Jorge A. Tavel, MD On behalf of the STALWART Protocol Team of the INSIGHT Network 5 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2009 Study of Aldesleukin with and without Antiretroviral Therapy

Patients ART-naïve (or off ART ≥ 1 year) with CD4 + T cells ≥ 300 /mm 3 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. thereafter Primary 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 1 14 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 naïve79% White race68% Female17% Age (mean years) 37.4

Frequency of Cycling Percent At least 3 cycles: IL-2 76% IL-2+ 67%

IL-2 with or without peri-cycle ART increases CD4+ cell counts CD4+ Study Week IL-2+ IL-2 Control Week 32 IL2489 IL2+542 Control418

CD4+ Changes from Baseline to Week 32 PatientsChange (SE) P-value* IL (24.6) <.001 IL (20.3) <.001 Control (10.2) ref. * compared to control

A greater number of participants assigned to no therapy started ART HRP-value IL IL Control1.00ref.

HIV RNA (log 10 ) Changes from Baseline to Week 32 PatientsChange (SE) P-value* IL (.09).009 IL (.05).003 Control (.11) ref. * compared to control Note: No significant differences when patients starting continuous ART are censored

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 IL Control8ref. Grade 4 IL IL Control3ref. Event p =.03 p <.001 HR

Opportunistic Events and Deaths GroupProximal CD4Event IL-2 148Tuberculosis 248Bact. Pneumonia (initial episode) 302Tuberculosis 371Ocular Toxoplasmosis 390PCP IL Non-Hodgkin’s lymphoma 368Motor Vehicle Accident* 438Coronary Artery Thrombosis* 465Bact. Pneumonia (initial episode) 474Bact. Pneumonia (initial episode) 524Candidiasis, Esophageal 550Herpes Zoster, Multidermal Control 548Herpes 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 TEAM ICC Representatives WashingtonBarbara Standridge CopenhagenDaniela Gey LondonNick Paton, Nicki Smith SydneyCate Carey, David Courtney-Rodgers StatisticiansAbdel Babiker Deb Wentworth SDMC CoordinatorNicole Wyman Community RepDave Munroe Protocol CliniciansGustavo Lopardo Norm Markowitz Juan Carlos Lopez Kiat Ruxrungtham Martin Fisher