Presentation on ESPRIT & STALWART Cycling Washington ICC Group Meeting, June 2007 CCG Training Session Prepared by: Dale C. Sattergren ESPRIT & STALWART

2 ESPRIT Study ESPRIT stands for Evaluation of Subcutaneous Proleukin in a Randomized International Trial

3 ESPRIT Purpose & Design Purpose: To compare the effects of subcutaneous recombinant Interelukin-2 and no SC rIL-2 on disease progression and death over a 5 year period in patients with HIV infection and CD4 cell count of > 300 who are taking combination antiretroviral therapy. ESPRIT was designed to investigate the strategy of using intermittent cycles of subcutaneous IL-2 to increase CD4 cells. The aim was to maintain participants’ CD4 cell counts at twice their baseline level or greater than 1000 cells/mm if participants entered the trial with more than 500/mm cells.

4 Study Treatment Eligible patients were randomized to receive SC rIL-2 therapy or no SC rIL-2. Recombinant IL-2 at a dose of 7.5 MIU daily is given for 5 consecutive days every 8 weeks for at least 3 cycles. Thus, during the first 6 months of follow-up, all patients randomized to SC rIL-2 will receive 3 cycles unless toxicities or other contraindications develop After the first 3 cycles, additional cycles will be given at the discretion of each patient in consultation with their physician As a guide, patients who enter with a CD4 cell count twice baseline. Those entering with CD4 > 500 cells will be encourage to receive additional cycles of therapy to maintain their CD4 > 1000 cells.

5 IL-2 Treatment Group IL-2 Group: This group will receive IL-2. IL-2 will be given at a dose of 7.5 million international units (MIU) by injection below the skin, twice a day for 5 days in a row. This will be followed by 7 weeks when you do not get IL-2. Another 5 day period of getting IL-2 by injection will follow after the 7 weeks of not getting IL-2. This routine will be repeated a third time. Then you may continue to get IL-2 by injection for 5 days in a row, starting no closer than 6 weeks apart, if your health care provider determines that IL-2 is helping you. If you were assigned to the arm that receive IL-2, your health care provider or study nurse would discuss with you, how you would receive your IL-2 injections.

6 Control Group Non IL-2 Group: This group would not receive IL-2 during the study. This group is very important to determine whether or not IL-2 makes a difference in slowing the progression of HIV disease.

7 ESPRIT Re-Cycling Unfortunately, not many IL-2 participants continue to use IL-2 to maintain these target CD4 cell goals, although over half did reach their goal at some point in the trial. The DSMB stressed (very strongly) that we need to do more to make sure that participants assigned to the IL- 2 arm actually receive the treatment per protocol instructions.

8 ESPRIT Re-Cycling Otherwise, we may end up having spent many years of time and effort only to fail to answer the study question, as we will not be truly comparing individuals taking IL-2 treatment to those taking no IL-2 treatment. This brings us to the topic of the Re-cycling.

9 Christiane Jones Length and interval of cycling How the patient is educated and prepared for side effects Medicines that are provided to prevent or reduce side effects Demonstration of the subcutaneous injections and how patients are taught to self-inject Equipment provided to patients such as needles, thermometers, energy drinks, etc. How the nurse communicates with the patient during the recycling process Discussion of the typical side-effects and how they are managed Case examples

10 IL-2 Side Effects Flu-like symptoms, including fever and muscle or joint pains Nasal and sinus congestion Nausea, vomiting and loss of appetite Diarrhea Fluid retention (swelling, edema) Dry eyes, Skin rash, itching and peeling Mouth sores or dry mouth Altered sleep patterns, insomnia, anxiety, or depression Injection site reactions

11 Strategies for Successful Re-cycling Make use of prophylactic medications Remove jewelry (due to potential for swelling) Report any recent illness of injury Drink plenty of fluids; have food and other essentials on-hand Massage and rotate injection sites; use ice before and after the injection Arrange for family/friends to help out if needed Plan to rest during re-cycling and to avoid heavy activity If there is any question or concern, contact study personnel

12 STALWART Study Stalwart Stands For; Study of Aldesleukin with and Without Anti-Retroviral Therapy

13 STALWART Purpose The purpose of this study is to compare the effects of subcutaneous (SC) recombinant interleukin 2 (rIL-2) administered with and without concomitant pericycle highly active antiretroviral therapy (HAART) to no therapy on CD4 count in patients with HIV-1 infection and CD4 count >300 cells/mm3. DESIGN: International, phase II, multi-site, open label, randomized, controlled trial

14 STALWART Study Treatment Eligible participants will be randomized in a 1:1:1 fashion to one of three groups. GROUP A: No therapy GROUP B: rIL million international units (MIU) subcutaneous (SC) twice a day (BID) for 5 consecutive days every 8 weeks for 3 cycles then as needed to maintain CD4 cell counts at or above goal. GROUP C: rIL MIU SC twice a day, for 5 consecutive days every 8 weeks with HAART beginning 3 days prior to each cycle, continuing through the cycle, and stopping 2 days after the last day of rIL-2 administration (For maximum of 10 days of HAART with each cycle) for 3 cycles then as needed to maintain CD4 cell counts at or above goal. Participants randomized to Groups B and C will receive cycles of rIL-2 unless toxicities or other contraindications develop.