Impact of Specific NRTI and PI Exposure on the Risk of Myocardial Infarction A Case-Control Study Nested within the French Hospital Database on HIV ANRS CO4 S Lang, M Mary-Krause, L Cotte, J Gilquin, M Partisani, A Simon, F Boccara, D Costagliola Unité 943

Background - I RR (95% CI) = 1.16 (1.10 –1.23) Mary-Krause M et al., AIDS 2003; 17: D:A:D Study Group, Friis-Møller N et al., N Engl J Med 2007; 356: Cumulative exposure to protease inhibitors (Pis) has been associated with an increased risk of myocardial infarction but the role of specific protease inhibitors has not been reported Risk of myocardial infarction and exposure to protease inhibitors

D:A:D study group, Sabin CA, et al., Lancet 2008; 371: The SMART/Insight and the D:A:D study groups, Lundgren JD et al., AIDS 2008; 22: F17-F24 D:A:D Study Patients with MI n = 517 Recent exposure to abacavir was associated with a higher risk of MI RR (95% CI) = 1.94 (1.48 –2.55) SMART Study Patients with MI n = 19 Current use of abacavir was associated with an increased risk of MI HR (95% CI) = 4.3 (1.4 –13.0) In these 2 studies, exposure to abacavir showed signals which were not completely concordant Background - II Risk of myocardial infarction according to exposure to abacavir Interactions with CVD risk factors were in the opposite direction in the two studies

Objectives In a nested case-control study within the French Hospital Database on HIV, to evaluate the association between the risk of myocardial infarction (MI) and cumulative to specific NRTIs recent (current or within last 6 months) and past exposure (>6 months ago) to specific NRTIs cumulative exposure to specific PIs

* Luepker R et al., Circulation 2003; 108: Cases Over HIV-infected patients have been enrolled into the FHDH between 1989 and 2006 Patients with a first MI prospectively reported between January 2000 and December 2006 were included Only definite or probable MI cases validated by a cardiologist (FB) according to the ASC/ESC criteria* were eligible Out of the 418 cases identified, 129 were excluded 45 had incomplete medical records 36 MIs occurred before the study period 2 cases of MI were undated 4 cases of MI occurred before the diagnosis of HIV infection 6 cases had a MI before being enrolled in the cohort 36 cases did not have a confirmed MI 289 cases

Controls HIV-infected patients with no history of MI, HIV-infected patients with no history of MI, followed at the time of MI diagnosis of the corresponding case Matched for Age at diagnosis of MI +3 years Sex Clinical center Matching based on these factors yields similar results in a nested case-control study to those obtained with the cohort approach used in our first study on the risk of MI * For each validated case, up to five matched controls randomly selected with replacement from the database Cases eligible as control up to the time of the diagnosis of MI 3 cases with 1 control, 11 with 2, 246 with 3, 24 with 4 and 5 with 5 controls * Guiguet M et al., Pharmacoepid Drug Saf, 2008; 17: controls

Methods Data collected for cases and controls Cardiovascular risk factors Smoking, family history, hypertension, hyperlipidemia, diabetes Treatments for lipid, metabolic and hypertensive disorders BMI, current IV drug use Validation of HIV data recorded in the database CD4 cell count, current (within 3 months of MI) and nadir CD4/CD8 ratio (within 3 months of MI) Plasma HIV-1 RNA (within 3 months of MI) ART treatment history Stage C (AIDS) before MI

Analyses - I Several conditional logistic regression models were constructed A first model including cumulative exposure to each ART A second model including cumulative exposure to each ART and exposure to each NRTI as a three-class variable: no exposure last use > 6 months (past) ongoing exposure or interruption < 6 months (current/recent) In these models, potential confounders which affected the association between any ART and the risk of MI by at least 10% in any of the models were included from Age, smoking, family history of CHD, BMI, hypertension, intravenous drug use CD4 cell nadir, plasma HIV-1 RNA, CD4 cell count, CD4/CD8 cells ratio within 3 months before MI and AIDS before MI

Analyses - II Odds Ratios (OR) are reported only for NRTIs and PIs with at least 100 exposed patients AZT, ddI, ddC, d4T, 3TC, ABC, TNF SQV, IDV, NFV, LPV, APV/fAPV although cumulative exposures to FTC, EFV, NVP, ATV and TPV were also accounted for in the analyses

Characteristics Cases (n = 289)Controls (n = 884) Sex, male, n (% )257 (88.9%)788 (89.1%) Age, years, median (IQR )46.9 ± (40.7 – 54.1)46.3 (40.2 – 53.7) Hypertension, n (%)59 (20.6%)102 (11.8%) Smoking, n (%)210 (72.7%)388 (43.9%) Family history of CHD, n (%)53 (18.5%)58 (6.7%) Hypercholesterolemia, n (%)148 (51.7%)282 (32.6%) Intravenous drug use, n (%)38 (13.3%)83 (9.5%) Number of CV risk factors : 0, n (%) 1-2 n, (%) ≥ 3 n, (%) 3 (1.0%) 172 (59.5%) 114 (39.4%) 163 (18.4%) 553 (62.6%) 168 (19.0%) Viral load, copies/mL, median (IQR)127 ( )50 (50 – 1368) Viral load <50 copies/mL, n (%)125 (43.3%)457 (51.7%) CD4 count, cells/mm 3 median (IQR)427 ( )451 (291 – 634) CD4/CD8 ratio  1, n (%) 19 (6.6%)116 (13.1%) No treatment before MI, n (%)11 (3.8%)55 (6.2%) 1 st treatment after inclusion in FHDH, n (%) 210 (72.7%)677 (76.6%)

Exposure to abacavir and risk of MI - I N exposed N exposed cases OR[ 95% CI ]p value Cum exposure to abacavir Model 1

Exposure to abacavir and risk of MI - II N exposed N exposed cases OR[ 95% CI ]p value Cumulative exp to abacavir Cumulative exp to abacavir No exposure Current/Recent exposure Past exposure Model 1 Model 2 For abacavir, there was evidence of an interaction between recent/past and cumulative exposure, while no such effect was observed for any other NRTI A final model including exposure to abacavir as a five-class variable and cumulative exposure to all other ART was constructed no exposure exposure <= 1 year and last use <= 6 months prior to the MI (current/recent) exposure 6 months prior to the MI (past) exposure > 1 year and last use <= 6 months prior to the MI (current/recent) exposure > 1 year and last use > 6 months prior to the MI (past)

Exposure to abacavir and other NRTIs and risk of MI - III Final model N exposed N exposed cases OR[ 95% CI ]p value No exposure Expo < 1 year, current/recent Expo < 1 year, past Expo > 1 year, current/recent Expo > 1 year, past Cum exp to zidovudine Cum exp to didanosine Cum exp to zalcitabine Cum exp to stavudine Cum exp to lamivudine Cum exp to tenofovir No interaction was found between exposure to abacavir and numbers of CV risk factors on the risk of MI (p = 0.384) Similar results were observed when restricting the analysis to patients with first ART after inclusion in the cohort

Cumulative exposure (per additional year) N exposed N exposed cases OR[ 95% CI ]p value Saquinavir +/-r – Indinavir +/-r – Nelfinavir – Lopinavir/r – Amprenavir/fos-amp +/-r – Final model Exposure to PIs and risk of MI Cumulative exposure (per additional year) N exposed N exposed cases OR[ 95% CI ]p value PI +/-r – 1.26<0.001 Saquinavir +/-r – Similar results were observed when restricting the analysis to patients with first ART after inclusion in the cohort Final model combining all PIs but SQV

Interpretation - I Exposure to abacavir and risk of MI  We found a signal slightly different from those of the D:A:D study and of the SMART Study  only early exposure to abacavir was associated with an increased risk of MI  no interaction between exposure to abacavir and CV risk factors on the risk of MI

Interpretation - II Exposure to other NRTIs and risk of MI  Trends towards an increased risk of MI by cumulative exposure to  Trends towards an increased risk of MI by cumulative exposure to AZT and to d4T were evidenced  In line with the original hypothesis in the D:A:D study  These associations deserve additional evaluations in independent studies   No signal was evidenced for the other NRTIs, including ddI and TNF

Exposure to PIs and risk of MI Interpretation - III Exposure to PIs and risk of MI  In our study the association between the risk of MI and cumulative exposure to PI was in concordance with that observed in the D:A:D study  Increased risk for all studied PIs, but saquinavir  Significant in specific analyses for lopinavir/r and amprenavir/fos-amprenavir  Significant in specific analyses for lopinavir/r and amprenavir/fos-amprenavir +/-r  Unlikely explained by selection biases and confounding  After 10 years of exposure, the risk would be increased by 4.4

Acknowledgments - I We thank the study team without whom it would have been impossible to complete the study in time We thank the study team without whom it would have been impossible to complete the study in time Lydie Béniguel, Sandra Firmin, Sophie Pakianather, Serge Rodrigues, Selma Trabelsi, Sarah William-Faltaos Lydie Béniguel, Sandra Firmin, Sophie Pakianather, Serge Rodrigues, Selma Trabelsi, Sarah William-Faltaos We are grateful to the following colleagues who read and provided comments on the analysis plan We are grateful to the following colleagues who read and provided comments on the analysis plan S Evans, M Hernán, C Sabin and I Weller S Evans, M Hernán, C Sabin and I Weller A special thank to Rob Murphy A special thank to Rob Murphy The study was funded by ANRS The study was funded by ANRS

Acknowledgments - II Clinical Epidemiology Group of the FHDH Clinical Epidemiology Group of the FHDH Scientific committee S Abgrall, F Barin, M Bentata, E Billaud, F Boué, C Burty, A Cabié, D Costagliola, L Cotte, P De Truchis, X Duval, C Duvivier, P Enel, L Fredouille-Heripret, J Gasnault, C Gaud, J Gilquin, S Grabar, C Katlama, MA Khuong, JM Lang, AS Lascaux, O Launay, A Mahamat, M Mary-Krause, S Matheron, JL Meynard, J Pavie, G Pialoux, F Pilorgé, I Poizot-Martin, C Pradier, J Reynes, E Rouveix, A Simon, P Tattevin, H Tissot-Dupont, JP Viard, N Viget Scientific committee S Abgrall, F Barin, M Bentata, E Billaud, F Boué, C Burty, A Cabié, D Costagliola, L Cotte, P De Truchis, X Duval, C Duvivier, P Enel, L Fredouille-Heripret, J Gasnault, C Gaud, J Gilquin, S Grabar, C Katlama, MA Khuong, JM Lang, AS Lascaux, O Launay, A Mahamat, M Mary-Krause, S Matheron, JL Meynard, J Pavie, G Pialoux, F Pilorgé, I Poizot-Martin, C Pradier, J Reynes, E Rouveix, A Simon, P Tattevin, H Tissot-Dupont, JP Viard, N Viget DMI2 coordinating centre French Ministry of Health (V Salomon), Technical Hospitalisation Information Agency, ATIH (N Jacquemet) DMI2 coordinating centre French Ministry of Health (V Salomon), Technical Hospitalisation Information Agency, ATIH (N Jacquemet) Statistical analysis centre U943 INSERM and UPMC (S Abgrall, D Costagliola, S Grabar, M Guiguet, E Lanoy, L Lièvre, M Mary-Krause, H Selinger-Leneman), INSERM-Transfert (JM Lacombe, V Potard) Statistical analysis centre U943 INSERM and UPMC (S Abgrall, D Costagliola, S Grabar, M Guiguet, E Lanoy, L Lièvre, M Mary-Krause, H Selinger-Leneman), INSERM-Transfert (JM Lacombe, V Potard) Clinical centres Clinical centres Paris area Ambroise Paré, Antoine Béclère, Avicenne, Bichat-Claude Bernard, Cochin, Henri Mondor, HEGP, Jean Verdier, Kremlin Bicêtre, Laennec, Lariboisière, Louis Mourier, Necker-adultes, Pasteur, Paul Brousse, Pitié Salpêtrière, Raymond Poincaré, Rothschild, Saint-Antoine, Saint-Denis, Saint-Joseph, Saint-Louis, Tenon Paris area Ambroise Paré, Antoine Béclère, Avicenne, Bichat-Claude Bernard, Cochin, Henri Mondor, HEGP, Jean Verdier, Kremlin Bicêtre, Laennec, Lariboisière, Louis Mourier, Necker-adultes, Pasteur, Paul Brousse, Pitié Salpêtrière, Raymond Poincaré, Rothschild, Saint-Antoine, Saint-Denis, Saint-Joseph, Saint-Louis, Tenon Outside Paris area Aix en Provence, Antibes, Arles, Avignon, Belfort, Besançon, Caen, Clermont-Ferrand, Digne les Bains, Dijon, Gap, Grenoble, Lyon, Marseille, Martigues, Montpellier, Mulhouse, Nancy, Nantes, Nice, Nîmes, Reims, Rennes, Rouen, Saint- Etienne, Strasbourg, Toulon, Toulouse, Tourcoing, Tours Outside Paris area Aix en Provence, Antibes, Arles, Avignon, Belfort, Besançon, Caen, Clermont-Ferrand, Digne les Bains, Dijon, Gap, Grenoble, Lyon, Marseille, Martigues, Montpellier, Mulhouse, Nancy, Nantes, Nice, Nîmes, Reims, Rennes, Rouen, Saint- Etienne, Strasbourg, Toulon, Toulouse, Tourcoing, Tours Overseas Guadeloupe, Guyane, La Réunion, Martinique, Saint-Martin Overseas Guadeloupe, Guyane, La Réunion, Martinique, Saint-Martin