wafaa el-sadr, md, mph icap-columbia university the world before smart

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SMART

Wafaa El-Sadr, MD, MPHICAP-Columbia University

The World Before SMARTThink Back

HIV eradication

...2.3 - 3.1 years of a completely inhibitory treatment would be required to eradicate HIV completely.HIV-Associated Lipodystrophy

New England Journal of Medicine (1998:339;1296). International Journal of STD and AIDS (1198;9:596). 4 Top left and right and bottom left53 year old man; HIV infected since at least 1987Received AZT + 3TCLater added IDV; 19 months of PI therapy Bottom right34 year old man; HIV infected since 1993Received AZT in 1993Added 3TC and IDV in April and June 1996Buffalo hump observed in December 1996

Myocardial Infarction and ART Exposure

MIs per 1,000 PY (95% CI)No. MIsNo. PY3 9 14 22 31 47 5,714 4,140 4,801 5,847 7,220 8,477Years on CARTTotal

126

36,199Test for trendp 350] Virologic Suppression (VS) Strategy[Use of ART to maintain viral load as low as possible throughout follow-up]CD4+ cell count >350 cells/mm3 n = 3000n = 3000Plan: 910 primary endpoints, 8 years average follow-up11Primary EndpointHIV clinical disease progression or deathOther Key Endpoints Death Serious HIV progression events Severe complications: cardiovascular, renal and hepatic 1213SMART Study

CPCRARCCSydneyRCCCopenhagenRCCLondonRCCBrazilCanadaPeruUnited StatesArgentinaAustraliaJapanNew ZealandAustriaBelgiumDenmarkFinlandGermanyNorwayPolandPortugalSpainFranceGreeceIrelandItalyMoroccoSwitzerlandUnited Kingdom

Baseline Characteristics

57%26%10%3%3%1%Countries: 33Sites: 318 Total enrollment: 5472Age: 46 yearsWomen: 27%Blacks: 30%14 SMART MeetingJanuary 2006

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 RELEASEWednesday, Jan. 29, 2006 Media Contact:Laurie K. Doepel(301) 402-1663niaidnews@niaid.nih.gov

18SMART Primary Outcome

SMART, NEJM 2006SMART-Non-AIDS Events

SMART, NEJM 2006Definitive Evidence from SMART- Treatment InterruptionBefore SMART resultsAfter SMART results2003200420052006200720082009Number1239140515781690180719432064Number interrupting ART regimen66 (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 individuals1535.41 1712.9 1840.82 1955.09 2071.98 2192.71 2254.07 Person-years spent on ART during year1351.36 (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 al21Reasons for ART InterruptionBefore SMART resultsAfter SMART results2003200420052006200720082009Number interrupted ART66 95 98 84 70 64 55 Reason for stoppingPatient 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 compliance5 (7.6%)5 (5.3%)2 (2.0%)1 (1.2%)3 (4.3%)1 (1.6%)2 (3.6%)Toxicity (any)A9 (13.6%)13 (13.7%)9 (9.2%)13 (15.5%)6 (8.6%)5 (7.8%)3 (5.5%)Smith, Phillips et al

Paradigm ShiftPathogenesis of HIV DiseaseA New Paradigm Time in YearsInfectionCD4+ cells Count10008006004002000Opportunistic Diseases1234567891011121314Ongoing Morbidity from HIVConclusionsSMART challenged the status quo Seeking definitive answers to tough questions is not easy, requires patience, may be costly, but is well worth itGetting 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

SMART - A Paradigm ShiftSTART - Another One?

Diagram11.50.10.54.112.24.91.62.95.32.23.85.82.84.37.145.5

Ark1None1.50.10.547.145.5

Ark2

Ark3