Workshop 1: Lanziano Moderatori: E. Sagnelli, F. Suter Discussant: F.v. Schloesser Come cominciare, quali farmaci e come risponde lanziano S. Lo Caputo

Lanziano Come cominciare, quali farmaci e come risponde lanziano Sergio Lo Caputo U.O. Malattie Infettive Azienda Sanitaria Firenze

Age and Natural History of HIV Immune system wanes with age Older age associated with faster progression to clinical AIDS and death (pre-HAART) [1-3] Mixed data in HAART era –Some studies suggest association of age with poorer outcomes [4,5] –Others show that with effective treatment, no effect of age [6,7] 1. Babiker AG, et al. J Clin Epidemiol. 2001;54(suppl 1):S16-S Carre N, et al. AIDS. 1994;8: Phillips AN, et al. J Acquir Immune Defic Syndr. 1991;4: Grabar S, et al. AIDS. 2004;18: Kauffman GR, et al. Arch Intern Med. 2003;163: Smith CJ, J Infect Dis. 2004;190: Porter K, et al. Lancet. 2003;362:

Impact of age on HAART response Favours young Favours oldNo difference Total no. of studies CD4 response 4149 Virological response Note: Data based largely on small non-randomised trials Based on interpretation of following studies. Manfredi R, Chiodo F. AIDS 2000;14:1475–7; Viard JP, et al. J Infect Dis 2001;183: Knobel H, et al. AIDS 2001;15:1591–3; Yamashita TE, et al. AIDS 2001;15:735–46; Manfredi R, et al. J AIDS 2003;33:112–4; Tumbarello M, et al. AIDS 2003;17:128– 31; Goodkin K,et al. AIDS 2004;18(Suppl 1):S87–98; Grabar S, et al. AIDS 2004;18:2029–38; Tumbarello M, et al. MBC Infect Dis 2004;4:46–56; Based on Gebo KA. Drugs Aging 2006: 23(11):897–913, with addition of: Sabin CA et al. CROI 2007, Poster 528 and Cuzin L, et al. Clin. Infect Dis. 2007:45:654–7

Total population 3015 patients, 50 years 401 (13.3%) CD4 cell reconstitution is significantly slower than in younger patients, despite a better virologic response This impaired immunologic response may explain their higher risk of clinical progression

Ten age strata were chosen: less than 2, 2–5, 6–12, 13–17, 18– 29, 30–39 (reference group), 40–49, 50–54, 55–59 and 60 years or older; those aged 6 years or more were included in multivariable analyses The four youngest age groups had 223, 184, 219 and 201 individuals and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age.

Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy CD4 cell counts, may place this group at increased clinical risk. Unadjusted and adjusted hazard ratios of the impact of age on time to (a) confirmed virological response and (b) confirmed immunological response

Retrospective analysis of an observational clinical cohort. 670 younger patients ( 50years) Older patients were more likely to be started on an NNRTI-based regimen than were younger patients (41.6 vs. 29.0%, P<0.01) The Johns Hopkins University AIDS Service HAART initiation dates between 13 December 1995 and 9 February Median followup time after HAART initiation was 46.1 months

Time to virologic suppression after HAART initiation was shorter in older patients CD4 response did not differ by age. Older patients had fewer opportunistic infections, but survival was shorter

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

Older Age and the Response to and Tolerability of Antiretroviral Therapy Michael J. Silverberg,, Wendy Leyden,; Michael A. Horberg, ARCH INTERN MED/VOL 167, APR 9, patients aged 18 to 39 years (reference group), 1834 patients aged 40 to 49 years, and 997 patients 50 years or older enrolled in an integrated health care system (from KPNC HIV registry). Despite a higher risk of adverse events, patients 50 years or older sustained high therapy adherence to maintain improved virological outcomes and to compensate for their early blunted CD4 T-cell count response compared with younger patients.

Age and toxicity in the first year of HAART (UK-CHIC) 8708 naïve patients initiating HAART, in 13 UK centres 2650 (30%) discontinued at least one drug for non- virological failure reasons Discontinuing was associated with: –Younger age (<30; RH 1.12) –Older age (>50; RH 1.14) Strong association between older age and: –Increased cholesterol –decreased haemoglobin –Increased triglycerides Sabin et al, HIV Medicine, 2008

n.casi: % Cambiamenti nella scelta del regime terapeutico iniziale nella coorte ICONA dal 2001 al 2010 Associazione tra regimi terapeutici ed età allinizio della terapia Anni P value <0.001

HIV Management in aging Starting HAART: –start HAART earlier in the older? Increased risk of disease progression to AIDS Increased risk of co-morbidities Maintain higher CD4 count Choosing HAART: –regimens to avoid toxicities that overlap with ageing? CVD, bone disease –chose HAART regimens that penetrate the CNS?

Age and HAART Specific regimen are not influenced by age Effect of age on antiviral response also variable –Adherence may be greater in older patients Antiretroviral tolerability decreases with age ART-induced organ toxicities may exacerbate preexisting age-related conditions Close monitoring is required to detect any emerging problems

AZT DDI 3TC TDF ABC FTC D4T TRV CBV KVX NVP EFV ETV SQV LPV TPV FPV DRV ATV RTV IDV NFV RAL ENF VCV MVC

PAZIENTE ANZIANO Il paziente HIV anziano (di età superiore ai 50 anni) si caratterizza (Tab.1) per la più rapida progressione verso eventi AIDS e morte [1, 2], la più veloce riduzione dei linfociti CD4+ [3], la coesistenza di patologie concomitanti [4] e lelevata frequenza di decessi per cause non HIV-correlate (eventi cardiovascolari - 22%, insufficienza epatica - 22%, tumori - 12%, altre cause - 44%) [5-7]. La diagnosi di infezione da HIV viene posta spesso in stadio clinico avanzato o al momento dellinsorgenza di patologie opportuniste [8].

Terapia antiretrovirale Non vi sono studi clinici randomizzati e controllati che valutino la efficacia e tollerabilità della HAART nel paziente anziano. Le osservazioni fornite dagli studi di coorte evidenziano come la HAART migliori la sopravvivenza [9, 10], pur persistendo, rispetto ai soggetti più giovani, un rischio di progressione clinica più elevato anche per valori di CD4+ > 350 cellule/μL [11, 12]. Non sono state evidenziate differenze significative delle diverse associazioni di farmaci in base alletà [9, 10]. I pazienti anziani raggiungono la risposta virologica in percentuale significativamente maggiore rispetto ai più giovani e ciò è correlato ad una migliore aderenza [4, 10, 13-15].