Slideset on: Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197: SMART: Early Initiation of Antiretroviral Therapy Associated With Decreased Risk of Opportunistic Disease, Death, and Serious Non-AIDS Events This program is supported by educational grants from Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC

clinicaloptions.com/hiv SMART: Decreased Risk of Opportunistic Disease, Death, Serious Non-AIDS Events Background  Limited studies evaluating optimal timing of antiretroviral therapy initiation  SMART trial assessed whether continuous or episodic antiretroviral therapy superior for safety and efficacy –Continuous therapy (viral suppression) arm: patients initiated therapy at start of trial (regardless of CD4+ cell count) and remained on antiretroviral therapy throughout trial –Episodic (drug conservation) arm: patients not treated until CD4+ cell counts 350 cells/mm 3 (all patients with CD4+ cell count > 350 cells/mm³ at baseline) –Trial stopped in January 2006 because of increased deaths in drug conservation arm  Current subgroup analysis compared major clinical outcomes in patients not receiving antiretroviral therapy at study entry who either initiated early antiretroviral therapy (when CD4+ cell count > 350 cells/mm 3 ) or deferred initiation (until CD4+ cell count < 250 cells/mm 3 ) Emery S, et al. J Infect Dis. 2008;197:

clinicaloptions.com/hiv SMART: Decreased Risk of Opportunistic Disease, Death, Serious Non-AIDS Events Summary of Study Design Emery S, et al. J Infect Dis. 2008;197: Deferred Arm Intermittent antiretroviral therapy (n = 2720; 228 not receiving antiretroviral therapy at trial start) Immediate Arm Continuous antiretroviral therapy (n = 2752; 249 not receiving antiretroviral therapy at trial start) Study halted prematurely; mean follow-up: 18 months HIV-infected patients with CD4+ cell count > 350 cells/mm 3 (N = 5472)  Treatment definitions for subanalysis –Deferred: antiretroviral therapy initiated when CD4+ cell count < 250 cells/mm 3, CD4+ cell percentage < 15%, or HIV symptoms –Immediate: antiretroviral therapy initiated immediately after randomization  Primary endpoints –OD or death from any cause (OD/death) –Fatal or nonfatal OD –Serious non-AIDS events –Fatal and nonfatal OD plus serious non-AIDS events

clinicaloptions.com/hiv SMART: Decreased Risk of Opportunistic Disease, Death, Serious Non-AIDS Events Main Findings  Patients in immediate arm had 5-fold greater antiretroviral therapy exposure compared with those in deferred arm –Measured as percent of follow-up period, during which antiretroviral therapy used –Immediate: 89% –Deferred: 18%  Antiretroviral therapy initiated at higher CD4+ cell counts in immediate arm vs deferred arm –Immediate arm –79% of patients initiated antiretroviral therapy at CD4+ cell count between cells/mm 3 –21% of patients initiated antiretroviral therapy at CD4+ cell count ≥ 550 cells/mm 3 –Deferred arm –Median CD4+ cell count at antiretroviral therapy initiation: 236 cells/mm 3 (interquartile ratio: ) Emery S, et al. J Infect Dis. 2008;197:

clinicaloptions.com/hiv SMART: Decreased Risk of Opportunistic Disease, Death, Serious Non-AIDS Events Main Findings (cont’d)  Immediate group experienced substantially fewer events compared with deferred group –Excess risk associated with deferring therapy: 5.4 events per 100 person- years Emery S, et al. J Infect Dis. 2008;197: Event, n (Rate per 100 Person-Yrs) Deferred Arm (n = 228) Immediate Arm (n = 249) HR (DC/VS) 95% CIP Value OD/death15 (4.8)5 (1.3) OD only11 (3.5)4 (1.1) Serious non- AIDS events 12 (3.9)2 (0.5) Composite21 (7.0)6 (1.6)

clinicaloptions.com/hiv SMART: Decreased Risk of Opportunistic Disease, Death, Serious Non-AIDS Events Main Findings (cont’d) Emery S, et al. J Infect Dis. 2008;197: CD4+ Cell Count, cells/mm < ≥ 500 Rate/100 Person-Yrs Deferred arm Immediate arm < ≥ 500 < ≥ 500 Total PopulationNo Previous AIDSNo Previous AIDS- Defining Illness

clinicaloptions.com/hiv SMART: Decreased Risk of Opportunistic Disease, Death, Serious Non-AIDS Events Other Outcomes  Higher grade 4 adverse events in deferred group –Deferred: 25 patients –Immediate: 18 patients –HR (deferred/immediate): 1.6; 95% CI: Emery S, et al. J Infect Dis. 2008;197:  OD events –Herpes zoster –Esophageal candidiasis –Tuberculosis –Mycobacterium avium complex –Herpes simplex –Death due to OD –Kaposi sarcoma –Non-Hodgkin’s lymphoma –Death due to non-Hodgkin’s lymphoma –Bacterial pneumonia  Serious non-AIDS events –Hepatic cirrhosis –End-stage renal disease –Death due to cardiovascular disease –Myocardial infarction –Coronary artery disease surgery –Silent myocardial infarction –Death from digestive system disease –Accidental death –Death due to renal disease –Death due to non-AIDS cancer

clinicaloptions.com/hiv SMART: Decreased Risk of Opportunistic Disease, Death, Serious Non-AIDS Events Summary of Key Conclusions  Reduced risk of both OD and serious non-AIDS events observed in patients who initiated and remained on antiretroviral therapy at CD4+ cell counts > 350 cells/mm 3 –Deferring antiretroviral therapy initiation until CD4+ cell count < 250 cells/mm 3 resulted in 4-fold higher risk of OD and serious non-AIDS events  Current study provided rationale for randomized trial to directly test risk-benefit ratio of early antiretroviral therapy initiation (ie, before decline of CD4+ cell count < 350 cells/mm 3 ) Emery S, et al. J Infect Dis. 2008;197: