The risk of MI in HIV-infected men increased with the duration of PI treatment, while other classes of drug treatment did not associate with MI risk.
Choosing 1 January 1996 as the starting point for the study shortened the time under NRTI in patients who started treatment before 1996. If time on NRTI was associated with MI (as suggested by David et al.  and by the fact that many side effects of HAART, such as the lipoatrophy, are probably in part caused by NRTI ), we might be unable to detect it. However, carrying out the analysis with 1 January 1992 as the starting point, showed no association between NRTI and MI but still found PI as an independent risk factor [relative hazard (RH), 1.40; 95% CI, 0.55–3.54 for NRTI; RH, 2.39; 95% CI, 1.36–4.21 for PI].
CHD risk factors in HIV-positive patients can be considered in two groups: those that are a consequence of treatment and ones independent of treatment. The first includes cholesterol, triglyceride or blood glucose levels, as different studies support a major role for PI in the pathogenesis of metabolic abnormalities such as increases in triglyceride and cholesterol. These parameters are known to undergo modifications in HIV-infected subjects and in healthy volunteers receiving PI [6,27]. The fact that our analysis was not adjusted for cholesterol, triglyceride or blood glucose levels [28–30] is unlikely to introduce a source of bias as these factors are likely to mediate a potential impact of antiretroviral treatment on the MI risk. In this light, it would have been interesting to use those data in a multivariate model to study whether change in these parameters could explain the impact of PI exposure on the risk of MI.
The second category includes known CHD risk factors such as age, familial and personal history of CHD, smoking, obesity and arterial hypertension. The Cox model used here to identify risk factors for MI was adjusted for an important CHD risk factor in the general population, age. Increasing age was found as an independent risk factor for MI in the study population. The relation of PI to MI occurrence (non-adjusted RH, 2.93; 95% CI, 1.48–5.82) did not modify if the Cox model was adjusted for age suggesting than PI was not prescribed according this risk factor.
The Cox models used were not adjusted for the other known CHD risk factors such as familial and personal history of CHD, smoking, obesity and arterial hypertension, which were not recorded in the FHDH cohort. While risk factors for CHD in general are also associated with the risk of MI, it is extremely unlikely that they influenced the decision to prescribe PI in the study population, as was observed for age. Indeed, during the study period, the PI treatment decision was solely based on prognostic factors for HIV disease. However, we could not exclude the possibility that CHD risk factors would be more prevalent in the patients who were exposed to a PI for longer, who would be those who received PI earlier in the study. If this hypothesis was true, one would expect that the risk of MI among those exposed for < 18 months would be higher if they begun HAART in 1996 than if they began later. This was not supported by an analysis of the incidence of MI among people with < 18 months PI exposure according to the year between 1996 and 1998 when the PI-containing regimen was started. Indeed, the incidences per 10 000 PY fluctuated but did not decrease over time (6.4 ± 2.4 in 1996, 10.9 ± 3.4 in 1997 and 8.6 ± 4.3 in 1998). Therefore, this hypothesis was not supported by the data for 1996–1998 and could be excluded as an explanation for the results seen in 1996–1999.
An ascertainment bias could have influenced our results given the way data are collected in the FHDH. Indeed, for patients who started PI-containing regimen in 1996, when PI were first introduced, physicians may have been less aware of having to suspect cardiovascular morbidity than in later years, possibly resulting in underreporting of MI in the earlier period covered by the study. If this ascertainment bias was major, one would expect to observe increasing risk of MI for a given duration of exposure in more recent years of PI institution. As shown for patients with < 18 months PI exposure, and also for analyses with longer duration of exposure stratified by PI starting year, the incidences fluctuated with no consistent pattern whatever the PI exposure duration. Therefore, even if some ascertainment bias did occur, it should not be considered as a major factor in the study. If the literature on the increased incidence of hyperlipidaema and insulin resistance among patients on PI published since 1999 influenced physicians and patients to discontinue PI use and thereby shorten PI exposure, this would actually be a form of negative confounding, biasing the study towards a negative result.
The incidence estimated among subjects not exposed to PI (2.24/10 000 PY; 95% CI, 0.92–3.57) in the FHDH was lower than expected in the general population with same age and sex. That is the reason why no comparison between the incidence among men exposed to PI and men not exposed to PI was made, as there will be a major bias in such comparison. To account for the possibility that MI was more efficiently diagnosed and reported in patients exposed to PI than in other patients, the second analysis was restricted to patients exposed to PI for whom this potential bias could not occur. Comparisons were done with the general population with same age and sex. As CHD risk factors in French HIV-infected patients are not the same as those in the French general population [31,32], comparisons were also made with HIV-infected men exposed to PI for < 18 months more likely to have similar CHD risk factors.
Both comparisons showed a relationship between the risk of MI and the duration of exposure to PI, particularly when the reference population consisted of patients exposed to PI for < 18 months. The observed effect of PI duration of use could not be explained by those who used PI having more risks for CHD because the risks obtained when the reference population consisted of patients exposed to PI for < 18 months were higher than those obtained when the reference was the general population.
If the results quoted in all the available literature are considered, it appears that exposure to PI does increase the risk of MI and this risk depends on the duration of PI exposure. Our results suggest an increasing risk of MI with the duration of PI treatment among HIV-infected men. However, the increase in life expectancy conferred by HAART clearly outweighs the associated risk of MI. In keeping with preliminary guidelines [41,42], the risk of CHD must be taken into account in PI treatment decisions, especially for patients with known risk factors for CHD. Cholesterol, triglycerides and blood glucose levels must be determined before and regularly during HAART in order to diagnose any abnormalities as they occur. If lipid-lowering drug therapy is indicated, it should be limited to those agents with a low risk of interaction with antiretroviral drugs.
Longer follow-up under PI is necessary to observe if the risk of MI will continue to increase with the duration of PI exposure, and further studies are necessary to confirm the impact of NNRTI on CHD occurrence as observed in the DAD study .
We are indebted to all the participants in the cohort, and especially the local research assistants, without whom this work would not have been possible. We also thank P. Ducimetière (Villejuif), P. Amouyel (Lille), D. Arveiler (Strasbourg) and J. Ferrières (Toulouse) for providing the Monica-France incidence data.
Sponsorship: This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Agence Nationale de Recherches sur le SIDA, the Fondation pour la Recherche Médicale and the French Health Ministry.
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Scientific committee: F. Bastides, E. Billaud, A. Boibieux, F. Boué, F. Bricaire, D. Costagliola, L. Cotte, L. Cuzin, P. Enel, S. Fournier, J. Gasnault, C. Gaud, J. Gilquin, S. Grabar, J. M. Lang, H. Laurichesse, C. Leport, M. Mary-Krause, S. Matheron, M. C. Meyohas, C. Michelet, J. Moreau, N. Petit, G. Pialoux, I. Poizot-Martin, C. Pradier, C. Rabaud, E. Rouveix, P. Saïag, D. Salmon-Ceron, H. Tissot-Dupont, Y. Yasdanpanah.
DMI2 coordinating centre: French Ministry of Health (E. Aronica, B. Haury, V. Tirard-Fleury, I. Tortay).
Statistical analysis centre: INSERM EMI 0214 (S. Abgrall, D. Costagliola, S. Grabar, E. Lanoy, L. Lièvre, M. Mary-Krause, V. Potard).
Paris area HIV treatment and information centres (CISIH): CISIH de Bichat-Claude Bernard (Hôpital Bichat-Claude Bernard: S. Matheron, J. P. Coulaud, J. L. Vildé, C. Leport, P. Yeni, C. Mandet, E. Bouvet, C. Gaudebout, B. Crickx, C. Picard-Dahan), CISIH de Paris-Centre (Hôpital Broussais: L. Weiss, D. Tisne-Dessus; G. H. Tarnier-Cochin: D. Sicard, D. Salmon; Hôpital Saint-Joseph: J. Gilquin, I. Auperin), CISIH de Paris-Ouest (Hôpital Necker adultes: J. P. Viard, L. Roudière; Hôpital Laennec: W. Lowenstein; Hôpital de l'Institut Pasteur), CISIH de Paris-Sud (Hôpital Antoine Béclère: F. Boué, R. Fior; Hôpital de Bicêtre: J. F. Delfraissy, C. Goujard; Hôpital Henri Mondor: Ph. Lesprit, C. Jung; Hôpital Paul Brousse), CISIH de Paris-Est (Hôpital Saint-Antoine: M. C. Meyohas, J. L. Meynard, O. Picard, N. Desplanque; Hôpital Tenon: J. Cadranel, C. Mayaud, G. Pialoux, W. Rozenbaum), CISIH de Pitié-Salpétrière (GH Pitié Salpétrière: F. Bricaire, C. Katlama, S. Herson, A. Simon), CISIH de Saint-Louis (Hôpital Saint-Louis: J. M. Decazes, J. M. Molina, J. P. Clauvel, L. Gerard; GH Lariboisière-Fernand Widal: J. M. Salord, Diermer), CISIH 92 (Hôpital Ambroise Paré: C. Dupont, H. Berthé, P. Saïag; Hôpital Louis Mourier: E. Mortier, C. Chandemerle; Hôpital Raymond Poincaré: P. de Truchis), CISIH 93 (Hôpital Avicenne: M. Bentata, P. Berlureau; Hôpital Jean Verdier: J. Franchi, V. Jeantils; Hôpital Delafontaine: Mechali, B. Taverne).
Other CISIH: CISIH Auvergne-Loire (CHU de Clermont-Ferrand: H. Laurichesse, F. Gourdon; CHRU de Saint-Etienne: F. Lucht, A. Fresard); CISIH de Bourgogne-Franche Comté (CHRU de Besançon; CHRU de Dijon; CH de Belfort: J. P. Faller, P. Eglinger); CISIH de Caen (CHRU de Caen: C. Bazin, R. Verdon), CISIH de Grenoble (CHU de Grenoble), CISIH de Lyon (Hôpital de la Croix-Rousse: D. Peyramond, A. Boibieux; Hôpital Edouard Herriot: J. L. Touraine, J. M. Livrozet; Hôtel-Dieu: C. Trepo, L. Cotte; CH de Lyon-Sud, Médecine Pénitentiaire: P. Barlet), CISIH de Marseille (Hôpital de la Conception: I. Ravaux, H. Tissot-Dupont; Hôpital Houphouët-Boigny: J. P. Delmont, J. Moreau; Institut Paoli Calmettes: J. A. Gastaut; Hôpital Sainte-Marguerite: I. Poizot-Martin, J. Soubeyrand, F. Retornaz; CHG d'Aix-En-Provence: P. A. Blanc, T. Allegre; Centre pénitentiaire des Baumettes: A. Galinier, J. M. Ruiz; CH d'Arles; CH d'Avignon: G. Lepeu; CH de Digne Les Bains: P. Granet-Brunello; CH de Gap: L. Pelissier, J. P. Esterni; CH de Martigues: M. Nezri, R. Cohen-Valensi; CHI de Toulon: A. Laffeuillade, S. Chadapaud), CISIH de Montpellier (CHU de Montpellier: J. Reynes; CHG de Nîmes), CISIH de Nancy (Hôpital de Brabois: T. May, C. Rabaud), CISIH de Nantes (CHRU de Nantes: F. Raffi, E. Billaud), CISIH de Nice (Hôpital Archet 1: C. Pradier, P. Pugliese; CHG Antibes Juan les Pins), CISIH de Rennes (CHU de Rennes: C. Michelet, C. Arvieux), CISIH de Rouen (CHRU de Rouen: F. Caron, F. Borsa-Lebas), CISIH de Strasbourg (CHRU de Strasbourg: J. M. Lang, D. Rey, P. Fraisse; CH de Mulhouse), CISIH de Toulouse (CHU Purpan: P. Massip, L. Cuzin, E. Arlet-Suau, M. F. Thiercelin Legrand; Hôpital la Grave; CHU Rangueil), CISIH de Tourcoing-Lille (CH Gustave Dron; CH de Tourcoing: S. Alfandari, Y. Yasdanpanah), CISIH de Tours (CHRU de Tours; CHU Trousseau).
Overseas CISIH: CISIH de Guadeloupe (CHRU de Pointe-à-Pitre), CISIH de Guyane (CHG de Cayenne: M. Sobesky, R. Pradinaud), CISIH de Martinique (CHRU de Fort-de-France), CISIH de La Réunion (CHD Félix Guyon: C. Gaud, M. Contant).