This study will examine whether interleukin-2 (IL-2) plus antiretroviral therapy (ART) slows
HIV disease progression in patients with low CD4+ T cell counts compared with patients
taking ART alone. CD4+ T cells are a subset of lymphocytes-white blood cells that are part
of the body's immune system. IL-2 is a protein that is naturally produced by lymphocytes.
Given in intermittent cycles, IL-2 can raise CD4+ T cell counts in some HIV-infected
patients taking antiretroviral drugs. This study will examine whether the increase in CD4+ T
cells lowers the risk of AIDS-related illnesses and death.
HIV-infected patients 18 years of age and older with a viral load under 10,000 copies per
milliliter and a CD4+ T cell count between 50 and 299 cells per cubic millimeter who are
taking antiretroviral therapy and who have not previously received IL-2 therapy may be
eligible for this study. Candidates will be screened with a medical history, physical
examination, and blood and urine tests. Participation in the study will be from 4.5 to 6
years, depending on what point in the duration of the study the individual patient is
Patients will be randomly assigned to receive IL-2 plus ART or ART alone. All participants
will be advised individually about the best ART regimen for them. Patients in the IL-2
treatment group will be taught how to self-inject IL-2 under the skin (similar to insulin
injections). They will inject IL-2 twice a day for 5 days every 8 weeks for the first year
(until week 49 of the study). From week 49 on they may receive 5-day cycles of IL-2 every 4
months when needed to maintain CD4+ T cell count elevations. An extra cycle may be given 2
months after the week 49 follow-up visit (see follow-up schedule below), depending on their
CD4+ T cell count. Patients whose cell counts have not increased after 12 to 16 months of
IL-2 treatment will discuss with the doctor the possibility of stopping IL-2. Those who do
stop IL-2 treatment will be asked to remain in the study for follow-up evaluations.
All patients will be followed in the clinic every 2 months for the first year of the study
(weeks 1, 9, 17, 25, 33, 41 and 49) and every 4 months during years 2-6 for a brief history
and physical exam, urine and blood tests, return of diary cards (record of drug side
effects) and medication review. During the visits from the second year on, patients will
also be asked about their ability to do certain ordinary tasks, such as taking care of
The purpose of this study is to compare the clinical results of individuals living with
advanced HIV infection who are treated with interleukin-2 (IL-2) plus active antiretroviral
therapy (ART) to a control group of individuals treated with stable ART alone. The primary
objective of the study is to determine if intermittent cycles of IL-2 delay the occurrence
of opportunistic infections and the progression of advanced HIV disease compared to ART
Patients will be assigned randomly to 1 of 2 groups. Patients in Group 1 will receive
subcutaneous IL-2 twice a day for 5 days, every 8 weeks, in addition to ART. Patients in
Group 2 will receive ART only. In both groups, CD4+ T cell counts and viral load are
- INCLUSION CRITERIA:
Subjects are eligible for this study if they have been on greater than or equal to 2 ART
for greater than or equal to 4 months prior to randomization, with no change in the type
of ART received during this 4-month period of time. For subjects who receive only 2 ART,
at least one of these two medications should be a protease inhibitor (PI). Subjects are
not eligible if ART is discontinued for a cumulative period of 7 or more days during the 4
months prior to randomization.
Subjects with documented HIV-1 infection. Acceptable documentation consists of either of
Positive HIV-1 ELISA test and Western Blot;
Detectable plasma viral load measurement (greater than 500 RNA copies/mL using an
ultrasensitive bDNA or PCR test or greater than 1500 RNA copies/mL using a
non-ultrasensitive bDNA or PCR test).
CD4+ T cell counts: mean of 2 points obtained within 4 calendar months of randomization
greater than or equal to 50 and less than 300 cells/mm(3). The first CD4+ count should be
the most recent documented historical value and should be greater than or equal to 50 and
less than 300 cells/mm(3); the second point should be pre-study visit 1.
Viral load less than 10,000 copies/mL, at 2 time points within 4 calendar months of
randomization. The first viral load should be the most recent documented historical value
and should be less than 10,000 copies/mL; the second time point should be pre-study visit
Karnofsky performance status greater than or equal to 80%.
Age greater than or equal to 18 years old.
Women of childbearing potential must have a negative urine or serum pregnancy test within
28 days prior to randomization. They must also understand that if they are randomized to
the IL-2 group, they must practice effective contraception during their first 2 years of
study participation. Pregnancy is discouraged among IL-2 recipients, but if an IL-2
recipient wishes to become pregnant after two years of trial participation she must alert
the investigator prior to interruption of contraception. The potential for risk to the
fetus must be carefully discussed with the subject before contraception is interrupted.
Effective contraception will be continued for at least 24 hours following the interruption
of IL-2 therapy. IL-2 will be held throughout the period of time during which the subject
is not practicing effective birth control, throughout the pregnancy, and throughout any
period of breast feeding. If oral contraceptive therapy is resumed after a period of
interruption, IL-2 dosing will be delayed for 1 month following the reinstatement of oral
contraceptive therapy. The subject must have a negative pregnancy test result prior to
dosing with IL-2 after a lapse in effective contraception.
The following laboratory criteria must be fulfilled within 28 days of enrollment in the
Serum AST of less than or equal to 5 times upper limit of normal range (ULN);
Serum bilirubin less than or equal 2 times ULN (patients with Gilbert's syndrome or
protease inhibitor-induced hyperbilirubinemia must have a serum bilirubin less than or
equal to five times ULN);
Amylase less than 2.0 times ULN (hyperamylasemia that is determined to be non-pancreatic
in origin does not necessarily constitute an exclusion to enrollment);
Less than 2 + proteinuria;
Serum creatinine less than or equal to 1.5 times ULN;
Absolute neutrophil count greater than or equal to 1000 cells/mm(3);
Hemoglobin of greater than or equal to 9.5 g/dL;
Platelet count of greater than or equal to 75,000/mm(3);
Negative HTLV-1 result.
Agree to participate in the study for 4.5 to 7.5 years.
Written informed consent.
Certain AIDS-defining illnesses. These conditions include:
Patients with no prior history of AIDS-defining events are eligible for SILCAAT;
Patients with a prior medical history of one or more of the following AIDS-defining events
are eligible only under the condition specified below:
Lymphoma (other than lymphoma of the brain): Patients with a history of successfully
treated lymphoma are eligible, provided full remission was obtained at least 5 years prior
to randomization. Full remission (or complete response) is defined as the absence of
clinically detectable disease with normalization of any previously abnormal radiographic
studies, and bone marrow examination. Patients with bone marrow positive lymphoma prior
to chemotherapy must have had two repeat bone marrow examinations negative for lymphoma
after chemotherapy at least 12 months prior to randomization.
Esophageal candidiasis; Patients with a prior history of successfully treated esophageal
candidiasis are eligible if they have been free of clinical symptoms in the absence of
antifungal suppressive therapy for at least 12 months prior to randomization.
Documentation of a negative endoscopy should ideally be on record.
Invasive cervical cancer: Patients with a prior history of invasive cervical cancer are
eligible if complete local cure of the cancer has been documented at least 5 years prior
to randomization and there has been no evidence of metastatic disease at any time.
Kaposi's sarcoma: Patients are eligible if mucocutaneous lesions have been resolved or
clinically stable for at least 12 months prior to randomization. Subjects with a history
of visceral KS are excluded.
Mycobacterium tuberculosis or M. kansasii: Patients are eligible if clinical resolution
of disease occurred at least 12 months prior to randomization and previously abnormal
imaging studies have been normal, or stable after improvement, for at least 12 months
prior to randomization. Documentation of microbiologic cure should ideally be on record.
Therapy for tuberculosis or M. kansasii must have been completed at least 12 months prior
Pneumocystis carinii pneumonia (PCP): Patients are eligible if clinical resolution of the
disease occurred at least 12 months prior to randomization and previously abnormal imaging
studies have been normal, or stable after improvement, for at least 12 months prior to
Recurrent pneumonia: Patients are eligible if there has been no evidence of pneumonia
within 12 months prior to randomization.
Recurrent Salmonella septicemia: Patients are eligible if there has been no evidence of
Salmonella septicemia within 12 months prior to randomization.
Wasting syndrome due to HIV: Patients are eligible for enrollment in SILCAAT if they have
had a stable or increasing weight for at least 12 months prior to randomization.
Toxoplasmosis of the brain: Patients are eligible if their disease has been clinically
resolved for at least 12 months prior to randomization. In addition, these patients must
have a MRI or contrast CT scan of the brain performed within 1 month prior to
randomization showing no sign of active disease.
Chronic intestinal cryptosporidiosis and chronic intestinal isosporiasis (greater than 1
month duration): Patients are eligible if their disease has been clinically resolved and
they have been off specific therapy for at least 12 months prior to randomization. In
addition, these patients must have at least one stool specimen documenting clearance of
parasitic infection obtained within 1 month prior to randomization.
Patients with a history of any other AIDS-defining conditions as listed in the CDC 1993
Case Definition are not eligible for SILCAAT.
Subjects must not have clinically significant cardiac, pulmonary, thyroid, kidney or
neurologic impairment, hemostasis disorder, or significant medical condition that would,
in the opinion of the principal investigator, affect patient safety and/or compliance. In
addition, subjects with the following conditions are specifically excluded: autoimmune
disease, inflammatory bowel disease, psoriasis, optic neuritis, congestive heart failure,
active ischemic heart disease, uncontrolled diabetes mellitus, moderate or severe
hemophilia ( less than or equal to 5% of normal factor VIII levels), seizure disorder,
uncontrolled hypothyroidism, cirrhosis and a prior medical history of transplantation. If
an investigator has any reservations about the safety of enrolling a particular subject,
he/she should consult with the medical monitor prior to screening the subject.
Psychiatric or cognitive disturbance or illness, or recreational drug/alcohol use that, in
the opinion of the principal investigator, would affect patient safety and/or compliance.
Malignancy requiring systemic chemotherapy within 12 months prior to randomization.
Current use or use within 4 weeks prior to randomization of systemic corticosteroid
therapy or any agent, licensed or experimental, with known immunomodulatory effects (use
of erythropoietin and anabolic steroids is allowed).
Current use, or use within 4 weeks of randomization of cytotoxic agents or
antimetabolites; current use or use within 4 months of randomization of hydroxyurea or
Pregnant or lactating subjects.
Prior therapy with IL-2.
Prior participation in an ongoing IL-2 trial, eg, the ESPRIT trial.
Protocol non-compliance in a previous IL-2 trial.
Subjects with evidence of active acute infection within 2 weeks of randomization.