Trial Information

Long-Term Assessment for Metabolic, Cardiovascular and Neurologic Complications In Subjects With Past CD4 Cells/mm3 Below 50 Who Increased CD4 Cells/mm3 to Above 100 on HAART

The currently available data on clinical events in patients receiving potent antiretroviral
therapy suggest that an alteration in the presentation of MAC disease may be seen and that
rates of MAC disease may be reduced when patients respond to antiretroviral therapy.
However, the extent of the protection and the timing of protection after initiation of
therapy remain unknown. The current study should provide validated measures of immune
restoration and clinical data to guide prophylaxis decisions for the many patients who are
now responding to therapy after years of immune depletion. [AS PER AMENDMENT 11/16/99: The
low rate of MAC in ACTG 362 patients after an average of 1 year of follow-up suggests that
prophylaxis specifically for MAC disease with azithromycin is not necessary for patients who
have experienced immune reconstitution. Prolonged follow-up will define durability of the
antiretroviral response and the experience with opportunistic conditions, neurologic
diseases, and survival, especially in those whose CD4 counts drop below 50 cells/mm3. It
will also allow assessment of the levels of CD4 cell number at which vulnerability to
opportunistic infection recur.] [AS PER AMENDMENT 03/18/03: During the extension of ACTG
362, serious complications of HAART have become better defined, including metabolic
complications, neurologic problems, atypical opportunistic infections, and malignancies.
Patients in ACTG 362 have been exposed to HAART longer than any other large group in the
ACTG, and appear to benefit from and suffer complications of their therapy. Continued
observation should provide estimates of expected complications and durability of long-term
potent antiretroviral treatment, and may detect unanticipated problems.]

Patients are stratified at baseline for prior use of MAC into 3 groups: no prophylaxis,
prior azithromycin prophylaxis, and other MAC prophylaxis. Patients are randomized to
receive azithromycin (Arm I) or matching placebo (Arm II) once weekly and are followed every
8 weeks until study closure or for 18 months (72 weeks) after the last patient is enrolled.
Patients who develop a drop in CD4 count below 50 cells/mm3 on 2 measurements at least 4
weeks apart are offered open-label azithromycin. [AS PER AMENDMENT 06/24/98: Patients remain
on open-label azithromycin regardless of subsequent CD4 counts.] [AS PER AMENDMENT 11/16/99:
The phase of Version 1.0 or Version 2.0 in which patients receive blinded-study medication
is now referred to as Step I. The phase of Version 1.0 or Version 2.0 in which patients
receive open-label azithromycin is now referred to as Step 2. Patients not currently on
open-label azithromycin provided by the study enter Step 3 and discontinue study drugs, but
remain blinded to the original treatment and are followed at 16-week intervals until study
closure which will occur in April 2002 (3 years following enrollment of the last study
participant). Any patient who develops a drop in CD4 count below 50 cells/mm3 on 2
measurements at least 4 weeks apart is offered open-label azithromycin. Patients currently
receiving open-label azithromycin and patients from Step 3 who are initiating open-label
azithromycin enter Step 4.] Patients undergo regular clinical and laboratory evaluations
that include physical examinations, CD4 counts, and viral load. [AS PER AMENDMENT 11/16/99:
Patients undergo clinical and laboratory evaluations every 16 weeks for 160 weeks that
include physical examinations, CD4 counts, and viral load as well as neuropsychologic and
cardiovascular assessments.] [AS PER AMENDMENT 01/18/01: All patients enrolled in the study
are followed until April 2002.] [AS PER AMENDMENT 03/18/02: All patients currently
participating in ACTG 362 are invited to continue follow up for an additional 5 years.
Patients not currently receiving open-label azithromycin enter Step 5. Patients currently
receiving open-label azithromycin enter Step 6, and continue to receive open-label treatment
throughout the study. Any patient who enters on Step 5 and develops a drop in CD4 below 50
cells/mm3 on 2 consecutive measurements at least 4 weeks apart is offered open-label
azithromycin and enters Step 6. Patients are assessed for metabolic, cardiovascular, and
neurologic complications and are evaluated for opportunistic infections, CD4 counts, and
viral load. Study visits occur at 32-week intervals until study closure.]