Effect of Intermittent Aldesleukin Treatment With or Without Anti-HIV Drugs in HIV Infected People (STALWART)

STALWART: A Randomized, Open-Label, International Study of Subcutaneous Recombinant Interleukin-2 With and Without Concomitant Antiretroviral Therapy in Patients With HIV-1 Infection and CD4+ Cell Counts of 300 Cells/mm3 or More

The purpose of this study is to determine the effect of short cycles of recombinant interleukin-2 (also known as rIL-2 or aldesleukin) given with or without anti-HIV drugs in HIV infected patients. The effects will be compared with a study group that receives no IL-2 or antiretroviral therapy.

Study hypothesis: Intermittent aldesleukin, when given without antiretroviral therapy to patients with early HIV infection, will produce no change in HIV viral load and increases in CD4+ T lymphocyte counts comparable to aldesleukin administered with antiretrovirals.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: IL-2

Detailed Description

Highly active antiretroviral therapy (HAART) has dramatically improved prognosis and lowered morbidity and mortality rates for HIV infected patients. However, significant drug toxicities, difficulties with patient compliance to HAART regimens, and development of drug resistance highlight the need for less toxic, immune-based strategies. Aldesleukin is a synthetic protein that can increase CD4 counts; it is currently approved by the Food and Drug Administration (FDA) for use in patients with metastatic melanoma and renal cell carcinoma. Previous studies of aldesleukin in HIV infected patients indicated that increased CD4 counts can persist for years after aldesleukin administration, and aldesleukin given with HAART may also lead to significant lowering of viral load. This study will examine the immunologic effects of intermittent cycles of aldesleukin administered with and without HAART as compared to no therapy in HIV infected patients.

This study will last approximately 31 months. Participants will be randomly assigned to one of three groups at study entry. Group A will receive no aldesleukin or HAART. Group B will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level. Group C will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level; Group C participants will also take HAART for 3 days prior to the start of each aldesleukin cycle, throughout the 5-day aldesleukin cycle, and for 2 days after the end of each aldesleukin cycle (for a maximum of 10 days with each aldesleukin cycle). HAART will not be provided by the study. Some Group B and C participants may take part in additional cycles of aldesleukin if they meet certain study criteria.

All participants in this study will have at least 8 study visits; these visits will occur at study entry and Weeks 4, 8, 12, 16, 20, 24, and 32. Blood collection will occur at all visits and will include tests for CD4 count and viral load. Groups B and C will have additional blood collection within 4 days prior to the start of each aldesleukin cycle. On the last day of each aldesleukin cycle, Groups B and C will be assessed for toxicities, adverse events, and adherence to the aldesleukin daily injections; they will also have another blood collection. Group C participants will have an additional blood collection for HIV genotyping after they have completed their third aldesleukin cycle. Extended follow-up visits will occur approximately every 4 months for an additional two years. Blood collection will occur at these visits and will include tests for CD4 count, viral load, and other laboratory tests.

• Study Type: Interventional
• Enrollment (Actual): 267
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Ciudad de Buenos Aires, Buenos Aires, Argentina, 1199
      • Hosp. Italiano de Buenos Aires, Infectious Diseases Section CRS
    • Ciudad de Buenos Aires, Buenos Aires, Argentina, 1221
      • Hosp. Gen. de Agudos JM Ramos Mejia, Servicio de Inmunocomprometidos CRS
    • Ciudad de Buenos Aires, Buenos Aires, Argentina, C1425-AWK
      • Funcei Crs
  • Provincia De Sante Fe
    • Rosario, Provincia De Sante Fe, Argentina
      • Caici Crs
• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital CRS
  • Queensland
    • Brisbane, Queensland, Australia, 4000
      • Queensland Health - AIDS Med. Unit CRS
    • Highgate Hill, Queensland, Australia, 4101
      • Gladstone Road Medical Ctr. CRS
    • Miami, Queensland, Australia, 4220
      • Gold Coast Sexual Health Clinic CRS
  • Victoria
    • Carlton, Victoria, Australia, 3053
      • Carlton Clinic CRS
• Chile
  • Santiago, Chile
    • Fundacion Arriaran CRS
• Italy
  • Milano, Italy, 20127
    • Ospedale San Raffaele S.r.l. CRS
  • Milano, Italy, 20157
    • Univ. of Milan, Ospedale Luigi Sacco, Institute of Infectious and Tropical Diseases CRS
• Morocco
  • Casablanca, Morocco
    • Univ. Hosp. Ctr. of the Med. School of Casablanca, Infectious Diseases Unit CRS
• Poland
  • Warsaw, Poland
    • Wojewodzki Szpital Zakazny CRS
• Portugal
  • Cascais, Portugal
    • Hospital de Cascais, HDDI, Departamento Medicina Interna CRS
  • Lisboa, Portugal
    • Hosp. de Santa Maria, Servico de Doencas Infecciosas CRS
  • Lisboa, Portugal
    • Hosp. de Egas Moniz, Servicio de Infecciologia e Medicina Tropical CRS
• Spain
  • Barcelona, Spain
    • Hosp. Clinico de Barcelona CRS
• Thailand
  • Chiangrai, Thailand
    • Chiang Rai Regional Hosp. INSIGHT CRS
  • Khon Kaen, Thailand
    • Khon Kaen Univ., Srinagarind Hosp., Div. of Infectious Diseases & Tropical Medicine, Dept. of Medici
  • Ratchathewi
    • Bangkok, Ratchathewi, Thailand
      • Chulalongkorn University Hospital CRS
• United Kingdom
  • Leicester, United Kingdom
    • Leicester Royal Infirmary, Dept. of Infection & Tropical Medicine CRS
  • London, United Kingdom, EC1A 7BE
    • St. Bartholomew's Hosp., Infection & Immunity Clinical Group CRS
  • London, United Kingdom, W2 1NY
    • St. Mary's Hosp. of London, Imperial College School of Medicine CRS
  • Brighton
    • Elm Grove, Brighton, United Kingdom
      • Brighton & Sussex Univ. Hosp. NHS Trust, HIV Research Office CRS
• United States
  • California
    • Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System, Infectious Diseases Section CRS
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Washington DC VAMC, Washington Regional AIDS Program, Infectious Diseases CRS
  • Maryland
    • Bethesda, Maryland, United States, 20814-9692
      • NIH Clinical Ctr., NIAID HIV Clinic CRS
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hosp. CRS
  • New York
    • Bronx, New York, United States, 10451
      • Lincoln Hosp. & Med. Ctr. CRS
    • New York, New York, United States, 10037
      • Harlem Hospital Ctr./Columbia University CRS (Gordin CTU)
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Med. Ctr., Ambulatory Care and Education Ctr. CRS
  • Texas
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VAMC CRS
    • Houston, Texas, United States, 77030
      • Thomas Street Clinic CRS
    • San Antonio, Texas, United States, 78229
      • South Texas Veterans Health Care System, Immunosuppression Clinic CRS
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth Univ. Medical Ctr. CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV infected
• CD4 count of 300 cells/mm3 or more
• Access to a HAART regimen consisting of 1 or more protease inhibitors (PIs) and 2 or more nucleoside or nucleotide reverse transcriptase inhibitors

Exclusion Criteria:

• Prior use of aldesleukin
• Approved or experimental antiretroviral drug (including hydroxyurea) within 1 year prior to study entry
• Evidence of virologic failure on a PI- or nonnucleoside-based HAART regimen
• Any current indication for continuous HAART, in the opinion of the investigator
• Any contraindication to HAART, in the opinion of the investigator
• Systemic corticosteroids, chemotherapy, or experimental cytotoxic drugs within 45 days of randomization
• Approved or experimental agents with clinically significant immunomodulatory effects within 8 weeks prior to randomization
• History of any AIDS-defining illness or certain other diseases. More information on this criterion can be found in the protocol.
• Concurrent cancer requiring cytotoxic therapy
• Any central nervous system (CNS) abnormality requiring ongoing treatment with antiseizure medication
• Current or prior autoimmune or inflammatory diseases, including inflammatory bowel disease, psoriasis, optic neuritis, or any other autoimmune or inflammatory diseases with potentially life-threatening complications
• Significant heart, lung, kidney, liver, gastrointestinal, CNS, or psychiatric disease OR illicit substance use or abuse that, in the opinion of the investigator, would interfere with the study
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No IL-2; Participants will receive no aldesleukin or HAART
Experimental: IL-2 without ART; Participants will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level. Some Group 2 participants may take part in additional cycles of aldesleukin if they meet certain study criteria.	Drug: IL-2; 7.5 MIU injected intramuscularly; one arm uses Proleukin together with HAART of choice (protease inhibitor and at least 2 nucleoside/nucleotide reverse transcriptase inhibitors); Other Names: Proleukin, Aldeskeukin
Experimental: IL-2 with pericycle HAART; Participants will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level; Group 3 participants will also take HAART for 3 days prior to the start of each aldesleukin cycle, throughout the 5-day aldesleukin cycle, and for 2 days after the end of each aldesleukin cycle (for a maximum of 10 days with each aldesleukin cycle). Some Group 3 participants may take part in additional cycles of aldesleukin if they meet certain study criteria. HAART is not supplied by the study, and choice of drugs is left to the participant and physician. The HAART regimen should include at least one protease inhibitor and at least 2 nucleoside/nucleotide reverse transcriptase inhibitors.	Drug: IL-2; 7.5 MIU injected intramuscularly; one arm uses Proleukin together with HAART of choice (protease inhibitor and at least 2 nucleoside/nucleotide reverse transcriptase inhibitors); Other Names: Proleukin, Aldeskeukin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in CD4+ T Lymphocyte Count	Change in CD4 count from baseline to week 32.	Week 32

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discontinuation of IL-2	Patients receiving fewer than 3 cycles of IL-2 by week 32	week 32
Plasma HIV RNA	change from baseline in HIV-RNA copies/ml (log10)	At Week 32
Change in CD4 T Lymphocyte Count	change from baseline to month 12 in CD4 T lymphocyte count	At Month 12
HIV-1 Genotype Changes	Patients who developed mutations associated with antiretroviral drugs.	after 3rd cycle of IL-2
Fasting Lipid Profile	total fasting cholesterol	week 32
Disease Progression or Death	occurrence of an opportunistic event (AIDS-defining infection or malignancy) or death	throughout study, through Feb 28 2009 (median followup of 19 months)
Initiation of Continuous ART	While patients were not taking ART at baseline or while undergoing IL-2 cycles (other than use of pericycle ART in one of the three groups), some chose to start an ART regimen during the study.	from randomization through February 28, 2009
Change in HIV-RNA Copies/ml (log10) From Baseline to Month 12		month 12
Thyroid Stimulating Hormone	Number of participants with thyroid stimulating hormone greater than the upper limit of normal	week 32
SGOT	Number of participants with aspartate aminotransferase (SGOT) greater than 5 times the upper limit of normal	week 32

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Chiron Corporation
• Investigators: Study Chair: Jorge Tavel, MD, National Institute for Allergy and Infectious Diseases, National Institutes of Health

Publications and helpful links

General Publications

• Pett SL, Kelleher AD. Cytokine therapies in HIV-1 infection: present and future. Expert Rev Anti Infect Ther. 2003 Jun;1(1):83-96. doi: 10.1586/14787210.1.1.83.
• Davey RT Jr, Murphy RL, Graziano FM, Boswell SL, Pavia AT, Cancio M, Nadler JP, Chaitt DG, Dewar RL, Sahner DK, Duliege AM, Capra WB, Leong WP, Giedlin MA, Lane HC, Kahn JO. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial. JAMA. 2000 Jul 12;284(2):183-9. doi: 10.1001/jama.284.2.183.
• Anaya JP, Sias JJ. The use of interleukin-2 in human immunodeficiency virus infection. Pharmacotherapy. 2005 Jan;25(1):86-95. doi: 10.1592/phco.25.1.86.55629.
• de Boer AW, Markowitz N, Lane HC, Saravolatz LD, Koletar SL, Donabedian H, Yoshizawa C, Duliege AM, Fyfe G, Mitsuyasu RT. A randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, and 5-day cycles of intravenous recombinant human interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100-300 CD4+ T cells. Clin Immunol. 2003 Mar;106(3):188-96. doi: 10.1016/s1521-6616(02)00038-4.
• Marchetti G, Franzetti F, Gori A. Partial immune reconstitution following highly active antiretroviral therapy: can adjuvant interleukin-2 fill the gap? J Antimicrob Chemother. 2005 Apr;55(4):401-9. doi: 10.1093/jac/dkh557. Epub 2005 Feb 24.
• Tavel JA; INSIGHT STALWART Study Group; Babiker A, Fox L, Gey D, Lopardo G, Markowitz N, Paton N, Wentworth D, Wyman N. Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: the STALWART study. PLoS One. 2010 Feb 23;5(2):e9334. doi: 10.1371/journal.pone.0009334.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: May 13, 2005
• First Submitted That Met QC Criteria: May 13, 2005
• First Posted (Estimate): May 16, 2005

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: November 2, 2021
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Treatment Naive; IL-2; rIL-2
• Additional Relevant MeSH Terms: Infections; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Aldesleukin
• Other Study ID Numbers: ESPRIT 002; 10053 (DAIDS ES Registry Number)