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HIV i envelliment

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

Dr. Antonio Delegido Sánchez-Migallón.Xarxa Sanitaria i Social Santa Tecla. Hospital Santa Tecla. Tarragona

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.

HIV y envejecimiento

Epidemiologia

Life expectancy of individuals on combination antiretroviraltherapy in high-incame countries: a collaborative analysis of 14 cohort studies (ART-CC)

The Lancet. Vol 372 July 26. 2008

Epidemiología

Kirk and Goetz. Journal of American Geriatrics Society 2009 (57): 2129-2138

A growing proportion of HIV diagnoses are in the over 50

• 12.9% of newly reported cases of HIV infection in Western Europe in 2007 were in people aged 50 years or older

Lazarus JV and Nielsen KK, HIV Medicine 2010; in press

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4

6

8

10

12

14

2003 2004 2005 2006 2007

Western Europe

Central Europe

Eastern Europe

Vigilancia Epidemiológica del VIH en España. Actualización 30 de junio 2009Ministerio de Sanidad y Política Social.

Nuevos diagnósticos de VIH. Distribución por edad y sexo. España.

Datos de 12 CCAA *. Año 2008

Historia natural y manifestaciones clínicas.

HIV-1 infection in subjects older than 70: a multicenter cross-sectional assessment in

Catalonia, Spain

Mothe B et al. Current HIV Research 2009, 7, 597-600

8 Centros (7 Barcelona + 1 Tarragona)N: 179: 1,5% de la serie (11815 pacientes seguidos en 2008)76% ♂Edad media: 74,6 años87% 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: 148550 cp/ml (57% > 100000 cp/ml)Coinfección VHB/C: 9,7%

Persons 50+ more often present with symptomatic HIV disease

Clinical stage at presentation of non-IDUs since 1990

Unpublished Swiss Cohort HIV Study

Ledergerber B et al., 15th CROI 2008, Boston, Massachusetts, USA. Abstract 108.

<30 30–39 40–49 50+0%

10%20%30%40%50%60%70%80%90%

100%

Age Group

CDC-Stage

n= 2199 3277 1721 1082

CBA

...and more often with a lower CD4 cell count

CD4 cell count at presentation of Caucasian heterosexually-infected persons (n=2877)

Unpublished Swiss Cohort HIV Study

0

100

200

300

400

500

600

700

800

1990–1994 1995–1998 1999–2002 2003–2007

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Ledergerber B et al., 15th CROI 2008, Boston, Massachusetts, USA. Abstract 108.

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.

* Although IDUs are more likely to experience delay in presenting for clinical care once diagnosed

Girardi E, et al. J Acquir Immune Defic Syndr, 2007

Girardi E, et al. J Acquir Immune Defic Syndr, 2007

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 presentation2.

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 infection3.

• New sexual infections could be reduced by 30% if all infected persons learn of their HIV status and adopt adequate behaviour3.

1Cianci1Ciancio B et al, 2006. 2BHIVA, 2007. 3Marks G et al, AIDS 2006.

Ciancio B et al, 2006. 2BHIVA, 2007. 3Marks G et al, AIDS 2006.

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 2009. 100 (4): 269-273

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

Sophie Grabar. AIDS 2004, 18: 2029-2038

Inmunological and clinical responses to highly active antiretroviraltherapy over 50 years of age.

Results from the French Hospital Database on HIV

HIV-1 infection is associated with accelerated vascular aging.Van Guilder G, Stauffer L, Mestek M

CROI 2009. Montreal, Canada. Abstract731

Risk of cardiovascular disease increased in HIV-infected persons

Triant VA et al. J Clin Endocrinol Metab 2007

RR: 1.75 (95% CI: 1.51-2.02; P < .0001)*

*Adjusted for age, sex, race, hypertension, diabetes, dyslipidemia.

0102030405060708090

18-34 35-44 45-54 55-64 65-74

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4.6510.13

18.74

33.39

77.68

0.88 3.34 7.5614.78

24.47

100

HIV positiveHIV negative

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

Factores de riesgo enfermedad neuropsicológica

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 aumentode 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

SCOPE: Decline in eGFR in HIV improved by ART

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 ModelFully 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 2009. Abstract 38

Assessment of renal function in 615 HIV+ pts enrolled in the SCOPE cohort

Fisiopatología de la inmunosenescencia e

Infección VIH.

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) 542-553

Respuesta inmunológica /virológica al TARGA.

Effect of age on HAART response: COHERE 2006

COHERE: Collaboration of Observational HIV Epidemiological Research Europe

COHERE Study Group. AIDS 2008, 22:1463–73.

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.

Virological response

0

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0.6

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1.2

1.4

1.6

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n=49,921

Immunological response

0

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p<0.0001p=0.02p=0.001

p=0.006

p=0.01p=0.31p=0.33

p=0.09

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p<0.0001

p<0.0001

p<0.0001

p<0.0001

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–

–

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

COHERE Collaboration. AIDS 2008; 22: 1463-1473COHERE Collaboration. AIDS 2008; 22: 1463-1473

Silverberg MJ. Arch Intern Med 2007; 167(7): 684-691

Older Age and the response to and Tolerabilityof Antiretroviral Therapy

Silverberg MJ. Arch Intern Med 2007; 167(7): 684-691

Older Age and the response to and Tolerability of Antiretroviral Therapy

Silverberg MJ. Arch Intern Med 2007; 167(7): 684-691

Sophie Grabar. AIDS 2004, 18: 2029-2038

Mean increase in CD4 cell after HAART iniciation acording to the age and HIV RNA level.

Inmunological and clinical responses to highly active antiretroviraltherapy over 50 years of age. Results from the French Hospital Databaseon HIV

Adherence in younger vs. older HIV patients

0

10

20

30

40

50

60

70

80

90

100

78.3

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Patient age, years

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Hinkin CH, et al., AIDS 2004, 8 (Suppl. 1):S19–S25

p=0.01

Efectos secundarios ytolerabilidad del Tratamiento Antirretroviral

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, 61:331–9.

2. Sherr et al., Psychology, Health & Medicine 2009,14:273–279.

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 2008 47: 542-53. (2) Sotaniemi EA et al., Clin Pharmacol Ther 1997, 61:331–9.

(3) George J. et al, Biochem Pharmacology 1995; 50: 727-30

(4)Court M. Drug Metab Rev. 2010; 42: 202-17

Both, NNRTI and PI, have interactions with cytochrome P450

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: 155-63(2) Gupta S CID 2005; 40 : 1559-85(3) Silverberg M. Arch Intern Med 2007; 167: 684-91(4)

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, 2006. Abstract #779.

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: 18-30(2) Kim R. J Clin Invest. 1998; 101: 289-94

Older Age and the response to and Tolerability of Antiretroviral Therapy

Silverberg MJ. Arch InternSilverberg MJ. Arch Intern Med 2007; 167(7): 684-691

Sabin CA et al. HIV Medicine 2009; 10:35-43

The associations between age and the development of laboratory abnormalitiesand treatment discontinuation for reasons other than virological failurein the first year of highly active antiretroviral therapy.

Sabin CA et al. HIV Medicine 2009; 10:35-43

The associations between age and the development of laboratory abnormalities and treatment discontinuation for reasons other than virological failure in the first yearof highly active antiretroviral therapy.

Comorbilidad y polimedicación.

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.

HIV-1 infection in subjects older than 70: a multicenter cross-sectional assessment in

Catalonia, Spain

Mothe B et al. Current HIV Research 2009, 7, 597-600

8 Centros (7 Barcelona + 1 Tarragona)N: 179: 1,5% de la serie (11815 pacientes seguidos en 2008)76% ♂Edad media: 74,6 años87% 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: 148550 cp/ml (57% > 100000 cp/ml)Coinfección VHB/C: 9,7%

HIV-1 infection in subjects older than 70: a multicenter cross-sectional assessment in

Catalonia, Spain

154 pacientes (86%) presentaban una co-morbilidad 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, 597-600

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, 597-600

Recomendaciones de

tratamiento.

Non-modifiable Risk Factors

Results from the D:A:D Study

Smith C, et al. CROI 2009. Oral presentation 145

NA-ACCORD: Survival Benefit With Earlier vs Deferred HAART (at 350-500 cells/mm3)

Kitahata MM, et al. NEJM 2009; 360: 1815-1826.

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

Parameter Associated With Risk of Death Relative Hazard (95% CI)

Older age (per 10 years)

BL CD4+ cell count (per 100 cells/mm3 increase)

1.6

1.0 2.50.1

Deferral of HAART until < 350 cells/mm3 (vs starting at 350-500 cells/mm3)

Female sex

0.9

1.7

1.1

P Value

< .001

.290

< .001

.083

Early Initiation of HAART Reduces Risk of Death by 70%

EACS 2009 DHHS GESIDA 2010• Symptomatic HIV disease• Asymptomatic; CD4+

count < 350 cells/mm3

• Asymptomatic; CD4+ count > 350 cells/mm3 if:

- Hepatitis C co-infection- Hepatitis B co-infection (requiring therapy).

- HIV nephropathyCONSIDER TREATMENT IF- Viral load > 1055 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

AgeCo-morbiditiesCD4+ cell decline Serodiscordant relationships

• Infección sintomática• Infección asintomática y

CD4+ < 350 cells/mm3

• Infección asintomática y CD4+ >350 – 500 cells/mm3 si:- Cirrosis hepática- Hepatitis crónica por virus C- Hepatitis B con indicación de

tratamiento- CV > 105 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: http://www.europeanaidsclinicalsociety.org/asp

2 DHHS guidelines. Available at: http://www.aidsinfo.nih.gov./Content Files/Adult and AdolescentGL.pdf. ( december-2009)3 GESIDA/PNS 2010. [on line]. Available from URL: www.gesida.seimc.org/

Guideline Recommendations for Initiation of ART in Established HIV Infection

¿ Cual es el TARGA de elección en pacientes HIV por encima

de 50 a ?

Conclusiones

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