Wafaa El-Sadr, MD, MPHICAP-Columbia University
The World Before SMART
Think 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).
Myocardial Infarction and ART Exposure
012345678
None <1 1-2 2-3 3-4 >4
MIs per 1,000 PY (95% CI)
No. MIs
No. PY3 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 trendp<0.00001
D:A:D, NEJM, 2003
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
The Story of SMARTThe 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 110th Street, Apt 14H• Outcome: Outline of the SMART design
Study name identified
SMART--The Beginning
9
The SMART Study Question
What is the optimal way to use ART?
Weighing Pros and Cons
DCVS
SMART Study Design
Drug Conservation (DC) Strategy
[Stop or defer ART until CD4+ < 250; then episodic ART based on
CD4+ cell count to increase counts to > 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 = 3000 n = 3000
Plan: 910 primary endpoints, 8 years average follow-up
Primary Endpoint
• HIV clinical disease progression or death
Other Key Endpoints
• Death• Serious HIV progression events• Severe complications: cardiovascular, renal and hepatic
13
SMART Study
CPCRARCC
SydneyRCC
CopenhagenRCC
LondonRCC
BrazilCanadaPeruUnited States
ArgentinaAustraliaJapanNew Zealand
AustriaBelgiumDenmarkFinlandGermanyNorwayPolandPortugalSpain
France
Greece
Ireland
Italy
Morocco
Switzerland
United Kingdom
Baseline Characteristics
North America
Europe
South America
Australia/NZ
Asia
Africa
57%
26%
10%
3%3% 1% Countries: 33
Sites: 318
Total enrollment: 5472
Age: 46 yearsWomen: 27%Blacks: 30%
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) [email protected]
SMART Primary Outcome
SMART, NEJM 2006
SMART-Non-AIDS Events
SMART, NEJM 2006
Definitive Evidence from SMART- Treatment Interruption
Before SMART results After SMART results
2003 2004 2005 2006 2007 2008 2009
Number 1239 1405 1578 1690 1807 1943 2064
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
1535.41 1712.9 1840.82 1955.09 2071.98 2192.71 2254.07
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
Reasons for ART Interruption Before SMART results After SMART results
2003 2004 2005 2006 2007 2008 2009
Number interrupted ART 66 95 98 84 70 64 55
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
Paradigm ShiftPathogenesis of HIV Disease
A New Paradigm
Time in YearsInfection
CD4+
cel
ls C
ount
1000
800
600
400
200
0
Opportunistic Diseases
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Ongoing Morbidity from HIV
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
SMART - A Paradigm ShiftSTART - Another One?
