoutprovenriskfactors 1.12(0.91–1.38) 1.10(0.90–1.36) 0.95(0.78–1.16) 0.92(0.75–1.12) Stratifiedontransmission-groupoftheoffspring: MSM: 1.10(0.91–1.31) 1.06(0.88–1.27) 1.13(0.96–1.32) 1.04(0.89–1.22) Heterosexually: 0.98(0.73–1.32) 0.99(0.74–1.33) 1.12(0.90–1.41) 1.09(0.87–1.36) IDU 1.85(1.38–2.49) 2.06(1.53–2.78) 1.20(0.88–1.62) 1.25(0.92–1.70) IRR,Incidencerateratio.95%CI:ConfidenceIntervalMAdjustedforage,calendaryearandcountryofbirth.MSM,menwhohavesexwithmen Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE:;QAD/202675;TotalnosofPages:13; QAD 202675 HIV and risk of cerebrovascular events Rasmussen et al. 7 access to several Danish registries allowed us to identify riskfactorsforstrokeinyoungadults[41].But,aswehad population-basedcomparisoncohortsandextractdataon no access to information on the drug itself, we included family members. Furthermore, data on study endpoints allIDU,registeredasrouteofHIVinfectioninDHCS,as and co-morbidity were obtained from the same data asurrogatemarkerofdrugabuseingeneral.Weareaware sources, thereby minimising the impact of misclassifi- of the potential bias this might introduce as some non- cation on our relative risk estimates. Importantly, we IDU drug abusers might have been lost and as the excluded patients with opportunistic cerebral infections, frequencyofthedrugabuseandtheeffectofbeingclean HIV dementia, non-HIV-associated cerebral infections, orinatreatmentprogramwithe.g.methadonecouldnot andCNSneoplasiainordertoavoidmisclassification.We be accounted for. adjusted the analyses for potential confounding factors andfurther stratifiedall analyseson the basisof IDU. To In a case-control study from South Africa, Hoffmann makesurethattheincreasedriskofCVEwasnotdueto et al. found that cryptogenic stroke, but not stroke in potential misclassification of individuals with IDU, we general, was more common in the HIV-positive performed a robustness analysis excluding all non-IDU population, than in an age- and gender-matched HIV- HIV-infected individuals with hepatitis C infection and negative control population [11]. In contrast, Engstrøm saw no changes in our estimates. We are not aware of et al. conducted a retrospective study of 1600 AIDS other studies with a similar design. patients with an age below 45 years (patients with competing opportunistic infections were not excluded) Duetothestudydesign,wehadnoaccesstopatientfiles and found that 0.75% had been diagnosed with cerebral or results of imaging techniques and had to rely on infarction,whichwascomparedwithanannualincidence hospital registry-based discharge diagnoses in order to of 0.025% for cerebral infarction in the background identifydiagnosesofCVE.Weareawarethattheremight population between 35 and 45 years [6]. Cole et al. be some misclassification in CVE diagnoses as well as in studied AIDS patients with no opportunistic CNS the diagnoses used to exclude individuals with CNS infections, HIV dementia or IDU, and found a relative comorbidity. Previous studies have shown that DNHR riskofstroke,whichwasincreasedbyafactor10(adjusted tends to overestimate the prevalence of cerebrovascular relativerisk10.4;95%CI:4.9–22.0)comparedtoanon- disease[42,43],buttheaccesstomoderndiagnostictools AIDS population from the same region [17]. HIV- has probably increased the validity of stroke diagnoses infected individuals however, who did not fulfil the today[42].AstheDanishNationalHospitalregistrywas criteriaforAIDSwereincludedinthecontrolgroup.In notinitiateduntilJanuary1977,someparentsmighthave accordance with Cole et al., we revealed that HIV- had a CVE prior to study inclusion, why some parents infected individuals with no concomitant cerebral mighthavestrokesequels categorised asendpointin our comorbidityhaveanincreasedriskofCVE.Wepresume study.Nevertheless,asageoftheparentsatstudyinclusion that the differences in the risk estimates in these reports was low and did not differ markedly between the rely on differences in characteristics of the study comparedgroups,wepresumethatthisphenomenonhas populations, definitions and access to data on cerebro- not biased our relative risk estimates substantially. vascular endpoints. We found a relative risk of CVE in Furthermore, sensitivity analysis, in which we excluded IDU HIV-infected individuals, which was more than individuals registered in DNHR with stroke sequels as twice that of the non-IDU HIV population which first ever CVE, did not change our risk estimates. Since emphasizes the impact of drug abuse. A number of weusedthesamesourceofdatatoascertainCVEforall possible mechanisms to explain this phenomenon have study subjects, we presume that any potential misclassi- beenthoroughlydiscussedelsewhere[41,46].Despitethe fication was non-differential and therefore did not awareness of drug abuse as a risk factor of CVE and the influence our estimates of relative risk. Low socio- linkbetweenHIVandIDU,mostriskestimatesin other economicstatus isassociatedwith ahigher riskof stroke studies are biased by this confounder [5–10,15,16,18– which is partlyexplained bya greater burden of classical 20,22]. risk factors [44]. We could not directly adjust for socioeconomic status. However, as we stratified the The increased risk of cerebrovascular disease in HIV- analysesonIDU,evaluatedtheimpactofriskfactorsand infectedindividualshasbeenascribedtoseveraldifferent analyzedtheriskofCVEintheparentsofthetwogroups, pathological mechanisms such as cerebral opportunistic this was indirectly accounted for. We did not have infections, associated vasculitis or vasculopathies, intra- information on non-antiretroviral medication or smok- cranial neoplasm, endocarditis and coagulation disorders ing status of which the latter is a highly important risk [46,47]. As studies have found a higher prevalence of factor. This could invalidate the potential causal smoking in HIV-infected individuals than in the general associationofCVEandHIV.However,COPD,excessive populationofthesameage[48,49],ithasbeenspeculated alcoholconsumptionandotherconventionalriskfactors whether a HIV-positive status simply serves as a marker were included in the analyses, manyof which arehighly for differences in the prevalence of conventionally risk associated with smoking [45]. Abuse of cocaine, factors [48]. .However, in our study an uneven amphetamine, ecstasy and related drugs are important distribution of risk factors could not solely explain the Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE:;QAD/202675;TotalnosofPages:13; QAD 202675 8 AIDS 2011, Vol 00 No 00 increased risk of CVE, as both the relative risk of CVE vaguely associated with increased risk of CVE in HIV- with and without proven risk factors were increased. infected individuals. SmokingisastrongpredictorofCVE[32,45].Inameta- analysis by Shinton et al. smoking increased the risk of strokealmost3foldinapopulationlessthan55years[45]. Acknowledgments Due to the lack of information on smoking in our comparison cohorts we were not able to address the Wearegratefultothestaffofourclinicaldepartmentsfor impact of this risk factor and cannot exclude that an their continuous support and enthusiasm. We thank increased frequency of smoking in the HIV-infected Preben and Anna Simonsen?s Foundation, the NOVO population partly explains the increased risk of CVE Nordic Foundation, University of Southern Denmark we observed. and the Clinical Institute of Copenhagen University for financial support. Inaccordancewithourresultssomestudieshaveobserved an increased risk of stroke in HIV-infected individuals AuthorContributions:Conceptionanddesign:Rasmus- withlowCD4counts[14,20].Whetherthisassociationis sen LD, Engsig FN, Christensen H, Obel N. duetotheimmunodeficiencyperse,anassociationwith the increased risk of cerebral opportunistic diseases or a Analysis and interpretation of the data: Rasmussen LD, general deteriorated condition in these patients has to Engsig FN, Obel N. be established. Drafting of the article: Rasmussen LD. FewstudieshaveexaminedtheimpactofHAARTonrisk of cerebrovascular disease [4,13,16,19,22,23]. The two Critical revision of the article for important intellectual content: largest studies, in which conflicting results of HAART- Rasmussen LD, Ensig FN, Pedersen C, Gerstoft J, exposurewerefound,usedcompositeendpoints[13,16]. Kronborg G, Christensen H, Obel N. Astudy fromThailand reporteda twofold increasedrisk of stroke after start of HAART which contrasts the Final approval of the article: Rasmussen LD, Engsig FN, observations from an American study which found no Pedersen C, Gerstoft J, Kronborg G, Christensen H, correlation [23], and a Spanish study which observed a Obel N. protective effect of HAART [22]. In our analyses HAART did not influence the risk of CVE. Provision of study materials or patients: Pedersen C, Kronborg G, Gerstoft J, Obel N. Abacavir has been associated with an increased risk of myocardial infarction, but the causal pathway for this Statistical expertise: Rasmussen LD, Engsig FN, Obel N. effect is still controversial [3,4,50]. An association between abacavir and risk of stroke however could not Obtaining of funding: Obel N. bedemonstratedintheD:A:Dstudy[4].Weobserveda higher risk of CVE in HIV-infected individuals on Administrative,technical,orlogisticsupport:Rasmussen abacavir irrespective of low CD4 cell count. PI, LD, Obel N. indinavir, didanosin and tenofovir on the contrary showed no such association. We presume that the Collection and assembly of data: Pedersen C, Kronborg G, mechanismsforthisphenomenonareequivalenttothat Gerstoft J, Obel N. seen for myocardial infarction, but we cannot exclude thatpatientswithanaprioriincreasedriskofCVEhada CentersintheDanishHIVCohortStudy:Departmentsof higherchanceofbeingtreatedwithabacavir(channelling Infectious Diseases at Copenhagen University Hospitals, bias) [3,50]. Rigshospitalet (J Gerstoft, N Obel) and Hvidovre (G Kronborg), Odense University Hospital (C Pedersen), WeregisteredanincreasedriskofCVEinparentsofIDU Aarhus University Hospitals, Skejby (CS Larsen) and HIV-infected individuals. This association suggests that Aalborg (G Pedersen), Herning Hospital (AL Laursen), family-related risk factors are a complex combination of Helsingør Hospital (L Nielsen) and Kolding Hospital (J shared socio-economic factors, a possible tendency to Jensen). ‘‘risk taking behaviour’’ and a genetic component [51,52]. Conflicts of interest: N Obel has received research funding from Roche, Bristol-Myers Squibb, Merck We conclude that HIV infection is associated with an Sharp&Dohme,GlaxoSmithKline,Abbott,Boehringer increased risk of CVE with and without proven risk Ingelheim, Janssen-Cilag and Swedish Orphan Drugs. factors. The risk is associated with IDU, low CD4 cell count, and treatment with abacavir, but not with FN Engsig has received research funding from Merck HAART in general. Family-associated risk factors seem Sharp & Dohme. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 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RasmussenLD,OmlandLH,PedersenC,GerstoftJ,KronborgG, cerebrovasculardiseaseonthesamedatewerecategorized JensenJ,etal.RiskofmyocardialinfarctioninparentsofHIV- infected Individuals: a population-based Cohort study. BMC with the specific diagnosis (subarachnoid haemorrhage, InfectDis2010;10:169. intracerebral haemorrhage, cerebral infarction, unspecified stroke and transient ischaemic attack) in preference for the unspecific diagnoses (other cerebral vascular disease or stroke sequels) and diagnoses belonging to the longest admission were preferred. Next the primary diagnosis (A-diagnosis) was chosen over the secondary Appendix I diagnosis (B-diagnosis). Cases in which this method did not identify a specific diagnosis were categorized as World Health Organization International Disease Classifi- unspecified stroke. cation (ICD) Codes, ICD-8 and ICD-10 used for the present classification. CEREBRAL COMORBIDITY: CEREBROVASCULAR DISEASE: CEREBRALINFECTIONSINCLUDINGOPPORTU- SUBARACHNOID HAEMORRHAGE: NISTIC DISEASES: ICD8: 43000-43099 ICD8: 013.00–013.99, 019.19, 036.09, 040.00–040.09, 045.09–045.99, 046.99, 052.01, 053.02, 054.03, 055.01, ICD 10: I 60.0–60.9 056.01, INTRACEREBRAL HAEMORRHAGE: 062.09–062.99, 063.09–063.99, 064.99, 065.99, 066.00– 066.09, 071.99, 072.02, 075.01, 090.49, 094.00–094.99, ICD8: 43100, 43108–43190, 43198-43199 130.09–130.99, 320.09–320.99, 322.00–322.09, 323.00– ICD 10: I61.0–61.9 323.01, 323.03–323.09, 324.00–324.09 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Risk of cerebrovascular events in persons with and without HIV

Similar Risk of cerebrovascular events in persons with and without HIV