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Atazanavir is not associated with an increased risk of cardio or cerebrovascular disease events

Monforte, Antonella d’Arminioa; Reiss, Peterb; Ryom, Lenec; El-Sadr, Wafaad; Dabis, Francoise,f; De Wit, Stephaneg; Worm, Signe W.c; Law, Mathew G.h; Weber, Raineri; Kirk, Olec; Pradier, Christianj; Phillips, Andrew N.k; Lundgren, Jens D.c; Sabin, Caroline A.k

doi: 10.1097/QAD.0b013e32835b2ef1
Clinical Science: Concise Communications

Objective: To investigate whether there is any association between exposure to atazanavir (ATV), either when boosted or unboosted by ritonavir, and myocardial infarction (MI) or stroke within the D:A:D: Study.

Design: Prospective cohort collaboration.

Methods: Poisson regression was used to investigate the association between cumulative exposure to ATV and MI/stroke risk after adjusting for known demographic and clinical confounders, as well as cumulative and recent exposure to specific antiretroviral drugs. Follow-up started on enrolment in the study and ended at the earliest of: a new MI/stroke event, death, 6 months after last clinic visit, or 1 February 2011.

Results: The incidence of MI varied from 0.28 [95% confidence interval (CI) 0.26–0.30)]/100 person-years of follow-up (PYFU) in those with no exposure to ATV to 0.20 (0.12–0.32)/100 PYFU in those with more than 3 years exposure. There was no evidence of an association between cumulative exposure to ATV and MI risk, either in univariate [relative rate/year 0.96 (95% CI 0.88–1.04)] or multivariable [0.95 (0.87–1.05)] analyses. The incidence of stroke was 0.17 (0.16–0.19)/100 PYFU in those with no exposure to ATV and 0.17 (0.10–0.27)/100 PYFU in those with more than 3 years exposure. As with the MI endpoint, there was no evidence of an association with ATV exposure in either univariate [1.02 (0.98–1.05)] or multivariable [0.95 (0.87–1.05)] analyses.

Conclusion: These results argue against a class-wide association between exposure to HIV protease inhibitors and the risk of cardio/cerebrovascular events.

aHospital San Paolo, University of Milan, Italy

bAcademic Medical Center, Amsterdam, The Netherlands

cCopenhagen HIV Programme, University of Copenhagen, Copenhagen, Denmark

dColumbia University/Harlem Hospital, New York, USA

eINSERM, Centre INSERM U897 ‘Epidémiologie et Biostatistique’

fUniversité Bordeaux Segalen, Institut de Santé Publique Epidémiologie Développement (ISPED), Bordeaux, France

gCHU Saint-Pierre Hospital, Department of Infectious Diseases, Brussels, Belgium

hKirby Institute, University of New South Wales, Sydney, Australia

iDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland

jCHU Nice Hopital de l’Archet, Nice, France

kResearch Department of Infection and Population Health, UCL, London, UK.

Correspondence to Professor Caroline Sabin, Research Department of Infection and Population Health, UCL, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Tel: +44 207 794 0500 ext. 34752; e-mail:

Received 4 September, 2012

Revised 2 October, 2012

Accepted 8 October, 2012

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HIV-positive patients are believed to experience several non-HIV-related diseases at a higher frequency than the general population. Several hypotheses have been proposed for this [1]. Firstly, HIV-positive individuals may experience premature ageing due to the chronic inflammation and immune activation that results from HIV infection [2]. Secondly, drug-related toxicities have been documented for most antiretroviral drugs; those related to lipid and glucose metabolism may, in turn, result in an increased risk of cardio and cerebrovascular disease (CCVD) [3]. Finally, lifestyle or behavioural factors may place those living with HIV at higher underlying risk of these diseases.

The D:A:D Study is an ongoing multicentre cohort study that was designed to ascertain possible links between CVD and antiretroviral drug usage, the main end-point being myocardial infarction (MI). Previous analyses of the D:A:D Study have shown that the duration of exposure to antiretroviral drugs and, in particular, to protease inhibitor-containing, but not non-nucleoside-containing combination antiretroviral therapy (cART), was associated with increased risk of MI [4]. Subsequent analyses have demonstrated that greater exposure to lopinavir or indinavir was associated with an increased risk of MI, whereas such an association was not seen for other protease inhibitors, particularly saquinavir and nelfinavir [5]. Due to the limited follow-up at the time among persons exposed to atazanavir (ATV), the association between exposure to this drug and MI was not previously investigated. However, sufficient person-years of follow-up (PYFU) have now accrued among those exposed to ATV to permit an investigation of the association between ATV and the risk of CCVD (MI or stroke).

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The D:A:D Study is an international collaboration of 11 cohorts, which captures information on more than 49 000 HIV-positive patients, regardless of prior antiretroviral use, from Europe, Australia, and the USA. Details of the study methods have been reported [6]. Information is collected annually on demographics, AIDS events and deaths, known risk factors for CCVD, laboratory markers for monitoring HIV and CCVD, antiretroviral use and treatments that modify CCVD risk. All information is transformed into a standardized format and merged centrally. The analyses reported in this study are based on data collected up to 1 February 2011.

All incident cases of MI are reported to the study co-ordinating office for validation and coding. Reported MIs are classified as: definite, possible, or unclassifiable, and are further distinguished as nonfatal (survival to at least 28 days after onset) or fatal (all other events). Reported strokes are classified as: definite/probable, stroke-like event, or not stroke (only definite/probable strokes were included in the present analysis), and are further classified by the type of lesion as infarction, haemorrhage or unknown. The classification of MI and stroke was conducted according to criteria applied in the WHO MONICA study [7].

Poisson regression was used to investigate the association between cumulative exposure to ATV and MI risk after adjusting for known demographic and clinical confounders for MI risk (sex, age, ethnicity, mode of HIV acquisition, participating clinical cohort, BMI, family history of coronary heart disease, smoking status, history of cardiovascular disease and calendar year) as well as cumulative exposure to each specific antiretroviral and recent exposure to each nucleoside reverse transcriptase inhibitor. Analyses of the stroke outcome were performed in a similar way, with adjustment for known stroke risk factors (sex, age, BMI, smoking status, history of cardiovascular disease, hypertension and calendar year) as well as cumulative and recent use of antiretroviral drugs, as described for the MI outcome. For each analysis, follow-up started on the date of enrolment in the D:A:D Study and ended at the earliest of a new MI/stroke event, death, 6 months after last clinic visit or 1 February 2011. Note that follow-up times for the two analyses could differ slightly as patient follow-up was not censored on the date of an MI for analyses of the stroke outcome, and vice versa. Thus, participants were followed for a total of 301 907 PYFU for analyses of MI, and 303 118 PYFU for analyses of stroke. The characteristics of the two patient sub-populations are, however, very similar, and therefore we present information on the MI sub-population below.

Analyses for the MI outcome were repeated after considering only definite MIs. Finally, as ATV has predominantly been used since 2005, we repeated our previous analyses of the associations between MI risk and specific protease inhibitor drugs after restricting the analysis to the period over which ATV was used (2005–2011).

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A total of 844 new MIs and 523 new strokes were diagnosed in the 49 734 D:A:D participants [incidence of 0.28/100 PYFU [95% confidence interval (CI) 0.26–0.30] and 0.18/100 PYFU (95% CI 0.16–0.19), respectively]. The diagnosis of MI was definite in 501 (59.4%), probable in 200 (23.7%) and unknown in 143 (16.9%) cases. One in five (n = 172, 20.4%) of the MIs were fatal, compared to 83 (15.6%) of the strokes.

Overall, 37 005 (12.3% of total) PYFU were contributed by patients who had ever been exposed to ATV, 31 502 (10.4%) by patients who had ever been exposed to ATV with boosted ritonavir (RTV) and 9611 (3.2%) by patients who had ever been exposed to ATV without RTV (patients may have received ATV in both its boosted and unboosted form, hence this sums to more than 37 005 PYFU). The characteristics of patients in the study, stratified by whether they were currently receiving an ATV-based regimen, other antiretroviral regimen or were not on antiretroviral therapy, are shown in Table 1. There were no major differences between the characteristics of patients receiving ATV or other regimens. As expected, ATV usage was more common in more recent calendar periods, with 71.9% of follow-up time on ATV occurring from 2007 to 2011, compared to 41.8% of follow-up time on non-ATV cART regimens. As a result, information on cardiovascular risk (Framingham score) was relatively more complete for those on ATV.

Table 1

Table 1

The incidence of MI was 0.28 (95% CI 0.26–0.30)/100 PYFU in those with no exposure to ATV and 0.20 (95% CI 0.12–0.32)/100 PYFU in those with more than 3 years ATV exposure (Table 2). In univariable analyses, there was no evidence of an association between cumulative exposure to ATV and MI risk, either overall [relative rate/year 0.96 (95% CI 0.88–1.04)], when boosted with RTV [0.99 (0.90–1.08)] or when unboosted [0.80 (0.61–1.03)]. Adjustment for demographic and clinical confounders, as well as cumulative/recent exposure to other antiretroviral drugs did not change the association with any exposure to ATV [0.95 (0.87–1.05)], nor did further adjustment for hypertension [0.95 (0.86, 1.04)]. Additional adjustment for the latest bilirubin level, in the subgroup of cohorts that provided this information, did not substantially modify the results [0.92 (0.83, 1.03)], although these results should be interpreted with caution as bilirubin levels were only available for a small proportion of patients in the study (analyses were based on 277 MIs over 118 390 PYFU). When the main analysis was repeated for definite MIs only, the results were again similar [0.96 (0.85, 1.09)].

Table 2

Table 2

The incidence of stroke was 0.17 (95% CI 0.16–0.19)/100 PYFU in those with no exposure to ATV and 0.17 (95% CI 0.10–0.27)/100 PYFU in those with more than 3 years ATV exposure (Table 2). As with the analyses of MI, there was no association between cumulative exposure to ATV and stroke risk either overall [1.02 (0.98–1.05)], when boosted with RTV [1.02 (0.98–1.06)] or when unboosted [0.80 (0.61–1.03)], or after adjustment for potential confounders and exposure to other antiretroviral drugs [0.95 (0.87–1.05)]. Additional adjustment for the latest bilirubin level in the subset of cohorts that provided this information did not modify the conclusions [0.98 (0.86, 1.11)].

Finally, analyses restricted to the period 2005–2011 revealed a similar lack of association between ATV and MI risk [0.95/year (0.86–1.04)]. Estimates relating to the other commonly used protease inhibitors (indinavir, saquinavir, lopinavir and nelfinavir) were consistent in both analyses (data not shown) and were similar to those reported previously from the D:A:D Study [5].

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In this analysis from the D:A:D Study, we have demonstrated that a longer duration of ATV usage as part of a cART regimen is not associated with an increased risk of CVD in HIV-positive individuals. As a consequence, we confirm that previously reported associations concerning lopinavir and indinavir are unlikely to reflect a class-wide association, as already suggested by our finding relating to nelfinavir and saquinavir [5].

We explored several possible explanations for this lack of association. Firstly, we evaluated whether potential confounders might have masked a genuine association. Our multivariable analyses included adjustment for factors known to influence a clinician's choice of cART, many of which are also known CCVD risk factors; adjustment did not, however, modify the findings. We also evaluated whether the documented effect of ATV on serum bilirubin levels could explain the lack of association, based on the inverse association between bilirubin level and risk of CCVD in HIV-negative persons [8]. We found no evidence that these findings were altered by adjustment for the latest bilirubin level; of note, only limited data were available for this analysis, due to the lack of bilirubin collection in several cohort databases. It could also be argued that our findings might be explained by differences in the population of patients receiving ATV as compared to those receiving other protease inhibitors, as ATV has only been used in more recent years and patient characteristics (e.g. smoking status) and lipid monitoring have also changed over time in the HIV-positive population [9,10]. We thus restricted the analyses to more recent years and re-evaluated the association between CCVD and exposure to the different protease inhibitors; our analyses reached similar conclusions, confirming the main analyses (data not shown).

There are several limitations of this study. Most importantly, the observational nature of the D:A:D Study means that our findings cannot be assumed to reflect casual associations and must be interpreted cautiously because of the potential for unmeasured confounding. Furthermore, the limited availability of ATV in the clinic means that our findings may be strengthened by the inclusion of individuals exposed to ATV for longer periods of time in the coming years.

In conclusion, data from the D:A:D Study argue against an association between exposure to ATV, either boosted or unboosted with ritonavir, and the risk of CCVD, which confirms that such risk is not a class-wide phenomenon, but rather restricted to particular individual HIV protease inhibitors. Finally, we should note that the rate of MI and stroke remains relatively low in more recent years – thus any findings on possible correlations between antiretroviral drugs must be interpreted in the context of the tremendous benefits of cART for the HIV-positive population.

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Funding: This work was supported by the Highly Active Antiretroviral Therapy Oversight Committee (HAART-OC), a collaborative committee with representation from academic institutions, the European Agency for the Evaluation of Medicinal Products, the United States Food and Drug Administration, the patient community and all pharmaceutical companies with licensed anti-HIV drugs in the European Union: Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb, Gilead Sciences Inc., Viiv Healthcare, Merck & Co Inc., Pfizer Inc, F. Hoffman-LaRoche Ltd and Janssen Pharmaceuticals.

Supported by a grant [grant number CURE/97–46486] from the Health Insurance Fund Council, Amstelveen, the Netherlands, to the AIDS Therapy Evaluation Project Netherlands (ATHENA); by a grant from the Agence Nationale de Recherches sur le SIDA [grant number Action Coordonnée no.7, Cohortes], to the Aquitaine Cohort; The Australian HIV Observational Database (AHOD) is funded as part of the Asia Pacific HIV Observational Database, a program of The Foundation for AIDS Research, amfAR, and is supported in part by a grant from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) (grant number U01-AI069907) and by unconditional grants from Merck Sharp & Dohme; Gilead Sciences; Bristol-Myers Squibb; Boehringer Ingelheim Pharmaceuticals Inc.; Roche; Pfizer; GlaxoSmithKline; Janssen Pharmaceuticals. The Kirby Institute is funded by The Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, The University of New South Wales. By grants from the Fondo de Investigación Sanitaria (grant number FIS 99/0887) and Fundación para la Investigación y la Prevención del SIDA en Espanã (grant number FIPSE 3171/00), to the Barcelona Antiretroviral Surveillance Study (BASS); by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants number 5U01AI042170–10, 5U01AI046362–03), to the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA); by grants from the BIOMED 1 (grant number CT94–1637) and BIOMED 2 (grant number CT97–2713) programs and the fifth framework program (grant number QLK2–2000–00773) of the European Commission and grants from Bristol-Myers Squibb, GlaxoSmithKline, Boehringer Ingelheim Pharmaceuticals Inc., and Roche, to the EuroSIDA study; by unrestricted educational grants of Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences Inc., GlaxoSmithKline, Pfizer Inc., Janssen Pharmaceuticals to the Italian Cohort Naive to Antiretrovirals (The ICONA Foundation); and by a grant from the Swiss National Science Foundation, to the Swiss HIV Cohort Study (SHCS).

The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.

Author contributions: J.D.L., Ad’.A.M. and C.A.S. developed the initial study protocol. S.W.W. and L.R. prepared study co-ordination, prepared the datasets for analysis and assisted with endpoint review. C.A.S. performed all statistical analysis and with Ad’.A.M. prepared the initial draft of the manuscript. All authors have provided management input to the D:A:D Study, contributed datasets, provided input to the development of the manuscript and have seen and approved the final version.

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Conflicts of interest

M.G.L. has received unconditional grants from Merck Sharp & Dohme; Gilead; Bristol-Myers Squibb; Boehringer Ingelheim; Roche; Pfizer; GlaxoSmithKline; Janssen-Cilag.

S.D.W. has received honoraria from Bristol-Myers Squibb and Viiv Healthcare.

R.W. has received travel grants from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp &Dohme, Pfizer, Roche, TRB Chemedica and Tibotec.

A.N.P. has received funding for consultancy from Gilead Sciences, Bristol-Myers Squibb, Johnson & Johnson, Viiv Healthcare and GSK Bio.

A.d’A.M. has received funding for Advisory Board membership for Bristol-Myer Squibb, Abbott, Janssen, Gilead Sciences and Viiv Healthcare.

P.R. has served as a scientific advisor to Bristol-Myers Squibb, Gilead Sciences, GrupoFerrer, GlaxoSmithKline, Janssen, Merck Sharp &Dohme and ViiV Healthcare. He has served on data safety monitoring boards and endpoint adjudication committees for Janssen and his institution has received honoraria for speaking engagements at scientific conferences from Bristol-Myers Squibb, Gilead Sciences and GSK. He has received research support from Gilead Sciences, Viiv Healthcare, Merck Sharp &Dohme, Janssen, Bristol-Myers Squibb, Abbott Laboratories, and Boehringer Ingelheim.

O.K. has received honoraria, consultancy, lecture fees and travel grants from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp &Dohme, Roche and Viiv Healthcare.

C.P. has received honoraria from Viiv Healthcare, Abbott Pharmaceuticals and Merck Sharp & Dohme.

C.A.S. has received funding for Advisory Board membership, speaker panels and provision of educational materials for Gilead Sciences, Abbott Pharmaceuticals, Merck Sharp & Dohme, Janssen-Cilag and Bristol-Myers Squibb.

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Appendix: D:A:D participating cohorts and Steering Committee (names marked with *)

Members of the D:A:D SC from the Oversight Committee: N. Shortman*, D. Butcher*, R. Rode*, X. Franquet *, W. Powderly*.

D:A:D Central Coordination: L. Ryom, C.A. Sabin*, D. Kamara, C. Smith, A. Phillips*, A. Mocroft, J. Tverland, J. Nielsen, J.D. Lundgren (chair).

D:A:D data managers: R. Salbøl Brandt (coordinator), M. Rickenbach, I. Fanti, E. Krum, M. Hillebregt, S. Geffard, A. Sundström, M. Delforge, E. Fontas, F. Torres, H. McManus, S. Wright, J. Kjær.

Endpoint verification Group: A. Sjøl (CVD primary endpoint), P. Meidahl (oncology), J. Helweg-Larsen (hematology), J. Schmidt Iversen (nephrology).

The members of the 11 cohorts are as follows:

ATHENA (AIDS Therapy Evaluation Project Netherlands): Central coordination: F. de Wolf, S. Zaheri, M Hillebregt L. Gras; Participating physicians (¤Site coordinating physicians): Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam: J.M. Prins¤, T.W. Kuijpers, H.J. Scherpbier, K. Boer, J.T.M. van der Meer, F.W.M.N. Wit, M.H. Godfried, P. Reiss*, T. van der Poll, F.J.B. Nellen, J.M.A. Lange, S.E. Geerlings, M. van Vugt, S.M.E. Vrouenraets, D. Pajkrt, M. van der Valk. Academisch Ziekenhuis Maastricht, Maastricht: G. Schreij¤, S. Lowe, A. Oude Lashof. Catharina-ziekenhuis, Eindhoven: M.J.H. Pronk¤, B. Bravenboer. Erasmus Medisch Centrum, Rotterdam: M.E. van der Ende¤, T.E.M.S. de Vries-Sluijs, C.A.M. Schurink, M. van der Feltz, J.L. Nouwen, L.B.S. Gelinck, A. Verbon, B.J.A. Rijnders, L. Slobbe. Erasmus Medisch Centrum–Sophia, Rotterdam: N.G. Hartwig, G.J.A. Driessen. Flevoziekenhuis, Almere: J. Branger¤. HagaZiekenhuis, Den Haag: R.H. Kauffmann¤, E.F. Schippers. Isala Klinieken, Zwolle: P.H.P. Groeneveld¤, M.A. Alleman, J.W. Bouwhuis. Kennemer Gasthuis: R.W. ten Kate¤, R. Soetekouw. Leids Universitair Medisch Centrum, 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. Jolink. Maasstadziekenhuis, Rotterdam: J.G. den Hollander¤, K. Pogany. Medisch Centrum Alkmaar, Alkmaar: G. van Twillert¤, W. Kortmann. Medisch Centrum Haaglanden, Den Haag: R. Vriesendorp, ¤ E.M.S. Leyten. Medisch Spectrum Twente, Enschede: C.H.H. ten Nape¤l, G.J. Kootstra. Onze Lieve Vrouwe Gasthuis, Amsterdam: K. Brinkman¤, W.L. Blok, P.H.J. Frissen, W.E.M. Schouten, G.E.L. van den Berk. Sint Elisabeth Ziekenhuis, Tilburg: J.R. Juttmann¤, M.E.E. van Kasteren, A.E. Brouwer. Sint Lucas Andreas Ziekenhuis, Amsterdam: J. Veenstra ¤,K.D. Lettinga. Slotervaartziekenhuis, Amsterdam: J.W. Mulder¤, E.C.M. van Gorp, P.M. Smit, S. Weijer. Stichting Medisch Centrum Jan van Goyen, Amsterdam: A. van Eeden*, D.W.M. Verhagen¤. Universitair Medisch Centrum Groningen, Groningen: H.G. Sprenger¤, R. Doedens, E.H. Scholvinck, S. van Assen, C.J. Stek. Universitair Medisch Centrum Sint Radboud, Nijmegen: P.P. Koopmans¤, R. de Groot, M. Keuter, A.J.A.M. van der Ven, H.J.M. ter Hofstede, M. van der Flier, A.M. Brouwer, A.S.M. Dofferhoff. Universitair Medisch Centrum Utrecht, Utrecht: A.I.M. Hoepelman¤, T. Mudrikova, M.M.E. Schneider, C.A.J.J. Jaspers, P.M. Ellerbroek, E.J.G. Peters, L.J. Maarschalk-Ellerbroek, J.J. Oosterheert, J.E. Arends, M.W.M. Wassenberg, J.C.H. van der Hilst. Vrije Universiteit Amsterdam, Amsterdam: S.A. Danner¤, 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 de Vaate. Wilhelmina Kinderziekenhuis, Utrecht: S.P.M. Geelen, T.F.W. Wolfs. Ziekenhuis Rijnstate, Arnhem: C. Richter, ¤ J.P. van der Berg, E.H. Gisolf. Ziekenhuis Walcheren, Vlissingen: M. van den Berge ¤, A. Stegeman. Medisch Centrum Leeuwarden, Leeuwarden: D.P.F. van Houte¤, M.B. Polée, M.G.A. van Vonderen. Sint Elisabeth Hospitaal, Willemstad - Curaçao: C. Winkel, A.J. Duits.

ANRS CO3 Aquitaine Cohort (France)

Composition of the Grouped’Epidémiologie Clinique du Sida en Aquitaine (GECSA):

Coordination: F. Dabis. Scientific committee: F. Bonnet, F. Dabis, M. Dupon, G. Chêne, H. Fleury, D. Lacoste, D. Malvy, P. Mercié, I. Pellegrin, P. Morlat, D. Neau, JL. Pellegrin, R. Thiébaut, K. Titier. Epidemiology and Methodology: M. Bruyand, G. Chêne, F. Dabis, S. Lawson-Ayayi, R. Thiébaut, L. Wittkop. Infectious Diseases and Internal Medicine: F. Bonnal, F. Bonnet, N. Bernard, L. Caunègre, C. Cazanave, J. Ceccaldi, D. Chambon, I. Chossat, K. Courtaud, FA. Dauchy, S. De Witte, M. Dupon, A. Dupont, P. Duffau, H. Dutronc, S. Farbos, V. Gaboriau, MC. Gemain, Y. Gerard, C. Greib, M. Hessamfar, D. Lacoste, P. Lataste, S. Lafarie-Castet, E. Lazaro, M. Longy-Boursier, D. Malvy, JP. Meraud, P. Mercié, E. Monlun, P. Morlat, D. Neau, A. Ochoa, JL. Pellegrin, T. Pistone, JM. Ragnaud, MC. Receveur, J. Roger-Schmeltz, S. Tchamgoué, P. Thibaut, MA. Vandenhende, JF. Viallard. Immunology: JF. Moreau, I. Pellegrin. Virology: H. Fleury, ME. Lafon, B. Masquelier, P. Trimoulet. Pharmacology: D. Breilh, K. Titier. Drug monitoring: F. Haramburu, G. Miremont-Salamé. Data collection and processing: MJ. Blaizeau, M. Decoin, J. Delaune, S. Delveaux, C. D’Ivernois, C. Hanappier, O. Leleux, B. Uwamaliya-Nziyumvira, X. Sicard. Computing and Statistical analysis: S. Geffard, J. Leray, G. Palmer, D. Touchard.

AHOD (Australian HIV Observational Database, Australia): Central coordination: M. Law *, K. Petoumenos, H. McManus, S. Wright, C. Bendall (Sydney, New South Wales); Participating physicians (city, state): R. Moore, S. Edwards, J. Hoy, K. Watson, N. Roth, J. Nicholson (Melbourne, Victoria); M Bloch, T. Franic, D. Baker, R. Vale, A. Carr, D. Cooper (Sydney, New South Wales); J. Chuah, M. Ngieng (Gold Coast, Queensland), D. Nolan, J. Skett (Perth, Western Australia).

BASS (Spain): Central coordination: G. Calvo, F. Torres, S. Mateu (Barcelona); Participating physicians (city): P. Domingo, M.A. Sambeat, J. Gatell, E. Del Cacho, J. Cadafalch, M. Fuster (Barcelona); C. Codina, G. Sirera, A. Vaqué (Badalona).

The Brussels St Pierre Cohort (Belgium): Coordination: S. De Wit*, N. Clumeck, M. Delforge, C. Necsoi. Participating physicians: N. Clumeck, S. De Wit*, AF Gennotte, M. Gerard, K. Kabeya, D. Konopnicki, A. Libois, C. Martin, M.C. Payen, P. Semaille, Y. Van Laethem.

CPCRA (USA): Central coordination: J. Neaton, G. Bartsch, W.M. El-Sadr*, E. Krum, G. Thompson, D. Wentworth; Participating physicians (city, state): R. Luskin-Hawk (Chicago, Illinois); E. Telzak (Bronx, New York); W.M. El-Sadr (Harlem, New York); D.I. Abrams (San Francisco, California); D. Cohn (Denver, Colorado); N. Markowitz (Detroit, Michigan); R. Arduino (Houston, Texas); D. Mushatt (New Orleans, Louisiana); G. Friedland (New Haven, Connecticut); G. Perez (Newark, New Jersey); E. Tedaldi (Philadelphia, Pennsylvania); E. Fisher (Richmond, Virginia); F. Gordin (Washington, DC); L.R. Crane (Detroit, Michigan); J. Sampson (Portland, Oregon); J. Baxter (Camden, New Jersey).

EuroSIDA (multinational) Coordinating Centre: J. Lundgren#, O. Kirk*, A. Mocroft, A. Cozzi-Lepri, D. Grint, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Kowalska, J. Tverland, A.H. Fischer, J. Nielsen Participating countries and physicians Argentina:(M. Losso), C. Elias, Hospital JM Ramos Mejia, Buenos Aires. Austria: (N. Vetter), PulmologischesZentrum der Stadt Wien, Vienna; R. Zangerle, Medical University Innsbruck, Innsbruck. Belarus: (I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk; V.M. Mitsura, Gomel State Medical University, Gomel; O. Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N. Clumeck), S. De Wit*, M Delforge, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp; L. Vandekerckhove, University Ziekenhuis Gent, Gent. Bosnia-Herzegovina: (V. Hadziosmanovic), KlinickiCentarUniverziteta Sarajevo, Sarajevo. Bulgaria: (K. Kostov), Infectious Diseases Hospital, Sofia. Croatia: (J. Begovac), University Hospital of Infectious Diseases, Zagreb. Czech Republic: (L. Machala), D. Jilich, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen. Denmark: (J. Nielsen), G. Kronborg, T. Benfield, M. Larsen, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, A-B.E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense; L. Ostergaard, Skejby Hospital, Aarhus. Estonia: (K. Zilmer), West-Tallinn Central Hospital, Tallinn; J. Smidt, Nakkusosakond Siseklinik, Kohtla-Järve. Finland: (M. Ristola), Helsinki University Central Hospital, Helsinki. France: (C. Katlama), Hôpital de la Pitié-Salpétière, Paris; J-P. Viard, Hôpital Necker-Enfants Malades, Paris; P-M. Girard, Hospital Saint-Antoine, Paris; J.M. Livrozet, Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l’Archet, Nice; F. Dabis*, D. Neau, Unité INSERM, Bordeaux. Germany: (J. Rockstroh), Universitäts Klinik Bonn; R. Schmidt, Medizinische Hochschule Hannover; J. van Lunzen, O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; H.J. Stellbrink, IPM Study Center, Hamburg; S. Staszewski, JW Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Greece: (J. Kosmidis), P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital; H. Sambatakou, Ippokration Genereal Hospital, Athens. Hungary: (D. Banhegyi), SzentLásló Hospital, Budapest. Ireland: (F. Mulcahy), St. James's Hospital, Dublin. Israel: (I. Yust), D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Rambam Medical Center, Haifa; S. Maayan, Hadassah University Hospital, Jerusalem. Italy: (S. Vella), IstitutoSuperiore di Sanità, Rome; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; C. Arici, OspedaleRiuniti, Bergamo; R. Pristera, OspedaleGeneraleRegionale, Bolzano; F. Mazzotta, A. Gabbuti, Ospedale S Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; A. Chirianni, E. Montesarchio, M. Gargiulo, Presidio Ospedaliero A.D. Cotugno, Monaldi Hospital, Napoli; G. Antonucci, A. Testa, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, A. Castagna, N. Gianotti, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan; A.d’ArminioMonforte*, Istituto Di ClinicaMalattieInfettive e Tropicale, Milan. Latvia: (B. Rozentale), I. Zeltina, Infectology Centre of Latvia, Riga. Lithuania: (S. Chaplinskas), Lithuanian AIDS Centre, Vilnius. Luxembourg: (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg. Netherlands: (P. Reiss*), AcademischMedisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (V. Ormaasen), A. Maeland, J. Bruun, Ullevål Hospital, Oslo. Poland: (B. Knysz), J. Gasiorowski, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostykii Terapii AIDS, Warsaw; A. Grzeszczuk, R. Flisiak, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, M. Parczewski, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, OsrodekDiagnostykiiTerapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk; E. Jablonowska, E. Malolepsza, K. Wojcik, WojewodzkiSzpitalSpecjalistyczny, Lodz. Portugal: (F. Antunes), M. Doroana, L. Caldeira, Hospital Santa Maria, Lisbon; K Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon. Romania: (D. Duiculescu), Spitalul de BoliInfectioase si Tropicale: Dr Victor Babes, Bucarest. Russia: (A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; N. Zakharova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod. Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: (M. Mokráš), D. Staneková, Dérer Hospital, Bratislava. Slovenia: (J. Tomazic), University Clinical Centre Ljubljana, Ljubljana. Spain: (J. González-Lahoz), V. Soriano, P. Labarga, J. Medrano, Hospital Carlos III, Madrid; S. Moreno, J.M. Rodriguez, Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, Hospital Germans TriasiPujol, Badalona; J.M. Gatell, J.M. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona. Sweden:(A. Karlsson), Venhaelsan-Sodersjukhuset, Stockholm; L. Flamholc, Malmö University Hospital, Malmö. Switzerland: (B. Ledergerber), R. Weber*, University Hospital, Zürich; P. Francioli, M. Cavassini, Centre HospitalierUniversitaireVaudois, Lausanne; B. Hirschel, E. Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel. Ukraine: (E. Kravchenko), N. Chentsova, Kiev Centre for AIDS, Kiev; V. Frolov, G. Kutsyna, Luhansk State Medical University; Luhansk; S. Servitskiy, Odessa Region AIDS Center, Odessa; M. Krasnov, Kharkov State Medical University, Kharkov. United Kingdom: (S. Barton), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, D. Mercey, University College London, London (University College Campus); A. Phillips, M.A. Johnson, A. Mocroft, Royal Free Hospital and University College London, London (Royal Free Campus); M. Murphy, Medical College of Saint Bartholomew's Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; C. Leen, Western General Hospital, Edinburgh.

HivBivus (Sweden): Central coordination: L. Morfeldt, G. Thulin, A. Sundström. Participating physicians (city): B. Åkerlund (Huddinge); K. Koppel, A. Karlsson (Stockholm); L. Flamholc, C. Håkangård (Malmö).

The IcoNA Foundation Study (Italy):

Governing body: M. Moroni (Chair), G. Angarano, A. Antinori, F. Castelli, R. Cauda, A. d’Arminio Monforte, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, C.F. Perno, O. Armignacco, P.L. Viale, F. Von Schlosser.

Scientific secretary: A.d’ArminioMonforte.

Steering committee: A. Ammassari, M. Andreoni, A. Antinori, C. Balotta, P. Bonfanti, S. Bonora, M. Borderi, M.R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, P. Cinque, A. Cozzi-Lepri, A. d’Arminio Monforte, A. De Luca, M. Gargiulo, C. Gervasoni, E. Girardi, A. Gori, G. Guaraldi, M. Lichtner, S. Lo Caputo, G. Madeddu, F. Maggiolo, G. Marchetti, S. Marcotullio, L. Monno, R. Murri, C. Mussini, M. Puoti, C. Torti.

Statistical and monitoring team: A. Cozzi-Lepri, P. Cicconi, I. Fanti, T. Formenti, L. Galli, P. Lorenzini.

Participating physicians and centers: Italy A. Giacometti, A Costantini, A. Riva (Ancona);G. Angarano, L. Monno, C. Carrisa,(Bari);F. Maggiolo, G. Lazzari (Bergamo); P.L. Viale, M. Borderi, G. Verucchi (Bologna);F. Castelli, C. Torti, C. Minardi, (Brescia);T. Quirino, C. Abeli (Busto Arsizio);P.E. Manconi, P. Piano (Cagliari); J. Vecchiet, K. Falasca (Chieti); L. Sighinolfi, D. Segala (Ferrara);F. Mazzotta, S. Lo Caputo (Firenze); G. Cassola, G. Viscoli, A. Alessandrini, R. Piscopo, G. Mazzarello (Genova);C. Mastroianni, V. Belvisi (Latina);P. Bonfanti, I. Caramma (Lecco); A. Chiodera, P. Castelli (Macerata);M. Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. d’Arminio Monforte, A.L. Ridolfo, R. Piolini, A. Castagna, S. Salpietro, A. Galli, A. Bigoloni, V. Spagnuolo, L. Carenzi, P. Zucchi, M.C. Moioli, R. Rossotti, P. Cicconi, T. Formenti (Milano); C. Mussini, L. Bisio (Modena); A. Gori, G. Lapadula (Monza), N. Abrescia, A. Chirianni, M.G. Guida, M. Gargiulo (Napoli); F. Baldelli, B. Belfiori (Perugia); G. Parruti, T. Ursini (Pescara); G. Magnani, M.A. Ursitti (Reggio Emilia);R. Cauda, M. Andreoni, A. Antinori, V. Tozzi, V. Vullo, A. De Luca, A. d’Avino, M. Zaccarelli, L. Gallo, E. Nicastro, R. Acinapura, M. Capozzi, R. Libertone, M. Lichtner, G. Tebano, (Roma);M.S. Mura, G. Madeddu (Sassari);P. Caramello, G. Di Perri, G.C. Orofino, M. Sciandra (Torino);G. Pellizzer, V. Manfrin (Vicenza).

Nice HIV Cohort (France): Central coordination: C. Pradier*, E. Fontas, C. Caissotti. Participatingphysicians: P. Dellamonica, E. Bernard, E. Cua, F. De Salvador-Guillouet, J. Durant, S. Ferrando, V. Mondain-Miton, A. Naqvi, I. Perbost, B. Prouvost-Keller, S. Pillet, P. Pugliese, V. Rahelinirina, P.M. Roger. Clinical research assistant: K. Dollet.

SHCS (Swiss HIV CohortStudy, Switzerland): J. Barth, M. Battegay, E. Bernasconi, J. Böni, H.C. Bucher, C. Burton-Jeangros, A. Calmy, M. Cavassini, C. Cellerai, R. Dubs, M. Egger, L. Elzi, J. Fehr, M. Flepp, P. Francioli (President of the SHCS), H. Furrer, C.A. Fux, M. Gorgievski, H. Günthard, B. Hasse, H.H. Hirsch, B. Hirschel, I. Hösli, C. Kahlert, L. Kaiser, O. Keiser, C. Kind, T. Klimkait, H. Kovari, B. Ledergerber, G. Martinetti, B. Martinez de Tejada, N. Müller, D. Nadal, G. Pantaleo, A. Rauch, S. Regenass, M. Rickenbach, C. Rudin, P. Schmid, D. Schultze, F. Schöni-Affolter, J. Schüpbach, R. Speck, P. Taffé, A. Telenti, A. Trkola, P. Vernazza, V. vonWyl, R. Weber*, S. Yerly.

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atazanavir; cardiovascular disease; cerebrovascular disease; HIV; myocardial infarction; stroke

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