1. Diego Ripamonti - Malattie Infettive - Bergamo Simposio HOT TOPICS Hot topics in HIV 2015

2. Disclosures Diego Ripamonti received advisory fees, speaker fees, travel and education from: - Abbott - BMS - ViiV - Janssen - Merk - Gilead 2

3. - START - Temprano UNAIDS OMS Universal treatment Convergence of International Guidelines CD4/CD8 ratio following HIV therapy new biomarkers of HIV disease Burden of non-AIDS morbidity HOT Topics – SIMIT 2015

4. INSIGHT START Study Group. NEJM 2015

5. START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive pts Immediate ART ART initiated immediately following randomization (n = 2326) Deferred ART Deferred until CD4+ cell count ≤ 350 cells/mm 3, AIDS, or event requiring ART (n = 2359) HIV-positive, ART-naive adults with CD4+ cell count > 500 cells/mm 3 (N = 4685) Study closed by DSMB (after interim analysis) HOT Topics – SIMIT 2015 INSIGHT START Study Group. NEJM 2015

6. HOT Topics – SIMIT 2015 INSIGHT START Study Group. NEJM 2015

7. Serious AIDS-related or serious non AIDS-related events (including death) Composite primary end-point HOT Topics – SIMIT 2015 INSIGHT START Study Group. NEJM 2015 68% events in pts with CD4 > 500 cells

8. HOT Topics – SIMIT 2015 The TEMPRANO ANRS Study Group. NEJM 2015

9. HOT Topics – SIMIT 2015 The TEMPRANO ANRS Study Group. NEJM 2015 In Ivory Coast Total pts: 2056 4 arms: - Def ART* - Def+ IPT - Early ART - Early + IPT * by WHO criteria 42% of clinical events are TB

10. HOT Topics – SIMIT 2015

11. UNAIDS: 90-90-90 Treatment Targets 100 80 60 40 20 0 HIV Positive People DiagnosedOn ARTViral Suppression 36.9 million 33.2 million 29.5 million 26.9 million Target 1: 90% of HIV+ people diagnosed Target 2: 90% of diagnosed people on ART Target 3: 90% of people on ART with HIV-1 RNA suppression 90% 81% 73% People (%) HOT Topics – SIMIT 2015

12. March 2015: UNAIDS announces that the goal of 15 million people on life-saving HIV treatment by 2015 has been met nine months ahead of schedule

13. HOT Topics – SIMIT 2015

14. Però.…

15. HOT Topics – SIMIT 2015 Mussini C et al. Lancet HIV 2015;2:e98-e106

16. HOT Topics – SIMIT 2015 Mussini C et al. Lancet HIV 2015;2:e98-e106 ICONA cohort 3236 pts with CD4/CD8 < 0.8 (median 0.39) From 1997-2013 on HAART Probability of normalization by 5 year: 29.4% Predictors: high baseline CD4, higher CD4/CD8 and CMV serology negative CD4/CD8 ratio < 0.30  higher risk of non-AIDS defining events or death

17. HOT Topics – SIMIT 2015 Serrano-Villar S, Deeks SG. Lancet HIV 2015;2:e76-7 CD4

18. HOT Topics – SIMIT 2015 Seng R et al. AIDS 2015; 29:595-607

19. HOT Topics – SIMIT 2015 HAARTN. ptsF-up since infection F-up since therapy CD4/CD8 > 1 Early2449.5 yrs4.8 yrs36.1% Deferred, continuous 2186.1 yrs3.0 yrs39.8% Cumulative viremiaRisk of achieving CD4/CD8 > 1 > 66rd percentile26.6% < 33rd percentile43.3% After controlling for: - baseline CD4/CD8 ratio - HAART duration - sex - age OR: 0.34 (95%CI 0.16-0.75), p=0.003 ANRS Primo Cohort Seng R et al. AIDS 2015; 29:595-607

20. 2015: Treat early and all 1996: Hit early and hard HOT Topics – SIMIT 2015

21. FINE

22. HOT Topics – SIMIT 2015 Only few patients normalise CD4/CD8 ratio, even after a long time on suppressive antiretorivral therapy. The incidence rate of non-AIDS defining events when the CD4/CD8 ratio was less than 0.30 was more than two-time higher than that observed when the CD4/CD8 ratio was more than 0.45. CD4/CD8 ratio may be a simple and inexpensive instrument to interprete the state of immune activation and risk of non-AIDS-defining events, even in patients with high CD4 count Mussini C et al. Lancet HIV 2015;2:e98-e106 Interpretation

23. HOT Topics – SIMIT 2015 Secondary end-points INSIGHT START Study Group. NEJM 2015

24. Increased risk of serious non-AIDS-related events and a low CD4/CD8 ratio. Case-control study: 109 cases, 298 controls - non-AIDS morbidity - non-AIDS mortality Serrano–Villar S et al. PLoS One 9 2014; 1: e85798.

25. HOT Topics – SIMIT 2015

28. INSIGHT START Study Group. NEJM 2015