Clinical trial NCT00110812: Effect of Intermittent Aldesleukin Treatment With or Without Anti-HIV Drugs in HIV Infected People
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Treatment Naive
IL-2
rIL-2
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Chiron Corporation
First posted: 2005-05-16
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean Change in CD4+ T Lymphocyte Count
timeFrame: Week 32
Secondary outcomes:
measure: Discontinuation of IL-2
timeFrame: week 32
measure: Plasma HIV RNA
timeFrame: At Week 32
measure: Change in CD4 T Lymphocyte Count
timeFrame: At Month 12
measure: HIV-1 Genotype Changes
timeFrame: after 3rd cycle of IL-2
measure: Fasting Lipid Profile
timeFrame: week 32
measure: Disease Progression or Death
timeFrame: throughout study, through Feb 28 2009 (median followup of 19 months)
measure: Initiation of Continuous ART
timeFrame: from randomization through February 28, 2009
measure: Change in HIV-RNA Copies/ml (log10) From Baseline to Month 12
timeFrame: month 12
measure: Thyroid Stimulating Hormone
timeFrame: week 32
measure: SGOT
timeFrame: week 32
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System, Infectious Diseases Section CRS
state: California
city: Washington
country: United States
facility: Washington DC VAMC, Washington Regional AIDS Program, Infectious Diseases CRS
state: District of Columbia
city: Bethesda
country: United States
facility: NIH Clinical Ctr., NIAID HIV Clinic CRS
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Hosp. CRS
state: Michigan
city: Bronx
country: United States
facility: Lincoln Hosp. & Med. Ctr. CRS
state: New York
city: New York
country: United States
facility: Harlem Hospital Ctr./Columbia University CRS (Gordin CTU)
state: New York
city: Portland
country: United States
facility: Providence Portland Med. Ctr., Ambulatory Care and Education Ctr. CRS
state: Oregon
city: Houston
country: United States
facility: Michael E. DeBakey VAMC CRS
state: Texas
city: Houston
country: United States
facility: Thomas Street Clinic CRS
state: Texas
city: San Antonio
country: United States
facility: South Texas Veterans Health Care System, Immunosuppression Clinic CRS
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth Univ. Medical Ctr. CRS
state: Virginia
city: Ciudad de Buenos Aires
country: Argentina
facility: Hosp. Italiano de Buenos Aires, Infectious Diseases Section CRS
state: Buenos Aires
city: Ciudad de Buenos Aires
country: Argentina
facility: Hosp. Gen. de Agudos JM Ramos Mejia, Servicio de Inmunocomprometidos CRS
state: Buenos Aires
city: Ciudad de Buenos Aires
country: Argentina
facility: Funcei Crs
state: Buenos Aires
city: Rosario
country: Argentina
facility: Caici Crs
state: Provincia De Sante Fe
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital CRS
state: New South Wales
city: Brisbane
country: Australia
facility: Queensland Health - AIDS Med. Unit CRS
state: Queensland
city: Highgate Hill
country: Australia
facility: Gladstone Road Medical Ctr. CRS
state: Queensland
city: Miami
country: Australia
facility: Gold Coast Sexual Health Clinic CRS
state: Queensland
city: Carlton
country: Australia
facility: Carlton Clinic CRS
state: Victoria
city: Santiago
country: Chile
facility: Fundacion Arriaran CRS
city: Milano
country: Italy
facility: Ospedale San Raffaele S.r.l. CRS
city: Milano
country: Italy
facility: Univ. of Milan, Ospedale Luigi Sacco, Institute of Infectious and Tropical Diseases CRS
city: Casablanca
country: Morocco
facility: Univ. Hosp. Ctr. of the Med. School of Casablanca, Infectious Diseases Unit CRS
city: Warsaw
country: Poland
facility: Wojewodzki Szpital Zakazny CRS
city: Cascais
country: Portugal
facility: Hospital de Cascais, HDDI, Departamento Medicina Interna CRS
city: Lisboa
country: Portugal
facility: Hosp. de Egas Moniz, Servicio de Infecciologia e Medicina Tropical CRS
city: Lisboa
country: Portugal
facility: Hosp. de Santa Maria, Servico de Doencas Infecciosas CRS
city: Barcelona
country: Spain
facility: Hosp. Clinico de Barcelona CRS
city: Bangkok
country: Thailand
facility: Chulalongkorn University Hospital CRS
state: Ratchathewi
city: Chiangrai
country: Thailand
facility: Chiang Rai Regional Hosp. INSIGHT CRS
city: Khon Kaen
country: Thailand
facility: Khon Kaen Univ., Srinagarind Hosp., Div. of Infectious Diseases & Tropical Medicine, Dept. of Medici
city: Elm Grove
country: United Kingdom
facility: Brighton & Sussex Univ. Hosp. NHS Trust, HIV Research Office CRS
state: Brighton
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary, Dept. of Infection & Tropical Medicine CRS
city: London
country: United Kingdom
facility: St. Bartholomew's Hosp., Infection & Immunity Clinical Group CRS
city: London
country: United Kingdom
facility: St. Mary's Hosp. of London, Imperial College School of Medicine CRS
Study officials:
affiliation: National Institute for Allergy and Infectious Diseases, National Institutes of Health
name: Jorge Tavel, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.