1. Workshop 4: Il late-presenter Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Limportanza della risposta immunologica S. Rusconi

2. Il late-presenter: limportanza della risposta immunologica Roma, preIAS journey - ISS 16 dicembre 2010 Stefano Rusconi DISC L.Sacco, Sezione di Malattie Infettive e Immunopatologia Università degli Studi di Milano

3. CD4 count at start of HAART, 2003-2005 Egger M, et al. CROI 2007. Abstract 62. Data from 42 countries, 176 sites; n=33,008 Since 2000, CD4+ cell count at initiation has increased in Sub-Saharan Africa from 50 to 100 cells/mm 3 ; in developed countries it has remained 150–200 cells/mm 3

4. Numero CD4 alla diagnosi

5. Prognosis from starting ART according to pre- therapy CD4 cell counts (cells/µL) ART CC. Egger et al, Lancet. 2002 Probability of AIDS or Death (%) Years From Starting ART 0-49 50-99 >350 100-199 200-349 0123 0 5 10 15 20 25

6. CASCADE: Nadir CD4+ Cell Count Predicts AIDS and Non-AIDS Events Marin B, et al. IAS 2007. Abstract WEPEB019. 1.000.011.00100.00 Nadir CD4+ cell count AIDS-Related Death 0.01100.00 200-349 vs 350 50-199 vs 350 < 50 vs 350 Non-AIDS–Related Death 1.000.01100.00 Non-AIDS Cancer Death 1.000.01100.00 Liver Disease Death 200-349 vs 350 50-199 vs 350 < 50 vs 350 200-349 vs 350 50-199 vs 350 < 50 vs 350 200-349 vs 350 50-199 vs 350 < 50 vs 350 CASCADE Collaboration cohort: N = 9858 Several clinical markers of HIV progression correlated with death due to AIDS-related causes, non-AIDS–related severe infection, liver diseases, and non-AIDS–related malignancies including – Latest and nadir CD4+ cell counts – Time spent with CD4+ cell count < 350 cells/mm 3

7. Gras L, et al. J Acquir Immun Defic Syndr. 2007;45:183-192. CD4 Cell Count (cells/mm 3 ) 04896144192240288366 0 100 200 300 400 500 600 700 800 900 1000 Week >500 (n=389) 350 – 500 (n=694) 200 – 350 (n=1,513) 50 – 200 (n=1,773) <50 (n=930) Baseline CD4 (cells/mm 3 ) 50% of those with CD4 nadir <200 fail to reach 500 after 7 years VL suppression. Suboptimal CD4 T Cell Gains Are Common Among Patients Who Initiate HAART Late (ATHENA)

8. CNICS: 40% of patients with a nadir CD4 < 200 fail to achieve a normal CD4+ cell count, even after 10 years of viral suppression (n=300) Kelley CF, et al. Clin Infect Dis 2009;48:787-794. 0246810 100 0 20 40 60 80 <200 200-350 >350 Nadir CD4 Year of HAART CD4+ T Cell > 500 cells/mm 3 (%)

9. Influence of Age on CD4 Cell recovery

10. e la qualità dei CD4…? C. Negri, S. Rusconi, A. Gori et al. AIDS, Dec. 1996, 10:1737-1738

11. More MVC Recipients Exceeded Clinically Relevant CD4 + Thresholds in MERIT 85 37 13 75 34 9 0 10 20 30 40 50 60 70 80 90 100 MVC (N = 123) EFV (N = 104) Percentage of Patients 200 Cells/µL 350 Cells/µL 500 Cells/µL CD4 + Count at Week 96 Patients with Baseline CD4 + Counts < 200 Cells/ L 78104 35 45169n= Lazzarin A, et al. HIV10, Glasgow 2010, O422

12. Conclusion LPV/r monotherapy failures occurred in first 24 weeks High failure rate was associated with low nadir CD4+ cell count (CD4+ <200 cells/mL) Kaplan-Meier analysis of failure by CD4+ count Gutman C, et al. 16 th CROI, Montreal 2009, #578 0 20 40 6080 0 20 40 60 80 100 % without failure CD4+ Nadir <200 CD4+ Nadir >200 weeks LPV/r monotherapy failures associated with low nadir CD4+ (MOST Study)