2/10/2015 1 Strategic Timing of AntiRetroviral Treatment (START) Study Jenny Hoy For the INSIGHT START Australian Study team START Study DHHS recommendations for initiating ART (April 2015) “ART is recommended for all individuals with HIV infection.” The strength of this recommendation varies on the basis of pretreatment CD4 count (stronger at lower CD4 levels) CD4 count >500 cells/μl – Grade of evidence BIII When to Start Reason START needed to be done • Evidence for initiating antiretroviral therapy (ART) at CD4+ counts >350 cells/mm 3 primarily comes from large cohort studies from which there are inconsistent findings. • There is uncertainty about the effects of early ART on serious non-AIDS conditions. • Most of the morbidity at high CD4+ counts is due to non- AIDS conditions. • The absolute risk of AIDS is low at higher CD4+ counts, therefore the adverse effects of early ART could easily outweigh the benefits of reducing the risk of AIDS. START Study START Study Design Primary composite endpoint (Anticipated target = 213 endpoints) • Serious AIDS or death from AIDS • Serious Non-AIDS Events and death not attributable to AIDS Cardiovascular Disease, End-Stage Renal Disease, decompensated liver disease, & non-AIDS defining cancers HIV-positive ART-naïve individuals with CD4 count >500 cells/μl Immediate ART Group Initiate ART immediately following randomization N=2,326 Deferred ART Group Defer ART until CD4+ count declines to <350 cells/mm 3 or AIDS N=2,359 START Study Randomised START recruited individuals from around the world between 9/4/2009 to 23/12/2013 507 (11%) 1,174 (25%) 1,000 (21%) 109 (2%) 356 (8%) 1,539 (33%) 35 countries and 215 sites 2530 (54%) from low- and middle-income countries START Study Baseline Characteristics - 1 Characteristic N = 4685 Age (years)* 36 (29, 44) Female sex [N, (%)] 1257 (26.8) Race [N, (%)] Asian 388 (8.3) Black 1410 (30.1) Latino/Hispanic 638 (13.6) White 2086 (44.5) Other 163 (3.5) * Median (IQR) START Study
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2/10/2015
1
Strategic Timing of
AntiRetroviral Treatment
(START) Study
Jenny Hoy For the INSIGHT START Australian Study
team
START Study
DHHS recommendations for initiating ART (April 2015)
“ART is recommended for all individuals with HIV infection.”
The strength of this recommendation varies on the basis of pretreatment CD4 count (stronger at lower CD4 levels)
CD4 count >500 cells/µl – Grade of evidence BIII
When to Start
Reason START needed to be done
• Evidence for initiating antiretroviral therapy (ART) at
CD4+ counts >350 cells/mm3 primarily comes from large
cohort studies from which there are inconsistent findings.
• There is uncertainty about the effects of early ART on
serious non-AIDS conditions.
• Most of the morbidity at high CD4+ counts is due to non-
AIDS conditions.
• The absolute risk of AIDS is low at higher CD4+ counts,
therefore the adverse effects of early ART could easily
outweigh the benefits of reducing the risk of AIDS.
Division of AIDS (DAIDS), National Institute of Allergy and Infectious
Diseases (NIAID), National Institutes of Health (NIH)
OTHER SUPPORT
• Department of Bioethics, NIH Clinical Center
• Division of Clinical Research (NIAID)
• National Cancer Institute (NCI)
• National Heart, Lung, and Blood Institute (NHLBI)
• National Institute of Child Health and Human Development (NICHD)
• National Institute of Mental Health (NIMH)
• National Institute of Neurological Disorders and Stroke (NINDS)
• National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) • Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS, France)
• Bundesministerium für Bildung und Forschung (BMBF, Germany)
• NEAT - European AIDS Treatment Network
• Australian National Health and Medical Research Council
(NHMRC) • UK National Institute for Health Research & Medical Research Council
• Danish National Research Foundation
START Study
Does early ART cause net harm ? Low risk of morbidity and mortality in early HIV
without ART; especially in young people
If ART beneficial: many treated for one to benefit
ART can adversely affect many organs - including kidney, bone, liver, CVD, depression, and cancer
Risk is low – many treated for one to be harmed
If the number needed for 1 to be harmed is higher than the number needed for 1 to benefit = ART is of net harm
When to Start
Number needed to treat for one person to benefit Immediate treatment event rate (ITER) – 1.8%