Workshop 1: Lanziano Moderatori: E. Sagnelli, F. Suter Discussant: F.v. Schloesser Recupero immunologico e progressione clinica G. Liuzzi

Guidelines and Clinical Expertise: the Italian Algorithm to build the future with the patients Lanziano Recupero immunologico e progressione clinica Giuseppina Liuzzi INMI Lazzaro Spallanzani

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

Age at Seroconversion vs Natural History: pre-HAART Lancet 2000; 355:1131 Median time to AIDS Age 15 – 24:11 years Age 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) OutcomeAdjusted HRP Value Progression to ADE or death Progression to new ADE HIV-1 RNA <500 copies/mL1.23<.05 Grabar S. AIDS. 2004;18(15): ADE, AIDS-defining event; BL, baseline; HR, hazard ratio; yoa, years of age

Cumulative mortality rate according to age group ( 50 yoa) untreated treated Perez JL, Moore RD Clin Infect Dis 2003; 36:

Disease Progression After HAART vs Age No prior AIDS or IDU; baseline CD4 100 – 199, VL > 10 5 May M et al. AIDS. 2007; 21: (supplementary materials Age

Older patients more likely to achieve HIV-1 RNA <500 copies/mL Kaiser Permanente study compared patients yoa and 50 yoa to patients yoa Patients >50 yoa more likely to achieve HIV-1 RNA <500 copies/mL vs patients yoa, even when adjusting for comorbidities Adherence major advantage for older patients Silverberg MJ. Arch Intern Med. 2007;167(7): years years CI, confidence interval; HR, hazard ratio; yoa, years of age HR (95% CI) 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: ; Lerner A, J Immunol 1989, 19: ; Ernst DN, J Immunol 1993, 151: ] –Reduction in T-cell proliferative ability Negoro S, Mech Aging Dev 1986, 33: ; Eylar EH, J AIDS 1994, 7: –Associated with reduced telomer length (T cell replicative senescence?) Bestilny LJ, AIDS 2000, 14 (7): –Increase in CD8 cell population that are CD28 – Choremi- Papadapoulou H, JAIDS 1994, 7: , Fagnoni FF, Immunology 1996, 88: –Decreased production of IL-2 and IL-2 receptor (involved in T- cell-mediated immune responses) Gillis S, J Clin Invest 1981, 67: ; 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 1 st 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 2 nd 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;

Influence of age on CD4 cell recovery Perez JL, Moore RD Clin Infect Dis 2003; 36: Percent with CD4 increase of /L Months since starting HAART P=.0026, log-rank test < Age quartiles

Monthly CD4 T-cell count increases significantly lower in patients 50 years of age Mean CD4 T-Cell Count Increase/Month, cells/mm 3 Immunologic response slower in patients aged 50 years or older Grabar S. AIDS. 2004;18(15): Viral Load Stratum Within first 6 months of HAART a After 6 months of HAART a Age <50 years Age 50 years Age <50 years Age 50 years BL HIV-1 RNA <5 log 10 copies/mL BL HIV-1 RNA 5 log 10 copies/mL a P<.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. COHERE. AIDS. 2008; 22: Younger patients:immunologic response > virologic response Older 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 sullutilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1 Luglio 2010 LHAART 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 linvoluzione timica caratteristica dellinvecchiamento. Il ridotto recupero immunologico, anche con HAART virologicamente efficace, e lelevata frequenza di comorbilità sono fra le cause della maggiore progressione clinica e mortalità e suggeriscono un inizio della terapia più precoce nei pazienti anziani.