ACTG 853 Schema

SCHEMA FOR ACTG 853

TITLE:EFFECTS OF TREATMENT FOR MAC INFECTION ON CYTOKINE EXPRESSION IN HIV-INFECTED PERSONS

DESIGN: This study is a laboratory pilot to determine if successful treatment of MAC infection in HIV-1 infected persons is associated with decreases in serum levels of TNF-alpha, IL-1 and IL-6.

Blood and urine will be obtained from each subject at the following timepoints:

Pre-Entry (within 7 days prior to study entry but no more than 72 hours after initiation of MAC treatment);
Week 4 (after initiation of MAC treatment); and
Week 8 (after initiation of MAC treatment).

From the samples collected at each timepoint, sites will process and ship the following samples to Case Western Reserve University according to the instructions specified in Appendix II:

Plasma (frozen at -70°C within 4 hours of the blood draw) for the cytokine assay.
Supernatants of the 20-hour culture of whole blood and LPS (frozen at -70°C) for ex vivo induction of TNF-alpha, IL-1 and IL-6.
Plasma (frozen at -70°C) for viral load analysis.
Serum (frozen at -70°C) for neopterin analysis.
Serum (frozen at -70°C) for M. avium alpha antigen analysis.
Urine (frozen at -70°C) for M. avium alpha antigen analysis.

The following assays and analyses will be performed by CWRU:

Measurement of cytokine levels by ELISA (plasma samples assayed and analyzed in batch at a later time).
Measurement of TNF-alpha, IL-1 and IL-6 (supernatants of the 20-hour culture of whole blood and LPS assayed and analyzed in batch at a later time).
Measurement of viral load by bDNA (plasma samples assayed and analyzed in batch at a later time).
Measurement of neopterin (CWRU will arrange for the serum samples to be assayed and analyzed in batch at a later time).
Measurement of serum and urine M. avium alpha antigen (assayed and analyzed in batch at a later time).

At each timepoint, sites will also ship a whole blood sample to the NTM laboratory for quantitative MAC blood culture for subjects NOT co-enrolled in ACTG 223 ["A Phase II/III Prospective, Multicenter, Randomized, Controlled Trial Comparing the Safety and Efficacy of Three Clarithromycin-Containing Combination Drug Regimens for the Treatment of Disseminated Mycobacterium Avium Complex (MAC) Disease in Persons with AIDS"].

SAMPLE SIZE: 24 subjects

POPULATION : Subjects who have been diagnosed with MAC disease and will initiate at least a two-drug, clarithromycin-containing regimen for the treatment of MAC disease.

OBJECTIVES:

Primary

To determine if treatment of MAC infection in HIV-1 infected persons is associated with decreases in plasma levels of TNF-alpha.

Secondary

To determine if treatment of MAC infection in HIV-1 infected persons is associated with decreases in plasma levels of IL-1 and IL-6.

To determine if changes in mycobacterial load in blood in HIV-1 infected persons correlate with changes in plasma levels of TNF-alpha, IL-1, and IL-6.

To ascertain if treatment for MAC disease in HIV infection is associated with decreases in ex vivo induction of TNF-alpha, IL-6 and IL-1 using the whole blood culture technique.

To determine if changes in plasma levels of TNF-alpha, IL-1, and IL-6 in persons co-infected with HIV-1 and MAC correlate with changes in viral load, as determined by the bDNA assay

To determine if changes in ex vivo induction of TNF-alpha, IL-1 and IL-6 are correlated with changes in viral load, as determined by the bDNA assay.

To compare serum neopterin levels before and during treatment for MAC in persons co-infected with MAC and HIV-1.

To ascertain if treatment for MAC is associated with decreases in plasma levels of HIV-1 as determined by the bDNA assay.

To determine the utility and sensitivity of the serum and urine M. avium alpha antigen assays for diagnosis and during therapy.

SELECTION AND ENROLLMENT OF SUBJECTS:

Inclusion Criteria

Subjects must be willing to sign an informed consent. Subjects <18 years of age must have written informed consent from a parent or guardian.
Age > or =13 years.
HIV infection documented prior to study entry by the presence of antibody (ELISA with Western Blot confirmation), serum p24 antigen, recovery of HIV in culture, or a diagnosis of AIDS based on the 1987 CDC criteria.
Subjects must have either:
Symptomatic MAC disease as defined by a history of clinical signs and symptoms including one or more of the following: 1) fever > 38°C on > or = 2 days per week; 2) night sweats > or = 2 days per week; 3) weight loss of > 5% body weight in the 30 days preceding Entry as clinically assessed by the patient or investigator; 4) diarrhea with > 3 unformed stools per day on > or = 2 days per week; 5) hepatomegaly (clinically assessed by exam); 6) splenomegaly (clinically assessed by exam); 7) elevation of alkaline phosphatase of > or = 2x upper normal limit; 8) severe anemia (Hct <25).

- plus -
One blood culture positive for MAC or AFB obtained within the previous 90 days (processed by the site or other laboratory).

- or -
Subjects with symptomatic MAC disease, as previously defined, may be presumptively enrolled if they have a positive culture for MAC or AFB from another normally sterile body site (bone marrow, liver, lymph node, CSF) within the previous 90 days (processed by the site or other laboratory), and may remain on the study only if they have a baseline blood culture as processed by the NTM Laboratory which is also positive for MAC.

Asymptomatic MAC disease as defined by two blood cultures (at least 24 hours apart) positive for MAC or AFB obtained within 90 days of Entry (processed by the site or other laboratory).

Subjects with a negative baseline blood culture for MAC as processed by the NTM Laboratory will be discontinued from the study.
Karnofsky performance status score > or = 40.
This protocol is targeted for subjects receiving initial treatment of MAC disease. Subjects who have received presumptive or empiric antimycobacterial therapy prior to study entry may be enrolled if they have been treated for no more than 72 hours prior to study entry.

Subjects who have been receiving prophylaxis with azithromycin, clarithromycin and/or rifabutin may be enrolled. No wash-out for previous prophylaxis will be required.
Laboratory values (to be obtained within 14 days before study entry): Absolute neutrophil count > 500/mm³; serum creatinine <2.5x upper normal limit or calculated creatinine clearance> 30 mL/min; AST (SGOT) and ALT (SGPT) < or = 10x upper normal limit.
Eligible subjects should have successfully completed therapy or be stable on therapy for any acute infectious processes other than MAC prior to study entry.
Subjects must be on a stable antiretroviral (ARV) regimen (same drug or combination of drugs; dose modifications allowed) for at least four weeks prior to study entry.

NOTE: Subjects will be requested NOT to modify or add new drugs to their stable ARV regimen for the duration of this study. Subjects who absolutely require ARV changes at any time prior to Week 8 will continue on-study, however, their data will be analyzed separately.

Exclusion Criteria

Subjects requiring use of any cytokine inhibitors; corticosteroids; thalidomide; pentoxifylline or any other immunomodulator; any interleukin; or colony stimulating factor (G-CSF or GM-CSF) within the 14 days immediately preceding study entry and for the duration of this study.
Subjects who have had an opportunistic infection (other than MAC) within the 14 days immediately preceding study entry.
Subjects who have received a vaccination within the 14 days immediately preceding study entry.
Subjects who have received a blood transfusion within the 14 days immediately preceding study entry.
Previous enrollment and permanent study drug discontinuation in ACTG 223 (NOTE: Co-enrollment in ACTG 223 and ACTG 853 is acceptable, however, enrollment in both studies MUST BE simultaneous).

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