COMORBILITATS i ENVELLIMENT

Transcription

1 COMORBILITATS i ENVELLIMENT EN PACIENTS AMB INFECCIÓ PEL VIH Eugènia Negredo Fundació Lluita contra la Sida Hospital Universitari Germans Trias i Pujol Badalona Gener 2016

2 SURVIVAL FOR HIV INFECTED PATIENTS

3 COMORBIDITIES AND RISK FACTORS THE PATIENT Individual and social factors: Higher rate of tradi=onal risk factors: smoking, dyslipidemia, HTN, diabetes Gene=c factors ComorbidiFes THE VIRUS HIV infec=on itself Ongoing inflamma=on despite HAART THE TREATMENT An=retroviral therapy and toxicity

4 CAUSES OF INCREASED COMORBIDITIES Low CD4+ T- cell nadir Persistent inflammafon CoinfecFons (hepaffs, CMV, EBV, and HPV) Increased comorbidifes Lifestyle (smoking, etc) CumulaFve cart exposure Aging Adapted from Deeks SG, et al. BMJ. 2009;338:a3172. Operskalski EA. Curr HIV/AIDS Rep. 2011;8:12-22.

5 CAUSES OF INCREASED COMORBIDITIES: 1. INFLAMMATION

6 CAUSES OF INFLAMMATION

7 CAUSES OF INFLAMMATION Deeks et al. Annual Review of Medicine 2011.

8 Plasma concentrafon of hscrp (ng/ml) CAUSES OF INCREASED COMORBIDITIES: 1. INFLAMMATION Markers of inflammafon may persist at elevated levels despite ART 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 HIV uninfected N=115 HIV- infected pafents N=30 HIV- uninfected matched controls * HIV infected, untreated HIV infected, 3 months of ART HIV infected, 12 months of ART * P<0.001 vs HIV uninfected ** P<0.001 vs HIV infected, untreated Adapted from Kristoffersen US, et al. 15th CROI 2008; Poster 953. **

9 CAUSES OF INFLAMMATION Deeks et al. Annual Review of Medicine 2011.

10 115 CONSEQUENCES OF INFLAMMATION Arterial inflammation as measured by PET-scan: Increased in HIV-infected patients as compared to VIH negative subjects with the same FRS Subramanian S, JAMA 2012

11 CONSEQUENCES OF INFLAMMATION InflammaFon Predicts Disease in Treated HIV InfecFon Cardiovascular Disease (Duprez, Atherosclerosis 2009) Cancer (Breen, Cancer Epi Bio Prev 2010; Borges, AIDS 2013) Venous Thromboembolism (Musselwhite, AIDS 2011) Type II Diabetes (Brown, Diabetes Care 2010) CogniFve DysfuncFon (Burdo, AIDS 2013; Letendre CROI 2012, Abs#82) Frailty (Erlandson, JID 2013) Mortality (Kuller, PLoS Med 2008; Tien, JAIDS, 2010; Jus=ce, CID 2012)

12 CONSEQUENCES OF INFLAMMATION

13 CAUSES OF INCREASED COMORBIDITIES: 1. INFLAMMATION ART HIV - INFLAMMATION Heart disease Kidney disease Liver disease Osteoporosis Cancer Cognitive declines A strong acute-phase inflammatory response was required for survival; however, inflammatory responses can also promote chronic diseases. COMORBIDITIES Adapted from Vance DE. Am J Nurs 2010

14 CAUSES OF INCREASED COMORBIDITIES: 2. AGING 25% 20% % 10% 5% 0% CDC HIV Surveillance Report 2004 and Luther VP. Clin Geriatr Med. 2007;23:

15 AGING From Wikipedia Ageing (Bri=sh English) or aging (American English) is the process of becoming older. In humans, ageing represents the accumula=on of changes in a human being over =me, encompassing physical, psychological, and social change.

16 AGING InflammaFon Hypothesis of Aging supports the molecular basis of the inflammatory process as a plausible cause of the aging process

17 INFLAMMAGING The aging immune system is characterized by a low level chronic systemic inflammatory state, termed InflammAging. This inflammatory phenotype is marked by elevated circula=ng levels of markers of: - Inflamma=on (e.g., C- reac=ve protein (CRP) - Pro- inflammatory cytokines (interleukin- 6 (IL- 6) and tumor necrosis factor- α (TNF- α)) It is associated with increased morbidity and mortality in older adults - Franceschi C, et al. Inflamm- aging. An evolu=onary perspec=ve on immunosenescence. Ann N YAcad Sci. 2000;908: De Mar=nis Met al. Inflamma=on markers predic=ng frailty and mortality in the elderly. Exp Mol Pathol. 2006;80(3): Roubenoff R, et al. Cytokines, insulin- like growth factor 1, sarcopenia, and mortality in very old community- dwelling men and women: the Framingham Heart Study. Am J Med. 2003;115(6):

18 IMMUNESENESCENCE Thymic atrophy Decreased bone marrow produc=on Decreased B and T cell ac=va=on and matura=on resul=ng in decreased humoral and cell- mediated immunity (naïve and memory cells). Increased frequency and severity of diseases such as chronic inflammafon disorders (neurodegenerafve, cardiovascular ) and autoimmunity And major suscepfbility to cancers and infecfons

19 IMMUNESENESCENCE

20 HIV and AGING

21 PHYSIOLOGICAL PROCESS OF AGING Immunosenescence Lower pulmonary capacity Brain atrophy, decreased cerebral blood flow, decrease in neurotransmitter concentrations Thyroid atrophy, adrenal glands atrophy, alterations in carbohydrate, and lipid metabolism Lower gastrointestinal motility, lower hepatic blood flow, lower gastrointestinal immunity Decreased elasticity, alterations in the heart Decreased glomerular filtration rate Lower bone density Muscle atrophy, alterations in the modulation of electrolyte

22 CLINICAL CONSEQUENCES OF AGING Fulop et al. Clinical interven=ons in aging 2007.

23 CONSEQUENCES OF VIH/INFLAMMATION and AGING ART HIV - INFLAMMATION Heart disease Kidney disease Liver disease Osteoporosis Cancer Cognitive declines AGING Heart disease Kidney disease Liver disease Osteoporosis Cancer Cognitive declines Adapted from Vance DE. Am J Nurs 2010

24 CAUSES OF INCREASED COMORBIDITIES: 2. AGING ART Accumulation HIV - INFLAMMATION of changes in a Heart disease Kidney disease Liver disease Osteoporosis Cancer Cognitive declines human being over time AGING Heart disease Kidney disease Liver disease Osteoporosis Cancer Cognitive declines AGING Adapted from Vance DE. Am J Nurs 2010

25 AGING Accentuated Is aging an accentuated process in HIV people? Pathai S et al. J Gerontol A Biol Sci Med Sci 2014

26 ACCENTUATED AGING Overall and age-specific incidence rates Outcome Adjusted Mean Difference in Age (years) Risk airr (95% CI) Myocardial infarction (-0.62 to 0.54) 1.81 ( ) End stage renal disease (-0.69 to 0.23) 1.43 ( ) HIV-associated cancers (-0.93 to -0.21) 1.84 ( ) Other cancers (-0.78 to -0.12) 0.95 ( ) Althoff KN et al. Clin Infect Dis 2014

27 ACCENTUATED AGING Hasse B. et al. Clin Infect Dis ;

28 FRAILTY SYNDROME Frailty is a dis=nct clinical en=ty, differing from: - Comorbidity as defined by the presence of 2 diseases. - Disability as measured by impairment in ac=vi=es of daily living (ADL) The frailty phenotype in older adults consists of three or more of the following: - Weakness (measured by grip strength), - Low physical ac=vity, - Slowed motor performance (measured by walking speed), - Exhaus=on, and - Uninten=onal weight loss.

29 FRAILTY SYNDROME Frailty is recognized as an important clinical syndrome in old age, which: - Results from age- related declines in physiologic reserve and complexity in res=ng dynamics involving mul=ple physiologic systems, - Manifests by maladapfve responses to every day or acute stressors, and - Leads to a vicious cycle towards func=onal decline and other serious adverse health outcomes. This chronic condi=on is commonly described by two conceptual models: - the phenotype model (frailty syndrome) - the cumula=ve deficit model (frailty index). It has not been validated in HIV- infected popula=ons.

30 FRAILTY PHENOTYPE Predicts a number of serious adverse health outcomes in community- dwelling older adults, including: - acute illness, - falls, - cogni=ve decline, - hospitaliza=on, - disability, - dependency, and - mortality, adjus=ng for comorbidi=es.

31 FRAILTY PHENOTYPE in HIV In the Mul=center AIDS Cohort Study: - A frailty- related phenotype of weight loss, exhaus=on, slowness, and low physical ac=vity was more common in enrollees with HIV infec=on compared with those who did not have HIV infec=on, - It predicted mortality independently of CD4 T- lymphocyte count and viral load. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci, 2007.

32 FRAILTY PHENOTYPE in HIV

33 FRAILTY PHENOTYPE in HIV Factors that have been associated with frailty in HIV+ populafons include: - age, - lower current or nadir CD4 T cell counts and - other HIV- infec=on- related inflamma=on, - hepa==s C co- infec=on, - other comorbidi=es, - depressive symptoms, and - certain social factors (e.g., lower educa=on, unemployment) Desquilbet L, et al. HIV- 1 infec=on is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62: Piggou DA, et al. Frailty, HIVinfec=on, and mortality in an aging cohort of injec=on drug users. PLoS ONE. 2013;8(1):e Terzian AS, et al. Factors associated with preclinical disability and frailty among HIV- infected and HIV- uninfected women in the era of cart. J Womens Health (Larchmt). 2009;18(12):

34 AGING Accentuated Accelerated??? Is aging an accelerated process in HIV people? Pathai S et al. J Gerontol A Biol Sci Med Sci 2014

35 ACCELERATED AGING A prospecfve comparafve cohort study Prevalence and incidence of age- associated non- communicable comorbidi=es (AANCC) and their risk factors in persons 45 yrs Started October 2010 Par=cipants: ü HIV- 1- infected: from the HIV outpa=ent clinic at the Academic Medical Center (Amsterdam) ü HIV- 1- uninfected: from the Amsterdam Public Health Service sexual health clinic, and the ongoing Amsterdam Cohort Studies on HIV/AIDS

36 HIV neg (n=524) HIV pos (n=540) p-value Age (years) 52.1 ( ) 52.9 ( ) 0.20 Male gender 85.1% 88.1% 0.15 Dutch 81.3% 72.2% <0.001 MSM 69.7% 73.9% Time since HIV-1 diagnosis (yrs) 12.1 ( ) Mean CD4 count at enrollment (cells/mm 3 ) 565 ( ) Nadir CD4 count (cells/mm 3 ) 180 (78-260) Viral load > 200 at or within 4 mos prior to enrolment among cart-treated participants 1.5% Prior clinical AIDS 31.3% On cart 95.7% 79.1% started R x -naive 20.9% started ART-exp. Years since ART was first initiated (yrs) 10.4 ( ) Duration of viral load < 200 (since last > 200) (yrs) 5.8 ( ) Known cumulative duration CD4 < 200(mos) 0.8 ( ) Data presented as median (IQR) or percentage as appropriate. P-value represents Wilcoxon Rank Sum or Chi2 as appropriate Schouten J et al. Clin Infect Dis. 2014

37 Comorbidity risk factors HIV neg (n=524) HIV pos (n=540) Smoking status currently / ever (%) 24.6 / 38.9% 32.0 / 35.0% p-value / 0.23 Smoking (packyears, smokers only) 15.0 ( ) 22.2 ( ) <0.001 Severe alcohol use 7.3% 4.8% Daily to monthly use of: cannabis cocaine ecstasy 11.6% 2.9% 8.6% 13.5% 3.7% 4.3% BMI (kg/m 2 ) 24.5 ( ) 24.2 ( ) Blood pressure systolic (mmhg) 133 ( ) 135 ( ) Blood pressure diastolic (mmhg) 79 (72-85) 81 (75-89) <0.001 Data presented as median (IQR) or percentage as appropriate. P-value represents Wilcoxon Rank Sum or Chi2 as appropriate Schouten J et al. Clin Infect Dis. 2014

38 Age-associated Noncommunicable Comorbidity Prevalence HIV neg (n=524) HIV pos (n=540) p-value 1 AANCC* (%) 61.8% 69.4% Number of AANCC (mean (SD) 1.0 (0.95) 1.3 (1.14) <0.001 Schouten J et al. Clin Infect Dis. 2014

39 Comorbidity in relation to age Schouten J et al. Clin Infect Dis. 2014

40 Frailty 10.6% 50.7% 2.7% 36.3% Risk factors for (pre- )frailty Age Smoking Higher waist- to- hip ra=o Chronic hepa==s C HIV infec=on HIV- infected par=cipants (Historic) BMI <20 kg/m 2 frail pre- frail robust K.Kooij et al; AIDS (in press)

41 Frailty More frailty and pre- frailty at any age in HIV+ parfcipants HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ K.Kooij et al; AIDS (in press)

42 Comorbidity in relation to age Schouten J et al. Clin Infect Dis. 2014

43 Comparative risk of hypertension, diabetes mellitus, renal failure, cardiovascular disease, and fracture, by age, among patients versus control subjects. Guaraldi et al. Clin Infect Dis. 2011;53:

44 VIH, INFLAMMATION and AGING INFLAMMATION HIV AGING Comorbidi=es Frailty

45 SURVIVAL FOR HIV INFECTED PATIENTS Population group control HIV+ only 0.6 HIV+ with HIV risk factors 0.4 HIV+ with comorbidity Years HIV+ with alcohol/drug abuse Based on Obel N et al. Plos One 2011

46 GRACIAS HUGTP Guumann ICO Badalona IrsiCaixa FLS IGTP BST IMPPC FJC Universitat Autònoma de Barcelona Can Ruti campus, Badalona, Catalonia