Interleukin-2 Plus Antiretroviral Therapy for HIV-Infected Patients With Low CD4+ Counts (SILCAAT Study)
Condition: HIV Infection
MeSH terms: HIV Infections
Intervention: Proleukin
Intervention description: Recombinant IL-2 was given at a dose of 4.5 MIU twice daily subcutaneously for 5 consecutive days every 8 weeks, in addition to antiretroviral therapy, for 6 cycles. After the first 6 cycles, additional cycles were given to either achieve or maintain the patient's CD4+ cell count goal.
Intervention MeSH terms: Aldesleukin; Interleukin-2
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1695.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV; Proleukin; IL-2; Adult; HAART; Treatment Experienced

Summary:

      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
      enrolled.

      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 themselves; ...
    

Eligibility criteria:

        -  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
        the following:

        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
        1.

        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
        study:

        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.

        EXCLUSION CRITERIA:

        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 to
        randomization.

        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
        randomization.

        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 intravenous
        immunoglobulin.

        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.