1. Wafaa El-Sadr, MD, MPH ICAP-Columbia University The World Before SMART

2. Think Back

3. HIV eradication “...2.3 - 3.1 years of a completely inhibitory treatment would be required to eradicate HIV completely.”

4. HIV-Associated Lipodystrophy New England Journal of Medicine (1998:339;1296). International Journal of STD and AIDS (1198;9:596).

5. Myocardial Infarction and ART Exposure MIs per 1,000 PY (95% CI) No. MIs No. PY 3 9 14 22 31 47 5,714 4,140 4,801 5,847 7,220 8,477 Years on CART Total 126 36,199 Test for trend p<0.00001 D:A:D, NEJM, 2003

6. Why Treatment Interruption? Lifelong use of ART inevitable in absence of cure Risk of complications low at lower CD4+ cell counts Adverse events from ART Serious complications e.g. CVD, hepatic and renal Difficulty in maintaining high rates of adherence HIV resistance likely with prolonged ART Pill-taking onerous and may be associated with decrease in quality of life Cost of ART is substantial, particularly in resource- limited countries

7. The Story of SMART The Beginning April 8, 2000 - Meeting in New York City Who: Cal Cohen, Wafaa El-Sadr, Fred Gordin, Birgit Grund, Carlton Hogan, Jim Neaton, Claire Rappaport, Debby Wentworth Where: 535 West 110 th Street, Apt 14H Outcome: Outline of the SMART design Study name identified

8. SMART--The Beginning

9. 9 The SMART Study Question What is the optimal way to use ART?

10. Weighing Pros and Cons DCVS

11. SMART Study Design Drug Conservation (DC) Strategy [Stop or defer ART until CD4+ 350] Virologic Suppression (VS) Strategy [Use of ART to maintain viral load as low as possible throughout follow-up] CD4+ cell count >350 cells/mm 3 n = 3000 Plan: 910 primary endpoints, 8 years average follow-up

12. Primary Endpoint HIV clinical disease progression or death Other Key Endpoints Death Serious HIV progression events Severe complications: cardiovascular, renal and hepatic

13. 13 SMART Study CPCRA RCC Sydney RCC Copenhagen RCC London RCC Brazil Canada Peru United States Argentina Australia Japan New Zealand Austria Belgium Denmark Finland Germany Norway Poland Portugal Spain France Greece Ireland Italy Morocco Switzerland United Kingdom

14. Baseline Characteristics 57% 26% 10% 3% 1% Countries: 33 Sites: 318 Total enrollment: 5472 Age: 46 years Women: 27% Blacks: 30%

15. SMART Meeting January 2006

17. International HIV/AIDS Trial Finds Continuous Antiretroviral Therapy Superior to Episodic Therapy The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), today announced that enrollment into a large international HIV/AIDS trial comparing continuous antiretroviral therapy with episodic drug treatment guided by levels of CD4+ cells has been stopped. Enrollment was stopped because those patients receiving episodic therapy had twice the risk of disease progression (the development of clinical AIDS or death), the major outcome of the study. FOR IMMEDIATE RELEASE Wednesday, Jan. 29, 2006 Media Contact: Laurie K. Doepel (301) 402-1663 niaidnews@niaid.nih.gov

19. SMART Primary Outcome SMART, NEJM 2006

20. SMART-Non-AIDS Events SMART, NEJM 2006

21. Definitive Evidence from SMART- Treatment Interruption Before SMART resultsAfter SMART results 2003200420052006200720082009 Number1239140515781690180719432064 Number interrupting ART regimen 66 (5.3%) 95 (6.8%) 98 (6.2%) 84 (5.0%) 70 (3.9%) 64 (3.3%) 55 (2.7%) Person-years in ART- experienced individuals 1535.411712.91840.821955.092071.982192.712254.07 Person-years spent on ART during year 1351.36 (88.0%) 1529.64 (89.3%) 1663.4 (90.4%) 1799.91 (92.1%) 1922.94 (92.8%) 2071.02 (94.5%) 2167.85 (96.2%) Smith, Phillips et al

22. Reasons for ART Interruption Before SMART resultsAfter SMART results 2003200420052006200720082009 Number interrupted ART66959884706455 Reason for stopping Patient choice (without adverse events) 39 (59.1%) 62 (65.3%) 71 (72.5%) 61 (72.6%) 56 (80.0%) 52 (81.3%) 44 (80.0%) Treatment failure (VL, CD4 or resistance) 9 (13.6%) 15 (15.8%) 5 (5.1%) 2 (2.4%) 1 (1.5%) 0 (0.0%) 0 (0.0%) Poor compliance 5 (7.6%) 5 (5.3%) 2 (2.0%) 1 (1.2%) 3 (4.3%) 1 (1.6%) 2 (3.6%) Toxicity (any) A 9 (13.6%) 13 (13.7%) 9 (9.2%) 13 (15.5%) 6 (8.6%) 5 (7.8%) 3 (5.5%) Smith, Phillips et al

23. Paradigm Shift Pathogenesis of HIV Disease

24. A New Paradigm Time in Years Infection CD4+ cells Count 1000 800 600 400 200 0 Opportunistic Diseases 1234567891011121314 Ongoing Morbidity from HIV

25. Conclusions SMART challenged the status quo Seeking definitive answers to tough questions is not easy, requires patience, may be costly, but is well worth it Getting an unexpected answer to a question is often more profound than getting the expected answer Other tough questions of the hour remain, and will require similar efforts to answer them

26. SMART - A Paradigm Shift START - Another One?