Mortalité et Morbidité à l ère des traitements antirétroviraux dans les Pays du Nord Laurence WEISS Hôpital Européen Georges Pompidou, Université Paris-Descartes Paris, France
Deaths per 100 Person-Years Effect of Protease Inhibitor-Containing Regimens on Mortality in Patients with <100 CD4+ cells 40 30 20 10 0 Deaths Antiretroviral Therapy 1994 1995 1996 1997 100 80 60 40 20 0 (% of patient-days) Therapy with a Protease Inhibitor Palella F, et al. N Engl J Med, 1998
Prognosis of HIV-1 infected patients starting HAART (1) ART-CC 12 574 adults starting HAART with a combination of at least 3 drugs Progression: combined end point of a new AIDS-defining event or death to death alone 24 310 PY of FU Probability of AIS or death according to baseline CD4 count or baseline VL Egger, Lancet 2002
Prognosis of HIV-1 infected patients starting HAART (2) AIDS or death Death Egger, Lancet 2002
Mortality (per 1000 person-years) Percent Receiving Therapy Change in Mortality over Time All cause AIDS HAART Non-AIDS Calendar Year Lau et al, JAIDS 2007
Causes of death in HIV-infected patients treated with ART, 1996-2006 39,272 patients in 13 HIV-1 cohorts (154,667 PY of FU) 1876 deaths AIDS related: 49.5% non-aids malignancies: 11.8% Non-AIDS infections: 8.2% Violence and/or drug-related causes: 7.7% Liver disease: 7.0% Cardiovascular disease: 6.5% ART-CC, CID 2010
Causes of death according to time since start of cart ART-CC, CID 2010
Total cumulative mortality partitioned by cause of death ART-CC, CID 2010
Causes of death in IVDU ART-CC, CID 2010
Survival in HIV-infected IDUs N= 3116 ARV naive HIV-infected patients, N= 915 (29.4%) IDU in Bristish Columbia, Canada Wood, JAMA 2008
Mortalité 2000 and 2005 surveys, France 2000 N= 964 2005 N= 1042 Lewden, JAIDS 2008
Virologic response under cart 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Annˇe CV < 500 cp/ml cart since at least 6 months FHDH data, D. Costagliola
Odds ratios (95% CI) for reaching HIV1 RNA concentrations 500 copies per ml at 6 months after starting HAART, by calendar year of starting HAART ART-CC, Lancet 2006
Virologic control under cart in IDUs Weber, HIV med 2009
Evolution du pourcentage de patients traités depuis au moins 6 mois avec une charge virale < 500 copies/ml et CD4 >= 500 cellules/mm3 FHDH data, D. Costagliola
Mortality rates according to CD4 cell counts under cart SMR: standardized mortality ratio Lewden, JAIDS 2007
An ageing population
FHDH data, D. Costagliola Proportion of patients > 50 year-old according to gender Site AP/HP 2010 1670 patients 77% male % > 50 year-old 41% of men 30% of women
Non AIDS comorbidities Risk of non-aids malignancies Cardiovascular diseases Chronic renal disease Liver disease
HIV and risk of lung cancer, independent of smoking CID 2007 AIDS 2007
HIV and risk of non-aids malignancies Meta-analysis: 444,172 people with HIV, 31,977 transplant patients For 20 / 28 cancers examined there was significantly increased incidence in both groups strongly suggesting a link with immunodeficiency Standardized Incidence Ratio HIV/AIDS Transplant Lung 2.7 2.2 Leukaemia 3.2 2.4 Kidney 1.5 6.8 Oesophagus 1.6 3.1 Stomach 1.9 2.0 Grulich et al, Lancet 2007
Possible mechanisms: Non-AIDS malignancies Immunodeficiency, leading to: - reduced control of oncogenic pathogens - damage due to infections and resulting chronic inflammation - loss of ability to identify transformed cells increase in life expectancy other cofactors associated with risk Littman et al. Cancer Epidemiol Biomarkers Prev 2005
Cardiovascular diseases in HIV-infected patients Triant, J Clin Endocrin Metab 2007; Grispoon, AIDS 2010; El-Sadr, NEJM 2006
SMART Study Participants with CD4 count > 350 84% on ART, 16% off ART Randomization n = 2720 n = 2752 Continuous ART 94% on ART 99% CD4 > 200 Follow-up Intermittent ART Stop or defer ART when CD4 count > 350, restart or start ART when CD4 count < 250 33% on ART 96% CD4 > 200 N Engl J Med 2006
Drug Conservation (DC) Strategy Associated with Increased Risk of Serious AIDS and Non-AIDS Events Endpoint No. of Patients with Events Rate** DC VS Hazard Ratio (DC/VS) (95% CI) Serious AIDS 59 1.3 0.4 3.6 Serious non-aids* 186 3.2 2.0 1.6 Serious AIDS or 239 4.4 2.4 non-aids Favors DC Cardiovascular, renal, hepatic, non-aids malignancy, others ** Per 100 person-years 1.9 0.1 1 10 Favors VS Curr Opin HIV AIDS 2008;3:112-117
Risk of serious non-aids events in SMART: patients ART naïve or off ART for > 6 months N = 477 patients Number of events Hazard ratio Deferred vs. Deferred Immediate Immediate ART ART ART (95% CI) p-value 12 2 7.02 (1.57 31.4) 0.01 Emery et al, JID
Possible mechanisms: Cardiovascular disease Association of HIV-infection with adverse changes in known or potential biomarkers for CVD. - HDL-cholesterol depletion - Inflammation (raised IL-6, C-reactive protein) - Endothelial activation/dysfunction (VCAM, ICAM) - Activation of coagulation (D-dimer) Several of the changes appear to be at least partially reversed by ART Riddler JAMA 2003 de Larranaga et al, Blood Coag. & Fibrinolys 2003 Lau et al, Arch Intern Med 2006 Wolf et al, J Infect Dis 2002
126 cases et 36 199 PY
HIV and risk of End Stage Renal disease U.S. Veterans without diabetes Hazard ratio for End Stage Renal Disease # people # ESRD Hazard ratio* White HIV -ve 1,201,870 3991 1.0 HIV +ve 6,139 13 0.8 (0.5 1.3) Black HIV -ve 206,636 1425 2.0 (1.9 2.2) HIV +ve 6,816 129 4.6 (3.4 6.1) *Adjusted for age, sex, baseline egfr category, CAD, HTN, heart failure, COPD, PVD, HCV infection, cerebrovascular disease, and SES. Little effect of HIV in diabetics Choi et al J Am Soc Nephr 2007
HIV and Liver disease 4865 men and boys with haemophilia (and probable HCV infection), of whom 1218 HIV-infected HIV (and haemophilia) status 25 year cumulative risk of liver death Severe haemophilia, not HIV 1.4 (0.7 3.0) Moderate / mild haemophilia, not HIV 1.2 (0.5 2.6) HIV-infected (all haemophilia severities) 6.5 (4.5 9.5) Similarly for HBV in MACS Thio et al, Lancet 2002 Darby et al, Lancet 1997
Conclusions Augmentation de la mortalité et morbidité de causes non SIDA à 15 ans de l introduction des traitements ARV hautement actifs Causes cardiovasculaires et cancers Nécessité d être maintenant plus agressifs dans le dépistage et le traitement et/ou la prise en charge des facteurs de risque chez ces patients (tabac, cocaïne, dyslipidémie, diabète, HTA )