Cristina Mussini Iniziare con CD4>500 cell: vantaggi e svantaggi Lunedì 8 marzo 17.30 - 19.00 II SESSIONE Quando iniziare Raccomandazioni internazionali a confronto sul management terapeutico del paziente HIV 18.00 - 18.10 Expert opinion Iniziare con CD4>500 cell: vantaggi e svantaggi Cristina Mussini Clinica di Malattie Infettive, Azienda Ospedaliera Universitaria, Policlinico di Modena 1

In un mondo ideale

L’approccio terapeutico all’infezione da HIV non dovrebbe differire da quello usato nei confronti delle altre infezioni e cioè la terapia dovrebbe essere iniziata immediatamente dopo la diagnosi.

Risk of death associated with deferral of ART, according to CD4+ count at baseline, with adjustment for HIV-RNA level, age, and sex Kitahata MM, et al. N Engl J Med, 2009

Hazard ratios for AIDS or death for deferral of cART to a lower CD4 cell count range versus initiation at a higher CD4 cell count range When To Start Consortium, Lancet, 2009

-24 -24 -18 -18 -12 -12 -6 -6 -24 -18 -12 -6 -24 -18 -12 -6 -24 -18 -12 -6 -24 -18 -12 -6 months (A) (B) (C) n = 411 median: +20 range: (-4; + 883) n = 403 median: - 182 range: (-626; -124) n = 800 median:- 56 range: (-125; -5) Legend figure 2: Box-plots showing CD4 24 months before HAART according to 3 different pre-HAART CD4 patterns (A, B and C: steeper, in-between and constant, respectively).

Legend fig 3: graphs representing pre- and post-HAART CD4 slopes Group A (steepest pre-HAART CD4 rate) pre-HAART CD4 slope: - 10.8 cells/mm3 /month (95% CI: from -12.7 to -8.9) post-HAART CD4 slope: + 23.0 cells/month (95% CI: from +19.2 to 26.9) Group B (moderate pre-HAART CD4 rate ) pre-HAART CD4 slope: - 3.9 cells//mm3 month (95% CI: from -4.6 to -3.1) post-HAART CD4 slope: + 14.8 cells/month (95%CI: from +13.3 to 16.2) Group C (shallowest pre-HAART CD4 rate) pre-HAART CD4 slope: + 0.11 cells//mm3 month (95% CI: from -2.0 to +2.2) post-HAART CD4 slope: + 11.1 cells/ month (95% CI: from +7.1 to +15.1) Legend fig 3: graphs representing pre- and post-HAART CD4 slopes estimated by linear mixed models for the three groups (A, B and C)

Duration of first STI period according to CD4 nadir Off therapy (days) Mean 95%CI 1306 1194 - 1419 1026 866 - 1187 538 350 - 725 259 162 - 356

CD4 naïve/memory cell ratios in patients with incomplete immunological response STRATUM 1: CD4 nadir 50 cell/L STRATUM 2: CD4 nadir 50 – 200 cell/L Robbins et al. CID 2009

T Cell Activation Declines Further During ART-mediated VL Suppression Hunt et al, JID, 2003 and 2008

La vita reale

CD4 counts are low at start of HAART 2003–2005 42 countries 176 sites 33,008 patients Although HAART is introduced in Europe at a CD4 cell count of approximately 200 cells/mm3, it is introduced at substantially lower counts in most other parts of the World. In several countries in Africa, therapy is initiated at counts <100 cells/mm3 This may partly be a reflection of poor resources. However, even in the USA and Canada, therapy is introduced at counts <200 cells/mm3 (the level below which guidelines recommend initiation even if patients are asymptomatic).1−3 In addition to resource constraints, poor awareness of guidelines and concern about adverse effects of HAART may discourage earlier initiation of HAART. References 1. EACS guidelines for the treatment and management of HIV-infected adults and adolescents in Europe, 2008. http://www.eacs.eu/guide/index.htm 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; 1-139. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. 3. Hammer S, et al. JAMA 2008;296:555–570 Adapted from Egger M, 14th CROI Los Angeles, CA, USA, 25–28 Feb 2007. Abstract 62. ART Cohort Collaboration. http://www.art-cohort-collaboration.org

Conclusions Regimens containing TDF/FTC or ABC/3TC increased limb fat and trunk fat and were not significantly different ATV/r led to greater gain in limb fat and trunk fat than EFV Lipoatrophy, even the mild protocol-defined form, occurred in 16% (95% CI 12-22 %) of the participants and was not significantly different between TDF/FTC and ABC/3TC or between EFV and ATV/r A5224s 15

Cumulative ARV Exposure and Risk of Chronic Kidney Disease in EuroSIDA s6843 HIV-infected patients with ≥ 3 serum creatinine measures and corresponding body weight measures from EuroSIDA study 21,482 patient-yrs of follow-up Cumulative exposure to TDF, ATV, LPV/RTV, or IDV each associated with increased risk of chronic kidney disease Risk of chronic kidney disease after stopping TDF remained elevated for 1 yr Within 12 mos, IRR: 4.05 (2.51-6.53) After 12 mos, IRR: 1.12 (0.63-1.99) Risk of chronic kidney disease after stopping ATV or LPV/RTV similar to patients never exposed Kirk O, et al. CROI 2010. Abstract 107LB.

19

Corsi e ricorsi storici Giambattista Vico (1668–1744) Corsi e ricorsi storici

Antiretroviral Therapy for HIV Infection in 1996: Recommendations of an International Panel Charles C. J. Carpenter; Margaret A. Fischl; Scott M. Hammer; Martin S. Hirsch; Donna M. Jacobsen; David A. Katzenstein; Julio S. G. Montaner; Douglas D. Richman; Michael S. Saag; Robert T. Schooley; Melanie A. Thompson; Stefano Vella; Patrick G. Yeni; Paul A. Volberding JAMA. 1996;276(2):146-154

Corsi e ricorsi storici Giambattista Vico (1668–1744) Corsi e ricorsi storici Il senso della storia è, per Vico, sia nella storia che, nello stesso tempo, fuori di essa: gli effetti delle azioni umane vanno sempre oltre l’intenzionalità specifica degli uomini; l’uomo fa più di quanto sa e spesso non sa quello che fa. La storia è caratterizzata, secondo Vico, da un andamento progressivo ma non nel senso che tutto quello che viene dopo sia migliore di quello che viene prima, ma solo nel senso che la storia procede in un modo non meccanico né uniforme verso l’idealità

CONCLUSIONI I clinici hanno sempre avuto buon senso nel seguire le linee guida e in questi anni hanno iniziato la terapia antiretrovirale senza seguire gli opposti estremismi. Vi sono ancora molte cose che non sappiamo e per rispondere non basterà uno studio randomizzato ma a breve termine. Certamente abbiamo spostato nella nostra pratica clinica l’inizio della terapia verso i 400 CD4 e non credo che i dati in nostro possesso siano in grado di far spostare il limite più in alto.