HIV i envelliment. Acadèmia de Ciències Mèdiques de Catalunya i Balears. Societat Catalanobalear de Medicina Interna Barcelona. 23 de febrer de 2011.

Transcripción

1 HIV i envelliment Acadèmia de Ciències Mèdiques de Catalunya i Balears. Societat Catalanobalear de Medicina Interna Barcelona. 23 de febrer de Dr. Antonio Delegido Sánchez-Migallón. Xarxa Sanitaria i Social Santa Tecla. Hospital Santa Tecla. Tarragona

2 HIV y envejecimiento HIV y envejecimiento Epidemiología Historia natural y manifestaciones clínicas. Fisiopatología de la inmunosenescencia e infección VIH. Respuesta inmunológica y virológica al TAR. Efectos secundarios y tolerabilidad al TAR. Comorbilidades y polimedicación. Recomendaciones de tratamiento. Conclusiones.

3 Epidemiologia

4 Life expectancy of individuals on combination antiretroviral therapy in high-incame countries: a collaborative analysis of 14 cohort studies (ART-CC) The Lancet. Vol 372 July

5 Epidemiología Kirk and Goetz. Journal of American Geriatrics Society 2009 (57):

6 A growing proportion of HIV diagnoses are in the over % of newly reported cases of HIV infection in Western Europe in 2007 were in people aged 50 years or older 14 % newly diagnosed HIV patients aged Western Europe Central Europe Eastern Europe Lazarus JV and Nielsen KK, HIV Medicine 2010; in press

7 Nuevos diagnósticos de VIH. Distribución por edad y sexo. España. Datos de 12 CCAA *. Año 2008 Vigilancia Epidemiológica del VIH en España. Actualización 30 de junio 2009 Ministerio de Sanidad y Política Social.

8 Historia natural y manifestaciones clínicas.

9 HIV-1 infection in subjects older than 70: a multicenter cross-sectional assessment in Catalonia, Spain 8 Centros (7 Barcelona + 1 Tarragona) N: 179: 1,5% de la serie (11815 pacientes seguidos en 2008) 76% Edad media: 74,6 años 87% contagio vía sexual (HTSx: 49,7%; HMX: 37.9%; UDVP: 0,6%) 69% diagnosticados en la sexta década < 200 CD4 cél/mm3: 52% (cohorte comparativa: 34%) (media al diagnóstico: 190) CV-VIH media: cp/ml (57% > cp/ml) Coinfección VHB/C: 9,7% Mothe B et al. Current HIV Research 2009, 7,

10 Persons 50+ more often present with symptomatic HIV disease Clinical stage at presentation of non-idus since % 90% 80% CDC-Stage 70% 60% C 50% B 40% A 30% 20% 10% 0% < Age Group n= Unpublished Swiss Cohort HIV Study Ledergerber B et al., 15 th CROI 2008, Boston, Massachusetts, USA. Abstract 108.

11 ...and more often with a lower CD4 cell count CD4 cell count at presentation of Caucasian heterosexually-infected persons (n=2877) Median (IQR) CD4 cells [mm 3 ] at presentation Age group Unpublished Swiss Cohort HIV Study Ledergerber B et al., 15 th CROI 2008, Boston, Massachusetts, USA. Abstract 108.

12 Factors associated with late presentation Generally related to those who are not perceived, or who do not perceive themselves, to be at high risk of infection. those who are not actively offered HIV testing. marginalized groups. More common in: heterosexuals in comparison with MSM or IDUs*. older age. immigrants. lower socioeconomic status. people living in low HIV prevalence areas. Girardi * Although E, et IDUs al. J are Acquir more Immune likely to Defic experience Syndr, delay 2007 in presenting for clinical care once diagnosed Girardi E, et al. J Acquir Immune Defic Syndr, 2007

13 Late presentation: importance For the individuals: Generates greater morbidity and mortality: More likely to die of AIDS defining illness: 77% of all AIDS related deaths occur in late presenters1. Risk of OI and death increases as immune function deteriorates: 24% of all HIV positive deaths due to late presentation 2. For public health: Represents a challenge to prevention of onward transmission: Estimated transmission is 3.5 times higher among persons who are unaware of their infection 3. New sexual infections could be reduced by 30% if all infected persons learn of their HIV status and adopt adequate behaviour 3. 1Cianci1Ciancio B et al, BHIVA, Marks G et al, AIDS Ciancio B et al, BHIVA, Marks G et al, AIDS 2006.

14 Circunstancias que influyen en la transmisión de la infección HIV en pacientes > 50 a. Desconocimiento de los factores de riesgo de transmisión inf. HIV. Menor tasa de empleo de preservativo Atrofia vaginal en mujeres de edad facilita la infección Falta de percepción del personal médico del riesgo de inf. VIH en paciente de avanzada edad. Baja tasa de utilización del test de detección VIH Vergüenza-miedo a la estigmatización Onen N.F. Missouri Medicine. July/Agost (4):

15 Differences in symptom expression in older HIV-positive patients: The Veterans Aging Cohort 3 site study and HIV Cost and Service utilization study experience Zingmond et al. JAIDS.2003:Vol 33, Suppl 2: S84-92

16 Inmunological and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV Sophie Grabar. AIDS 2004, 18:

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18 HIV-1 infection is associated with accelerated vascular aging. Van Guilder G, Stauffer L, Mestek M CROI Montreal, Canada. Abstract731

19 Risk of cardiovascular disease increased in HIV-infected persons MI Events per 1000 Person-Yrs RR: 1.75 (95% CI: ; P <.0001)* Age Group (Yrs) HIV positive HIV negative Triant VA et al. J Clin Endocrinol Metab 2007 *Adjusted for age, sex, race, hypertension, diabetes, dyslipidemia. 2-fold higher risk of ischemic heart disease in HIV-infected patients on ART compared with adjusted uninfected population Obel N et al. Clin Infect Dis 2007

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22 Factores de riesgo enfermedad neuropsicológica

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25 NNDS-Relacionadas con 10% de los pacientes VIH desarrollan cáncer y el 71% de estos cánceres serán NNDS. Se relaciona su aparición con la raza blanca y la edad. Se han dado diversas explicaciones para justificar este aumento de incidencia: mayor supervivencia, mayor edad mayor impacto de factores de riesgo clásicos para cáncer alta incidencia de virus potencialmente oncogénicos : -virus del papiloma humano, -virus de Epstein-Barr y -virus de la hepatitis C Crum-Cianflone N et al. AIDS 2009

26 SCOPE: Decline in egfr in HIV improved by ART Assessment of renal function in 615 HIV+ pts enrolled in the SCOPE cohort Baseline characteristics (Mean or %) Age (years) 45.3 Female 13.2% Race White 50.7% Black 28.5% Hispanic 9.6% CD4 Count (cells/mm3) 434 HIV RNA (log10 c/ml) 3.1 Observation Time (years) 2.7 Number GFR Measurements 10 Multivariable Model Fully adjusted effect on GFR slope (ml/min/1.73m2 per year) Age (years) -0.7 (-0.9, - 0.5) Female -1.8 (-3.1, -0.6) Diabetes -4.4 (-8.4, -0.4) Hyperlipidaemia -2.7 ( -4.7, -0.7) Overall unadjusted rate of GFR: -2.6 (95% CI -3.0, -2.1) ml/min/1.73m2 per year (age expected rate 0.4) Average rate of GFR decline (ml/min/1.73m2 per year) pre-art: -4.7 (95% CI -6.7, -2.6) post-art: -1.9 (95% CI -3.7, -0.1) Improvement in egfr not evident in blippers Untreated noncontrollers showed most impact on egfr; Untreated controllers least Choi A, et al. CROI Abstract 38

27 Fisiopatología de la inmunosenescencia e Infección VIH.

28 Efects of HIV infection and aging on immunity. B cells and antibody production The number of memory B cells can vary but naive B cell decreases. Clinical evidence of B cell dysfunction is evident, manifested by increase risk of serius infection (pneumonia due to Streptococcus pneumoniae) T cell function Activity of thymus diminish after first year of life Decrease in the subpopulation of T naive lymphocytes (CD4+ and CD8+) with aging and HIV Decrease proliferative capacity of T cells and IL-2 production Increasing number of cytotoxic lymphocytes (CD8 CTLs) Shortness telomeres. Mucosal immunity and gastrointestinal lymfoid tissues (GALT) HIV replicates intensely in gut-associated lymphoid tissue (GALT) -> CD4+ GALT, don t recover after HAART Effect of aging on GALT is not known, but increase incidence of infections suggest that there are likely to be age-related changes in GALT. Effros R et al. HIV. CID 2008: 47 (august)

29 Respuesta inmunológica /virológica al TARGA.

30

31 Effect of age on HAART response: COHERE Virological response 2.0 Immunological response Relative hazard (95% CI) p< p< p=0.09 p< p< p< p=0.01 Relative hazard (95% CI) p< p=0.001 p=0.33 p=0.006 p=0.02 p=0.31 p= n=49, n=49, Age group (years) Age group (years) Unadjusted (red) and adjusted (blue) relative hazards for confirmed virological and immunological responses in the different age groups. Estimates are adjusted for year of starting cart, pre-cart CD4 and VL, AIDS, gender, ethnic origin and initial cart regimen. COHERE: Collaboration of Observational HIV Epidemiological Research Europe COHERE Study Group. AIDS 2008, 22:

32 Response to combination antiretroviral therapy: variation by age. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group. COHERE Collaboration. AIDS 2008; 22: COHERE Collaboration. AIDS 2008; 22:

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34 Older Age and the response to and Tolerability of Antiretroviral Therapy Silverberg MJ. Arch Intern Med 2007; 167(7):

35 Older Age and the response to and Tolerability of Antiretroviral Therapy Silverberg MJ. Arch Intern Med 2007; 167(7):

36

37 Inmunological and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV Mean increase in CD4 cell after HAART iniciation acording to the age and HIV RNA level. Sophie Grabar. AIDS 2004, 18:

38 Adherence in younger vs. older HIV patients Proportion of patients adherent to therapy (%) p= <50 Patient age, years 50 Hinkin CH, et al., AIDS 2004, 8 (Suppl. 1):S19 S25

39 Efectos secundarios y tolerabilidad del Tratamiento Antirretroviral

40 Why might age impact on HAART tolerability? Pharmacological handling: Decreased hepatic and renal function with age Decreased CYP450 concentrations1 Predisposition to toxicities: Increased cardiovascular risk Lower bone mineral density Increased renal disease Polypharmacy 1. Sotaniemi EA et al., Clin Pharmacol Ther 1997, 61: Sherr et al., Psychology, Health & Medicine 2009,14:

41 Descenso del metabolismo hepático con la edad Con la edad aparece una : reducción del tamaño hepático, descenso de la circulacion sanguínea, descenso del nº de hepatocitos, descenso de la capacidad regenerativa (1) Se ha estimado que la capacidad hepática de metabolizar se reduce más de un 30 % en pacientes > 65 a. (2) Muchos antirretrovirales se metabolizan por el cit P450, que se asocia negativamente con la edad (3) La glucouronoconjugación que es activa hasta situaciones terminales del funcionalismo hepático (< 20% de actividad metabólica), no se afecta por la edad. (4) (1) Effros R. CID : (2) Sotaniemi EA et al., Clin Pharmacol Ther 1997, 61: (3) George J. et al, Biochem Pharmacology 1995; 50: (4)Court M. Drug Metab Rev. 2010; 42:

42 Both, NNRTI and PI, have interactions with cytochrome P450

43 Descenso del metabolismo renal con la edad La circulación arterial renal disminuye aproximadamente un 1% por año por encima de los 50 a de edad. El parénquima renal disminuye con la edad. En ausencia de otras enfermedades, la edad avanzada ya justifica un descenso del clearance de creatinina. (1) Rowe J. J Gerontology. 1976; 31: (2) Gupta S CID 2005; 40 : (3) Silverberg M. Arch Intern Med 2007; 167: (4)

44 Toxicidad renal Tomar un régimen con tenofovir aumenta el riesgo de deterioro renal en un 60% comparado con pacientes que no lo toman. Presentación como tubulopatía proximal - Pérdida de fosfato - Acidosis metabólica - Glucosúria - Creatinina elevada 1-2% de los pacientes desarrollan toxicidad grave Lo más frecuente son anormalidades subclínicas Los pacientes con más de 50 años fueron 3 5 veces más propensos a sufrir deterioro grave Heffelfinger J et al. Renal impairment associated with the use of tenofovir. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, Abstract #779.

45 Absorción intestinal Factores relacionados con la formulacion: Concentration, dispersation, solubilidad, Factores relacionados con el paciente: Vaciamiento gástrico, acidez gástrica, area de absorción, flujo sanguineo. En el caso de los IP, la absorción puede alterarse por la actividad del cit P450 y glicoproteína P en células intestinales. (2) No hay estudios que analizen la absorción intestinal en pacientes con edad avanzada. (1) Blanco JR. AIDS rev 2010; 12: (2) Kim R. J Clin Invest. 1998; 101:

46 Older Age and the response to and Tolerability of Antiretroviral Therapy Silverberg MJ. Arch InternSilverberg MJ. Arch Intern Med 2007; 167(7):

47 The associations between age and the development of laboratory abnormalities and treatment discontinuation for reasons other than virological failure in the first year of highly active antiretroviral therapy. Sabin CA et al. HIV Medicine 2009; 10:35-43

48 The associations between age and the development of laboratory abnormalities and treatment discontinuation for reasons other than virological failure in the first year of highly active antiretroviral therapy. Sabin CA et al. HIV Medicine 2009; 10:35-43

49 Comorbilidad y polimedicación.

50 Polypharmacy in older patients Older patients often take concurrent medications for other conditions Vigilance is needed to avoid drug drug interactions Overlapping toxicities Altered plasma drug levels, necessitating dose adjustments Increased metabolism of ARVs, decreasing bioavailability Commonly used drugs that may interact include Statins, antiarrhythmics, gastric acid inhibitors, warfarin, SSRIs, erectile dysfunction agents, anticonvulsants Simone MJ et al., Geriatrics 2008, 63:6 12.

51 HIV-1 infection in subjects older than 70: a multicenter cross-sectional assessment in Catalonia, Spain 8 Centros (7 Barcelona + 1 Tarragona) N: 179: 1,5% de la serie (11815 pacientes seguidos en 2008) 76% Edad media: 74,6 años 87% contagio vía sexual (HTSx: 49,7%; HMX: 37.9%; UDVP: 0,6%) 69% diagnosticados en la sexta década < 200 CD4 cél/mm3: 52% (cohorte comparativa: 34%) (media al diagnóstico: 190) CV-VIH media: cp/ml (57% > cp/ml) Coinfección VHB/C: 9,7% Mothe B et al. Current HIV Research 2009, 7,

52 HIV-1 infection in subjects older than 70: a multicenter cross-sectional assessment in Catalonia, Spain 154 pacientes (86%) presentaban una comorbilidad por lo menos: 54% Dislipemia (cohorte comparativa cc-: 28%) 36% HTA 30% hiperglicemia/diabetes (cc: 17%) 23% Enfermedad cardiovascular 18% Insuficiencia renal crónica 17% Neoplasia (actual o anterior) (cc: 7%) 11% Deterioro cognitivo 58% Lipodistrofia Mothe B et al. Current HIV Research 2009, 7,

53 HIV-1 infection in subjects older than 70: a multicenter cross-sectional assessment in Catalonia, Spain Polifarmacia: además de los antirretrovirales (99% en HAART): toman una media de 2.97 fármacos (límites: 1-10): Hipolipemiantes (19%) Antihipertensivos (16%) ADO/insulina (11%) Antiagregantes (11%) Psicofármacos (6%) Antiácidos (3%) Nitratos (2%) Anticoagulantes orales (2%) Allopurinol (2%) Mothe B et al. Current HIV Research 2009, 7,

54 Recomendaciones de tratamiento.

55 Results from the D:A:D Study Non-modifiable Risk Factors Smith C, et al. CROI Oral presentation 145

56 NA-ACCORD: Survival Benefit With Earlier vs Deferred HAART (at cells/mm 3 ) Early Initiation of HAART Reduces Risk of Death by 70% Parameter Associated With Risk of Death Relative Hazard (95% CI) P Value Deferral of HAART until < 350 cells/mm3 (vs starting at cells/mm3) 1.7 <.001 Female sex Older age (per 10 years) BL CD4+ cell count (per 100 cells/mm3 increase) < Increased relative hazard of death with deferral of HAART remained unchanged when adjusted for IDU or for HCV coinfection, which were both independent predictors of mortality Kitahata MM, et al. NEJM 2009; 360:

57 Guideline Recommendations for Initiation of ART in Established HIV Infection EACS 2009 DHHS GESIDA 2010 Symptomatic HIV disease Asymptomatic; CD4+ count < 350 cells/mm 3 Asymptomatic; CD4+ count > 350 cells/mm 3 if: - Hepatitis C co-infection - Hepatitis B co-infection (requiring therapy). - HIV nephropathy CONSIDER TREATMENT IF - Viral load > c/ml - CD4 decline>50-100/mm/year -Age > 55 - Pregnancy - High cardiovascular risk - malignancy Symptomatic HIV disease Asymptomatic; CD4+ count < 350 cells/mm3 Asymptomatic; CD4+ count > 350 cells/mm3 if: - Pregnant women - HBV co-infection - HIV-associated nephropathy - Other considerations Age Co-morbidities CD4+ cell decline Serodiscordant relationships Infección sintomática Infección asintomática y CD4+ < 350 cells/mm 3 Infección asintomática y CD4+ > cells/mm 3 si: - Cirrosis hepática - Hepatitis crónica por virus C - Hepatitis B con indicación de tratamiento -CV > 10 5 cp/ml - CD4+ < 14% - Edad > 55 años - Riesgo CV elevado - Nefropatía VIH 1 European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV infected adults in Europe 2009 [on line]. Available from URL: 2 DHHS guidelines. Available at: Files/Adult and AdolescentGL.pdf. ( december-2009) 3 GESIDA/PNS [on line]. Available from URL:

58 Cual es el TARGA de elección en pacientes HIV por encima de 50 a?

59 Conclusiones

60 Conclusiones Incidencia de nuevos diagnósticos VIH creciente en pacientes > 50 a Retraso diagnóstico late presenters supone una situación de riesgo. Nuevos esfuerzos en diagnostico precoz (atención primaria, campañas sanitarias,...). El VIH afecta múltiples órganos (no solo pensar en infecciones oportunistas). Buena respuesta virológica al tratamiento (buena adherencia) Peor respuesta inmunológica ( por la inmunosenescencia) Mayor tasa de efectos secundarios relacionados con el TAR, por un lógico descenso del metabolismo hepato/renal. Atención a la polimedicación y al riesgo de interacciones medicamentosas. El inicio de tratamiento no debe diferirse. La pauta de tratamiento debe individualizarse