ESPRIT: An International Study to Evaluate Recombinant Interleukin-2 in HIV Positive Patients Taking Anti-retroviral Therapy

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00004978
• Collaborator: Chiron Corporation (Industry)
• Enrollment: 4,150
• Locations: 248
• Arms: 2
• Duration (Months): 104
• Patients Per Site: 16.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to see if it is effective to give HIV positive patients recombinant interleukin-2 (rIL-2) in addition to anti-HIV therapy. Patients will be followed over a minimum of 4 years to study the long-term effects of rIL-2 on their HIV disease progression.

Anti-HIV therapy has been very successful in treating HIV positive patients and in keeping viral load (level of HIV in the blood) low. However, anti-HIV drugs cannot completely rid the body of the virus, and the immune system is never completely restored in HIV positive patients. Doctors hope that giving patients recombinant interleukin-2 (rIL-2) in addition to their anti-HIV therapy will help improve their immune systems and keep them healthier over a longer period of time. rIL-2 is a hormone naturally produced by the body during an immune response to a microbial infection.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Recombinant interleukin-2 (rIL-2)	Phase 3

Detailed Description

Much progress has been made in implementing potent antiretroviral therapy that is able to maximally suppress viral replication. However, these drug combinations do not result in viral eradication and, for many patients, virologic and immunologic control cannot be maintained. Even among patients with apparent virologic control, a "ceiling effect" seems to exist with failure of CD4 cell counts to rise on average more than 100 to 150 cells/mm^3, at least during the first 2 years of therapy. The incomplete recovery of immune function after initiation of therapy remains an obstacle in the management of HIV. Preservation of immune function by direct expansion of CD4 lymphocytes with rIL-2 could represent a significant additional treatment strategy. It also has been speculated recently that rIL-2 in combination with potent antiretroviral therapy may be a useful approach for purging HIV from the latently infected CD4 cells. It is hoped that intervention with rIL-2 therapy in combination with antiretroviral therapy at an early stage of HIV infection can prevent CD4 T-cell depletion and result in fewer AIDS-defining illnesses than with antiretroviral therapy alone.

Patients are randomized to receive subcutaneous (SC) rIL-2 therapy or no rIL-2 therapy. All patients must be taking a regimen of combination antiretroviral treatment, with the choice of therapy at the discretion of the treating clinician. Antiretroviral medications are not provided by this study. Recombinant IL-2 is given SC for 5 consecutive days every 8 weeks for at least 3 cycles unless toxicities or other contraindications develop. After the first three cycles, additional cycles are given at the discretion of each patient's physician, with a general goal of maintaining the patient's CD4 cell count at twice the baseline level or at 1,000 cells/mm^3 or above for as long as possible. Patients in the no rIL-2 group receive no injections. Patients in both treatment groups are seen every 4 months for follow-up data collection to monitor viral load and CD4 cell counts. All patients are followed for a minimum of 4 years. During the trial, patients in the no SC rIL-2 group are not given rIL-2 at any point. However, at the end of the study, if rIL-2 is found to be effective in reducing the rate of disease progression [AS PER AMENDMENT 12/15/00: (new and recurrent events)], including death, all patients are offered rIL-2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Phase III, International Study of Subcutaneous Recombinant IL-2 in Patients With HIV-1 Infection and CD4+ Cell Counts 300/mm^3 or Greater: Evaluation of Subcutaneous Proleukin in a Randomized International Trial
• Study Start Date: Mar 1, 2000
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rIL-2 Recombinant interleukin-2 (rIL-2) therapy used with combination anti-HIV medication of choice.	Drug: Recombinant interleukin-2 (rIL-2); Recombinant interleukin-2 at a dose of 7.5 MIU given twice daily subcutaneously for 5 consecutive days every 8 weeks for at least 3 cycles.; Other Names: Proleukin IL-2 Aldesleukin
No Intervention: No rIL-2 Control arm uses anti-HIV medication of choice without rIL-2.

Outcome Measures

Primary Outcome Measures

1. New or Recurrent HIV Disease Progression Event Including Death [from randomization through study end - median of 7.6 years follow-up]

   Participants who die or experience at least one: any CDC Category C 1993 AIDS-defining events or one of the following: invasive aspergillosis, bartonellosis, Chagas disease, Herpes zoster, visceral Leishmaniasis, Hodgkin's lymphoma, non-Hodgkin's lymphoma (all cell types), microsporidiosis, nocardiosis, disseminated Penicillium marneffii, extrapulmonary Pneumocystis carinii, and Rhodococcus equi disease

Secondary Outcome Measures

1. New or Recurrent Serious HIV Disease Progression Event Including Death [from randomization through study end - median of 7.6 years follow-up]

   Patients with at least one: progressive multifocal leukoencephalopathy, lymphoma, visceral Kaposi's sarcoma, AIDS dementia complex, toxoplasmosis, histoplasmosis, cryptococcosis, Mycobacterium avium complex, wasting syndrome, and cytomegalovirus disease.

2. Number of Participants Who Died From Any Cause [from randomization through study end - median of 7.6 years follow-up]

3. Participants With a New Disease Progression Event or Death [from randomization through 15 November 2008 - median of 7.6 years follow-up]

   Includes first new episode of: CDC Category C 1993 AIDS-defining events plus invasive aspergillosis, bartonellosis, Chagas disease, Herpes zoster, visceral Leishmaniasis, Hodgkin's lymphoma, non-Hodgkin's lymphoma (all cell types), microsporidiosis, nocardiosis, disseminated Penicillium marneffii, extrapulmonary Pneumocystis carinii, and Rhodococcus equi disease

4. Absolute CD4 Cell Counts Averaged Throughout Followup [from randomization through study end - median of 7.6 years follow-up]

   Average of all available CD4+ cell counts measured at follow-up visits

5. Plasma HIV RNA Levels [From randomization through study end - median of 7.6 years follow-up]

   log10 HIV-RNA averaged throughout follow-up

6. Number of Participants With Changes in Anti-retroviral Treatment (ART) [From randomization through study end - median of 7.6 years follow-up]

   Number of participants who changed ART at least once during the study period.

7. Grade 4 Signs and Symptoms [From randomization through study end - median of 7.6 years follow-up]

   Participants with at least one grade 4 sign or symptom (except those limited to a laboratory measurement), other than AIDS-defining conditions. Events were graded according to a standardized toxicity table. Events not specifically contained in the toxicity table were considered Grade 4 if they resulted in extreme limitation in activity or required significant medical intervention/therapy, hospitalization or hospice care. Grade 4 events by type are given under the adverse events section.

8. Pattern of Use of Prophylaxis for Opportunistic Infections [last followup visit - median of 7.6 years follow-up]

   Number of participants using pneumocystis pneumonia (PCP) prophylaxis at the last attended followup visit.

9. Hepatic, Metabolic, and Cardiac Conditions [From randomization through study end - median of 7.6 years follow-up]

   Number of participants experiencing a "serious non-AIDS" event defined as first serious cardiovascular, renal, or hepatic event, or non-AIDS malignancy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• HIV positive

• Have a CD4 cell count of 300 cells/mm3 or more within 45 days of study entry

• Are on combination anti-HIV therapy or are beginning anti-HIV therapy at the time of study entry

• Are at least 18 years old

Exclusion Criteria:

• Have received IL-2 before

• Have cancer requiring chemotherapy

• Have evidence of active clinical disease within the past year for any AIDS-defining illness or certain other conditions such as herpes zoster or Chagas disease. (This study has been changed. Previously, patients were ineligible if they had a history of any AIDS-defining illness or certain other conditions.)

• Have used certain medications, such as corticosteroids or drugs affecting the immune system, in the 45 days before study entry

• Have a nervous system disorder requiring antiseizure medication

• Have an autoimmune or inflammatory disease such as inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), psoriasis, optic neuritis, or any autoimmune/inflammatory diseases with potentially life-threatening complications

• Are pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Greater Los Angeles Healthcare System, Infectious Diseases Section CRS	Los Angeles	California	United States	90073
2	Dr. M. Estes Med. Practice CRS	Mill Valley	California	United States	94941-3013
3	Dr. Robert Scott Med. Practice CRS	Oakland	California	United States	94609
4	East Bay AIDS Ctr. CRS	Oakland	California	United States	94705
5	Dr. Shawn Hassler Med. Practice CRS	San Francisco	California	United States	94102
6	Positive Health Program Clinic (San Francisco Gen. Hosp.) CRS	San Francisco	California	United States	94110-0242
7	Positive Health Practice West/ Dr. Steve Deeks CRS	San Francisco	California	United States	94110
8	Dr. William Owen Med. Practice CRS	San Francisco	California	United States	94114-1010
9	Dr. Martin Mass Med. Practice CRS	San Francisco	California	United States	94114
10	San Francisco VAMC, Infectious Diseases Clinic CRS	San Francisco	California	United States	94121
11	UCSF PHP, Gen. Internal Medicine Practice CRS	San Francisco	California	United States	94143
12	Castro-Mission Health Ctr. CRS	San Francisco	California	United States	94144
13	Dr. Virginia Cafaro Med. Practice CRS	San Francisco	California	United States
14	Denver Infectious Diseases Consultants CRS	Denver	Colorado	United States	80204-4507
15	Denver Public Health CRS	Denver	Colorado	United States
16	Univ. of Colorado Health Science Ctr. CRS	Denver	Colorado	United States
17	Whitman-Walker Clinic CRS	Washington	District of Columbia	United States	20009
18	George Washington Univ. Med. Ctr. Infectious Diseases - Clinical Trials Unit CRS	Washington	District of Columbia	United States	20037
19	Walter Reed Army Med. Ctr., Infectious Disease Clinic CRS	Washington	District of Columbia	United States	20307
20	Washington DC VAMC, Washington Regional AIDS Program, Infectious Diseases CRS	Washington	District of Columbia	United States	20422
21	Dr. Timothy A. Price Med. Practice CRS	Washington	District of Columbia	United States
22	Miami VAMC CRS	Miami	Florida	United States	33125
23	Univ. of Miami, Infectious Diseases Clinical Research Unit CRS	Miami	Florida	United States	33136
24	ARCA, Central Clinc CRS	Atlanta	Georgia	United States	30308
25	Emory Univ. Crawford Long Hosp. CRS	Atlanta	Georgia	United States	30308
26	Atlanta VAMC CRS	Decatur	Georgia	United States	30033
27	Klein & Slotten Medical Associates CRS	Chicago	Illinois	United States	60610
28	Jesse Brown VAMC CRS	Chicago	Illinois	United States	60612
29	Univ. of Illinois Family Ctr. for Infectious Disease CRS	Chicago	Illinois	United States	60612
30	Lakeshore Infectious Disease Associates CRS	Chicago	Illinois	United States	60657
31	North Side Family Medicine CRS	Chicago	Illinois	United States	60657
32	Northwestern Memorial Physicians Group CRS	Chicago	Illinois	United States	60657
33	Med. Ctr. of Louisiana at New Orleans, HIV Outpatient Clinics CRS	New Orleans	Louisiana	United States	70112
34	Tulane University Health Sciences Center, Louisiana Community AIDS Research Program(LaCARP) CRS	New Orleans	Louisiana	United States	70112
35	New Orleans VAMC CRS	New Orleans	Louisiana	United States	70146
36	NIH Clinical Ctr., NIAID HIV Clinic CRS	Bethesda	Maryland	United States	20814-9692
37	National Naval Med. Ctr., Infectious Diseases Special Immunology Clinic CRS	Bethesda	Maryland	United States	208995000
38	Henry Ford Hosp. CRS	Detroit	Michigan	United States
39	Wayne State Univ. CRS	Detroit	Michigan	United States
40	St. John Hosp. & Med. Ctr., Infectious Diseases Dept. CRS	Grosse Pointe Woods	Michigan	United States	48236
41	William Beaumont Hosp., Infectious Disease Research CRS	Royal Oak	Michigan	United States	48073
42	Abbott Northwestern Hosp., Clinic 42 CRS	Minneapolis	Minnesota	United States	55404
43	Mayo Clinic INSIGHT CRS	Rochester	Minnesota	United States	55905
44	Cooper Univ. Hosp. CRS	Camden	New Jersey	United States	07754
45	ID Care Inc. - Hillsborough CRS	Hillsborough	New Jersey	United States	08844
46	Jersey Shore Univ. Med. Ctr. CRS	Neptune	New Jersey	United States	07754
47	New Jersey Community Research Initiative, Jeffrey Bomser Clinic CRS	Newark	New Jersey	United States	07103
48	Cathedral Healthcare System, St. Michael's Med. Ctr. CRS	Newark	New Jersey	United States
49	St. Joseph's Hosp. & Med. Ctr. of New Jersey CRS	Paterson	New Jersey	United States
50	Raritan Bay Med. Ctr., Perth Amboy Division CRS	Perth Amboy	New Jersey	United States	08861
51	ID Care - Randolph CRS	Randolph	New Jersey	United States	07869
52	Infectious Disease Specialists of N.J., North Jersey Community Research Initiative CRS	Union	New Jersey	United States	07083
53	The Early Intervention Program at Kennedy Hosp. CRS	Voorhees	New Jersey	United States	08043
54	Jacobi Med. Ctr., Ambulatory Care Pavillion CRS	Bronx	New York	United States	10461
55	Bronx VAMC CRS	Bronx	New York	United States	10468
56	St. Vincent Hosp. & Med. Ctr. CRS	New York	New York	United States	10011
57	Harlem Hospital Ctr./Columbia University CRS (Gordin CTU)	New York	New York	United States	10037
58	Oregon Health & Sciences Univ. Internal Medicine (L-475) CRS	Portland	Oregon	United States	97201
59	Multnomah County Health Dept., HIV Health Services Ctr. CRS	Portland	Oregon	United States	97204
60	The Research & Education Group-Portland CRS	Portland	Oregon	United States	97209
61	Providence Portland Med. Ctr., Ambulatory Care and Education Ctr. CRS	Portland	Oregon	United States	97213
62	Kaiser Immune Deficiency Clinic of Portland CRS	Portland	Oregon	United States	97227
63	Legacy Clinic Emanuel CRS	Portland	Oregon	United States	97301
64	Salem Hosp. CRS	Salem	Oregon	United States	97301
65	Kaiser Permanente Lancaster Clinic CRS	Salem	Oregon	United States	97305
66	Temple Univ. School of Medicine CRS	Philadelphia	Pennsylvania	United States	19140
67	Michael E. DeBakey VAMC CRS	Houston	Texas	United States	77030
68	Northwest Clinic CRS	Houston	Texas	United States	77030
69	Thomas Street Clinic CRS	Houston	Texas	United States	77030
70	Univ. Clinical Research Ctr., Memorial Hermann Hosp. CRS	Houston	Texas	United States	77030
71	Legacy Community Health Services, Inc., Montrose Clinic, Inc.	Houston	Texas	United States
72	South Texas Veterans Health Care System, Immunosuppression Clinic CRS	San Antonio	Texas	United States	78284
73	Hanover Med. Park (Mechanicsville, VA) CRS	Mechanicsville	Virginia	United States	23116
74	Naval Med. Ctr. Portsmouth CRS	Portsmouth	Virginia	United States	23708
75	CrossOver Health Ctr. CRS	Richmond	Virginia	United States	23224
76	South Richmond Health Care Ctr. CRS	Richmond	Virginia	United States	23224
77	Hunter Holmes McGuire VAMC CRS	Richmond	Virginia	United States	23249
78	Virginia Commonwealth Univ. Medical Ctr. CRS	Richmond	Virginia	United States
79	Hosp. de Clinicas Jose de San Martin, Div. Infectologia CRS	Ciudad de Buenos Aires	Buenos Aires	Argentina	1020
80	Hosp. Italiano de Buenos Aires, Infectious Diseases Section CRS	Ciudad de Buenos Aires	Buenos Aires	Argentina	1199
81	Hosp. Gen. de Agudos JM Ramos Mejia, Servicio de Inmunocomprometidos CRS	Ciudad de Buenos Aires	Buenos Aires	Argentina	1221
82	Hospital de Infecciosas F.J. Muniz CRS	Ciudad de Buenos Aires	Buenos Aires	Argentina	1282
83	Funcei Crs	Ciudad de Buenos Aires	Buenos Aires	Argentina	1425
84	Hosp. Gen. de Agudos Juan A. Fernandez CRS	Ciudad de Buenos Aires	Buenos Aires	Argentina	1425
85	Hosp. Gen. de Agudos 'Teodoro Alvarez' CRS	Ciudad de Buenos Aires	Buenos Aires	Argentina
86	Hospital Nacional Professor Alejandro Posadas CRS	El Palomar	Buenos Aires	Argentina	1706
87	Hospital Interzonal de Agudos Oscar Alende, Sala de Infectologia CRS	Mar del Plata	Buenos Aires	Argentina	7600
88	Caici Crs	Rosario	Provincia De Santa Fe	Argentina	2000
89	Hosp. Rawson CRS	Cordoba		Argentina	5000
90	Hosp. Interzonal de Agudos San Juan de Dios CRS	La Plata		Argentina	1900
91	Hosp. Central, Immunology Dept. CRS	Mendoza		Argentina	5500
92	Interchange General Practice CRS	Canberra	Australian Capital Territory	Australia	2601
93	Canberra Hosp., Canberra Sexual Health Clinic CRS	Woden	Australian Capital Territory	Australia	2606
94	Burwood Road Gen. Practice CRS	Burwood	New South Wales	Australia	2134
95	St. Vincent's Hospital CRS	Darlinghurst	New South Wales	Australia	2010
96	Taylor Square Private Clinic CRS	Darlinghurst	New South Wales	Australia	2010
97	Holdsworth House Gen. Practice CRS	Darlinghurst	New South Wales	Australia
98	John Hunter Hosp., Immunology & Infectious Diseases Unit CRS	Newcastle	New South Wales	Australia	2305
99	407 Doctors CRS	Surry Hills	New South Wales	Australia	2010
100	Albion Street Ctr. CRS	Surry Hills	New South Wales	Australia
101	Queensland Health - AIDS Med. Unit CRS	Brisbane	Queensland	Australia
102	Cairns Base Hosp., Sexual Health Services CRS	Cairns	Queensland	Australia	4870
103	Gladstone Road Medical Ctr. CRS	Highgate Hill	Queensland	Australia	4101
104	Nambour Gen. Hosp. CRS	Nambour	Queensland	Australia	4560
105	Royal Adelaide Hosp. CRS	Adelaide	South Australia	Australia	5000
106	The Care & Prevention Programme CRS	Adelaide	South Australia	Australia	5000
107	Carlton Clinic CRS	Carlton	Victoria	Australia
108	The Alfred Hosp., Clinical Research - Infectious Diseases Unit CRS	Melbourne	Victoria	Australia	3004
109	Prahran Market Clinic CRS	Melbourne	Victoria	Australia
110	Northcote Clinic CRS	Northcote	Victoria	Australia	3070
111	Royal Melbourne Hosp., Victorian Infectious Diseases Service CRS	Parkville	Victoria	Australia	3052
112	The Ctr. Clinic INSIGHT CRS	St. Kilda	Victoria	Australia
113	Royal Perth Hospital CRS	Perth	Western Australia	Australia
114	Gold Coast Sexual Health Clinic CRS	Miami, Queensland		Australia
115	Univ. of Vienna Med. School, Div. of Allergy, Immunology & Infectious Diseases - Sued B CRS	Vienna		Austria	A-1090
116	SMZ Baumgartner Hoehe, Immunambulanz Pavillion Wienerwald Parterre CRS	Wien		Austria	A-1140
117	Ctr. Hospitalier Universitaire, St Pierre, Div. of Infectious Diseases (PL5) CRS	Bruxelles		Belgium
118	Centro de Referencia e Treinamento em DST/AIDS - Sao Paulo CRS	Vila Mariana	Sao Paulo	Brazil	04121-000
119	Instituto de Infectologia Emilio Ribas CRS	Sao Paulo		Brazil	01246-900
120	Universidade Federal de Sao Paulo,IDIPA-Instituto Paulista de Doencas Infecciosas e Parasitarias CRS	Sao Paulo		Brazil	04040-002
121	Univ. of Alberta Hosp., Clinical Research Office CRS	Edmonton	Alberta	Canada
122	Cool Aid Community Health Ctr. CRS	Victoria	British Columbia	Canada
123	Q.E. II Health Sciences Ctr., Captial District Authority, Victoria Gen. Hosp. CRS	Halifax	Nova Scotia	Canada
124	McMaster Univ. Med. Ctr. Hamiton Health Sciences, SIS Clinic CRS	Hamilton	Ontario	Canada
125	St. Joseph's Health Ctr. of London, HIV Care Programme CRS	London	Ontario	Canada	N5Y 3H6
126	Ottawa Hosp., Gen. Campus CRS	Ottawa	Ontario	Canada	K1H 8L6
127	The HAVEN Program, Sudbury Regional Hosp., Laurentian Site CRS	Sudbury	Ontario	Canada	P3E 5J1
128	Toronto Gen. Hosp. Infectious Diseases CRS	Toronto	Ontario	Canada
129	Windsor Regional Hosp., HIV Care Program CRS	Windsor	Ontario	Canada
130	CHUS - Hopital Fleurimont, Centre de Recherche Clinique CRS	Fleurimont	Quebec	Canada	J1H 5N4
131	Hopital Maisonneuve-Rosemont, Dept. de Microbiologie CRS	Montreal	Quebec	Canada	H1T 2M4
132	CHUM - Campus Notre-Dame CRS	Montreal	Quebec	Canada	H2L 4M1
133	Royal Victoria Hosp., Montreal Chest Institute CRS	Montreal	Quebec	Canada
134	Centre Hospitalier Universitaire de Quebec - CHUL, Centre de Recherche en Indectiologie CRS	Sainte-Foy	Quebec	Canada
135	Royal Univ. Hosp. CRS	Saskatoon	Saskatchewan	Canada	S7N 0W8
136	Aalborg Hosp., Dept. of Infectious Diseases CRS	Aalborg		Denmark
137	Skejby Sygehus, Department of Infectious Diseases Q (ambulatoriet) CRS	Aarhus		Denmark	DK-8200
138	Rigshospitalet, Department of Infectious Diseases, M5112 CRS	Copenhagen		Denmark
139	Hvidovre Univ. Hosp., Dept. of Infectious Diseases CRS	Hvidovre		Denmark
140	Odense Univ. Hosp., Med. Dept. C CRS	Odense		Denmark
141	Centre Hospitalier de la Region Annecienne, Service des Maladie Infectieuses CRS	Cedex	Pringy	France
142	CHRU d'Angers, Service de Maladies Infectieuses CRS	Angers		France	49033
143	Hopital Saint-Jacques, Service des Maladies Infectieuses et Tropicales CRS	Besancon		France	25030
144	Hopital Avicenne, Service de Medecine B CRS	Bobigny		France	93009
145	Hopital Antoine Beclere Service d'Immunologie Clinique CRS	Clamart		France	92141
146	Hopital Louis Mourier, Service de Medecine Interne CRS	Colombes		France	92701
147	Hopital Henri Mondor, Immunopathologie Clinique CRS	Creteil		France	94010
148	Hopital Raymond Poincare - Vidal 2, Service des Maladies Infectieuses et Tropicales CRS	Garches		France	92380
149	Hopital de Bicetre, Service de Medecine Interne CRS	Le Kremlin-Bicetre		France	94275
150	Hopital Sainte Marguerite, CISIH Hopital de Jour CRS	Marseille		France	13009
151	Hopital de la Conception, Service des Maladies Infectieuses CRS	Marseille		France	13385
152	Hopital Gui de Chauliac, Service des Maladies Infectieuses et Tropicales CRS	Montpellier		France	34295
153	Hopital de l'Archet 1, Service de Medecine Interne 2 Hematologie Clinique CRS	Nice		France	06202
154	Hopital Saint-Antoine, Service de Maladies Infectieuses CRS	Paris		France	75012
155	Hopital de La Salpetriere, Service de Medecine Interne CRS	Paris		France	75651
156	Hopital Cochin, Service de Medecine Interne 2 CRS	Paris		France	75674
157	Hopital Necker, Service des Maladies Infectieuses CRS	Paris		France	75743
158	Hopital Europeen Georges Pompidou, Service d'Immunologie Clinique CRS	Paris		France	75908
159	Hopital Tenon, Service de Maladies Infectieuses et Tropicales CRS	Paris		France	75970
160	C.H.U. Bichat - Claude Bernard Service des Maladies Infectieuses et Tropicales CRS	Paris		France
161	CHRU de Strasbourg (France) CRS	Strasbourg		France	67091
162	Hopital Foch, Service de Medecine Interne CRS	Suresenes		France	92151
163	Univ. Hosp. Charite, Dept of Infectious Diseases CRS	Berlin		Germany	13353
164	Ruhr-Univ., Interdiszipl. Immunolog. Ambulanz CRS	Bochum		Germany
165	Medizinische Universitaetsklinik - Bonn, Immunologische Ambulanz CRS	Bonn		Germany	53105
166	Ctr. for HIV & Hepatogastroenterology, HIV Specialised Practice (Private Practice) CRS	Duesseldorf		Germany	40237
167	Johann Wolfgang Goethe Univ. Hosp., Infektionsambulanz CRS	Frankfurt		Germany	60590
168	IPM Study Ctr. (Hamburg) CRS	Hamburg		Germany
169	Univ. Hosp. Heidelberg, Dept. of Dermatology CRS	Heidelberg		Germany	69115
170	Klinik I fur Innere Medizin der Universitat zu Koln, Studienburo fur Infektiologie u. HIV CRS	Koln		Germany
171	Klinikum Innenstadt, Infektionsambulanz und Tagesklinik CRS	Munchen		Germany
172	Univ. of Wuerzburg, Medizinische Poliklinik, Schwerpunkt Hepatologie/Infektiologie CRS	Wuerzburg		Germany
173	St. James' Hosp., Guide Clinic CRS	Dublin		Ireland
174	Rambam Med. Ctr., Immunology, Allergy & AIDS Institute, B. Rappaport Faculty of Medicine, Technion	Haifa		Israel	31096
175	Kaplan Med. Ctr., Ben Ari Institute of Clinical Immunology CRS	Rehovot		Israel
176	Tel Aviv Sourasky Med. Ctr., Clinical Immunology Unit and AIDS Ctr. CRS	Tel Aviv		Israel	64239
177	Civili di Brescia, 1st Division of Infectious Diseases CRS	Brescia		Italy	25123
178	Civili di Brescia, Dept of Infectious & Tropical Disease, Hosp.Spedali Civili of Brescia CRS	Brescia		Italy	25123
179	Ospedale S. Maria Annunziata, U.O. Malattie Infettive CRS	Firenze		Italy	50011
180	Ospedale San Raffaele, Centro San Luigi - Divisione Malattie Infettive CRS	Milano		Italy
181	Univ. of Milan, Ospedale Luigi Sacco, Institute of Infectious and Tropical Diseases CRS	Milano		Italy
182	Universita degli Studi di Modena e Reggio Emilia, Clinica delle Malattie Infettive e Tropicali CRS	Modena		Italy
183	San Matteo Hospital - University of Pavia, Division of Infectious and Tropical Diseases CRS	Pavia		Italy	27100
184	Universita La Sapienza, Clinica Universita La Sapienza CRS	Roma		Italy	00185
185	Osaka National Hosp. AIDS Ctr., Clinical Research Institute CRS	Osaka		Japan
186	International Med. Ctr. of Japan CRS	Tokyo		Japan
187	Univ. of Tokyo, Research Hosp. of the Institute of Medical Science CRS	Tokyo		Japan
188	Univ. Hosp. Ctr. of the Med. School of Casablanca, Infectious Diseases Unit CRS	Casablanca		Morocco
189	OLVG -- locatie Prinsengracht, Dept. of Internal Medicine II CRS	Amsterdam		Netherlands	1017 JZ
190	Academisch Medisch Centrum CRS	Amsterdam		Netherlands	1150 AZ
191	Stichting Medisch Centrum Jan van Goyen, Dept. of Internal Medicine CRS	Amsterdam		Netherlands
192	Groningen Univ. Hosp., Department of Internal Medicine CRS	Groningen		Netherlands	9713 GZ
193	Kennemer Gasthuis, Lokatie EG CRS	Haarlem		Netherlands
194	St. Elisabeth Ziekenhuis CRS	Tilburg		Netherlands
195	Ulleval Hosp., Dept. of Infectious Diseases CRS	Oslo		Norway
196	Szpital Specjalistyczny, Osrodek Diagnostyki i Terapii AIDS CRS	Chorzow		Poland	41-500
197	Pomeranian Academy of Medicine (PAM), Dept. of Infectious Diseases and Hepatology CRS	Szczecin		Poland	71-455
198	Wojewodzki Szpital Zakazny CRS	Warsaw		Poland	01-201
199	Wroclaw Univ., School of Med., Dept. of Infectious Diseases, Liver Diseases and AIDS CRS	Wroclaw		Poland	51-171
200	Hospital de Cascais, HDDI, Departamento Medicina Interna CRS	Cascais		Portugal	2775
201	Hosp. de Egas Moniz, Servicio de Infecciologia e Medicina Tropical CRS	Lisboa		Portugal	1349-019
202	Hosp. de Santa Maria, Servico de Doencas Infecciosas CRS	Lisboa		Portugal
203	Tan Tock Seng Hosp., Infectious Diseases Research Ctr. CRS	Singapore		Singapore	308433
204	Hosp. Donostia CRS	San Sebastian	Guipuzcoa	Spain	E-20011
205	Hosp. Juan Canalejo, Dept. of Internal Medicine CRS	A Coruna		Spain
206	Hosp. Santa Creu i Sant Pau, Servicio de Medicina Interna CRS	Barcelona		Spain	E-08025
207	Hosp. Clinico de Barcelona CRS	Barcelona		Spain	E-08036
208	Hosp. del Mar, Internal Medicine-Infectious Diseases CRS	Barcelona		Spain
209	Hosp. Universitari Germans Trias i Pujol, HIV Unit and Retrovirology Lab. CRS	Barcelona		Spain
210	Hosp. Universitario Gregorio Maranion, Microbiology & Infectious Diseases Unit CRS	Madrid		Spain	E-28007
211	Centro de Investigacion Carlos III, Infectious Diseases Dept. CRS	Madrid		Spain	E-28029
212	Hosp. Severo Ochoa, Internal Medicine and Infectious Diseases CRS	Madrid		Spain	E-28911
213	Hosp. 12 de Octubre, Pabellon de Medicina Communitaria CRS	Madrid		Spain
214	Hosp. Clinico San Carlos CRS	Madrid		Spain
215	Hosp. la Princesa, Internal Medicine and Infectious Diseases Service CRS	Madrid		Spain
216	Hosp. Ramon y Cajal (Madrid) CRS	Madrid		Spain
217	Hosp. Universitario La Paz CRS	Madrid		Spain
218	Hosp. Universitario Principe de Asturias CRS	Madrid		Spain
219	Hosp. Universitario Morales Meseguer CRS	Murcia		Spain
220	Hosp. Virgen del Rocio, Infectious Diseases Service CRS	Sevilla		Spain	E-41013
221	Karolinska Univ. Hosp. Huddinge, Dept. of Infectious Diseases CRS	Stockholm		Sweden	SE-141 86
222	Venhalsan, Soder Hosp., Dept. of Infectious Diseases, Karolinska Univ. Hosp. CRS	Stockholm		Sweden
223	Regional Hosp. of Lugano (Sede Civico), Ospedale Civico di Lugano, Infectious Diseases Unit CRS	Lugano	Ticino	Switzerland	CH-6903
224	Siriraj Hosp., Mahidol Univ. INSIGHT CRS	Bangkok	Ratchathewi	Thailand	10700
225	Chulalongkorn Univ. Hosp., HIV-NAT Research Collaboration CRS	Bangkok	Ratchathewi	Thailand
226	Chiang Rai Regional Hosp. INSIGHT CRS	Chiangrai		Thailand
227	Chonburi Regional Hosp., Dept. of Internal Medicine CRS	Chonburi		Thailand
228	Khon Kaen Univ., Srinagarind Hosp., Div. of Infectious Diseases & Tropical Medicine, Dept. of Medici	Khon Kaen		Thailand	40002
229	Brighton & Sussex Univ. Hosp. NHS Trust, HIV Research Office CRS	Elm Grove	Brighton	United Kingdom	BN2 1ES
230	Royal Victoria Hosp. Dept. of Genitourinary Medicine CRS	Belfast	Northern Ireland	United Kingdom
231	Churchill Hosp. John Warin Ward CRS	Headington	Oxford	United Kingdom	OX3 9DU
232	Western Gen. Hosp., Regional Infectious Diseases Unit CRS	Edinburgh	Scotland	United Kingdom
233	Gartnaval Gen. Hosp., Brownlee Ctr. CRS	Glasgow	Scotland	United Kingdom
234	Heartlands Hosp. Dept. of Infection & Tropical Disease Outpatients CRS	Birmingham		United Kingdom	B9 5ST
235	Royal Devon & Exeter NHS Foundation Trust, Heavitree Hosp., Dept. of GU Medicine CRS	Exeter		United Kingdom	EX1 2ED
236	Leicester Royal Infirmary, Dept. of Infection & Tropical Medicine CRS	Leicester		United Kingdom	LE1 5WW
237	Royal London Hosp., Ambrose King Ctr. CRS	London		United Kingdom	E1 1BB
238	St. Thomas' Hosp., Dept. of GU Medicine CRS	London		United Kingdom	SE1 7EH
239	St. George's Hosp. Clinical Infection UnitCRS	London		United Kingdom	SW17 0RE
240	Chelsea & Westminster Hosp., St. Stephens Ctr. CRS	London		United Kingdom
241	King's College Hosp., Caldecot Ctr. Dept. of Sexual Health CRS	London		United Kingdom
242	Royal Free Hosp., Dept. of Infection & Immunity, Ian Charleson Day Ctr. CRS	London		United Kingdom
243	St. Bartholomew's Hosp., Infection & Immunity Clinical Group CRS	London		United Kingdom
244	St. Mary's Hosp. of London, Imperial College School of Medicine CRS	London		United Kingdom
245	Univ. College London Med. School, Ctr. for Sexual Health & HIV Research CRS	London		United Kingdom
246	Newcastle Gen. Hosp., Dept of Infection & Tropical Medicine CRS	Newcastle Upon Tyne		United Kingdom	NE4 6BE
247	Edith Cavell Hosp. Dept. of Sexual Health, Clinic E CRS	Peterborough		United Kingdom
248	Royal Hallamshire Hosp., Dept. of GU Medicine Communicable Diseases Unit CRS	Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Chiron Corporation

Investigators

• Study Chair: Donald Abrams, MD, University of California, San Francisco
• Study Chair: Marcelo Losso, MD, Hospital Jose Maria Ramos Mejia, Buenos Aires, Argentina

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the ESPRIT International IL-2 Study for HIV-infected Persons Web Site

Publications

• Chun TW, Engel D, Mizell SB, Hallahan CW, Fischette M, Park S, Davey RT Jr, Dybul M, Kovacs JA, Metcalf JA, Mican JM, Berrey MM, Corey L, Lane HC, Fauci AS. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med. 1999 Jun;5(6):651-5.
• Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, Metcalf JA, Walker RE, Falloon J, Baseler M, Feuerstein I, Masur H, Lane HC. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med. 1997 May;3(5):533-40.
• Emery S, Abrams DI, Cooper DA, Darbyshire JH, Lane HC, Lundgren JD, Neaton JD; ESPRIT Study Group. The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT. Control Clin Trials. 2002 Apr;23(2):198-220.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00004978
• Other Study ID Numbers: ESPRIT 001; 5U01AI046957; 00 I-0071; 3U01AI046957-05S2; 3U01AI046957-05S3; 10118; NCT00004737
• First Posted: Aug 31, 2001
• Last Update Posted: Nov 5, 2021
• Last Verified: Oct 1, 2012

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Recombinant Proteins; Injections, Subcutaneous; HIV-1; Interleukin-2; Drug Therapy, Combination; CD4 Lymphocyte Count; Disease Progression; Follow-Up Studies; Anti-HIV Agents
• Additional relevant MeSH terms: Infections; Aldesleukin; Interleukin-2

Study Results

Participant Flow

Recruitment Details	Patients were enrolled to ESPRIT between 2000 and 2003. As per the ESPRIT protocol, patients from previous Vanguard studies (in Thailand, Argentina, and the U.S., enrolled 1997-1999) were followed and included in the analysis cohort of this study if at least 90% of patients from that site consented to ESPRIT.

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Period Title: Overall Study
STARTED	2090	2060
COMPLETED	1846	1790
NOT COMPLETED	244	270

Baseline Characteristics

Arm/Group Title	rIL-2	No rIL-2	Total
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication	Total of all reporting groups
Overall Participants	2090	2060	4150
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2071 99.1%	2032 98.6%	4103 98.9%
>=65 years	19 0.9%	28 1.4%	47 1.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.8 (8.8)	40.9 (9.1)	40.8 (9.0)
Sex: Female, Male (Count of Participants)
Female	388 18.6%	381 18.5%	769 18.5%
Male	1702 81.4%	1679 81.5%	3381 81.5%
Region of Enrollment (participants) [Number]
Argentina	276 13.2%	278 13.5%	554 13.3%
Australia	107 5.1%	98 4.8%	205 4.9%
Austria	16 0.8%	18 0.9%	34 0.8%
Belgium	39 1.9%	41 2%	80 1.9%
Brazil	48 2.3%	50 2.4%	98 2.4%
Canada	74 3.5%	67 3.3%	141 3.4%
Denmark	39 1.9%	33 1.6%	72 1.7%
France	86 4.1%	96 4.7%	182 4.4%
Germany	136 6.5%	130 6.3%	266 6.4%
Ireland	3 0.1%	1 0%	4 0.1%
Israel	31 1.5%	33 1.6%	64 1.5%
Italy	50 2.4%	54 2.6%	104 2.5%
Japan	14 0.7%	11 0.5%	25 0.6%
Morocco	12 0.6%	14 0.7%	26 0.6%
Netherlands	29 1.4%	25 1.2%	54 1.3%
Norway	3 0.1%	5 0.2%	8 0.2%
Poland	48 2.3%	52 2.5%	100 2.4%
Portugal	51 2.4%	56 2.7%	107 2.6%
Singapore	10 0.5%	10 0.5%	20 0.5%
Spain	151 7.2%	157 7.6%	308 7.4%
Sweden	4 0.2%	3 0.1%	7 0.2%
Switzerland	5 0.2%	5 0.2%	10 0.2%
Thailand	182 8.7%	183 8.9%	365 8.8%
United Kingdom	165 7.9%	163 7.9%	328 7.9%
United States	511 24.4%	477 23.2%	988 23.8%
CD4+ cell count (cells/mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm^3]	465	451	458

Outcome Measures

1. Primary Outcome

Title	New or Recurrent HIV Disease Progression Event Including Death
Description	Participants who die or experience at least one: any CDC Category C 1993 AIDS-defining events or one of the following: invasive aspergillosis, bartonellosis, Chagas disease, Herpes zoster, visceral Leishmaniasis, Hodgkin's lymphoma, non-Hodgkin's lymphoma (all cell types), microsporidiosis, nocardiosis, disseminated Penicillium marneffii, extrapulmonary Pneumocystis carinii, and Rhodococcus equi disease
Time Frame	from randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2071	2040
Number [participants]	159 7.6%	165 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.55
	Comments	P-value is 2-sided using an alpha of .05.
	Method	Regression, Cox
	Comments	Hazard ratio is from unadjusted proportional hazards regression model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is for rIL-2 vs control.

2. Secondary Outcome

Title	New or Recurrent Serious HIV Disease Progression Event Including Death
Description	Patients with at least one: progressive multifocal leukoencephalopathy, lymphoma, visceral Kaposi's sarcoma, AIDS dementia complex, toxoplasmosis, histoplasmosis, cryptococcosis, Mycobacterium avium complex, wasting syndrome, and cytomegalovirus disease.
Time Frame	from randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2071	2040
Number [participants]	126 6%	130 6.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.62
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants Who Died From Any Cause
Time Frame	from randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2071	2040
Number [participants]	107 5.1%	116 5.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.42
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Participants With a New Disease Progression Event or Death
Description	Includes first new episode of: CDC Category C 1993 AIDS-defining events plus invasive aspergillosis, bartonellosis, Chagas disease, Herpes zoster, visceral Leishmaniasis, Hodgkin's lymphoma, non-Hodgkin's lymphoma (all cell types), microsporidiosis, nocardiosis, disseminated Penicillium marneffii, extrapulmonary Pneumocystis carinii, and Rhodococcus equi disease
Time Frame	from randomization through 15 November 2008 - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2071	2040
Number [participants]	154 7.4%	164 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.41
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Absolute CD4 Cell Counts Averaged Throughout Followup
Description	Average of all available CD4+ cell counts measured at follow-up visits
Time Frame	from randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

CD4+ cell counts averaged over all participants with at least one CD4+ measurement recorded during follow-up.

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2053	2024
Mean (Standard Deviation) [cells/mm^3]	715.4 (273.1)	556.3 (193.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	159
	Confidence Interval	(2-Sided) 95%; 145 to 174
	Parameter Dispersion	Type: Value:
	Estimation Comments	treatment difference (rIL2 - no rIL2) estimated from a longitudinal model that considers CD4+ measured at followup visits

6. Secondary Outcome

Title	Plasma HIV RNA Levels
Description	log10 HIV-RNA averaged throughout follow-up
Time Frame	From randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

HIV-RNA measurement averaged over followup visits for all participants with at least one follow-up measurement.

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2065	2036
Mean (Standard Deviation) [log10 HIV-RNA]	2.20 (0.65)	2.17 (0.61)

7. Secondary Outcome

Title	Number of Participants With Changes in Anti-retroviral Treatment (ART)
Description	Number of participants who changed ART at least once during the study period.
Time Frame	From randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2071	2040
Number [participants]	1760 84.2%	1751 85%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.07
	Comments
	Method	Regression, Cox
	Comments	Hazard ratio (rIL-2 vs. no rIL-2) for first change in antiretroviral treatment.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Grade 4 Signs and Symptoms
Description	Participants with at least one grade 4 sign or symptom (except those limited to a laboratory measurement), other than AIDS-defining conditions. Events were graded according to a standardized toxicity table. Events not specifically contained in the toxicity table were considered Grade 4 if they resulted in extreme limitation in activity or required significant medical intervention/therapy, hospitalization or hospice care. Grade 4 events by type are given under the adverse events section.
Time Frame	From randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2071	2040
Number [Participants]	466 22.3%	383 18.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.003
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 1.07 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR (IL-2 vs control) for first grade 4 event, ITT analysis.

9. Secondary Outcome

Title	Pattern of Use of Prophylaxis for Opportunistic Infections
Description	Number of participants using pneumocystis pneumonia (PCP) prophylaxis at the last attended followup visit.
Time Frame	last followup visit - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT) - Medication use recorded on the last followup visit attended among all participants attending at least one followup visit.

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2028	2005
Number [participants]	54 2.6%	53 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.97
	Comments
	Method	Chi-squared
	Comments

10. Secondary Outcome

Title	Hepatic, Metabolic, and Cardiac Conditions
Description	Number of participants experiencing a "serious non-AIDS" event defined as first serious cardiovascular, renal, or hepatic event, or non-AIDS malignancy.
Time Frame	From randomization through study end - median of 7.6 years follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rIL-2	No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy	Control group - no study-assigned medication
Measure Participants	2071	2040
Number [participants]	134 6.4%	136 6.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rIL-2, No rIL-2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.74
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Grade 4 events were reportable from randomization through study end (15 November 2008), irrespective of whether patient was taking a study treatment.
Adverse Event Reporting Description	Adverse events are grade 4 events (excluding AIDS-defining events and events limited to abnormal laboratory values), reportable in both treatment arms. All grade 4 events are included under "serious adverse events", categorized according to MedDRA HLGT. Common adverse events of any grade are reported under "other adverse events" by MedDRA PT.
Arm/Group Title	rIL-2		No rIL-2
Arm/Group Description	Subcutaneous recombinant interleukin-2 (rIL-2) therapy		Control group - no study-assigned medication
All Cause Mortality
	rIL-2		No rIL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	rIL-2		No rIL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	466/2071 (22.5%)		383/2040 (18.8%)
Blood and lymphatic system disorders
Anaemias nonhaemolytic and marrow depression	7/2071 (0.3%)		9/2040 (0.4%)
Platelet disorders	1/2071 (0%)		3/2040 (0.1%)
Spleen, lymphatic, and reticuloendothelial system disorders	3/2071 (0.1%)		1/2040 (0%)
White blood cell disorders	0/2071 (0%)		5/2040 (0.2%)
Cardiac disorders
cardiac arrhythmias	6/2071 (0.3%)		4/2040 (0.2%)
cardiac valve disorders	3/2071 (0.1%)		0/2040 (0%)
Coronary artery disorders	41/2071 (2%)		46/2040 (2.3%)
Heart failures	6/2071 (0.3%)		0/2040 (0%)
Myocardial disorders	0/2071 (0%)		2/2040 (0.1%)
Pericardial disorders	2/2071 (0.1%)		1/2040 (0%)
Congenital, familial and genetic disorders
Muscuoloskeletal and connective tissue disorders congenital	1/2071 (0%)		0/2040 (0%)
Ear and labyrinth disorders
Inner ear and VIIIth cranial nerve disorders	2/2071 (0.1%)		0/2040 (0%)
Middle ear disorders (excl congenital)	1/2071 (0%)		0/2040 (0%)
Endocrine disorders
Adrenal gland disorders	1/2071 (0%)		0/2040 (0%)
Thyroid gland disorders	5/2071 (0.2%)		2/2040 (0.1%)
Eye disorders
Ocular infections, irritations and inflammations	2/2071 (0.1%)		0/2040 (0%)
Ocular neuromuscular disorders	0/2071 (0%)		1/2040 (0%)
Ocular structural change, deposit and degeneration NEC	1/2071 (0%)		2/2040 (0.1%)
Vision disorders	1/2071 (0%)		0/2040 (0%)
Gastrointestinal disorders
Abdominal hernias and other abdominal wall conditions	3/2071 (0.1%)		6/2040 (0.3%)
Anal and rectal conditions NEC	1/2071 (0%)		5/2040 (0.2%)
Benign neoplasms gastrointestinal	1/2071 (0%)		0/2040 (0%)
Diverticular disorders	1/2071 (0%)		1/2040 (0%)
Exocrine pancreas conditions	8/2071 (0.4%)		11/2040 (0.5%)
Gastrointestinal conditions NEC	0/2071 (0%)		2/2040 (0.1%)
Gastrointestinal haemorrhages NEC	8/2071 (0.4%)		9/2040 (0.4%)
Gastrointestinal inflammatory conditions	1/2071 (0%)		3/2040 (0.1%)
Gastrointestinal motility and defaecation conditions	11/2071 (0.5%)		9/2040 (0.4%)
Gastrointestinal signs and symptoms	15/2071 (0.7%)		13/2040 (0.6%)
Gastrointestinal stenosis and obstruction	2/2071 (0.1%)		2/2040 (0.1%)
Gastrointestinal ulceration and perforation	5/2071 (0.2%)		1/2040 (0%)
Gastrointestinal vascular conditions	2/2071 (0.1%)		2/2040 (0.1%)
Peritoneal and retroperitoneal conditions	0/2071 (0%)		3/2040 (0.1%)
General disorders
Administration site reactions	0/2071 (0%)		1/2040 (0%)
Body temperature conditions	15/2071 (0.7%)		4/2040 (0.2%)
General system disorders NEC	17/2071 (0.8%)		6/2040 (0.3%)
Therapeutic and nontherapeutic effects (excl toxicity)	1/2071 (0%)		0/2040 (0%)
Tissue disorders NEC	2/2071 (0.1%)		0/2040 (0%)
Hepatobiliary disorders
Bile duct disorders	3/2071 (0.1%)		1/2040 (0%)
Gallbladder disorders	10/2071 (0.5%)		10/2040 (0.5%)
Hepatic and hepatobiliary disorders	13/2071 (0.6%)		8/2040 (0.4%)
Immune system disorders
Allergic conditions	3/2071 (0.1%)		2/2040 (0.1%)
Immune disorders NEC	1/2071 (0%)		1/2040 (0%)
Infections and infestations
Bacterial infectious disorders	20/2071 (1%)		17/2040 (0.8%)
Fungal infectious disorders	3/2071 (0.1%)		0/2040 (0%)
Infections - pathogen unspecified	47/2071 (2.3%)		42/2040 (2.1%)
Mycobacterial infectious disorders	1/2071 (0%)		1/2040 (0%)
Protozoal infectious disorders	0/2071 (0%)		1/2040 (0%)
Viral infectious disorders	19/2071 (0.9%)		18/2040 (0.9%)
Injury, poisoning and procedural complications
Bone and joint injuries	15/2071 (0.7%)		8/2040 (0.4%)
Chemical injury and poisoning	4/2071 (0.2%)		4/2040 (0.2%)
Injuries NEC	9/2071 (0.4%)		13/2040 (0.6%)
Medication errors	5/2071 (0.2%)		1/2040 (0%)
Procedural and device related injuries and complications NEC	1/2071 (0%)		1/2040 (0%)
Investigations
Enzyme investigations NEC	1/2071 (0%)		0/2040 (0%)
Gastrointestinal investigations	1/2071 (0%)		0/2040 (0%)
Haematology investigations (incl blood groups)	1/2071 (0%)		3/2040 (0.1%)
Hepatobiliary investigations	6/2071 (0.3%)		1/2040 (0%)
Lipid analyses	1/2071 (0%)		0/2040 (0%)
Metabolic, nutritional and blood gas investigations	1/2071 (0%)		0/2040 (0%)
Physical examination topics	2/2071 (0.1%)		0/2040 (0%)
Renal and urinary tract investigations and urinalyses	1/2071 (0%)		0/2040 (0%)
Metabolism and nutrition disorders
Acid-base disorders	3/2071 (0.1%)		3/2040 (0.1%)
Electrolyte and fluid balance conditions	2/2071 (0.1%)		4/2040 (0.2%)
Glucose metabolism disorders (incl diabetes mellitus)	6/2071 (0.3%)		5/2040 (0.2%)
Lipid metabolism disorders	2/2071 (0.1%)		0/2040 (0%)
Diabetic complications	1/2071 (0%)		0/2040 (0%)
Musculoskeletal and connective tissue disorders
Bone disorders (excl congenital and fractures)	3/2071 (0.1%)		5/2040 (0.2%)
Connective tissue disorders (excl congenital)	1/2071 (0%)		0/2040 (0%)
Fractures	3/2071 (0.1%)		0/2040 (0%)
Joint disorders	4/2071 (0.2%)		4/2040 (0.2%)
Muscle disorders	1/2071 (0%)		4/2040 (0.2%)
Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders)	2/2071 (0.1%)		5/2040 (0.2%)
Musculoskeletal and connective tissue disorders NEC	2/2071 (0.1%)		6/2040 (0.3%)
Synovial and bursal disorders	0/2071 (0%)		1/2040 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast neoplasms malignant and unspecified (incl nipple)	1/2071 (0%)		5/2040 (0.2%)
Endocrine neoplasms benign	1/2071 (0%)		1/2040 (0%)
Endocrine neoplasms malignant and unspecified	1/2071 (0%)		3/2040 (0.1%)
Gastrointestinal neoplasms benign	1/2071 (0%)		0/2040 (0%)
Gastrointestinal neoplasms malignant and unspecified	20/2071 (1%)		8/2040 (0.4%)
Haematopoietic neoplasms (excl leukaemias and lymphomas)	2/2071 (0.1%)		1/2040 (0%)
Hepatic and biliary neoplasms benign	1/2071 (0%)		0/2040 (0%)
Hepatobiliary neoplasms malignant and unspecified	1/2071 (0%)		3/2040 (0.1%)
Leukaemias	1/2071 (0%)		1/2040 (0%)
Metastases	1/2071 (0%)		1/2040 (0%)
Miscellaneous and site unspecified neoplasms benign	1/2071 (0%)		0/2040 (0%)
Miscellaneous and site unspecified neoplasms malignant and unspecified	6/2071 (0.3%)		9/2040 (0.4%)
Renal and urinary tract neoplasms malignant and unspecified	0/2071 (0%)		2/2040 (0.1%)
Reproductive neoplasms female benign	4/2071 (0.2%)		5/2040 (0.2%)
Reproductive neoplasms female malignant and unspecified	3/2071 (0.1%)		1/2040 (0%)
Reproductive neoplasms male malignant and unspecified	1/2071 (0%)		4/2040 (0.2%)
Respiratory and mediastinal neoplasms malignant and unspecified	8/2071 (0.4%)		8/2040 (0.4%)
Skin neoplasms malignant and unspecified	9/2071 (0.4%)		4/2040 (0.2%)
Soft tissue neoplasms benign	1/2071 (0%)		1/2040 (0%)
Soft tissue sarcomas	0/2071 (0%)		1/2040 (0%)
Nervous system disorders
Central nervous system infections and inflammations	1/2071 (0%)		0/2040 (0%)
Central nervous system vascular disorders	16/2071 (0.8%)		11/2040 (0.5%)
Cranial nerve disorders (excl neoplasms)	2/2071 (0.1%)		0/2040 (0%)
Demyelinating disorders	1/2071 (0%)		0/2040 (0%)
Encephalopathies	1/2071 (0%)		2/2040 (0.1%)
Headaches	5/2071 (0.2%)		6/2040 (0.3%)
Increased intracranial pressure and hydrocephalus	1/2071 (0%)		0/2040 (0%)
Movement disorders (incl parkinsonism)	3/2071 (0.1%)		0/2040 (0%)
Neurological disorders NEC	9/2071 (0.4%)		12/2040 (0.6%)
Neuromuscular disorders	2/2071 (0.1%)		0/2040 (0%)
Peripheral neuropathies	2/2071 (0.1%)		4/2040 (0.2%)
Seizures (incl subtypes)	8/2071 (0.4%)		4/2040 (0.2%)
Spinal cord and nerve root disorders	1/2071 (0%)		0/2040 (0%)
Structural brain disorders	1/2071 (0%)		1/2040 (0%)
Pregnancy, puerperium and perinatal conditions
Abortions and stillbirth	3/2071 (0.1%)		1/2040 (0%)
Foetal complications	0/2071 (0%)		1/2040 (0%)
Maternal complications of pregnancy	1/2071 (0%)		1/2040 (0%)
Postpartum and puerperal disorders	1/2071 (0%)		0/2040 (0%)
Psychiatric disorders
Anxiety disorders and symptoms	4/2071 (0.2%)		1/2040 (0%)
Deliria (incl confusion)	0/2071 (0%)		1/2040 (0%)
Depressed mood disorders and disturbances	13/2071 (0.6%)		9/2040 (0.4%)
Disturbances in thinking and perception	1/2071 (0%)		0/2040 (0%)
Eating disorders and disturbances	0/2071 (0%)		1/2040 (0%)
Impulse control disorders NEC	0/2071 (0%)		1/2040 (0%)
Manic and bipolar mood disorders and disturbances	2/2071 (0.1%)		0/2040 (0%)
Mood disorders and disturbances NEC	1/2071 (0%)		1/2040 (0%)
Personality disorders and disturbances in behaviour	0/2071 (0%)		1/2040 (0%)
Psychiatric disorders NEC	3/2071 (0.1%)		5/2040 (0.2%)
Schizophrenia and other psychotic disorders	4/2071 (0.2%)		3/2040 (0.1%)
Suicidal and self-injurious behaviours NEC	18/2071 (0.9%)		10/2040 (0.5%)
Renal and urinary disorders
Bladder and bladder neck disorders (excl calculi)	1/2071 (0%)		0/2040 (0%)
Nephropathies	1/2071 (0%)		1/2040 (0%)
Renal disorders (excl nephropathies)	9/2071 (0.4%)		10/2040 (0.5%)
Urethral disorders (excl calculi)	1/2071 (0%)		0/2040 (0%)
Urinary tract signs and symptoms	6/2071 (0.3%)		4/2040 (0.2%)
Urolithiases	3/2071 (0.1%)		5/2040 (0.2%)
Reproductive system and breast disorders
Breast disorders	0/2071 (0%)		1/2040 (0%)
Cervix disorders (excl infections and inflammations)	2/2071 (0.1%)		3/2040 (0.1%)
Menstrual cycle and uterine bleeding disorders	1/2071 (0%)		1/2040 (0%)
Ovarian and fallopian tube disorders	1/2071 (0%)		0/2040 (0%)
Prostatic disorders (excl infections and inflammations)	1/2071 (0%)		0/2040 (0%)
Testicular and epididymal disorders	1/2071 (0%)		1/2040 (0%)
Uterine, pelvic and broad ligament disorders	3/2071 (0.1%)		1/2040 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchial disorders (excl neoplasms)	9/2071 (0.4%)		7/2040 (0.3%)
Lower respiratory tract disorders (excl obstruction and infection)	0/2071 (0%)		4/2040 (0.2%)
Pleural disorders	3/2071 (0.1%)		3/2040 (0.1%)
Pulmonary vascular disorders	6/2071 (0.3%)		5/2040 (0.2%)
Respiratory disorders NEC	8/2071 (0.4%)		6/2040 (0.3%)
Skin and subcutaneous tissue disorders
Angioedema and urticaria	1/2071 (0%)		0/2040 (0%)
Epidermal and dermal conditions	6/2071 (0.3%)		3/2040 (0.1%)
Skin and subcutaneous tissue disorders NEC	1/2071 (0%)		0/2040 (0%)
Skin appendage conditions	0/2071 (0%)		1/2040 (0%)
Social circumstances
Skin vascular abnormalities	0/2071 (0%)		1/2040 (0%)
Legal issues	0/2071 (0%)		1/2040 (0%)
Surgical and medical procedures
Hepatobiliary therapeutic procedures	0/2071 (0%)		1/2040 (0%)
Obstetric and gynaecological therapeutic procedures	0/2071 (0%)		2/2040 (0.1%)
Vascular disorders
Aneurysms and artery dissections	1/2071 (0%)		1/2040 (0%)
Arteriosclerosis, stenosis, vascular insufficiency and necrosis	6/2071 (0.3%)		2/2040 (0.1%)
Decreased and nonspecific blood pressure disorders and shock	5/2071 (0.2%)		0/2040 (0%)
Embolism and thrombosis	9/2071 (0.4%)		3/2040 (0.1%)
Vascular disorders NEC	2/2071 (0.1%)		0/2040 (0%)
Vascular haemorrhagic disorders	1/2071 (0%)		1/2040 (0%)
Vascular hypertensive disorders	6/2071 (0.3%)		3/2040 (0.1%)
Venous varices	0/2071 (0%)		1/2040 (0%)
Other (Not Including Serious) Adverse Events
	rIL-2		No rIL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	133/2071 (6.4%)		92/2040 (4.5%)
Blood and lymphatic system disorders
Anaemia	9/2071 (0.4%)		10/2040 (0.5%)
Cardiac disorders
Acute myocardial infarction	16/2071 (0.8%)		15/2040 (0.7%)
Coronary artery disease	12/2071 (0.6%)		9/2040 (0.4%)
Myocardial infarction	14/2071 (0.7%)		18/2040 (0.9%)
Gastrointestinal disorders
Diarrhoea	16/2071 (0.8%)		10/2040 (0.5%)
Vomiting	13/2071 (0.6%)		3/2040 (0.1%)
General disorders
Pyrexia	18/2071 (0.9%)		9/2040 (0.4%)
Infections and infestations
Appendicitis	10/2071 (0.5%)		8/2040 (0.4%)
Nervous system disorders
Cerebrovascular accident	12/2071 (0.6%)		4/2040 (0.2%)
Psychiatric disorders
Depression	14/2071 (0.7%)		7/2040 (0.3%)
Suicide attempt	11/2071 (0.5%)		10/2040 (0.5%)
Vascular disorders
Deep vein thrombosis	10/2071 (0.5%)		2/2040 (0.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.