Situación actual de los pacientes VIH+ Esteban Martínez Hospital Clínic Barcelona

Situación actual de los pacientes VIH+ Esteban Martínez Hospital Clínic Barcelona

Mortality per 1 patient-years HIV infection has changed from a fatal disease into a chronic condition This means long-term exposure to ART 3 8 ACTIVE PATIENTS 7 5 6 5 4 Deaths 15 3 1 1 New patients 5 Number of patients 84 86 88 9 9 94 96 98 4 6 Data from Hospital Clinic, Barcelona

Patients with VL >5 copies/ml on ARV Better immunological and virological responses to ART 4143 subjects from 5 clinic cohorts in Europe and Canada 1 % with >5 copies/ml* Median CD4+ increase 15 15 9 8 7 6 5 4 3 1 97 4.8 3. 119 1 11 17.3 1.4 1. 17 15 8. 8.4 135 1 15 9 75 6 45 3 15 Median CD4+ increase 1996 1997 1998 1999 1 *Data from 3111 patients on any ARV therapy at viral load measurement Lampe FC, et al. Conference on Retroviruses and Opportunistic Infections, 5

Probability of survival At least a 1-year shorter expected survival than age- and gender-matched controls 1 Survival from age 5 years (N=3,99).75 Population controls.5.5 5 3 35 4 45 5 55 6 65 7 Late HAART ( 5) Early HAART (1997 1999) Pre-HAART (1995 1996) Age, years Lohse N, et al. Ann Intern Med 7; 146: 87 95.

Adults with HIV diagnosed at increasing age Median, IQR CASCADE: age at seroconversion by year 4 35 3 5 15 n= 383 943 945 783 311 198 1985 199 1995 5 Year of SC Slide courtesy of Krishran Bharakan

Changing spectrum of causes of death in HIV-infected patients Mortality (n=964) France Mortality 5 1 st quarter (n=45) Proportion (%) Proportion (%) 1 3 4 5 6 4 6 AIDS 47 AIDS 39 Cancer 11 Cancer 15 HCV 9 HCV 1 Cardiovascular 7 Cardiovascular 9 Bacterial infection 6 Suicide 6 Suicide 4 Non-AIDS related infection 4 Liver disease Accident Accident HBV Overdose Neurological disorder 1 Iatrogenic Overdose 1 HBV Metabolic 1 Bronchopulmonary disease Renal failure 1 1 Other infection Unknown 1 3 Liver disease Psychiatric illness Antiretroviral treatment 1 Other Unknown Lewden C, et al. Int J Epidemiol. 5;34:11 13. Lewden C et al. J Acquir Immune Defic Syndr 8; 48: 59-8

Traditional health related risk factors more prevalent among HIV-infected patients MACS/WIHS cohorts Some risk factors are higher in HIVinfected adults, many of which may be causally related to HIV and hence not a true confounder (lipids, DM) Closed circles, HIV+men; closed triangles, HIV+women. Open circles, HIV- men; open triangles, HIV- women Kaplan RC et al. Clin Infect Dis 7; 5:174-181

Plasma concentration of hscrp (ng/ml) Markers of inflammation may persist at elevated levels despite ART 4, 35, 3, 5,, 15, 1, 5, N=115 HIV-infected patients N=3 HIV-uninfected matched controls * ** HIV uninfected HIV infected, untreated HIV infected, 3 months of ART HIV infected, 1 months of ART * P<.1 vs HIV uninfected ** P<.1 vs HIV infected, untreated Adapted from Kristoffersen US, et al. 15th CROI 8; Poster 953.

Percentage of activated CD4+ T cells Percentage of activated CD8+ T cells ART decreases immune activation, but levels remain high vs HIV-negative subjects CD4+ CD8+ 3 P<.1 3 P<.1 P<.1 P<.1 1 1 HIV infected untreated (N=13) HIV infected treated (N=99) HIV uninfected (N=6) HIV infected untreated (N=13) HIV infected treated (N=99) HIV uninfected (N=6) Adapted from Hunt PW et al. J Infect Dis 3; 187: 1534 1543

ARTERIAL WALL ARTERIAL WALL HIV infects artery walls and Tat promotes endothelial dysfunction, and inflammation Monocyte MCP-1, VCAM-1, ICAM-1 Inflammation Endothelial dysfunction Tat Endothelin-1 CD4+ T Vasoconstriction Endothelial dysfunction 1. Eugenin EA et al. Am J Pathol 8; Liu K et al. Am J Physiol Lung Cell Mol Physiol 5; 3. Park IW et al. Blood 1; 4. Kanmogne GD et al. Biochem Biophys Res Commun 5

ARTERIAL WALL ARTERIAL WALL HIV promotes lipid accumulation in arterial walls leading to atherosclerosis Monocyte VIH Nef Nef Tat LDL LDL-ox HDL (PON-1) CD4+ T MCP-1, SDF-1, CXC3L1, RANTES. Foam cell HDL-inf VCAM, ICAM, proteoglycans. CD36

HIV favours plaque rupture and thrombus development leading to ischemic disease Induction of metaloproteases 1 Apoptosis of endothelial cells 1. Lopez-Herrera A et al. Biochim Biophys Acta 5;. Yano M et al. AIDS 7;

Endotheliumdependent FMD (%) Endotheliumdependent FMD (%) High sensitivity CRP (mg/l) ART decreases inflammation, but cannot restore endothelial integrity 7 6 5 4 3 1 P =.3 HIV Negative Untr eated HAART 1 16.1 1 8 6 HAART Untreated 14 1 1 8 4 6 4 5 1 15 5 3 CRP HIV Negative Untreated HAART Hsue P, et al. CROI 1

HIV is an important independent risk factor for atherosclerosis Characteristic Estimated effect (mm) Internal carotid Common carotid HIV infection.15**.33* Male.13***.54*** Current smoker.17***.** Past smoker.9***.*** Diabetes.1***.6*** Age (per 1 years).16***.73*** Systolic BP (per 1 mmhg).5***.5*** Diastolic BP (per 1 mmhg) -.7*** -.6*** Total cholesterol (per 1 mg/dl).9***.4*** HDL (per 1 mg/dl) -.*** -.11*** *p<.1, **p<.1, ***p<.1; There was a significant gender interaction Grünfeld C et al. AIDS 9

Aging Drug consumption Tobacco Alcohol Cocaine Other? The risk of CV disease is increased in HIVinfected patients Metabolic abnormalities Dyslipidemia Insulin resistance / DM Patient Body fat changes Lipoatrophy Lipoaccumulation Degree of immunedeficiency CV disease Other? Antiretroviral drugs HIV (and other infections) PIs Dyslipidemia Insulin resistance? Body fat changes? Other? NRTIs Dyslipidemia? Insulin resistance? Body fat changes? Other? HIV, HCV, HBV?, other? Dyslipidemia Systemic inflammation Inmune activation Vascular infection

Poly-pathology is more common with increasing age and HIV Poly-pathology prevalence in cases and controls, stratified by age categories. The following co-morbidities were analysed: Hypertension, Type Diabetes, Cardiovascular Disease and Osteoporosis. Poly-pathology prevalence was higher in cases than controls in all age strata (all p-values <.1). Poly-pathology prevalence in cases aged 41-5 was similar to that in controls aged >6 (p=.8). Guaraldi G et al. Poster 77 - CROI 1

HIV infection leads to premature ageing Normal ageing (average age in many clinics now around 5) Lifestyle risk factors (smoking, drug and alcohol misuse) Drug toxicity (for example tenofovir and renal disease) Persistent immune dysfunction and inflammation Premature ageing Adapted from Deeks SG, Phillips AN. Br Med J 9; 338:a317

Emerging co-morbidities in HIV+: HIV+ ~1-15 years older than HIV- Renal dysfunction 3% of HIV+ patients have abnormal kidney function 1 Reduced bone mineral density Increased prevalence of osteoporosis or osteopenia in spine, hip or forearm: 63% of HIV+ patients 1. Gupta SK et al. Clin Infect Dis 5;4:1559 85.. Brown TT et al. J Clin Endocrinol Metab 4;89(3):1 6. 3. Clifford DB. Top HIV Med 8;16():94 98. 4. Triant VA et al. J Clin Endocrinol Metab 7;9:56 1. 5. Patel P et al. Ann Intern Med 8;148:78 36. Cancer Increased risk of non- AIDS-defining cancers e.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal 5 Neurocognitive dysfunction Neurological impairment present in 5% HIV+ patients 3 Cardiovascular disease 75% increase in risk of acute MI 4 Frailty Increased frailty phenotype if HIV infected 3-14x; Associated with CD4 count

Events Per 1 PYs Events Per 1 PYs HIV-infected patients have a higher incidence of myocardial infarction A 1 n = 3,851 RR 1.75 p <.1* B 1 1 8 n = 1,44,589 8 6 6 4 4 HIV+ HIV- # of MI 189 6,14 18-34 35-44 45-54 55-64 65-74 Age Group (Years) * Adjusted for age, gender, race, hypertension, diabetes and dyslipidaemia. Proportion of patients with hypertension, diabetes and dyslipidaemia significantly higher in HIV-positive vs HIV-negative cohort Triant V et al., JCEM, 7

Reduced Bone Mineral Density in HIV+ Patients risk with age, duration HIV infection and CD4 count Brown TT & Qaqish RB. AIDS. 6; :165-174. Overton T et al. CROI 7. Abstract 836

Fracture prevalence/1 persons Greater rate of fractures in HIV-infected versus uninfected individuals 3.5 3.5 HIVp<.1 Population-based study 8,55 HIV-infected patients,8,79 non HIV-infected patients HIV+ 1.5 1.5 P<.1 p=.1 p<.1 All Vertebral Hip Wrist Adapted from Triant VA et al. J Clin Endocrinol Metab 8;93:3499 354

Liver and kidney comorbidities more common in HIV+ patients Liver Disease Renal Disease* Goulet J. Clin Infect Dis 7; 45: 1593-161

Non-AIDS defining cancer rates higher in HIV+ patients vs general population Cancer Type, Observed Rate per 1, Person-Years (95% CI) ASD/HOPS (157,819 Person-Years) SEER (334,8,11 Person-Years) SRR* (95% CI) Anal 51.4 (4.8-63.9) 1.5 (1.4-1.5) 4.9 (34.1-53.3) Vaginal 33.9 (18.-57.9) 3. (3.-3.3) 1. (11.-35.9) Hodgkin s lymphoma 51.4 (4.9-63.9) 3.3 (3.3-3.4) 14.7 (11.6-18.) Liver 31.7 (3.5-41.8) 5.3 (5.-5.4) 7.7 (5.7-1.1) Lung 88.8 (74.7-14.8) 67.5 (67.-67.7) 3.3 (.8-3.9) Melanoma 4.7 (17.6-33.8) 18.4 (18.3-18.6).6 (1.9-3.6) Oropharyngeal 33. (4.6-43.3) 16.1 (16.-16.).6 (1.9-3.4) Leukemia 15. (9.8-.7) 1. (1.1-1.3).5 (1.6-3.8) Colorectal 47. (36.9-59.) 5. (51.7-5.).3 (1.8-.9) Renal 14. (8.8-1.1) 13. (1.8-13.1) 1.8 (1.1-.7) Prostate 3.7 (3.3-44.7) 173.5 (17.9-174.1).6 (.4-8) ASD, Adult and Adolescent Spectrum of Disease Project; HOPS, HIV Outpatient Study; SEER, Surveillance, Epidemiology, and End Results, 199 3; *SRR, standardized rate ratio calculated as ASD/HOPS to SEER populations. Patel P et al. Ann Intern Med 8; 148: 78-736

http://www.europeanaidsclinicalsociety.org/guidelinespdf/_non_infectious_co_morbidities_in_hiv.pdf

Summary The HIV infected population is ageing HIV may affect the natural ageing process Co-morbidities are increasingly apparent ART needs to be chosen not only for providing long-term efficacy but also for having the lowest impact on ageing comorbidities