jorge a. tavel, md on behalf of the stalwart protocol team of the insight network 5 th ias...
TRANSCRIPT
Jorge A. Tavel, MDOn behalf of the STALWART Protocol Team
of the INSIGHT Network
5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
19-22 July 2009
Study of Aldesleukin with and without Antiretroviral Therapy
Patients ART-naïve (or off ART ≥ 1 year) with CD4+ T cells ≥ 300 /mm3
IL-2
IL-2 alone
IL-2+
IL-2 with peri-cycle ART
Control
No IL-2 or ART
Follow-up: Every 4 weeks until week 32, q 4 mo. thereafterPrimary Endpoint: CD4+ cell count at week 32
STALWART Study Design
N=89 N=87 N=91
IL-2 Cycles
• Subcutaneous injections twice daily for 5 consecutive days
• Starting dose 7.5 MIU; reduce in decrements of 1.5 MIU as necessary to control toxicities
• 3 cycles, 8 weeks apart
Peri-cycle ART in the IL-2+ group
≥ 1 PI and ≥ 2 nRTIs
Cycle 114 days 5 days 2 days
Subsequent Cycles
3 days 5 days 2 days
IL-2
STALWART Study Closure
• Two large HIV studies, ESPRIT and SILCAAT, were unblinded January 8, 2009
• IL-2 did not result in a reduction of opportunistic disease or mortality but was associated with an increased risk of adverse events
• Because of these findings:– STALWART IL-2 cycling was stopped– STALWART results were unblinded early– Planned follow-up ended February 28, 2009
Participant Characteristics
CD4+ median (IQR) 419 (359, 511)
HIV-RNA median (IQR) 22,000 (7k – 61k)
ART naïve 79%
White race 68%
Female 17%
Age (mean years) 37.4
Asia24%
Australia10%
Europe26%
North America
10%
South America
30%
Frequency of Cycling
0
20
40
60
80
<3 3 >3
IL-2
IL-2+
No. Cycles
Percent
At least 3 cycles:IL-2 76%IL-2+ 67%
IL-2 with or without peri-cycle ART increases CD4+ cell counts
0
100
200
300
400
500
600
700
0 4 8 12 16 20 24 28 32 36 40 44 48 52
CD4+
Study Week
IL-2+
IL-2
Control Week 32
IL2 489
IL2+ 542
Control 418
CD4+ Changes from Baseline to Week 32
Patients Change (SE) P-value*
IL-2 78 113.7 (24.6) <.001
IL-2+ 74 110.4 (20.3) <.001
Control 83 -21.8 (10.2) ref.
* compared to control
A greater number of participants assigned to no therapy started ART
HR P-value
IL-2 0.61 .07
IL-2+ 0.34 .001
Control 1.00 ref.
HIV RNA (log10) Changes from Baseline to Week 32
Patients Change (SE) P-value*
IL-2 79 -.07 (.09) .009
IL-2+ 73 -.01 (.05) .003
Control 82 -.40 (.11) ref.
* compared to control
Note: No significant differences when patients starting continuous ART are censored
0.1 1 10
IL-2 use is associated with a greater number of adverse events
Favors Control ►
►
Favors IL-2
Patients with Events
HR(95% CI)
Grade 3 or 4
IL-2 17 2.60
IL-2+ 24 4.05
Control 8 ref.
Grade 4
IL-2 6 2.53
IL-2+ 5 2.11
Control 3 ref.
Event
p = .03
p < .001
HR
Opportunistic Events and DeathsGroup Proximal CD4 Event
IL-2
148 Tuberculosis
248 Bact. Pneumonia (initial episode)
302 Tuberculosis
371 Ocular Toxoplasmosis
390 PCP
IL-2 +
311 Non-Hodgkin’s lymphoma
368 Motor Vehicle Accident*
438 Coronary Artery Thrombosis*
465 Bact. Pneumonia (initial episode)
474 Bact. Pneumonia (initial episode)
524 Candidiasis, Esophageal
550 Herpes Zoster, Multidermal
Control 548 Herpes Zoster, Multidermal
SUMMARY
• The groups assigned to receive IL-2:– Experienced CD4+ cell count increases – Started continuous ART less frequently– Experienced a greater number of
opportunistic events or deaths
• Combined with the results of ESPRIT and SILCAAT, this calls into question the functionality of CD4+ cells induced by IL-2
STALWART PROTOCOL TEAMICC Representatives
Washington Barbara StandridgeCopenhagen Daniela GeyLondon Nick Paton, Nicki SmithSydney Cate Carey, David Courtney-Rodgers
Statisticians Abdel BabikerDeb Wentworth
SDMC Coordinator Nicole Wyman
Community Rep Dave MunroeProtocol Clinicians Gustavo Lopardo
Norm MarkowitzJuan Carlos LopezKiat RuxrungthamMartin Fisher