Mortalité et Morbidité à l ère des traitements antirétroviraux dans les Pays du Nord

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1 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

2 Deaths per 100 Person-Years Effect of Protease Inhibitor-Containing Regimens on Mortality in Patients with <100 CD4+ cells Deaths Antiretroviral Therapy (% of patient-days) Therapy with a Protease Inhibitor Palella F, et al. N Engl J Med, 1998

3 Prognosis of HIV-1 infected patients starting HAART (1) ART-CC 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 PY of FU Probability of AIS or death according to baseline CD4 count or baseline VL Egger, Lancet 2002

4 Prognosis of HIV-1 infected patients starting HAART (2) AIDS or death Death Egger, Lancet 2002

5 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

6 Causes of death in HIV-infected patients treated with ART, ,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

7 Causes of death according to time since start of cart ART-CC, CID 2010

8 Total cumulative mortality partitioned by cause of death ART-CC, CID 2010

9 Causes of death in IVDU ART-CC, CID 2010

10 Survival in HIV-infected IDUs N= 3116 ARV naive HIV-infected patients, N= 915 (29.4%) IDU in Bristish Columbia, Canada Wood, JAMA 2008

11 Mortalité 2000 and 2005 surveys, France 2000 N= N= 1042 Lewden, JAIDS 2008

12 Virologic response under cart 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Annˇe CV < 500 cp/ml cart since at least 6 months FHDH data, D. Costagliola

13 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

14 Virologic control under cart in IDUs Weber, HIV med 2009

15 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

16 Mortality rates according to CD4 cell counts under cart SMR: standardized mortality ratio Lewden, JAIDS 2007

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18 An ageing population

19 FHDH data, D. Costagliola Proportion of patients > 50 year-old according to gender Site AP/HP patients 77% male % > 50 year-old 41% of men 30% of women

20 Non AIDS comorbidities Risk of non-aids malignancies Cardiovascular diseases Chronic renal disease Liver disease

21 HIV and risk of lung cancer, independent of smoking CID 2007 AIDS 2007

22 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 Leukaemia Kidney Oesophagus Stomach Grulich et al, Lancet 2007

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25 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

26 Cardiovascular diseases in HIV-infected patients Triant, J Clin Endocrin Metab 2007; Grispoon, AIDS 2010; El-Sadr, NEJM 2006

27 SMART Study Participants with CD4 count > % 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 < % on ART 96% CD4 > 200 N Engl J Med 2006

28 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 Serious non-aids* Serious AIDS or non-aids Favors DC Cardiovascular, renal, hepatic, non-aids malignancy, others ** Per 100 person-years Favors VS Curr Opin HIV AIDS 2008;3:

29 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 ( ) 0.01 Emery et al, JID

30 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

31 126 cases et PY

32 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, HIV +ve 6, ( ) Black HIV -ve 206, ( ) HIV +ve 6, ( ) *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

33 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 ( ) Moderate / mild haemophilia, not HIV 1.2 ( ) HIV-infected (all haemophilia severities) 6.5 ( ) Similarly for HBV in MACS Thio et al, Lancet 2002 Darby et al, Lancet 1997

34 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 )