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Associations between immune depression and cardiovascular events in HIV infection Caroline A. Sabina, Lene Ryomb, Stephane De Witc, Amanda Mocrofta, Andrew N. Phillipsa, Signe W. Wormb, Rainer Weberd, Antonella D’Arminio Monfortee, Peter Reissf, David Kamaraa, Wafaa El-Sadrg, Christian Pradierh, Francois Dabisi,j, M Matthew Lawk, Jens Lundgrenb,l, for the D:A:D Study Group

Objective: To consider associations between the latest/nadir CD4þ cell count, and time spent with CD4þ cell count less than 200 cells/ml (duration of immune depression), and myocardial infarction (MI), coronary heart disease (CHD), stroke, or cardiovascular disease (CVD) (CHD or stroke) in 33 301 HIV-positive individuals. Design: Longitudinal cohort study. Methods: Analyses were undertaken using Poisson regression. To investigate whether analyses of stroke were robust to the type of endpoint, we additionally included stroke- like events and rejected strokes into the stroke endpoint. Results: Participants experienced 716 MI, 1056 CHD, 303 stroke, and 1284 CVD events. Whereas there was no evidence of a higher MI/CHD risk in those with lower latest/nadir CD4þ cell counts after adjustment [current CD4þ <100 cells/ml: relative rate (95% confidence interval) 0.96 (0.62–1.50) for MI, 0.89 (0.30–2.36) for CHD; nadir CD4þ <100 cells/ml: 1.36 (0.57–3.23) for MI, 0.98 (0.45–2.16) for CHD], stroke and CVD rates were higher in those with a latest CD4þ cell count less than 100 cells/ml [2.26 (1.29–3.94) and 1.14 (0.84–1.56), respectively]. All events occurred less frequently in those who had not experienced immune depression, although evidence for a linear association with duration of immune depression was weak. The association between stroke risk and the latest CD4þ cell count strengthened as stroke-like and rejected strokes were included; conversely, associations with established stroke risk factors weakened. Conclusion: We do not find strong evidence that HIV-positive individuals with a low CD4þ cell count are more likely to experience MI/CHD. Although strokes appear to occur more commonly at low CD4þ cell counts, this may be partly explained by misclassification or other biases. ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2013, 27:2735–2748 Keywords: bias, cardiovascular disease, CD4þ lymphocyte count, myocardial infarction, stroke aResearch Department of Infection and Population Health, UCL, London, UK, bCopenhagen HIV Programme, University of Copenhagen, Copenhagen, Denmark, cDepartment of Infectious Diseases, CHU Saint-Pierre Hospital, Brussels, Belgium, dDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, eHospital San Paolo, University of Milan, Milan, Italy, fAcademic Medical Center, and Stichting HIV Monitoring, Amsterdam, The Netherlands, gICAP-Columbia University/Harlem Hospital, New York, USA, hDe´partement de Sante´ Publique, Centre Hospitalier Universitaire, Nice, iINSERM, Centre INSERM U897 ‘Epide´miologie et Biostatistique’, jUniversite´ Bordeaux Segalen, Institut de Sante´ Publique Epide´miologie De´veloppement (ISPED), Bordeaux, France, kKirby Institute, University of New South Wales, Sydney, Australia, and lEpidemiklinikken M5132, Copenhagen University Hospital/Rigshospitalet, Copenhagen, Denmark. Correspondence to Professor Caroline Sabin, Research Department of Infection and Population Health, UCL, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Tel: +44 207 7940500x34752; e-mail: [email protected] See Acknowledgements section for full listing of study group. Received: 1 May 2013; revised: 5 June 2013; accepted: 13 June 2013.

DOI:10.1097/01.aids.0000432457.91228.f3

ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 2735 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 2736 AIDS 2013, Vol 27 No 17

Introduction Europe, Australia, and the United States [5]. The primary study aim is to investigate associations between use of The evidence for a potential role of immune depression antiretroviral drugs and risk of CVD and other major (CD4þ lymphocyte depletion) in the development of disease events. Data are collected prospectively during cardiovascular disease (CVD) among individuals with routine clinic visits; the standardized dataset includes HIV infection is conflicting. Whereas several studies information on sociodemographic factors, AIDS events have reported a higher risk of CVD in HIV-positive and deaths, known risk factors for CVD, laboratory individuals with a low CD4þ cell count [1–3], others markers for monitoring HIV and CVD, antiretroviral have reported only a modest association [4] or no treatment, and treatments that influence CVD risk. The association at all [5–9]. Although such an association, if present analysis includes the 33 301 participants from present, might be indicative of an inflammatory effect of enrolment cohorts I (1999–2000) and II (2004) only. untreated HIV infection [10,11], it may also reflect bias resulting from increased monitoring frequency in those For the analyses reported herein, we considered the first with low CD4þ cell counts, residual confounding, or occurrence of each of the following centrally validated misdiagnosis of HIV events as CVD. outcomes: MI – definite, possible, or unclassifiable events; CHD – MI, sudden cardiac death (fatal cases in One possible explanation for the inconsistent findings from which the underlying cause of death could not be the different studies is the variation in the endpoint that is established as a MI, but wherein cardiovascular risks were assessed. Whereas some studies have considered endpoints present at death, and there was no evidence of other based on a well defined and prospectively validated out- noncardiovascular causes of death), or invasive procedure come [e.g. myocardial infarction (MI), ischemic stroke], (coronary artery bypass graft, carotid endarterectomy, or others have considered composite CVD or coronary heart angioplasty); stroke; or CVD – first CHD or stroke event. disease (CHD) outcomes and studies may vary in whether The approach to data collection and classification was nonfatal as well as fatal events are considered. Study designs established at the initiation of the study with steps taken to may differ in respect to the methods used to capture ensure that any CVD events would be distinguishable information on outcomes, exposures, and potential con- from advanced HIV disease. In brief, information on all founders and the study setting may also have an impact on incident cases of MI/stroke is reported to the co- the completeness and reliability of outcome ascertainment. ordinating center via a study event form, which captures Finally, HIV-positive individuals may have infections that detailed information about the event and circumstances can cause symptoms similar to MI and stroke via non- surrounding it (and, for strokes, neuroimaging and atherosclerotic pathways. The clinical presentation of some cerebrospinal fluid data, wherever available). Each event is opportunistic infections [e.g. cytomegalovirus (CMV) validated and coded using criteria applied in the WHO infection, central nervous system (CNS) infections] may MONICA Study [15] and blind to information on the mimic the symptoms of CVD (angina and stroke, respec- patient’s clinical status (e.g. antiretroviral treatment status, tively) and syphilis may lead to stroke [12]. Furthermore, CD4þ cell count, viral load). Full details are provided in the lifestyles of many HIV-positive individuals mean that [16,17]. some may present with CVD or stroke secondary to recreational drug use [13,14]. As some of these factors may Classification of myocardial infarctions be more common in those with low CD4þ cell counts, the Reported MIs are classified as definite, possible or inadvertent inclusion of such events into analyses may unclassifiable, or are rejected if there was insufficient introduce bias when considering associations with the evidence to verify that the event was an MI. The diagnosis CD4þ cell count. and subsequent classification was based on an established algorithm [15] adapted from standardized criteria that The main aim of this study was to consider associations included relevant symptoms, relevant increase and decline between the latest and nadir CD4þ cell count, and time in cardiac enzymes, ischemic changes in electrocardio- spent with a CD4þ cell count less than 200 cells/ml graphic readings and, in cases of death, autopsy results (’duration of immune depression’), and incident CVD. if available. Secondary objectives were to assess the robustness of any associations seen to the type of event included in the Classification of strokes endpoint, and to investigate the possible impact of the Confirmed (hemorrhagic or ischemic) strokes are events inclusion of different types of events on reported in which symptoms persisted for more than 24 h, in prognostic values of established CVD risk factors. which there was a sudden symptom onset, in which there were specific neurological symptoms indicative of stroke, Methods and in which there was no evidence of any nonatherosclerotic CNS events. Reported events that did not meet Study design these criteria were classified as either stroke-like events The D:A:D Study is an observational study of more than or rejected events: stroke-like events were those 49 000 HIV-positive patients from 11 cohorts from resembling a true stroke, but wherein there was a known

nonatherosclerotic and nonhemorrhagic cause; rejected strokes and stroke-like events; C. confirmed strokes, events were those wherein the symptom duration was less stroke-like events, or rejected strokes. Finally, to than 24 h and/or wherein the neurological symptoms investigate whether the inclusion of nonstroke events were unspecified. Note that our definition of stroke does was likely to introduce bias, we investigated whether the not include transient ischemic attacks due to the shorter associations between the traditional stroke risk factors and length of symptom duration. each event differed in those with a high or low CD4þ cell count through the inclusion of interaction terms with Statistical methods each stroke risk factors and the latest CD4þ cell count Individuals were followed from study entry to the earliest (<200 or 200 cells/ml). of each endpoint, death, 1 February 2011, or 6 months after last clinic visit. Each individual’s follow-up was split into a series of consecutive 1-monthly periods and his/ Results her clinical, immunologic, and virologic status at the start of each period was established. Each individual’s latest/ By 1 February 2011, the individuals in the D:A:D Study nadir CD4þ cell count at the start of each month was had experienced 716 MI (over 223 242 person-years), categorized (<100; 100–199; 200–299; 300–399; 400– 1056 CHD (222 290 person-years), 303 confirmed stroke 499; 500 cells/ml) as was the duration of immune (224 581 person-years), and 1284 CVD (221 505 person- depression (none; 2; >2, 4; >4, 6; >6, 8; >8, years) events. Event rates (95% confidence interval, CI) 10; >10 years) and event rates were calculated for were 3.2 (3.0–3.4), 4.8 (4.5–5.0), 1.4 (1.2–1.5), and 5.8 each stratum. (5.5–6.1)/1000 person-years, respectively. The characteristics of patients at the time of experiencing each event Analyses were performed using Poisson regression with the are shown in Table 1. latest CD4þ, nadir CD4þ, and duration of immune depression included as time-updated covariates. Models In unadjusted analyses, individuals with a lower latest initially considered each measure of immune depression CD4þ cell count generally experienced higher rates of all separately. As the latest and nadir CD4þ cell counts would endpoints (Fig. 1(a)). After controlling for potential not be expected to differ substantially in untreated confounders, however, the adjusted associations did not individuals, analyses that included all three measures were support a linear association with the latest CD4þ cell considered only in patients who had been exposed to count for the MI/CHD endpoints (Table 2a). Stroke antiretroviral treatment. Multivariable models included rates, however, remained substantially higher in those adjustment for potential confounders. Because of the small with a lower latest CD4þ cell count; although there was a number of strokes, analyses of this endpoint only included weak association with the latest CD4þ cell count for the adjustment for key stroke risk factors (sex, age, previous CVD outcome, this appeared to be driven by the strong CVD, BMI, smoking status, and hypertension); analyses of association with stroke. Associations with the nadir CD4þ the other endpoints additionally included adjustment for cell count (Fig. 1(b), Table 2a) were broadly similar. All clinical cohort, mode of HIVacquisition, ethnicity, family events occurred less frequently in individuals who had historyof CVD,calendar year, cumulative exposure to each never experienced immune depression (Fig. 1(c)), specific antiretroviral drug, and recent exposure to each although evidence for a strong linear association between nucleoside reverse transcriptase inhibitor drugs. each event and duration of immune depression after adjustment was weak (Table 2a). We then investigated the apparent associations between the latest CD4þ cell count and strokes further. First, as Among patients exposed to antiretroviral therapy, the MI ongoing CMV infection has been reported to be and CHD outcomes continued to show only weak, at associated with an increased risk of CVD in the general most, linear associations with any of the measures of population [18], we investigated a possible modifying immune depression. Linear trends were apparent between effect of the development of a CMVAIDS-defining event all three markers and the stroke outcome (Table 2b). (as a time-updated covariate), as a surrogate for recent CMV infection, on the reported associations with In our sensitivity analyses, a prior CMV AIDS-defining immune depression. Second, to investigate whether event and a prior non-CMV, AIDS-defining opportu- any association with a low CD4þ cell count and/or CMV nistic infection were both associated with an increased could be explained by bias due to increased monitoring stroke rate [unadjusted relative rates of 1.75 (0.96–3.19) frequency in those with an opportunistic infection, and 1.79 (1.40–2.28), respectively]. However, adjust- sensitivity analyses also considered adjustment for the ment for these events did not modify the association development of other, non-CMV, AIDS-defining between the latest or nadir CD4þ cell count and the risk opportunistic infections. Third, to investigate whether of stroke (data not shown). the analyses of stroke were robust to the type of endpoint included in the analyses, we compared associations using In addition to the 303 confirmed strokes, 46 patients had a three endpoints: A. confirmed strokes only; B. confirmed stroke-like event and 38 patients had a rejected stroke

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 2738 AIDS 2013, Vol 27 No 17 stroke Rejected event Stroke-like ion were assumed not to have hypertension. stroke Confirmed ranscriptase inhibitors; PIs, protease inhibitors. Invasive procedure 2.3 mmol/l, or receipt of lipid-lowering medication; individuals in whom no Characteristics of patients at the time of each event death Sudden 0.9 mmol/l, triglyceride MI All patients at D:A:D entry 3053 (9.2) 330 (46.1) 118 (39.1) 362 (57.6) 136 (44.9) 11 (23.9) 10 (26.3) 12788 (38.4) 538 (75.1) 203 (67.2) 507 (80.7) 191 (63.0) 23 (60.9) 20 (52.6) 2630 21345 (64.1) 4124 (12.4) 366 (51.1) 86 (12.0) 119 (39.4) 16 (5.3) 354 (56.4) 85 169 (13.5) (55.8) 30 22 (9.9) (47.8) 16 (42.1) 7 (15.2) 7 (18.4) (%) exposed(%) exposed(%) exposed 23983 (72.0) 19325 (58.0) 704 (98.3) 11076 (33.3) 639 (89.3) 292 (96.7) 494 (69.0) 261 (86.4) 614 (97.8) 198 (65.6) 563 (89.7) 286 (95.4) 459 (73.1) 248 (81.9) 185 40 (61.1) (87.0) 34 (73.9) 28 35 (60.9) (92.1) 27 (71.1) 23 (60.5) 1818, 26, 30 1003 (3.0) 1465 (4.4) 21 (2.9) 38 (5.3) 13 (4.3) 20 (6.6) 17 (2.7) 24 (3.8) 16 (5.3) 16 (5.3) 2 (4.4) 2 (4.4) 4 (10.5) 2 (5.3) IDUHeterosexualOther/not known 10023 2839 (30.1) (8.5) 6017 (18.1) 152 (21.2) 43 (6.0) 114 (15.9) 58 (19.2) 31 (10.3) 68 (22.5) 144 (22.9) 43 (6.9) 70 (11.2) 80 (26.4) 35 (11.6) 48 (15.8) 8 (17.4) 3 (6.5) 9 (19.6) 11 (29.0) 10 (26.3) 2 (5.3) < > > Unknown 5364 (16.1) 205 (28.6) 134 (44.4) 148 (23.6) 72 (23.8) 13 (28.3) 9 (23.7) NonwhiteNot knownEx-smokerNever smokerUnknown 4603 10835 (13.8) (32.5) 8764 6949 (26.3) (20.9) 266 41 (37.2) (5.7) 6313 (19.0) 191 (26.7) 80 (11.2) 114 (37.8) 21 (7.0) 87 (12.2) 103 (34.1) 31 225 (10.3) (35.8) 59 20 (19.5) (3.2) 168 (26.8) 102 121 (16.2) (39.9) 49 (7.8) 74 30 (24.4) (9.9) 65 16 (21.5) (34.8) 45 13 (14.9) (28.3) 14 11 3 (30.4) (29.0) (6.5) 5 4 (10.9) (10.5) 9 (23.7) 6 (15.8) 16 (42.1) n Median (range) yearsn Median (range) yearsn 3.0 (0.0, 15.9)Median (range) years 2.3 (0.0, 6.8 13.9) (0.0, 20.5) 0.9 (0.0, 4.2 14.7) (0.0, 6.4 13.3) (0.1, 20.1) 2.5 (0.1, 3.8 13.0) (0.1, 7.3 12.9) (0.0, 22.4) 2.5 (0.1, 4.6 10.9) (0.0, 6.4 13.3) (0.1, 18.6) 2.7 (0.0, 3.7 11.9) (0.1. 5.8 13.1) (0.0, 11.2) 2.4 (0.0, 3.2 10.7) (0.0, 5.4 8.8) (0.0, 16.7) 2.2 (0.0, 7.8) 3.8 (0.0, 12.1) 1.6 (0.0, 9.4) 6.2 mmol/l, high-density lipoprotein (HDL) cholesterol (%) 10783 (33.6) 424 (59.3) 161 (53.5) 408 (65.0) 187 (62.1) 17 (37.8) 14 (37.8) n (%) 2527 (7.6) 108 (15.1) 40 (13.3) 125 (19.9) 29 (9.6) 2 (4.4) 2 (5.3) l) n m (%) 962 (2.9) 103 (14.4) 47 (15.6) 106 (16.9) 42 (13.9) 5 (10.9) 3 (7.9) (%) 5058 (15.2) 71 (9.9) 34 (11.3) 40 (6.4) 27 (8.9) 7 (15.2) 2 (5.3) (%) 7736 (23.2) 278 (38.8) 123 (40.7) 226 (36.0) 117 (38.6) 26 (56.5) 17 (44.7) (%) 1572 (4.7) 30 (4.2) 14 (4.6) 22 (3.5) 16 (5.3) 0 (–) 0 (–) b a n n n n (%) MSM 14422 (43.3) 407 (56.8) 145 (48.0) 371 (59.1) 140 (46.2) 26 (56.5) 15 (39.5) (%) (%) (%) n n n (%) 1250 (3.8) 339 (47.4) 118 (39.1) 309 (49.2) 62 (20.5) 6 (13.0) 5 (13.2) n (%) 24671 (74.1) 652 (91.1) 259 (85.8) 578 (92.0) 251 (82.8) 40 (87.0) 28 (73.7) (%) White 17863 (53.6) 409 (57.1) 167 (55.3) 383 (61.0) 152 (50.2) 27 (58.7) 21 (55.3) 50 copies/ml, (%) Current 11275 (33.9) 358 (50.0) 109 (36.1) 309 (49.2) 119 (39.2) 14 (30.4) 9 (23.7) n ), 2 n n n cell count (cells/ þ Defined as reported in Methods section; individuals in whom no information was available on blood pressure measurements or antihypertensive medicat Defined as total cholesterol Table 1. Characteristics of all patients at entry in the D:A:D Study, as well as at the time of experiencing each event. Number of patientsMale sex, Age (years)HIV exposure, Ethnicity, Median (range) 38 (3, 92) 33301 49 (24, 92) 716 52 (24, 93) 52 (29, 90) 302 53 (25, 91) 51 628 (30, 74)a 55 (24, 81) b 303 46 38 HCV coinfection, LatestNadirHIV RNA Median (range) Median (range) 408 (0, 2670) 211 (0, 2580) 441 (1, 1814) 125 (0, 1020) 360 (1, 2484) 122 (0, 950) 462 (2, 1884) 136 (0, 1464) 431 (3, 2484) 132 (0, 1464) 274 (0, 1010) 101 (0, 294) 273 (5, 1120) 90 (0, 727) Hypertension, information was available on lipid measurements or use of lipid-lowering drugs were assumed not to have dyslipidemia. Smoking, BMI (kg/m Diabetes mellitus, Prior AIDS event, HBV coinfection, Prior CVD, Family history of CVD, Dyslipidemia, Use of ART NRTIs PIs NNRTIs ART, antiretroviral therapy; CVD, cardiovascular disease; NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside reverse t CD4

(a) HIV through the MSM route, more likely to have Latest CD4+ count unknown ethnicity, more likely to be a current smoker or 25 2 MI ex-smoker, and to have normal (18, 26 kg/m )BMI. CHD They were also more likely to exhibit traditional CVD risk 20 Stroke factors, including a prior personal or family history of CVD CVD, dyslipidemia, or hypertension. CD4þ cell counts 15 (current and nadir) were higher in those with conﬁrmed

10 strokes and patients were more likely to be on antiretroviral therapy with a suppressed viral load. In contrast, differences

5 between patients with conﬁrmed strokes and stroke-like

Rate (/1000 person-years) events were less marked, although there were differences in 0 gender, mode of HIV acquisition, ethnicity, and current <100 100–199 200–299 300–399 400–499 ≥500 smoking. Latest CD4+ count (cells/µl) þ (b) Associations between the latest CD4 cell count, Nadir CD4+ count established stroke risk factors, and the three stroke 25 þ MI endpoints are shown in Table 3. The CD4 cell count CHD gradient appeared to strengthen with the inclusion of 20 Stroke stroke-like and rejected stroke events. Similarly, the CVD association with a low BMI also appeared to increase after 15 inclusion of stroke-like and rejected stroke events.

10 In contrast, associations with current smoking and hypertension were both attenuated as the endpoint 5 was broadened to include the stroke-like and rejected

Rate (/1000 person-years) events. 0 <100 100–199 200–299 300–399 400–499 ≥500 When only conﬁrmed strokes were included in the + µ Nadir CD4 count (cells/ l) endpoint, there was no evidence that any of the (c) associations with stroke risk factors differed signiﬁcantly Duration of immune suppression between those with low or high CD4þ cell counts 25 MI (Table 4). However, when stroke-like events were CHD included, there was some evidence that the impact of 20 Stroke hypertension (P value for interaction: 0.01) and a previous CVD 15 CVD event (P ¼ 0.08) were both reduced in those with low CD4þ cell counts. When the endpoint was 10 expanded to additionally include rejected events, the prognostic values of age (P value for interaction: 0.08), 5 a previous CVD event (P ¼ 0.05), and hypertension Rate (/1000 person-years) þ 0 (P ¼ 0.002) were all reduced in those with low CD4 None ≤2 >2,≤4 >4,≤6 >6,≤8 >8,≤10 >10 cell counts. Duration of immunosuppression (years)

Fig. 1. Crude event rates (/1000 person-years of follow-up) for myocardial infarction, coronary heart disease, stroke, R and cardiovascular disease stratiﬁed by the (a) latest CD4 Discussion R cell count, (b) nadir CD4 count, and (c) duration of immune þ depression. CHD, coronary heart disease; CVD, cardiovas- Although it appears that individuals with a low CD4 cell cular disease; MI, myocardial infarction. count were more likely to experience a new MI or CHD event over follow-up, this association is largely explained by the higher prevalence of CVD risk factors in these individuals. In contrast, stroke events appear to occur event. Three-hundred and forty-two patients met the more commonly in those with low CD4þ cell counts, criteria for endpoint B [event rate: 1.52 (1.37–1.68)/ and it is this association that appears to drive a weak 1000 person-years], and 366 for endpoint C [1.63 (1.46– association with the CVD endpoint. However, the 1.80)/1000 person-years]. Established stroke risk factors reduced association of events occurring at low CD4þ cell at the time of an event among individuals experiencing counts with the traditional stroke risk factors suggests each event are shown in Table 1. Compared with those that, even with extremely careful central review with rejected stroke events, patients with conﬁrmed stroke and endpoint validation, a proportion of strokes that were more likely to be men, more likely to be infected with occur in individuals with low CD4þ cell counts may be

Table 2. Association between various markers of immune depression and myocardial infarction, coronary heart disease, stroke, and cardiovascular disease events.

Type of event

MI CHD Stroke CVD

(a) Unadjusted for each other marker of immune depression Latest CD4þ cell count (cells/ml) <100 1.07 (0.71, 1.64) 0.96 (0.68, 1.37) 2.02 (1.20, 3.38) 1.19 (0.89, 1.60) 100–199 0.98 (0.71, 1.36) 1.00 (0.78, 1.30) 1.49 (0.96, 2.31) 1.04 (0.83, 1.32) 200–299 Ref. Ref. Ref. Ref. 300–399 1.03 (0.79, 1.34) 0.91 (0.73, 1.13) 0.65 (0.42, 1.00) 0.89 (0.73, 1.08) 400–499 0.88 (0.66, 1.16) 0.80 (0.64, 1.01) 0.74 (0.74, 1.13) 0.84 (0.68, 1.03) 500 0.90 (0.71, 1.14) 0.83 (0.68, 1.00) 0.75 (0.53, 1.06) 0.84 (0.71, 1.00) Nadir CD4þ count (cells/ml) <100 1.15 (0.93, 1.43) 1.13 (0.94, 1.34) 1.10 (0.81, 1.50) 1.09 (0.93, 1.28) 100–199 0.96 (0.76, 1.21) 0.96 (0.80, 1.16) 1.09 (0.79, 1.52) 0.99 (0.83, 1.17) 200–299 Ref. Ref. Ref. Ref. 300–399 0.79 (0.57, 1.09) 0.81 (0.63, 1.05) 0.63 (0.38, 1.04) 0.77 (0.61, 0.98) 400–499 0.62 (0.38, 1.01) 0.61 (0.41, 0.92) 0.51 (0.25, 1.08) 0.62 (0.43, 0.88) 500 1.11 (0.75, 1.63) 1.20 (0.88, 1.64) 0.58 (0.29, 1.17) 1.01 (0.75, 1.36) Duration of immune depression (years) None Ref. Ref. Ref. Ref. 2 1.09 (0.91, 1.31) 1.06 (0.91, 1.24) 1.27 (0.98, 1.66) 1.09 (0.95, 1.25) >2, 4 1.33 (1.04, 1.70) 1.29 (1.05, 1.58) 1.44 (1.00, 2.07) 1.29 (1.07, 1.55) >4, 6 1.33 (0.98, 1.81) 1.34 (1.04, 1.73) 1.16 (0.70, 1.92) 1.25 (0.99, 1.58) >6, 8 0.86 (0.54, 1.35) 1.04 (0.74, 1.48) 1.23 (0.64, 2.37) 1.01 (0.73, 1.39) >8, 10 1.61 (1.01, 2.57) 1.27 (0.84, 1.93) 0.91 (0.34, 2.49) 1.20 (0.81, 1.78) >10 1.13 (0.61, 2.13) 1.38 (0.87, 2.19) 2.50 (1.29, 4.82) 1.64 (1.11, 2.42) (b) Mutually adjusted for each other marker of immune depression (patients exposed to antiretroviral therapy only) Latest CD4þ cell count (cells/ml) <100 0.96 (0.62, 1.50) 0.89 (0.30, 2.63) 2.26 (1.29, 3.94) 1.14 (0.84, 1.56) 100–199 0.95 (0.68, 1.33) 0.99 (0.76, 1.29) 1.63 (1.03, 2.59) 1.04 (0.82, 1.33) 200–299 Ref. Ref. Ref. Ref. 300–399 1.09 (0.83, 1.43) 0.93 (0.75, 1.17) 0.69 (0.44, 1.09) 0.92 (0.75, 1.13) 400–499 0.96 (0.72, 1.29) 0.85 (0.67, 1.07) 0.80 (0.52, 1.25) 0.89 (0.72, 1.10) 500 1.01 (0.78, 1.32) 0.88 (0.71, 1.09) 0.83 (0.56, 1.21) 0.91 (0.75, 1.10) Nadir CD4þ count (cells/ml) <100 1.36 (0.57, 3.23) 0.98 (0.45, 2.16) 1.36 (0.54, 3.43) 1.20 (0.65, 2.23) 100–199 1.17 (0.50, 2.74) 0.89 (0.41, 1.93) 1.54 (0.63, 3.79) 1.16 (0.64, 2.13) 200–299 Ref. Ref. Ref. Ref. 300–399 0.78 (0.56, 1.09) 0.86 (0.66, 1.12) 0.66 (0.39, 1.13) 0.81 (0.64, 1.04) 400–499 0.73 (0.45, 1.19) 0.73 (0.48, 1.10) 0.62 (0.28, 1.36) 0.73 (0.51, 1.06) 500 1.27 (0.85, 1.92) 1.34 (0.96, 1.89) 0.80 (0.38, 1.69) 1.18 (0.85, 1.63) Duration of immune depression (years) None Ref. Ref. Ref. Ref. 2 0.79 (0.34, 1.82) 1.05 (0.49, 2.26) 0.67 (0.28, 1.57) 0.83 (0.46, 1.49) >2, 4 0.92 (0.39, 2.16) 1.20 (0.55, 2.62) 0.69 (0.28, 1.69) 0.94 (0.51, 1.72) >4, 6 0.93 (0.39, 2.23) 1.23 (0.56, 2.72) 0.54 (0.21, 1.39) 0.90 (0.48, 1.67) >6, 8 0.60 (0.24, 1.52) 0.95 (0.42, 2.17) 0.52 (0.18, 1.47) 0.71 (0.37, 1.37) >8, 10 1.13 (0.44, 2.90) 1.14 (0.48, 2.69) 0.35 (0.10, 1.27) 0.83 (0.42, 1.68) >10 0.81 (0.29, 2.26) 1.24 (0.51, 2.99) 0.86 (0.30, 2.42) 1.10 (0.55, 2.21)

Results shown are relative rate and 95% conﬁdence interval, and include adjustment for potential confounders as described in the Methods section. ART, antiretroviral therapy; CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction.

caused by HIV-associated CNS disorders and not by consider stroke as an outcome (or as part of a composite traditional atherosclerotic pathophysiological processes. outcome). Such misclassification will most likely occur at low CD4þ cell counts (when these other disorders are more Concern about the type of endpoint that is included prevalent) and will likely be greater in studies that do not within a broad definition of MI has been raised by Crane apply a similar level of critical review to reported et al. [19] who reported that of 271 definite/probable MIs endpoints. Although inclusion of these events into reported to five sites in the Centers for AIDS Research analyses may result in an increased number of events, (CFAR) Network of Integrated Clinical Systems, 127 and thus greater statistical power, their inclusion may also (47%) were secondary or type 2 MI events (i.e. they lead to misleading conclusions regarding the role of risk occurred due to myocardial supply/demand mismatch factors for stroke. These findings may at least partly in the setting of sepsis or hypoxia). Such events might explain some of the inconsistencies between studies that be expected to demonstrate weaker associations with

R Table 3. Association between established stroke risk factors, the latest CD4 cell count, and the three stroke endpoints.

Endpoint A Endpoint B Endpoint C

Relative rate Relative rate Relative rate (95% CI) P value (95% CI) P value (95% CI) P value

Age Per 5 years older 1.41 (1.35, 1.49) 0.0001 1.41 (1.35, 1.48) 0.0001 1.41 (1.35, 1.48) 0.0001 Male sex 1.19 (0.88, 1.62) 0.26 1.25 (0.93, 1.67) 0.13 1.21 (0.91, 1.60) 0.18 Smoking status Current smoker 1.52 (1.12, 2.06) 0.008 1.42 (1.07, 1.89) 0.02 1.38 (1.05, 1.81) 0.02 Ex-smoker 1.04 (0.74, 1.45) 0.82 1.01 (0.74, 1.38) 0.95 0.96 (0.71, 1.29) 0.78 Never smoker 1 – 1 – 1 – Unknown 1.59 (1.07, 2.37) 0.02 1.34 (0.92, 1.96) 0.12 1.44 (1.01, 2.05) 0.04 BMI (kg/m2) <18 2.06 (1.32, 3.24) 0.002 2.02 (1.32, 3.08) 0.0001 2.07 (1.39, 3.09) 0.0004 18, 261–1–1– >26, 30 0.77 (0.55, 1.08) 0.14 0.75 (0.54, 1.03) 0.08 0.79 (0.58, 1.07) 0.13 >30 1.02 (0.64, 1.62) 0.95 1.02 (0.66, 1.59) 0.92 1.00 (0.65, 1.55) 0.99 Unknown 0.68 (0.39, 1.19) 0.18 0.73 (0.44, 1.22) 0.23 0.71 (0.43, 1.17) 0.18 Previous CVD event 1.40 (1.02, 1.90) 0.03 1.35 (1.00, 1.81) 0.05 1.36 (1.02, 1.81) 0.04 Hypertension 2.14 (1.66, 2.75) 0.0001 1.96 (1.54, 2.49) 0.0001 1.91 (1.51, 2.41) 0.0001 Latest CD4þ cell count Per doubling 0.81 (0.74, 0.89) 0.0001 0.77 (0.71, 0.84) 0.0001 0.75 (0.70, 0.81) 0.0001

Three endpoints are as follows: A. confirmed strokes only; B. confirmed strokes þ stroke-like events; and C. confirmed strokes, stroke-like events, and nonstroke events. CI, confidence interval; CVD, cardiovascular disease.

traditional MI risk factors; patients with secondary MIs Associations were reported between the CVD rate and tended to have lower CD4þ cell counts than those with both the baseline and latest CD4þ cell count. As the primary MIs, suggesting that an association with a low authors found no association with antiretroviral treat- CD4þ cell count may be induced if such events are ment, analyses were not adjusted for treatment use. The included in endpoints. French APROCO-COPILOTE study reported a strong association between a CD4þ cell count less than There is increasing evidence that HIV, or its associated 200 cells/ml and a lower risk of a major coronary or inflammation and/or thrombosis, may lead to an arterial disease event (MI, stroke, coronary and peripheral increased risk of CVD [20–22]. However, findings from arterial disease, or cardiovascular surgery), although only the literature surrounding a possible association between 49 events occurred in 1154 participants [24]. cardiovascular/cerebrovascular events (CVEs) and CD4þ cell count are conflicting. Triant et al. [1] considered the In the Strategies for Management of Antiretroviral risk of acute MI (ICD-9-CM code 410.xx [23]) in HIV- Therapy (SMART) trial [7], no association was found diagnosed patients in two hospitals in Boston. Whereas between the baseline CD4þ cell count and the risk of a 41.4% of the 273 patients with acute MI had a latest major CVD event (death from CVD, clinical MI, silent CD4þ cell count less than 200 cells/ml, only 25.4% of MI, nonfatal stroke, or coronary artery disease requiring 6244 controls had a CD4þ cell count in the same range. surgery or invasive procedure), although only 72 events The association with the latest CD4þ cell count remained occurred in the trial, limiting statistical power. All trial after adjustment for several demographic and cardiovas- endpoints were captured using a detailed clinical case cular risk factors, although an association with the nadir definition, and were reviewed and classified centrally. CD4þ cell count was less supported. Of note, only 59% of Ford et al. [9] considered patients participating those with acute MI had a CD4þ cell count available for in National Institutes of Allergy and Infectious analysis in comparison to 70% of those without acute MI, Diseases (NIAID) clinical protocols; 52 patients were raising the possibility that some of the association may be a identified from electronic medical records as having consequence of unmeasured confounding. In a study CVD (acute MI, silent MI, coronary revascularization, from the French Hospitals Database on HIV [8], whereas acute coronary syndrome, cardiovascular accident, lower nadir CD4þ counts were slightly lower in individuals extremity revascularization, or sudden cardiovascular with an MI than in matched controls without an MI, death). There was no significant difference in the CD4þ cell counts at the event did not differ significantly. nadir CD4þ count between cases and matched controls, Although a standard definition of MI was used, events nor in the latest CD4þ cell count, either measured within were classified up to 6 years retrospectively and may, the 4 months prior to the event or 2 years prior to therefore, be subject to ascertainment bias. Lichtenstein the event, with traditional CVD risk factors being the et al. [3] followed patients attending clinics participating only factors that predicted an individual’s case/control in the HIV Outpatient Study (HOPS). Signs, symptoms, status. and diagnoses were extracted from medical charts and were reviewed centrally for quality. CVD was defined as Other related outcomes have also been considered, an MI, nonembolic/nonhemorrhagic stroke, coronary including studies of the metabolic syndrome [25–27] and artery disease, angina, or peripheral arterial disease. diabetes [28,29], few of which have reported strong

M þ

3 associations with the CD4 cell count. There is some

value evidence from other studies of an association between a

P þ

l low CD4 cell count and coronary artery calciﬁcation m score [30], dyslipidemia [31], arterial stiffness [32], carotid intima–media thickness [33], brachial artery ﬂow- mediated dilation [34], and carotid lesions [35], although 200 cells/

results from studies are often inconsistent [36]. þ Fewer studies have considered stroke as an endpoint. l CD4

m Chow et al. [6] reported no association between the latest CD4þ cell count and the risk of ischemic stroke. Rasmussen et al. [2] considered the incidence of CVEs in

200 cells/ the Danish HIV-positive population through linkage <

þ between several national databases and registry studies. CVE was deﬁned as an episode of nontraumatic CD4

M subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, unspeciﬁed stroke, or transient value

P ischemic attack. Among noninjection drug users in the

l þ m m study, those with a CD4 cell count of 200 cells/ l or less not on HAARTwere over twice as likely to experience a cell count. CVE compared to those with a higher CD4þ cell count R þ 200 cells/

l. not on HAART. Interestingly, those with a CD4 cell m

þ count of 200 cells/ml or less who were on HAARTwere also at slightly higher risk of CVE, although this

l CD4 difference was weaker. More recently, Vinikook et al. 200 cells/ m

[37] reported 42 CVEs (stroke or transient ischemic attack) among HIV-positive individuals in North Carolina, with no evidence of a difference in CD4þ 200 vs. 200 cells/ < < cell count between patients who did and did not þ experience an event. CD4 M

cell count Although MI rates were higher in those with a CMV

þ AIDS-defining event, consistent with findings in the value P stroke-like events; and C. confirmed strokes, stroke-like events, and nonstroke events. CI, confidence interval; CVD, general population of an association between CMV l þ m infection and CVD [18], this association was not specific to CMV. These results suggest that opportunistic infection development may identify a group of individuals 200 cells/

with advanced immune depression that is not captured by þ CD4þ cell count history. Alternatively, our ﬁndings may be suggestive of bias due to increased patient monitoring Endpoint A Endpoint B Endpoint C l CD4

m (and thus earlier MI diagnosis) in individuals who are sick.

Relative rate (95% CI) Relative rate (95% CI)Of Relative rate (95% CI) note, as the study does not capture information on infection with CMV, we used a CMV AIDS-deﬁning

200 cells/ event as a surrogate marker of recent infection; this will, < þ however, underestimate the rate of recent CMV infection

CD4 in the cohort and analyses that capture CMV serostatus may reach different conclusions.

Limitations 2630 0.92 (0.41, 2.06) 0.75 1 (0.52, 1.08) 0.35 0.74 (0.33, 1.63) 0.74 (0.52, 1.05) 1 0.66 0.73 (0.35, 1.53) 0.79 – (0.56, 1.10) 0.78 1 1 – 1 1 –

Although our study is large and beneﬁts from a long

1818, 26, 30 2.30 (1.10, 4.82) 1.93 (1.09, 3.42) 0.72 (0.17, 2.99) 0.29 1.05 (0.64, 1.72) 2.27 (1.17, 4.42) 0.33duration 1.89 (1.09, 3.27) 0.60 (0.14, 2.48) 0.52 1.07 (0.67, 1.72) 2.09of (1.11, 3.93) 0.81 follow-up, 2.10 (1.25, 3.52) 0.75 (0.23, 2.42) 0.78 1.03 (0.65, 1.65) the 0.97 use of established clinical Ex-smokerNever smokerUnknown 0.80 (0.35, 1.85) 1.08 1.53 (0.75, (0.69, 1.55) 3.37) 1 1.57 0.56 (0.99, 2.49) 0.81 (0.40, 0.84 1.64) 1.19 1.05 (0.59, (0.74, 2.41) 1.48) 1 1.42 0.55 (0.91, 2.22) 0.67 (0.34, 0.98 1.33) 1.29 1.02 (0.70, (0.73, 2.41) 1.44) – 1.50 0.26 (0.98, 2.30) 0.95 1 1 – 1 1 – < > > Unknown 0.34 (0.08, 1.44) 0.77 (0.42, 1.42) 0.82 0.53definitions (0.19, 1.47) 0.76 (0.42, 1.38) 0.62 for 0.54 (0.22,outcomes 1.37) 0.73 (0.41, 1.31) 0.73 and central validation of events, some limitations must be noted. First, as the definition of stroke used in the D:A:D study was not specifically ) 2 designed to separate atherosclerotic and nonatherosclerotic causes, our study may also suffer from some

values relate to a test of interaction between the covariate of interest andmisclassification. a CD4 Second, the low number of stroke-like P Table 4. Associations between established stroke risk factors and the three stroke endpoints stratified by the latest CD4 AgeMale sexSmoking status Current smokerBMI (kg/m 1.26 Per (0.62, 5 2.57) years older 1.36 1.54 (1.21, (1.10, 1.53) 2.16) 1.43 (1.35, 0.93 1.51) 1.01 0.14 (0.54, 1.89) 1.06 (0.55, 2.03) 1.38 (1.25, 1.50 1.53) (1.09, 2.06) 1.23M (0.87, 1.74) 1.42 (1.34, 0.51 1.50) 0.51 0.93 0.20 (0.52, 1.17 1.66) (0.65, 2.13) 1.37 (1.25, 1.47 1.50) (1.08, 1.28 2.01) (0.92, 1.80) 1.42 0.3 (1.35, 1.50) 0.55 0.08 0.98 (0.58, 1.65) 1.32 (0.95, 1.83) 0.18 Previous CVD eventHypertensionThree endpoints are as follows:cardiovascular A. confirmed disease. strokes only; B. confirmed strokes 0.98and (0.29, 3.36) 1.49 (1.07, rejected 2.08) 1.59 (0.84, 2.99) 0.13 2.28 (1.72, 3.01) 0.97 (0.45, events 2.12) 0.08 1.45 (1.05, 2.00) 1.14 (0.62, 2.08)results 0.08 2.20 (1.69, 2.87) 0.98 (0.47,in 2.04) 0.01 a 1.47 (1.08, 2.01)loss 1.05 (0.59, 1.87) 0.05 of 2.19 (1.69, 2.84) power 0.002 to detect

differences between the various endpoints. Third, contributed datasets, provided comments on the initial although our analyses incorporate historic CD4þ cell analysis plan, feedback on the draft manuscript, and have count information that is available prior to an individual’s seen and approved the final version that was submitted inclusion in the study, this information may be for publication. incomplete for some patients; thus, our estimates of exposure to immune depression may be underestimated. D:A:D participating cohorts and Steering Committee The frequency with which CD4þ cell counts are (names marked with ) monitored may vary between patients, adding further variability to any assessment of exposure to immune Members of the D:A:D SC from the Oversight depression. Finally, even if the associations with CD4þ Committee: N. Shortman, D. Butcher, R. Rode,X. cell count are believed to reflect true associations, further Franquet, W. Powderly research is needed to establish whether these associations are causal or reflect bias/unmeasured confounding. D:A:D Central Coordination: L. Ryom, C.A. Sabin, D. Kamara, C. Smith, A. Phillips, A. Mocroft, J. In summary, we do not find strong evidence that Tverland, J. Nielsen, J.D. Lundgren (chair) individuals with a low CD4þ cell count are more likely to experience a new MI or CHD event. Although stroke D:A:D data managers: R. Salbøl Brandt (coordinator), events appear to occur more commonly in those with low M. Rickenbach, I. Fanti, E. Krum, M. Hillebregt, S. CD4þ cell counts, some of this association may be Geffard, A. Sundstro¨m, M. Delforge, E. Fontas, F.Torres, explained by misclassification of events at low CD4þ cell H. McManus, S. Wright, J. Kjær. counts or other biases. These findings may explain some of the inconsistencies in the literature regarding Endpoint verification Group: A. Sjøl (CVD primary associations between the CD4þ cell count and various endpoint), P. Meidahl (oncology), J. Helweg-Larsen outcomes, and lend support to the use of clearly defined (hematology), J. Schmidt Iversen (nephrology). and well validated outcomes in any study. Although our analyses focus on an HIV-positive population, in which The members of the 11 Cohorts are as follows: the underlying rates of such events remain low, our findings may also have implications for non-HIV ATHENA (AIDS Therapy Evaluation Project Nether- immunodeficient populations (e.g. transplant recipients) lands): Central coordination: F. de Wolf, S. Zaheri, M in whom an excess risk of CVD may be seen [38]. Hillebregt L.Gras; Participating physicians (¤Site coordinating physicians): Academisch Medisch Centrum bij de Universiteit van Amsterdam, Acknowledgements Amsterdam: J.M. Prins¤, T.W. Kuijpers, H.J. Scherp- bier, K. Boer, J.T.M. van der Meer, F.W.M.N. Wit, M.H. C.S. contributed to the initial design of the study and Godfried, P.Reiss, T. van der Poll, F.J.B. Nellen, J.M.A. development of the study protocol, had access to all study Lange, S.E. Geerlings, M. van Vugt, S.M.E. Vrouenraets, data, performed all statistical analyses, was responsible for D. Pajkrt, M. van der Valk. Academisch Ziekenhuis preparing the initial draft manuscript and all tables/ Maastricht, Maastricht: G. Schreij¤, S. Lowe, A. Oude figures, and for writing the final version. Lashof. Catharina-ziekenhuis, Eindhoven: M.J.H. Pronk¤, B. Bravenboer. Erasmus Medisch Centrum, L.R. and S.W.W.co-ordinated the data collection from all Rotterdam: M.E. van der Ende¤, T.E.M.S. de Vries- participating sites, prepared the datasets for analysis, and Sluijs, C.A.M. Schurink, M. van der Feltz, J.L. Nouwen, assisted with endpoint review. They both contributed to L.B.S. Gelinck, A. Verbon, B.J.A. Rijnders, L. Slobbe. the initial design of the study and development of the Erasmus Medisch Centrum–Sophia, Rotterdam: study protocol. N.G. Hartwig, G.J.A. Driessen. Flevoziekenhuis, Almere: J. Branger¤. HagaZiekenhuis, Den Haag: A.N.P. contributed to the initial design of the study and R.H. Kauffmann¤, E.F. Schippers. Isala Klinieken, development of the study protocol. Zwolle: P.H.P. Groeneveld¤, M.A. Alleman, J.W. Bouwhuis. Kennemer Gasthuis: R.W. ten Kate¤, R. D.K. generated statistical datasets and performed quality Soetekouw. Leids Universitair Medisch Centrum, control checks of the data. Leiden: F.P. Kroon¤, P.J. van den Broek, J.T. van Dissel, S.M. Arend, C. van Nieuwkoop, M.G.J. de Boer, H. J.D.L. designed the initial concept of the D:A:D Study Jolink. Maasstadziekenhuis, Rotterdam: J.G. den and obtained all funding and contributed to the Hollander¤, K. Pogany. Medisch Centrum Alkmaar, development of the study protocol. Alkmaar: G. van Twillert¤, W. Kortmann. Medisch Centrum Haaglanden, Den Haag: R. Vriesendorp¤, S.dW., A.M., R.W., A.dM., P.R., W.E-S., C.P., F.D., and E.M.S. Leyten. Medisch Spectrum Twente, M.L. provided management input to the D:A:D Study, Enschede: C.H.H. ten Napel¤, G.J. Kootstra. Onze

Lieve Vrouwe Gasthuis, Amsterdam: K. Brinkman¤, Data collection and processing: MJ. Blaizeau, M. W.L. Blok, P.H.J. Frissen, W.E.M. Schouten, G.E.L. van Decoin, J. Delaune, S. Delveaux, C. D’Ivernois, C. den Berk. Sint Elisabeth Ziekenhuis, Tilburg: J.R. Hanappier, O. Leleux, B. Uwamaliya-Nziyumvira, X. Juttmann¤, M.E.E. van Kasteren, A.E. Brouwer. Sint Sicard. Computing and Statistical analysis: S. Lucas Andreas Ziekenhuis, Amsterdam: J. Veen- Geffard, J. Leray, G. Palmer, D. Touchard. stra¤, K.D. Lettinga. Slotervaartziekenhuis, Amster- dam: J.W. Mulder¤, E.C.M. van Gorp, P.M. Smit, S. AHOD (Australian HIV Observational Database, Aus- Weijer. Stichting Medisch Centrum Jan van Goyen, tralia): Central coordination: M. Law, K. Petoumenos, Amsterdam: A. van Eeden, D.W.M. Verhagen¤. H. McManus, S. Wright, C. Bendall (Sydney, New South Universitair Medisch Centrum Groningen, Gro- Wales); Participating physicians (city, state): R. Moore, S. ningen: H.G. Sprenger¤, R. Doedens, E.H. Scholvinck, Edwards, J. Hoy, K. Watson, N. Roth, J. Nicholson S. van Assen, C.J. Stek. Universitair Medisch Centrum (Melbourne, Victoria); M Bloch, T. Franic, D. Baker, R. Sint Radboud, Nijmegen: P.P. Koopmans¤, R. de Vale, A. Carr, D. Cooper (Sydney, New South Wales); J. Groot, M. Keuter, A.J.A.M. van der Ven, H.J.M. ter Chuah, M. Ngieng (Gold Coast, Queensland), D. Nolan, Hofstede, M. van der Flier, A.M. Brouwer, A.S.M. J. Skett (Perth, Western Australia). Dofferhoff. Universitair Medisch Centrum Utrecht, Utrecht: A.I.M. Hoepelman¤, T. Mudrikova, M.M.E. BASS (Spain): Central coordination: G. Calvo, F. Schneider, C.A.J.J. Jaspers, P.M.Ellerbroek, E.J.G. Peters, Torres, S. Mateu (Barcelona); Participating physicians L.J. Maarschalk-Ellerbroek, J.J. Oosterheert, J.E. Arends, (city): P. Domingo, M.A. Sambeat, J. Gatell, E. Del M.W.M. Wassenberg, J.C.H. van der Hilst. Vrije Cacho, J. Cadafalch, M. Fuster (Barcelona); C. Codina, Universiteit Amsterdam, Amsterdam: S.A. Dan- G. Sirera, A. Vaque´ (Badalona). ner¤, M.A. van Agtmael, J. de Vocht, R.M. Perenboom, F.A.P. Claessen, W.F.W. Bierman, E.V. de Jong, E.A. bij The Brussels St Pierre Cohort (Belgium): Coordina- de Vaate. Wilhelmina Kinderziekenhuis, Utrecht: tion: S. De Wit, N. Clumeck, M. Delforge, C. Necsoi. S.P.M. Geelen, T.F.W. Wolfs. Ziekenhuis Rijnstate, Participating physicians: N. Clumeck, S. De Wit, AF Arnhem: C. Richter¤, J.P. van der Berg, E.H. Gisolf. Gennotte, M. Gerard, K. Kabeya, D. Konopnicki, A. Ziekenhuis Walcheren, Vlissingen: M. van den Libois, C. Martin, M.C. Payen, P. Semaille, Y. Van Berge¤, A. Stegeman. Medisch Centrum Leeuwar- Laethem. den, Leeuwarden: D.P.F. van Houte¤, M.B. Poleé, M.G.A. van Vonderen. Sint Elisabeth Hospitaal, CPCRA (USA): Central coordination: J. Neaton, G. Willemstad - Curaçao: C. Winkel, A.J. Duits. Bartsch, W.M. El-Sadr, E. Krum, G. Thompson, D. Wentworth; Participating physicians (city, state): R. ANRS CO3 Aquitaine Cohort (France) Luskin-Hawk (Chicago, Illinois); E. Telzak (Bronx, New York); W.M. El-Sadr (Harlem, New York); D.I. Abrams Composition of the Groupe d’Epide´miologie Clinique (San Francisco, California); D. Cohn (Denver, Colorado); du Sida en Aquitaine (GECSA): N. Markowitz (Detroit, Michigan); R. Arduino (Hous- ton, Texas); D. Mushatt (New Orleans, Louisiana); G. Coordination: F. Dabis. Scientific committee: F. Friedland (New Haven, Connecticut); G. Perez (New- Bonnet, F. Dabis, M. Dupon, G. Cheˆne, H. Fleury, D. ark, New Jersey); E. Tedaldi (Philadelphia, Pennsylvania); Lacoste, D. Malvy, P. Mercie´, I. Pellegrin, P. Morlat, D. E. Fisher (Richmond, Virginia); F. Gordin (Washington, Neau, JL. Pellegrin, R. Thie´baut, K. Titier. Epide- DC); L.R. Crane (Detroit, Michigan); J. Sampson miology and Methodology: M. Bruyand, G. Cheˆne, F. (Portland, Oregon); J. Baxter (Camden, New Jersey). Dabis, S. Lawson-Ayayi, R. Thie´baut, L. Wittkop. Infectious Diseases and Internal Medicine:F. EuroSIDA (multinational) Coordinating Centre: J. Bonnal, F. Bonnet, N. Bernard, L. Caune`gre, C. Lundgren#, O. Kirk, A. Mocroft, A. Cozzi-Lepri, D. Cazanave, J. Ceccaldi, D. Chambon, I. Chossat, K. Grint, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Courtaud, FA. Dauchy, S. De Witte, M. Dupon, A. Kowalska, J. Tverland, A.H. Fischer, J. Nielsen Parti- Dupont, P. Duffau, H. Dutronc, S. Farbos, V. Gaboriau, cipating countries and physicians Argentina: (M. MC. Gemain, Y. Gerard, C. Greib, M. Hessamfar, D. Losso), C. Elias, Hospital JM Ramos Mejia, Buenos Aires. Lacoste, P. Lataste, S. Lafarie-Castet, E. Lazaro, M. Austria: (N. Vetter), Pulmologisches Zentrum der Stadt Longy-Boursier, D. Malvy, JP. Meraud, P. Mercie´,E. Wien, Vienna; R. Zangerle, Medical University Monlun, P. Morlat, D. Neau, A. Ochoa, JL. Pellegrin, T. Innsbruck, Innsbruck. Belarus: (I. Karpov), A. Vassilenko, Pistone, JM. Ragnaud, MC. Receveur, J. Roger- Belarus State Medical University, Minsk; V.M. Mitsura, Schmeltz, S. Tchamgoue´, P.Thibaut, MA. Vandenhende, Gomel State Medical University, Gomel; O. Suetnov, JF. Viallard. Immunology: JF. Moreau, I. Pellegrin. Regional AIDS Centre, Svetlogorsk. Belgium: (N. Virology: H. Fleury, ME. Lafon, B. Masquelier, P. Clumeck), S. De Wit, M Delforge, Saint-Pierre Hospital, Trimoulet. Pharmacology: D. Breilh, K. Titier. Drug Brussels; R. Colebunders, Institute of Tropical Medicine, monitoring: F. Haramburu, G. Miremont-Salame´. Antwerp; L. Vandekerckhove, University Ziekenhuis

Gent, Gent. Bosnia-Herzegovina: (V. Hadziosmanovic), Maeland, J. Bruun, Ulleva˚l Hospital, Oslo. Poland: (B. Klinicki Centar Univerziteta Sarajevo, Sarajevo. Bulgaria: Knysz), J. Gasiorowski, Medical University, Wroclaw; A. (K. Kostov), Infectious Diseases Hospital, Sofia. Croatia: Horban, E. Bakowska, Centrum Diagnostyki i Terapii (J. Begovac), University Hospital of Infectious Diseases, AIDS, Warsaw; A. Grzeszczuk, R. Flisiak, Medical Zagreb. Czech Republic: (L. Machala), D. Jilich, Faculty University, Bialystok; A. Boron-Kaczmarska, M. Pynka, Hospital Bulovka, Prague; D. Sedlacek, Charles Univer- M. Parczewski, Medical Univesity, Szczecin; M. sity Hospital, Plzen. Denmark: (J. Nielsen), G. Kron- Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii borg,T. Benfield, M. Larsen, Hvidovre Hospital, AIDS, Chorzow; H. Trocha, Medical University, Copenhagen; J. Gerstoft, T. Katzenstein, A-B.E. Hansen, Gdansk; E. Jablonowska, E. Malolepsza, K. Wojcik, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Wojewodzki Szpital Specjalistyczny, Lodz. Portugal: (F. Odense University Hospital, Odense; L. Ostergaard, Antunes), M. Doroana, L. Caldeira, Hospital Santa Skejby Hospital, Aarhus. Estonia: (K. Zilmer), West- Maria, Lisbon; K Mansinho, Hospital de Egas Moniz, Tallinn Central Hospital, Tallinn; J. Smidt, Nakkusosa- Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon. kond Siseklinik, Kohtla-Ja¨rve. Finland: (M. Ristola), Romania: (D. Duiculescu), Spitalul de Boli Infectioase Helsinki University Central Hospital, Helsinki. France: si Tropicale: Dr Victor Babes, Bucarest. Russia: (A. (C. Katlama), Hoˆpital de la Pitie´-Salpe´tie`re, Paris; J-P. Rakhmanova), Medical Academy Botkin Hospital, St Viard, Hoˆpital Necker-Enfants Malades, Paris; P-M. Petersburg; N. Zakharova, St Petersburg AIDS Centre, St Girard, Hospital Saint-Antoine, Paris; J.M. Livrozet, Peterburg; S. Buzunova, Novgorod Centre for AIDS, Hoˆpital Edouard Herriot, Lyon; P. Vanhems, University Novgorod. Serbia: (D. Jevtovic), The Institute for Claude Bernard, Lyon; C. Pradier, Hoˆpital de l’Archet, Infectious and Tropical Diseases, Belgrade. Slovakia: Nice; F. Dabis, D. Neau, Unite´ INSERM, Bordeaux. (M. Mokra´ˇs), D. Stanekova´,De´rer Hospital, Bratislava. Germany: (J. Rockstroh), Universita¨ts Klinik Bonn; R. Slovenia: (J. Tomazic), University Clinical Centre Schmidt, Medizinische Hochschule Hannover; J. van Ljubljana, Ljubljana. Spain: (J. Gonza´lez-Lahoz), V. Lunzen, O. Degen, University Medical Center Ham- Soriano, P. Labarga, J. Medrano, Hospital Carlos III, burg-Eppendorf, Infectious Diseases Unit, Hamburg; Madrid; S. Moreno, J.M. Rodriguez, Hospital Ramon y H.J. Stellbrink, IPM Study Center, Hamburg; S. Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Staszewski, JW Goethe University Hospital, Frankfurt; Puig, I. Bravo, Hospital Germans Trias i Pujol, Badalona; J. Bogner, Medizinische Poliklinik, Munich; G. Fa¨tken- J.M. Gatell, J.M. Miro´, Hospital Clinic i Provincial, heuer, Universita¨tKo¨ln, Cologne. Greece: (J. Kosmidis), Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. P.Gargalianos, G. Xylomenos, J. Perdios, Athens General Sambeat, Hospital Sant Pau, Barcelona. Sweden: (A. Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Karlsson), Venhaelsan-Sodersjukhuset, Stockholm; L. Hospital; H. Sambatakou, Ippokration Genereal Hospi- Flamholc, Malmo¨ University Hospital, Malmo¨. Switzer- tal, Athens. Hungary: (D. Banhegyi), Szent La´slo´ land: (B. Ledergerber), R. Weber, University Hospital, Hospital, Budapest. Ireland: (F. Mulcahy), St. James’s Zu¨rich; P. Francioli, M. Cavassini, Centre Hospitalier Hospital, Dublin. Israel: (I. Yust), D. Turner, M. Burke, Universitaire Vaudois, Lausanne; B. Hirschel, E. Boffi, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Hospital Cantonal Universitaire de Geneve, Geneve; H. Rambam Medical Center, Haifa; S. Maayan, Hadassah Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital, Jerusalem. Italy: (S. Vella), Istituto University Hospital Basel. Ukraine: (E. Kravchenko), N. Superiore di Sanita`, Rome; R. Esposito, I. Mazeu, C. Chentsova, Kiev Centre for AIDS, Kiev; V. Frolov, G. Mussini, Universita` Modena, Modena; C. Arici, Ospe- Kutsyna, Luhansk State Medical University; Luhansk; S. dale Riuniti, Bergamo; R. Pristera, Ospedale Generale Servitskiy, Odessa Region AIDS Center, Odessa; M. Regionale, Bolzano; F.Mazzotta, A. Gabbuti, Ospedale S Krasnov, Kharkov State Medical University, Kharkov. Maria Annunziata, Firenze; V. Vullo, M. Lichtner, United Kingdom: (S. Barton), St. Stephen’s Clinic, University di Roma la Sapienza, Rome; A. Chirianni, Chelsea and Westminster Hospital, London; A.M. E. Montesarchio, M. Gargiulo, Presidio Ospedaliero AD Johnson, D. Mercey, University College London, Cotugno, Monaldi Hospital, Napoli; G. Antonucci, A. London (University College Campus); A. Phillips, Testa, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto M.A. Johnson, A. Mocroft, Royal Free Hospital and Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; University College London, London (Royal Free A. Lazzarin, A. Castagna, N. Gianotti, Ospedale San Campus); M. Murphy, Medical College of Saint Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Bartholomew’s Hospital, London; J. Weber, G. Scullard, Milan; A. d’Arminio Monforte, Istituto Di Clinica Imperial College School of Medicine at St. Mary’s, Malattie Infettive e Tropicale, Milan. Latvia: (B. London; M. Fisher, Royal Sussex County Hospital, Rozentale), I. Zeltina, Infectology Centre of Latvia, Brighton; C. Leen, Western General Hospital, Edin- Riga. Lithuania: (S. Chaplinskas), Lithuanian AIDS burgh. Centre, Vilnius. Luxembourg: (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg. Netherlands: (P.Reiss), HivBivus (Sweden): Central coordination: L. Mor- Academisch Medisch Centrum bij de Universiteit van feldt, G. Thulin, A. Sundstro¨m. Participating physi- Amsterdam, Amsterdam. Norway: (V. Ormaasen), A. cians (city):B.A˚ kerlund (Huddinge); K. Koppel, A.

Karlsson (Stockholm); L. Flamholc, C. Ha˚kanga˚rd Guillouet, J. Durant, S. Ferrando, V. Mondain-Miton, A. (Malmo¨). Naqvi, I. Perbost, B. Prouvost-Keller, S. Pillet, P. Pugliese, V. Rahelinirina, P.M. Roger. Clinical research The IcoNA Foundation Study (Italy): assistant: K. Dollet

GOVERNING BODY: M. Moroni (Chair), G. SHCS (Swiss HIV Cohort Study, Switzerland): J. Barth, Angarano, A. Antinori, F. Castelli, R. Cauda, A. M. Battegay, E. Bernasconi, J. Bo¨ni, H.C. Bucher, C. d’Arminio Monforte, G. Di Perri, M. Galli, R. Iardino, Burton-Jeangros, A. Calmy, M. Cavassini, C. Cellerai, R. G. Ippolito, A. Lazzarin, C.F.Perno, O. Armignacco, P.L. Dubs, M. Egger, L. Elzi, J. Fehr, M. Flepp, P. Francioli Viale, F. Von Schlosser. (President of the SHCS), H. Furrer, C.A. Fux, M. Gorgievski, H. Gu¨nthard, B. Hasse, H.H. Hirsch, B. SCIENTIFIC SECRETARY: A. d’Arminio Monforte Hirschel, I. Ho¨sli, C. Kahlert, L. Kaiser, O. Keiser, C. Kind, T. Klimkait, H. Kovari, B. Ledergerber, G. STEERING COMMITTEE: A. Ammassari, M. Martinetti, B. Martinez de Tejada, N. Mu¨ller, D. Nadal, Andreoni, A. Antinori, C. Balotta, P. Bonfanti, S. G. Pantaleo, A. Rauch, S. Regenass, M. Rickenbach, C. Bonora, M. Borderi, M.R. Capobianchi, A. Castagna, F. Rudin, P. Schmid, D. Schultze, F. Scho¨ni-Affolter, J. Ceccherini-Silberstein, P. Cinque, A. Cozzi-Lepri, A. Schu¨pbach, R. Speck, P. Taffe´, A. Telenti, A. Trkola, P. d’Arminio Monforte, A. De Luca, M. Gargiulo, C. Vernazza, V. von Wyl, R. Weber, S. Yerly. Gervasoni, E. Girardi, A. Gori, G. Guaraldi, M. Lichtner, S. Lo Caputo, G. Madeddu, F.Maggiolo, G. Marchetti, S. This work was supported by the Highly Active Marcotullio, L. Monno, R. Murri, C. Mussini, M. Puoti, Antiretroviral Therapy Oversight Committee (HAART- C. Torti OC), a collaborative committee with representation from academic institutions, the European Agency for the STATISTICAL AND MONITORING TEAM: A. Evaluation of Medicinal Products, the United States Food Cozzi-Lepri, P. Cicconi, I. Fanti, T. Formenti, L. Galli, and Drug Administration, the patient community, and all P. Lorenzini pharmaceutical companieswith licensed anti-HIV drugs in the European Union: Abbott Laboratories, Boehringer PARTICIPATING PHYSICIANS AND CEN- Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb, TERS: Italy A. Giacometti, A Costantini, A. Riva Gilead Sciences Inc., Viiv Healthcare, Merck & Co Inc., (Ancona); G. Angarano, L. Monno, C. Carrisa, (Bari); F. Pfizer Inc, F. Hoffman-LaRoche Ltd, and Janssen Maggiolo, G. Lazzari (Bergamo); P.L. Viale, M. Borderi, Pharmaceuticals. G. Verucchi (Bologna); F. Castelli, C. Torti, C. Minardi, (Brescia); T. Quirino, C. Abeli (Busto Arsizio); P.E. Supported by a grant [grant number CURE/97-46486] Manconi, P. Piano (Cagliari); J. Vecchiet, K. Falasca from the Health Insurance Fund Council, Amstelveen, (Chieti); L. Sighinolfi, D. Segala (Ferrara); F.Mazzotta, S. the Netherlands, to the AIDS Therapy Evaluation Project Lo Caputo (Firenze); G. Cassola, G. Viscoli, A. Netherlands (ATHENA); by a grant from the Agence Alessandrini, R. Piscopo, G. Mazzarello (Genova); C. Nationale de Recherches sur le SIDA [grant number Mastroianni, V. Belvisi (Latina); P. Bonfanti, I. Caramma Action Coordonneé no.7, Cohortes], to the Aquitaine (Lecco); A. Chiodera, P. Castelli (Macerata); M. Galli, A. Cohort; The Australian HIV Observational Database Lazzarin, G. Rizzardini, M. Puoti, A. d’Arminio (AHOD) is funded as part of the Asia Pacific HIV Monforte, A.L. Ridolfo, R. Piolini, A. Castagna, S. Observational Database, a program of The Foundation Salpietro, A. Galli, A. Bigoloni, V.Spagnuolo, L. Carenzi, for AIDS Research, amfAR, and is supported in part by a P. Zucchi, M.C. Moioli, R. Rossotti, P. Cicconi, T. grant from the U.S. National Institutes of Health’s Formenti (Milano); C. Mussini, L. Bisio (Modena); A. National Institute of Allergy and Infectious Diseases Gori, G. Lapadula (Monza), N. Abrescia, A. Chirianni, (NIAID) [grant number U01-AI069907] and by uncon- M.G. Guida, M. Gargiulo (Napoli); F.Baldelli, B. Belfiori ditional grants from Merck Sharp & Dohme; Gilead (Perugia); G. Parruti, T. Ursini (Pescara); G. Magnani, Sciences; Bristol-Myers Squibb; Boehringer Ingelheim M.A. Ursitti (Reggio Emilia); R. Cauda, M. Andreoni, Pharmaceuticals Inc.; Roche; Pfizer; GlaxoSmithKline; A. Antinori, V. Tozzi, V. Vullo, A. De Luca, A. d’Avino, Janssen Pharmaceuticals. The Kirby Institute is funded by M. Zaccarelli, L. Gallo, E. Nicastro, R. Acinapura, M. The Australian Government Department of Health and Capozzi, R. Libertone, M. Lichtner, G. Tebano, (Roma); Ageing, and is affiliated with the Faculty of Medicine, M.S. Mura, G. Madeddu (Sassari); P. Caramello, G. Di The University of New South Wales. By grants from the Perri, G.C. Orofino, M. Sciandra (Torino); G. Pellizzer, Fondo de Investigacioń Sanitaria [grant number FIS 99/ V. Manfrin (Vicenza). 0887] and Fundacioń para la Investigacioń y la Prevencioń del SIDA en Espana˜ [grant number FIPSE 3171/00], to Nice HIV Cohort (France): Central coordination: C. the Barcelona Antiretroviral Surveillance Study (BASS); Pradier, E. Fontas, C. Caissotti. Participating physicians: by the National Institute of Allergy and Infectious P. Dellamonica, E. Bernard, E. Cua, F. De Salvador- Diseases, National Institutes of Health [grants number

5U01AI042170-10, 5U01AI046362-03], to the Terry L.R., A.M., S.W.W.,F.D., W.E.S., D.K., and J.D.L. report Beirn Community Programs for Clinical Research on no disclosures. AIDS (CPCRA); by grants from the BIOMED 1 [grant number CT94-1637] and BIOMED 2 [grant number Some of these data have been presented previously at CT97-2713] programs and the fifth framework program the 19th Conference on Retroviruses and Opportunis- [grant number QLK2-2000-00773] of the European tic Infections, Seattle, 5–8 March 2012, paper number Commission and grants from Bristol-Myers Squibb, 822. GlaxoSmithKline, Boehringer Ingelheim Pharmaceuticals Inc., and Roche, to the EuroSIDA study; by unrestricted References educational grants of Abbott Laboratories, Bristol-Myers 1. Triant VA, Regan S, Lee H, Sax PE, Beigs JB, Grinspoon SK. Squibb, Gilead Sciences Inc., GlaxoSmithKline, Pfizer Association of immunologic and virologic factors with myo- Inc., Janssen Pharmaceuticals to the Italian Cohort Naive cardial infarction rates in a US healthcare system. J Acquir to Antiretrovirals (The ICONA Foundation); and by a Immune Defic Syndr 2010; 55:615–619. 2. Rasmussen LD, Engsig FN, Christensen H, Gerstoft J, Kronborg grant from the Swiss National Science Foundation, to the G, Pedersen C, et al. Risk of cerebrovascular events in persons Swiss HIV Cohort Study (SHCS). with and without HIV: a Danish nationwide population-based cohort study. AIDS 2011; 25:1637–1646. 3. Lichtenstein KA, Armon C, Buchacz K, Chmiel JS, Buckner K, R The content of this publication is solely the responsibility Tedaldi EM, et al. Low CD4 T cell count is a risk factor for of the authors and does not necessarily represent the cardiovascular disease events in the HIV Outpatient Study. Clin official views of any of the institutions mentioned above. 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