Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men
Mary-Krause, Muriellea; Cotte, Laurentb; Simon, Annec; Partisani, Mariad; Costagliola, Dominiquea; and the Clinical Epidemiology Group from the French Hospital Database
From aINSERM EMI 0214, Paris, bHôtel Dieu, Lyon, cPitié-Salpétrière, Paris and dCHRU Strasbourg, France. *See the Appendix for Group members.
See also p. 2529
Correspondence to: M. Mary-Krause, INSERM EMI 0214, 56 Boulevard Vincent Auriol, BP 335, 75625 Paris Cedex 13, France.
Received: 6 June 2002; revised: 3 April 2003; accepted: 15 April 2003.
Background: In the current context of dyslipidaema, hyperglycaema and lipodystrophia observed among HIV-seropositive subjects, it is important to study the risk of myocardial infarction (MI) in this population. The French Hospital Database on HIV, which includes a large number of seropositive subjects followed for substantial periods, offers the opportunity to analyse the impact of protease inhibitors (PI) on the risk of MI among men.
Methods: Cox model was used to study the risk factors of MI occurrence. Standardized morbidity ratios (SMR) in men exposed to PI were calculated with data from the French general male population (FGMP) of the same age as reference.
Results: Between 1996 and 1999, MI was diagnosed in 60 men among 88 029 person-years (PY), including 49 cases among men exposed to PI. In the Cox model, exposure to PI was associated with a higher risk of MI [relative hazard (RH), 2.56; 95% confidence interval (CI), 1.03-6.34]. The expected incidence in the FGMP was 10.8/10 000 PY. The SMR relative to the FGMP was 0.8 (95% CI, 0.5-1.3) for men exposed to PI for < 18 months (G1), 1.5 (95% CI, 0.8-2.5) for men exposed for 18-29 months (G2) and 2.9 (95% CI, 1.5-5.0) for men exposed for ≥ 30 months (G3). With G1 as reference, the SMR was 1.9 (95% CI, 1.0-3.1) for G2 and 3.6 (95% CI, 1.8-6.2) for G3.
Conclusion: Our results point to a duration-related effect relationship between PI and MI, with a higher MI incidence rate among men exposed to PI for 18 months or more.
With the advent of more effective therapies for HIV infection, including protease inhibitor drugs (PI), the morbidity of AIDS-defining illnesses has been reduced  and HIV-infected patients are living longer . Although abnormalities of lipid metabolism in HIV-infected patients were described well before the advent of highly active antiretroviral therapy (HAART) [3,4], several class-specific metabolic effects of PI therapy may have a deleterious effect on the heart, including increased insulin resistance, abnormalities of lipid metabolism, and a lipodystrophy syndrome [5-7]. HAART has occasionally been implicated in the aggravation of coronary heart disease and other vascular complications [8-13]. However, the impact of PI on the risk of coronary heart disease (CHD) and myocardial infarction (MI) in particular remains controversial.
The French Hospital Database on HIV (FHDH), which includes a large number of subjects and substantial follow-up, offers an opportunity to analyse the impact of PI on the risk of myocardial infarction. The present study uses the dataset to analyse risk factors for MI, including PI, in HIV-infected men. The incidence rate of MI according to the estimated duration of PI therapy is compared with the expected incidence in the general population of men of the same age.
The methodology of the FHDH has been described in detail elsewhere . Briefly, it is a clinical epidemiological network started in 1992 in 68 French University Hospitals belonging to 29 HIV treatment and information centres. The only FHDH inclusion criteria are HIV-1 or HIV-2 infection and written informed consent. Data are collected prospectively by trained research assistants, using DMI2 software (property of the French Ministry of Health). The standardized data collection form includes the transmission group, values of usual biological markers such as CD4 cell counts and HIV RNA levels, clinical manifestations, treatments, clinical trials in which the patient is enrolled, and death and cause of death as reported in the medical records. A follow-up form is completed at least every 6 months, and/or at each visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed, or a change in biological markers is noted.
By the end of 1999, data on 73 336 seropositive subjects were included in the database, with a median follow-up of 32 months.
PI became widely available in France in late March 1996. Entry to this study was therefore defined as 1 January 1996 for subjects who were enrolled in the FHDH before this date and were still alive, and as the date of enrolment in the FHDH for subjects enrolled after this date. Only patients aged at least 15 years with at least two follow-up visits after entry to the study, or those dying before the second visit or hospital admission, were included in this analysis. Exclusion criteria were ongoing MI at entry or a history of MI. Women were excluded from the analysis, as only six women in the database had MI and the expected incidence in the general female population of the same age is very low, suggesting a lack of statistical power.
Definition of myocardial infarction
In the FHDH, clinical events were recorded according to the International Disease Codification (IDC) version 9  until the end of 1996 and version 10  thereafter. The codes for MI were 410 (myocardial infarction) prior to 1997, and I21 (myocardial infarction) thereafter. Both non-fatal and fatal MI were analysed.
For each MI, a questionnaire was sent to the study centres to validate the diagnosis and to collect data on any preexisting cardiovascular disorders not recorded in the FHDH. MI was defined by a rise and fall in troponin, or a rise and fall in creatine kinase-myglobin, plus at least one of the following signs: (i) ischaema, (ii) pathological Q waves on electrocardiograph, (iii) electrocardiographic changes indicative of ischaema (ST segment elevation or depression), or (iv) coronary artery intervention (e.g. coronary angioplasty) .
Statistical analysis of risk factors for myocardial infarction
Factors associated with the risk of MI were analysed using univariate and multivariate Cox proportional hazards models . A censoring method recommended for cohort studies  was used to take the reporting delay into account. Surviving patients for whom the last follow-up data were obtained in the 6-month period before 31 December 1999 (last database update) were censored on 31 December 1999.
The following variables were assessed for their impact on the risk of MI during the period 1996-1999: age, HIV exposure group, initial CD4 cell count, CD4 cell count < 50 × 106 cells/l, AIDS-associated illnesses, and antiretroviral regimens; the last three parameters were studied as time-dependent covariates. An intention-to-continue-treatment approach was used to analyse antiretroviral treatment , each treatment taking the value 0 until a patient started treatment and remaining at 1 thereafter. AIDS diagnosis was based on the clinical criteria of the 1993 revised case definition . Three antiretroviral treatment variables were analysed, as follows: nucleoside reverse transcriptase inhibitor (NRTI) therapy, non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy and PI therapy.
Age (a known risk factor for CHD), initial CD4 cell count and treatment variables were included in the multivariate Cox model. All analyses were performed using SAS statistical software version 8.2 (SAS Institute, Cary, North Carolina, USA).
Statistical analysis of myocardial infarction incidence rates and comparison with the general population
The incidence rate of MI among subjects exposed to PI between 1996 and 1999 was estimated according to the duration of PI therapy. Exposure durations were initially categorized by 6-month intervals. The final analysis was based on three durations: < 18 months (group 1), 18-29 months (group 2) and ≥ 30 months (group 3). These particular intervals were chosen on the basis of an adequate number of person-years (PY) and close incidences.
Incidence data for MI in the general French population of the same age and sex as subjects exposed to PI were obtained from myocardial infarction and coronary death population registries in three French regions (Lille, Strasbourg and Toulouse). These registries, which cover approximately 1 million inhabitants each, participated in the WHO Monica project during the period 1984-1993 . Since 1997, all clinically diagnosed MI (lethal and non-lethal) and coronary death have been recorded by systematic review of hospital data and death certificates for men and women aged < 65 years and living in these regions. Age- and sex-specific incidence rates (first events) were computed, and data are available for the period 1997-1998 .
The 1996-1999 MI incidence rates estimated from the FHDH dataset were compared with the 1997-1998 incidence rates estimated from the general male population using standardized morbidity ratios (SMR) . Then, in order to take into account potentially different CHD risk factor profiles (age, sex, family history of CHD, smoking, hypertension and diabetes mellitus) between the general population and the HIV-infected population, the MI incidence rates in groups 2 and 3 were compared with those in group 1.
MI was recorded in 66 patients. Following the validation survey, six subjects were excluded from the analysis because they had a past history of MI. All the other cases corresponded with the definition. The analysis, therefore, included 34 976 men with a follow-up corresponding to 88 029 PY. MI was diagnosed in 49 subjects among 39 023 PY of exposure to PI. The main characteristics of the patients in the groups with and without MI are shown in Table 1. Significant differences were observed from Cox univariate models in terms of age, the CD4 cell count at entry, and exposure to PI.
In the multivariate analysis, initial CD4 cell counts, exposure to NRTI and exposure to NNRTI did not influence the risk of MI (Table 2).
MI was more likely in older patients and those exposed to PI. The risk of MI increased by 42% per 10-year age increment, and more than twofold in patients exposed to PI.
Among the patients exposed to PI for < 18 months, there were 21 MI (25 734 PY); there were 15 MI among those exposed for 18-29 months (9440 PY) and 13 among those exposed for ≥ 30 months (3849 PY) (Table 3). The expected incidence of MI in the general male population with same age distribution was 10.8/10 000 PY. In the FHDH dataset, the estimated incidence was 8.2/10 000 PY (95% CI, 4.7-11.7) in patients exposed to PI for < 18 months, 15.9 (95% CI, 7.9-23.9) in those exposed for 18-29 months, and 33.8 (95% CI, 15.4-52.1) in those exposed for ≥ 30 months (Fig. 1). No significant difference in incidence was observed between the general population and patients treated with PI for < 18 months. The risk of MI was increased, but not significantly, among patients treated with PI for 18-29 months. In contrast, the risk of MI among patients exposed to PI for ≥ 30 months was three times that of the general population (SMR, 2.9; 95% CI, 1.5-5.0). Compared with patients exposed to PI for < 18 months, those treated for ≥ 18 months were at an increased risk of MI (SMR, 1.9; 95% CI, 1.0-3.1 and SMR, 3.6; 95% CI, 1.8-6.2 for exposure of 18-29 and ≥ 30 months, respectively).
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.
Previous studies have either shown [33-37] or not shown [25,38-40] a link between the risk of CHD and exposure to PI. Some of these studies suffered from methodological problems, such as the sample size, median duration of PI treatment of < 12 months in two studies, and likely underreporting relative to the general population. A recent study showed no increase in the rate of admission for or death from cardiovascular or cerebrovascular disease between 1995 and 2001 in a large population of HIV-infected US veterans despite the introduction and increasing use of HAART . A direct comparison of these results with those of our study is impossible because the two studies did not examine the same type of events. In our study, we looked at the admissions and the deaths from MI whereas Bozzette et al.  only looked at the admissions for cardiovascular diseases. In their study, death or admissions were grouped for cardiovascular and cerebrovascular diseases. However, Holmberg et al. , who suggested an effect of PI on the risk of MI, did not highlight any risk for cerebrovascular disease with PI exposure. Moreover, the ICD-9 codes used to define cardiovascular disease by Bozzette et al.  included 410, 411, 413, 414, which cover a number of pathologies (while we only used ICD 410); it would be interesting to study the impact of PI on each kind of disease separately. Related to this, it should be noted that a higher, although not significant, risk was observed among subjects exposed to PI who were admitted with cardiovascular diseases (RH, 1.23). In addition, the incidence of admission for cardiovascular diseases > 10/1000 PY observed by Bozzette et al. is much higher than the incidence rate of CHD observed among American seropositive subjects exposed to PI in other studies (5.9-7.1 events/1000 PY) [37,39].
In the recently presented DAD study , the relationship between exposure to antiretroviral therapy including PI or NNRTI and the risk of MI was similar to the one observed in our study. Similarly, an increased risk of CHD was also identified in PI-exposed patients by Moore et al. .
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). Cited Here...
myocardial infarction; antiretroviral therapy; protease inhibitors; risk factors; HIV infection
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