Two cohorts (CPCRA and the Brussels St. Pierre cohort) were included later in the DAD study and their patient characteristics at baseline not analysed in this manuscript.
More than 8% of the study population had hypertension. In a univariable logistic model, using the antiretroviral therapy-naive group as reference, regimens containing NNRTI, PI or both drug classes were associated with an increased risk of being hypertensive (Table 4). But after adjustment for other factors which univariably were associated with the presence of hypertension, the associations with antiretroviral therapy disappeared or were reversed (Table 4). This was explained mainly by a strong correlation of hypertension with other factors (age, sex and BMI).
We further examined the effect of duration of exposure to the drug classes. As current and previous antiretroviral therapy exposures were highly correlated, these parameters were fitted in separate models. In a univariable logistic model for cumulative antiretroviral therapy exposure time, the OR for elevated total cholesterol was 1.00 (IQR, 0.98–1.02; P = 0.81), 1.39 (IQR, 1.31–1.47; P < 10−4) and 1.42 (IQR, 1.38–1.47; P < 10−4) per year of exposure to NRTI, NNRTI and PI, respectively. After controlling for other risk factors for dyslipidaemia, these associations remained essentially unchanged (data not shown; the model included sex, age, smoking, family history of coronary heart disease, previous cardiovascular disease, BMI, HIV transmission category, CD4 cell count, HIV RNA and duration of NRTI, NNRTI and PI therapy).
In a univariable logistic model for cumulative antiretroviral drug exposure time, the OR for elevated triglycerides was 1.05 (IQR, 1.03–1.07), 1.28 (IQR, 1.21–1.35) and 1.38 (IQR, 1.34–1.42) per year of exposure to NRTI, NNRTI and PI respectively (all, P < 10−4). In the multivariable model these associations remained essentially unchanged (data not shown).
The association with CD4 cell count and HIV viral load differed between regimens. Among patients who were antiretroviral therapy-naive, previously exposed, but not currently receiving any antiretroviral therapy, or currently receiving a regimen containing NRTI only, the adjusted risk of elevated triglycerides increased with increasing HIV RNA [OR, 1.18 (IQR, 1.07–1.31) per 1 log10 increase; P = 0.001], whereas there was no significant association with CD4 cell count [OR, 1.06 (IQR, 0.99–1.13) per twofold increase; P = 0.12].
Among patients receiving NNRTI, PI or a regimen containing both drug classes, the risk of elevated triglycerides increased with increasing HIV viral load [adjusted OR, 1.13 (IQR, 1.06–1.21) per 1 log10 increase; P < 10−4] and also increased with increasing CD4 cell count [OR, 1.20 (IQR, 1.15–1.26) per twofold increase in CD4 cell count; P < 10−3].
All regimens were associated with an increased risk of low HDL-cholesterol except regimens containing NNRTI, when compared to naive subjects (Table 4). In a univariable logistic model for cumulative antiretroviral drug exposure time, the OR for decreased HDL-cholesterol per year of exposure to NRTI, NNRTI and PI respectively, was 1.08 (IQR, 1.05–1.11; P < 10−4), 0.87 (IQR, 0.80–0.95; P < 0.002) and 1.01 (IQR, 0.97–1.06; P = 0.53). The multivariable model showed similar associations.
The associations of CD4 cell count and HIV viral load were similar for the absolute value of HDL-cholesterol as for total cholesterol, i.e., the risk of having decreased HDL-cholesterol is highest among patients with low CD4 cell count and high HIV viral load.
When assessed as an explanatory variable, lipodystrophy was associated with the presence of several of the CVD risk factors discussed above. In a multivariable model including the total study population, and adjusting for co-variables as listed in Table 4, the adjusted OR for the association of lipodystrophy with elevated total cholesterol was 1.56 (IQR, 1.41–1.72; P < 10−4), elevated triglycerides 2.16 (IQR, 1.98–2.37; P < 10−4) and decreased HDL 1.53 (IQR, 1.35–1.73; P < 10−4). The presence of lipodystrophy was associated with an increased risk of hypertension and diabetes [OR, 1.34 (IQR, 1.17–1.54) and 2.05 (IQR, 1.63–2.58), respectively; both P < 10−4].
Dyslipidaemia was most strongly correlated with antiretroviral regimens currently being used, and less with a history of previous exposure to the different drug classes. This finding corresponds with previous reports, in which the dyslipidaemia associated with PI occurred shortly after beginning therapy (in the fraction of patients prone to develop this adverse effect) [8,46] and the rate of increase in lipid levels abated within months of initiation of the drugs. It is also consistent with studies that have shown that switch from PI to NNRTI-based or NRTI-only regimens is associated with attenuation or resolution of dyslipidaemia  within a short period of time (i.e., a few months). However, the cumulative time of exposure to various antiretroviral drug classes (with the concomitant risk of raised lipid levels) is likely to be relevant when predicting the risk of future CVD.
The association between PI therapy and elevated levels of total cholesterol and serum triglycerides has been noted previously in smaller cohort studies. The average increases in lipid levels in the largest series published to date [9,10,48,49], comparing levels during PI therapy with either pre-therapy levels or levels in PI-naive HIV-infected patients, were 28% for total cholesterol and 96% for triglycerides. We observed no difference in risk of low HDL-cholesterol among patients treated with PI, NRTI or not currently receiving antiretroviral therapy, and patients in these groups all had lower HDL-cholesterol levels than treatment-naive individuals. Consistent with most other studies, duration of PI therapy did not influence the level of HDL-cholesterol , whereas duration of NRTI was associated with a higher risk of low HDL-cholesterol.
An increase in total cholesterol with no increase in the HDL fraction is of particular concern, because it implies an elevation of the atherogenic non-HDL-cholesterol. The risk of elevated total cholesterol was increased per additional drug included in the regimen, and for longer exposure time to PI. Additional analysis to assess possible differences between individual PI is underway to examine these associations in more detail .
In contrast with previous observations of an association of PI use and dyslipidaemia, our finding of an association between NNRTI-containing regimens and dyslipidaemia has not been widely investigated. Phase I studies of efavirenz in HIV-uninfected subjects revealed increases in total cholesterol levels of 10–20% in some subjects , and no differences between different NNRTI were reported in HIV-infected individuals . In concordance with our results, an increase in (protective) HDL-cholesterol with NNRTI has recently been reported [53,54]. More detailed analyses to assess possible differences between individual NNRTI are ongoing .
Consistent with previous reports, NRTI-only therapy was not associated with elevated cholesterol [52,56]. With regards to triglycerides, recent studies have indicated differences among drugs in the NRTI drug class, with a higher propensity for high triglyceride levels associated with stavudine use [56,57]. Future analyses from the DAD study will further assess differences between individual drugs within the NRTI drug class.
So far, few studies have examined factors which predispose HIV-infected patients to treatment-associated lipid abnormalities [58–60]. We have identified several factors that are significantly associated with the presence of dyslipidaemia in HIV infected subjects receiving antiretroviral therapy. We found a strong association between elevated total cholesterol level and higher CD4 cell counts, which was present within each treatment category but not in the antiretroviral therapy-naive group. Nevertheless, within each CD4 cell count stratum, the effect of antiretroviral therapy was clearly observed, which indicates that the effect of antiretroviral substances certainly cannot solely be explained by a reversal to ‘normal’ pre-disease cholesterol levels as a result of improved cellular immunity. The CD4 cell count level remained independently associated with elevated total cholesterol also after adjustment for duration of treatment. This does not rule out, however, that the observed association may still – at least in part – be due to residual confounding of the effect of antiretroviral therapy, either directly via a dose–response effect (i.e., higher CD4 cell count and lower plasma viral load are surrogates of better adherence and hence higher exposure to causative drugs) or indirectly via lowering HIV-RNA levels (see below).
The level of HDL-cholesterol, although to a lesser extent, likewise increased with more conserved cellular immunity, consistent with observations in the pre-HAART era , while no clear association was observed for levels of triglycerides after adjusting for therapy.
For total cholesterol, the association with HIV viral load was the inverse of the association with CD4 cell count. Thus we found increasing levels of total cholesterol with lower HIV RNA, and similarly for HDL-cholesterol. The latter has also been reported from other studies . Conversely, overall and after adjustment for other factors, levels of triglycerides increased with increasing HIV viral load, consistent with the findings in the pre-PI era of elevated triglycerides linked to HIV disease progression .
Whether the presence of fat redistribution in itself – by way of abnormal fat loss and/or gain – represents an independent risk for CVD remains unresolved. A large collaboration is ongoing with the purpose of establishing a case definition for the lipodystrophy syndrome , which will facilitate the evaluation of the different clinical patterns and their possible influence on risk of CVD.
The strength of our results is primarily related to the substantial size of the study population. The diversity of the study population, including patients from a variety of geographical areas and a substantial number of women and minorities, ensures that the study is representative of the HIV infected population in industrialized countries.
The limitations are mainly related to the observational design of the study and the cross-sectional nature of the current analyses. Firstly, the results presented are only associations from which no conclusions regarding causality can or should be drawn. Secondly, due to the observational design of the study, many measurements are expected not to be always conducted in a uniform manner. This includes measurement of blood pressure and laboratory analyses of lipid levels. However, even in the absence of uniform standards for this study, national and international standardization of serum lipid measurements have been accomplished through collaboration of the Centers for Disease Control and Prevention and the World Health Organization, and comparable results can be obtained globally because of these standardization efforts . Thirdly, the relatively high proportion of missing data should be noted (Table 3), which amongst other things implies that the prevalence of the individual risk factors is imprecise. Measures have been taken to complete the collection of pending baseline data during follow-up. Finally, information concerning certain other potential risk factors for CVD was not collected in our study, including genetic factors, physical activity, diet and alcohol consumption.
The present analysis shows that, especially among older patients, the use of potent antiretroviral therapy resulting in more profound virus suppression and more preserved immunity, was associated with a high both relative and absolute risk of exhibiting risk factors for coronary heart disease.
Using these results, work is in progress to model the estimated risk of CVD based on validated algorithms . Such projections assume that the induced risk factors can be directly transposed, which is likely to be a simplification as there presumably will be a time lag from when factors known to accelerate the atherosclerotic process are induced (i.e., when PI and/or NNRTI are started) and until clinical manifestations of atherosclerotic vascular disease will occur. As many of these factors are likely to act synergistically, and as the underlying HIV infection itself and its various manifestations may also contribute, current knowledge does not permit reliable assessment of the duration of the above mentioned time-lag. However, comparison of the estimated expected with the observed CVD event rate in the DAD study may provide some understanding.
Sponsorship: The ATHENA study was supported by a grant (CURE/97-46486) from the Health Insurance Fund Council, Amstelveen, the Netherlands. The Aquitaine Cohort was supported by a grant from the ‘Agence Nationale de Recherches sur le SIDA’ (ANRS, Action Coordonnée no.7, Cohortes). The BASS study was supported by grants from the ‘Fondo de Investigación Sanitaria’ (FIS 99/0887) and ‘Fundación para la Investigación y la Prevención del SIDA en Espanã’ (FIPSE 3171/00). The EuroSIDA study was supported by grants from the European Commission BIOMED 1 (CT94-1637) and BIOMED 2 (CT97-2713) programs, from Pharmacia & Upjohn, GlaxoSmithKline, Roche and Merck. The ICONA network was supported by an unrestricted educational grant from Glaxo Wellcome, Italy. The Swiss HIV Cohort Study was supported by a grant (3345-062041) from the Swiss National Science Foundation. Support for the DAD study was provided by the ‘Oversight Committee for The Evaluation of Metabolic Complications of HAART', a collaborative committee with representation from academic institutions, the EMEA, the FDA and all pharmaceutical companies with licensed anti-HIV drugs in the US marked, i.e., Abbott, Agouron, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfizer, Pharmacia & Upjohn, Hoffman-La Roche.
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DAD Steering Committee: Persons with * below (#: chair) and F. Houyez, T. Mertenskoetter, I. Weller.
DAD Central Coordination: N. Friis-Møller, C. Sabin, J.D. Lundgren.
DAD data managers: A. Sawitz and P. Ricks (coordination), M. Rickenbach, P. Pezzotti, E. Krum, R. Meester, V. Lavignolle, A. Sundström, B. Poll, E. Fontas, F. Torres, K. Petoumenos, J. Kjœr.
The members of the 11 Cohorts
ATHENA (AIDS Therapy Evaluation Project Netherlands)
Coordinating centre: F. de Wolf, J. Lange, E. van der Ven, H. Tissing, T. Hantke, R. Meester.
Participating physicians (city): W. Bronsveld (Alkmaar); H. Weigel, K. Brinkman, P. Frissen, J. ten Veen, M. Hillebrand, P. van Dam, S. Schieveld, J. Mulder, E. van Gorp, P. Meenhorst, A. van Eeden, S. Danner, F. Claessen, R. Perenboom, D. Blanckenberg, S. Blank, J. K. Eeftinck Schattenkerk, M. Godfried, S. Lowe, J. van der Meer, F. Nellen, K. Pogany, T. van der Poll, J. Prins, P. Reiss*, T. Ruys, M. van der Valk, A. Verbon, F. Wit (Amsterdam); C. Richter, R. van Leusen (Arnhem); R. Vriesendorp, F. Jeurissen (Den Haag); R. Kauffmann, E. Koger (Den Haag); B. Bravenboer (Eindhoven); C. ten Napel (Enschede); H.G. Sprenger, G. Law (Groningen); R.W. ten Kate (Haarlem); M. Leemhuis (Leeuwarden); F. Kroon, E. Schippers (Leiden); G. Schrey, S. van der Geest, A. van der Ven (Maastricht); P. Koopmans, M. Keuter, D. Telgt (Nijmegen); M. van der Ende, I. Gyssens, S. de Marie (Rotterdam); J. Juttmann, C. van der Heul (Tilburg); M. Schneider, J. Borleffs, L. Hoepelman, C. Jaspers, A. Matute, C. Schurink (Utrecht); W. Blok (Vlissingen).
Scientific committee: R. Salamon (chair), J. Beylot, M. Dupon, M. Le Bras, J.L. Pellegrin, J.M. Ragnaud; Coordinating centre staff: F. Dabis*, G. Chêne, N. Bernard, D. Lacoste, D. Malvy, D. Neau, M. Dupon, J.-F. Moreau, P. Morlat, P. Mercié, J.L. Pellegrin, J.M. Ragnaud, D. Commenges, H. Jacqmin-Gadda, R. Thiébaut, S. Lawson-Ayayi, V. Lavignolle, M.J. Blaizeau, M. Decoin, A.M. Formaggio, S. Delveaux, S. Labarerre, B. Uwamaliya, E. Vimard, L. Merchadou, G. Palmer, D. Touchard, D. Dutoit, F. Pereira, B. Boulant; Participating physicians (city): J. Beylot, P. Morlat, N. Bernard, M. Bonarek, F. Bonnet, B. Coadou, P. Gelie, D. Jaubert, C. Nouts, D. Lacoste, M. Dupon, H. Dutronc, G. Cipriano, S. Lafarie, J.Y. Lacut, J.L. Pellegrin, P. Mercie, J.F. Viallard, I. Faure, P. Rispal, C. Cipriano, B. Leng, M. Le Bras, F. Djossou, D. Malvy, J.P. Pivetaud, J.M. Ragnaud, C. De La Taille, D. Neau, T. Galperine, A. Ochoa, D. Chambon (Bordeaux).
AHOD (Australian HIV Observational Database, Australia)
Coordinating centre: M. Law*, K. Petoumenos (Sydney, New South Wales).
Participating sites (city, state): J. Anderson, J. Bal (Melbourne, Victoria), D. Austin, A. Gowers, D. Baker, R. McFarlane, A. Carr, D. Cooper (Sydney, New South Wales), J. Chuah, W. Fankhauser (Gold Coast, Queensland), S. Mallal, J. Skett (Perth, Western Australia), A. Mijch, K. Watson (Melbourne, Victoria), N. Roth, H. Wood (Melbourne, Victoria).
Coordinating centre: G Calvo*, F Torres, S Mateu (Barcelona).
Participating physicians: P. Domingo, M.A. Sambeat, J. Gatell, E. Del Cacho (Barcelona), G. Sirera, G. Viñas (Badalona).
The Brussels St Pierre Cohort (Belgium)
N. Clumeck, S. De Wit*, M. Gerard, P. Hermans, M. Hildebrand, K. Kabeya, D. Konopnicki, M.C. Payen, B. Sommereijns, Y. Van Laethem.
Central coordination: J. Neaton, G. Bartsch*, W. El-Sadr, E. Krum, D. Wentworth.
Participating physicians (city, state): R. Luskin-Hawk (Chicago, Illinois), E. Telzak (Bronx, 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 Study Group (Multinational)
Central coordination: O Kirk*, A Mocroft, AN Phillips*, JD Lundgren*#.
Participating countries and physicians (city): Austria, N. Vetter (Vienna); Belgium, N. Clumeck, P. Hermans (Brussels), R. Colebunders (Antwerp); Czech Republic, L. Machala (Prague); Denmark, J. Nielsen, T. Benfield, J. Gerstoft, T. Katzenstein, B. Røge, P Skinhøj (Copenhagen), C. Pedersen (Odense); France, C. Katlama, J.-P. Viard (Paris), T. Saint-Marc, P. Vanhems (Lyon); Germany, M. Dietrich, C. Manegold, J. van Lunzen (Hamburg); V. Miller, S. Staszewski, M. Bieckel (Frankfurt), F.D. Goebel (Munich), B. Salzberger (Cologne), J. Rockstroh (Bonn); Greece, J. Kosmidis, P. Gargalianos, H. Sambatakou, J. Perdios, G. Panos, I. Karydis, A. Filandras (Athens); Hungary, D. Banhegyi (Budapest); Ireland, F. Mulcahy (Dublin); Israel, I Yust, D. Turner (Tel Aviv), S. Pollack, Z. Ben-Ishai (Haifa), Z. Bentwich (Rehovot), S. Maayan (Jerusalem); Italy, S. Vella, A. Chiesi (Rome), C. Arici (Bergamo), R. Pristerá (Bolzano), F. Mazzotta, A. Gabbuti (Florence), R. Esposito, A. Bedini (Modena), A. Chirianni, E. Montesarchio (Naples), V. Vullo, P. Santopadre, P. Narciso, A. Antinori, P. Franci, M. Zaccarelli (Rome), R. Finazzi (Milan); Luxembourg, R. Hemmer, T. Staub (Luxembourg); Norway, J. Bruun, A. Maeland, V. Ormaasen (Oslo); Poland, B. Knysz, J. Gasiorowski (Wroclaw), A. Horban (Warsaw), D. Prokopowicz (Bialystok), A. Boron-Kaczmarska, M. Pynka (Szczecin), M. Beniowski (Chorzow), H. Trocha (Gdansk); Portugal, F. Antunes, K. Mansinho, R. Proenca (Lisbon); Spain, J. González-Lahoz, B. Diaz, T. García-Benayas, L. Martin-Carbonero, V. Soriano (Madrid), B. Clotet, A. Jou, J. Conejero, C. Tural (Badalona), J.M. Miró (Barcelona); Sweden, A. Blaxhult, B. Heidemann, P. Pehrson (Stockholm); United Kingdom, M. Fisher (Brighton), R. Brettle (Edinburgh), S. Barton, A.M. Johnson, D. Mercey, C. Loveday, M.A. Johnson, A. Pinching, J. Parkin, J. Weber, G. Scullard (London).
Central coordination: L. Morfeldt*, G. Thulin, A. Sundström.
Participating physicians (city): B. Åkerlund (Huddinge), K. Koppel, A. Karlsson (Stockholm), L. Flamholc, C. Håkangård (Malmö).
Central coordination: A. D'Arminio Monforte*, P. Pezzotti.
Participarting physicians: M. Moroni, A. d'Arminio Monforte, A. Cargnel, S. Merli, G.M. Vigevani, C. Pastecchia, A. Lazzarin, R. Novati, L. Caggese, C. Moioli (Milano), M.S. Mura, G. Madeddu (Sassari), F. Suter, C. Arici (Bergamo), P.E. Manconi (Cagliari), F. Mazzotta (Firenze), A. Poggio, G. Bottari (Verbania), G. Pagano, A. Alessandrini (Genova), A. Scasso, A. Vincenti (Lucca), V. Abbadesse, S. Mancuso (Palermo), F. Alberici, M. Sisti (Piacenza), M. Arlotti, P. Ortolani (Rimini), F. De Lalla, G. Tositti (Vicenza), N. Piersantelli, R. Piscopo (Genova), E. Raise, S. Pasquinucci (Venezia), F. Soscia, L. Tacconi (Latina), U. Tirelli, G. Nasti (Aviano) E. Rinaldi, L. Pusterla (Como), G. Carosi, F. Castelli (Brescia), G. Cadeo, D. Vangi (Brescia), G. Carnevale, D. Galloni (Cremona), G. Filice, R. Bruno (Pavia), A. Sinicco, M. Sciandra, P. Caramello, L. Gennero, M.L. Soranzo, A. Macor (Torino), G. Rizzardini, C. Abeli (Busto Arsizio), F. Chiodo, V. Colangeli (Bologna), L. Bonazzi, M. Ursitti (Reggio Emilia), F. Menichetti, A. Smorfa (Pisa), R. Esposito, C. Mussini (Modena), F. Ghinelli, L. Sighinolfi (Ferrara), F. Gritti, O. Coronado (Bologna), T. Zauli, G. Ballardini (Ravenna), M. Montroni, A. Costantini (Ancona), E. Petrelli, A. Cioppi (Pesaro), L. Ortona, A. De Luca, N. Petrosillo, P. Noto, P. Narciso, G. D'Offizi, A. Antinori, P. De Longis, V Vullo, M. Lichtner (Roma), G. Pastore, M.L. Perulli (Bari), A. Chirianni, L. Loiacono, M. Piazza, S. Nappa, N. Abrescia, M. De Marco (Napoli), A. Colomba, T. Prestileo (Palermo), C. De Stefano, A. La Gala (Potenza), T. Ferraro, A. Scerbo (Catanzaro), P. Grima, P. Tundo (Lecce), E. Pizzigallo, F. Ricci (Chieti), B. Grisorio, S. Ferrara (Foggia).
Nice Cohort (France)
Central coordination: C. Pradier*, E. Fontas, C. Caissotti.
Participating physicians: P. Dellamonica, L. Bentz, E. Bernard, S. Chaillou, F. De Salvador-Guillouet, J. Durant, R. Guttman, L. Heripret, V. Mondain-Miton, I. Perbost, B. Prouvost-Keller, P. Pugliese, V. Rahelinirina, P.M. Roger, F. Vandenbos.
SHCS (The Swiss HIV Cohort Study, Switzerland)
Scientific Committee: R. Amiet, M. Battegay (chair), E. Bernasconi, H. Bucher, P. Bürgisser, M. Egger, P. Erb, W. Fierz, M. Flepp, P. Francioli, H. J. Furrer, M. Gorgievski, H. Günthard, P. Grob, B. Hirschel, C. Kind, T. Klimkait, B. Ledergerber, U. Lauper, M. Opravil, F. Paccaud, G. Pantaleo, L. Perrin, W. Pichler, J. C. Piffaretti, M. Rickenbach, C. Rudin, P. Sudre, V. Schiffer, J. Schupbach, A. Telenti, P. Vernazza, R. Weber*.
Participating physicians (city): H. C. Bucher, M. Battegay (Basel), H. J. Furrer, M. Egger (Bern), A. Calmy, B. Hirschel (Geneve), A. Telenti (Lausanne), E. Bernasconi, L. Magenta (Lugano), T. Wagels, P. Vernazza (St. Gall), M. Flepp, R. Weber (Zürich).