Workshop 1: “L’anziano”Moderatori: E. Sagnelli, F. SuterDiscussant: F.v. Schloesser

Recupero immunologico e progressione clinicaG. Liuzzi

Age and natural history of HIV

1.Older age associated with faster progression to clinical AIDS and death (pre-ART)

– mixed data in ART era

2.Effect of age on antiviral response also variable– Adherence may be greater in older patients

3. Immune recovery may be less effective– Younger patients may have faster CD4 increases,

although long-term data are less clear

4.Antiretroviral tolerability decreases with age

0

2

4

6

8

10

12

14

15 24 25 34 35 44 45 54 55 64 >=65

Age

Med

ian

Tim

e (Y

ears

)

Survival AIDS

Age at Seroconversion vs Natural History: pre-HAART

Lancet 2000; 355:1131Lancet 2000; 355:1131

Median time to AIDS Age 15 – 24: 11 yearsAge 65: 5 years

Higher risk of clinical progression in patients ≥50 years of age

• Patients ≥50 yoa are at higher risk of clinical progression but show a better virologic response than patients <50 yoa

• Prospective cohort study of 3015 treatment-naive patients initiating ART– ≥ 50 years: n=401– < 50 years: n=2614

• Median follow-up: 31.5 months• At BL, older patients more likely to have

– AIDS-defining event (P =.0001)– Lower CD4 T-cell count (P =.0002)

– Higher HIV-1 RNA level (P =.0001)

Outcome Adjusted HR P Value

Progression to ADE or death 1.52 .0035

Progression to new ADE 1.50 .0087

HIV-1 RNA <500 copies/mL 1.23 <.05

Grabar S. AIDS. 2004;18(15):2029-2038.

ADE, AIDS-defining event; BL, baseline;

HR, hazard ratio; yoa, years of age

Cumulative mortality rate according to age group

(<50 vs >50 yoa)

untreated

treated

Perez JL, Moore RD Clin Infect Dis 2003; 36: 212-218

Disease Progression After HAART vs Age No prior AIDS or IDU; baseline CD4 100 – 199, VL > 105

May M et al. AIDS. 2007; 21:1185-1197. (supplementary materials - May M et al. AIDS. 2007; 21:1185-1197. (supplementary materials - http://www.art-cohort-collaboration.org/http://www.art-cohort-collaboration.org/

16 - 29 30 - 39 40 - 49 ≥50Age

Older patients more likely to achieve HIV-1 RNA <500 copies/mL

• Kaiser Permanente study compared patients 40-49 yoa and ≥50 yoa to patients 18-39 yoa• Patients >50 yoa more likely to achieve HIV-1 RNA <500 copies/mL vs patients 18-39 yoa,

even when adjusting for comorbidities• Adherence major advantage for older patients

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

≥50 years

40-49 years

CI, confidence interval;HR, hazard ratio; yoa, years of age

1.3

0.6

0.7

0.8

0.9

1.0

1.1

1.21.15

0.97

0.95

1.03

0.97

1.15

0.97

1.07

HR

(95

% C

I)

Model: Age Age + Adherence

Age + Modified Charlson

Comorbidity

All Predictors

Outcomes for Older Individuals: Immunological response to ARV

• Rationale: Aging and HIV share some common immune dysfunction which include:– Shift from a naïve to a memory T-cell phenotype DePaoli P, Clin

Immunol Immunopathol 1988, 48: 290-296; Lerner A, J Immunol 1989, 19:977-982; Ernst DN, J Immunol 1993, 151: 575-587]

– Reduction in T-cell proliferative ability Negoro S, Mech Aging Dev 1986, 33:313-322; Eylar EH, J AIDS 1994, 7:124-128

– Associated with reduced telomer length (T cell replicative senescence?) Bestilny LJ, AIDS 2000, 14 (7): 771-780

– Increase in CD8 cell population that are CD28 – Choremi-Papadapoulou H, JAIDS 1994, 7:245-253, Fagnoni FF, Immunology 1996, 88:501-507

– Decreased production of IL-2 and IL-2 receptor (involved in T-cell-mediated immune responses) Gillis S, J Clin Invest 1981, 67: 937-942; Eyler EH, Cell Mol Biol 1995, 41:S25-S33

Outcomes for Older Individuals: Immunological response to ARV

• With some exceptions [Hernando K, AIDS 2001, 15 (12): 1591] most papers show a less favorable CD4 rise in older patients– At 12 months and 24 months in 55+ years old Goetz MB, AIDS 2001, 15

(12): 1576; Operskalski EA, JAIDS 1997, 15 (3): 243

– From 3 to 36 months for maximal CD4 rise, maximal attained CD4 and time to maximum CD4 Viard JID 2001;183:1290

• Is this explained by changes in thymic output?– No significant difference in 1st phase (approx 4 – 8 weeks) response to

ARV; thought to be due to redistribution of existing cells; however, a decrease in naïve CD4 rise during the 2nd phase, thought to represent thymic production Lederman MM, AIDS 2000; 14: 2635

– May be due to involution of the thymus with age as naïve cell rise correlates with thymic size Smith KY, JID 2000; 181:141 and thymic output (TRECs) Douek DC, Nature 1998, 396; 690-695

Influence of age on CD4 cell recovery

Perez JL, Moore RD Clin Infect Dis 2003; 36: 212-218

Per

cen

t w

ith

CD

4 in

crea

se o

f≥

200. 1

06 /L

Months since starting HAART

0 6 12 18 24 30 36

80

70

60

50

40

30

20

10

0P=.0026, log-rank test

<32.7

32.7-37.1

37.2-44.4

≥44.5

Age quartiles

• Monthly CD4 T-cell count increases significantly lower in patients ≥50 years of age

Mean CD4 T-Cell Count Increase/Month, cells/mm3

Immunologic response slower in patients aged 50 years or older

Grabar S. AIDS. 2004;18(15):2029-2038.

Viral Load Stratum

Within first 6 months of HAARTa After 6 months of HAARTa

Age <50 years

Age ≥50 years

Age <50 years

Age ≥50 years

BL HIV-1 RNA <5 log10 copies/mL

17.3 14.1 11.1 9.8

BL HIV-1 RNA ≥5 log10 copies/mL

42.9 36.9 17.9 15.6

aP<.0001 for <50 yoa vs ≥50 yoa in all subgroups.BL, baseline; yoa, years of age

Age vs 12 Month Virologic & Immunologic Response to CART

0%

10%

20%

30%

40%

50%

60%

70%

18 - 29 30 - 39 40 - 49 50 - 54 55 - 59 60

Age at Initiation of CART

VL < 50 100 cell CD4 increase

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

Younger patients: immunologic response > virologic responseOlder patients: virological response > immunologic response

Outcomes for Older Individuals: Immunological response to ARV

• Age related changes in the immunological system may have implications for response to HIV and HAART– Involution of the Thymus – critical to “training” new t-cells

• Immunosenescence

• Natural decline in CD4 function

Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1

Luglio 2010

• L’HAART migliora la sopravvivenza pur persistendo, rispetto ai soggetti più giovani, un rischio di progressione clinica più elevato anche per valori di CD4+ > 350 cellule/μL.

• I pazienti anziani raggiungono la risposta virologica in percentuale significativamente maggiore rispetto ai più giovani e ciò è correlato ad una migliore aderenza.

• Risultati non univoci vi sono rispetto alla risposta immunologica: secondo la maggior parte degli autori vi è un più lento recupero dei linfociti CD4+, in particolare nel primo anno di terapia, correlato con l’involuzione timica caratteristica dell’invecchiamento.

• Il ridotto recupero immunologico, anche con HAART virologicamente efficace, e l’elevata frequenza di comorbilità sono fra le cause della maggiore progressione clinica e mortalità e suggeriscono un inizio della terapia più precoce nei pazienti anziani.