Risk of cerebrovascular events in persons with and without HIV

13 Pages·2011·0.41 MB·English

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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-infectedindivid-
uals 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 immunodefi-
ciency, 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:[phone]; fax: [phone];e-mail: [email protected]
Received:10December 2010;revised: 23May2011;accepted: 27May2011.
DOI:10.1097/QAD.0b013e3283493fb0
ISSN 0269-9370 Q 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 1
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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.
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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
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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,
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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.
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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;
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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.
CE:;QAD/202675;TotalnosofPages:13;
QAD 202675
HIV and risk of cerebrovascular events Rasmussen et al. 9
C. Pedersen has received research funding from 16. D’ArminioA,SabinCA,PhillipsAN,ReissP,WeberR,KirkO,
Abbott, Roche, Bristol-Myers Squibb, Merck Sharp & etal.WritingcommitteeoftheD:A:DStudyGroup.Cardio-and
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18. PatelVB,SacoorZ,FrancisP,BillPL,BhigjeeAI,ConnollyC.
Roche, Bristol-Myers Squibb, Mecrk Sharp & Dohme,
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Pharmasia, GlaxoSmithKline, Swedish Orphan Drugs Natal,SouthAfrica.Neurology2005;65:759–761.
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2006;13:233–239.
shipsfromBoehringer-Ingelheim,Abbott/Solvay,Med-
20. Ortiz G, Koch S, Romano JG, Forteza AM, Rabinstein AA.
tronics, Sanofi-Avensis and Atrietech. MechanismsofischemicstrokeinHIV-infectedpatients.Neu-
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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.