1. HIV and serious non-AIDS conditions Five Years after the SMART Study, a Paradigm Shifting Trial INSIGHT Symposium XIX International AIDS Conference Washington DC, 22 July 2012

2. “Serious non-AIDS” endpoint in SMART -Designed as a composite reflecting conditions potentially caused or exacerbated by ART (CVD, renal disease, liver disease) -Expected that risk of primary endpoint of AIDS/death might be increased somewhat with ART interruption but considered might be balanced by decrease in risk of non AIDS conditions -Careful collection of non-AIDS endpoints with adjudication by endpoint review committee

3. “Serious non-AIDS” endpoint in SMART -Designed as a composite reflecting conditions potentially caused or exacerbated by ART (CVD, renal disease, liver disease) -Expected that risk of primary endpoint of AIDS/death might be increased somewhat with ART interruption but considered might be balanced by decrease in risk of non AIDS conditions -Careful collection of non-AIDS endpoints with adjudication by endpoint review committee

4. “Serious non-AIDS” endpoint in SMART -Designed as a composite reflecting conditions potentially caused or exacerbated by ART (CVD, renal disease, liver disease) -Expected that risk of primary endpoint of AIDS/death might be increased somewhat with ART interruption but considered might be balanced by decrease in risk of non AIDS conditions -Careful collection of non-AIDS endpoints with adjudication by endpoint review committee

5. Risk of serious non-AIDS events in SMART SMART Study Group, NEJM 2006 & Neaton et al, Current Opinion in HIV/AIDS 2008 1 2 Renal 9 2 Liver 10 7 All serious non-AIDS CVD 48 31 Non-AIDS malignancy 27 24 Other non-AIDS death 30 16 0.5 Hazard ratio for intermittent (DC) vs. continuous (VS) ART Number of events Intermittent Continuous ART (DC) ART (VS) 3510 113 73 92% of deaths were from non-AIDS causes p=0.003

6. Paradigm shift in the wake of SMART result -Net effects of ART in people in the mid CD4 count range (~ 250 – 400) almost entirely positive -Clinical event risk at high CD4 count nearly all relates to non-AIDS conditions - events not collected in most cohorts -Appreciation that ART when initiated should be lifelong – risks with interrupting that cannot be tracked with the viral load and CD4 count -Immediate push for ART initiation when CD4 count reaches 350

7. INSIGHT SMART & ESPRIT Study Groups AIDS 2010; 24(12):1877, NEJM 2006; 355:2283-2296, Ann Int Med 2008; 149:289-299 % of Total (n=407) Events in SMART / ESPRIT control arms

8. CD4 count and risk of death: DAD 200 – 350 – > 500 349 499 CD4 count Rate / 100 person years 95% CI Non-AIDS causes All causes Weber at al Arch Int Med 2006 200 – 350 – > 500 349 499 0.0 0.5 1.0 1.5 2.0

9. Drugs used in SMART SMART (unpublished) zidovudine D4T DDI tenofovir abacavir FTC nevirapine efavirenz delavirdine atazanavir lopinavir saquinavir nelfinavir fos/ amprenavir indinavir

10. Paradigm shift in the wake of SMART result -Net effects of ART in people in the mid CD4 count range (~ 250 – 400) almost entirely positive -Clinical event risk at high CD4 count nearly all relates to non-AIDS conditions - events not collected in most cohorts -Appreciation that ART when initiated should be lifelong – risks with interrupting that cannot be tracked with the viral load and CD4 count -Immediate push for ART initiation when CD4 count reaches 350

11. Trends in death rate in people with HIV: D:A:D Smith CJ et al;D:A:D; Abstract Th 99-00 01-02 03-04 05-06 07-08 09-11 Year Rate per 100 person- yrs Liver CVD AIDS Other/unknown Cancer All causes

12. Implications for further research - 1 - Need for a trial of very early ART initiation -Effects of ART drugs themselves on risk of serious non- AIDS seems to be very low, but we know it is not zero -For people with very high CD4 count, question is whether the low risk due to ART is out-weighed by the low risk of untreated HIV - Nearly all the clinical risk is non-AIDS -Needed a randomized trial with carefully adjudicated endpoints to answer this

13. Implications for further research - 2 -Led to study of non-AIDS conditions as a group, as understanding grew of a potential shared aetiology -A key potential thread in shared aetiology was identified as inflammation -Potentially leads to pointers to pathogenesis of these non-AIDS conditions with implications well beyond HIV itself

14. Where next ? Research agenda on risk of clinical disease in people with successful HIV viral load suppression -What is the ongoing excess risk of morbidity due to HIV in people with successful viral suppression on ART ? -Increased inflammation compared with HIV-ve 1 -Reduced CD4 count 2 -Potential adverse effects of ART -Can we reduce that risk with additional interventions ? 1. Neuhaus et al, JID 2010; 2. Young et al, COHERE 2012; DAD unpublished

15. Age Number Person- Rate group with an years event 45-49 184 9878 1.86 (1.59, 2.13) 50-54 106 4583 2.31 (1.87, 2.75) 55-59 100 3258 3.07 (2.47, 3.67) 60+ 59 3866 4.11 (3.47, 4.75) Rate of serious non-AIDS or death according to age in people with viral suppression and CD4 < 500: D:A:D Source: Sabin et al; D:A:D (unpublished)

16. Residual non-AIDS mortality risk in people with viral suppression: implications for life expectancy Fold risk of non- AIDS death 1.078.5 1.575.0 2.069.1 3.065.7 Life expectancy Nakagawa et al, AIDS 2011, & unpublished Assuming HIV diagnosis rate and good adherence to ART For males in UK

17. Key lessons learned -Recognise presence of uncertainty and do large, well powered randomized trials with endpoints of the ultimate clinical impact to resolve the uncertainty. -Collect information on potential adverse clinical events with same rigor as for other major events.

18. Key lessons learned -Such trials serve as the ideal source for excellent basic science by providing the most valuable possible samples for investigation of the effect of interventions on biomarkers, and of biomarkers on disease. -Investing in large, well designed trials brings unexpected benefits as well as the expected ones.

19. Acknowledgements Investigators and participants in the following: SMART ESPRIT D:A:D Comments and additional analyses from: Wafaa El-Sadr, Jacquie Neuhaus, Jim Neaton, Steve Deeks, Fumiyo Nakagawa, Colette Smith, Jason Baker, Caroline Sabin, Alim Kamara, Jens Lundgren