Discontinuation of Mycobacterium avium Complex Prophylaxis in Patients with Antiretroviral Therapy–Induced Increases in CD4⁺ Cell Count

A Randomized, Double-Blind, Placebo-Controlled Trial

3 October 2000 | Volume 133 Issue 7 | Pages 493-503

Background: Patients infected with HIV who experience increases in CD4⁺ cell counts are at reduced risk for opportunistic infections. However, the safety of discontinuing prophylaxis against Mycobacterium avium complex has been uncertain.

Objective: To compare the rate of M. avium complex infection in patients with increased CD4⁺ cell counts who receive azithromycin and those receiving placebo.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: 29 university-based clinical centers in the United States.

Participants: 643 HIV-1–infected patients with a previous CD4⁺ cell count less than 0.05 x 10⁹ cells/L and a sustained increase to greater than 0.10 x 10⁹ cells/L during antiretroviral therapy.

Intervention: Azithromycin, 1200 mg once weekly (n = 321), or matching placebo (n = 322).

Measurements: Mycobacterium avium complex cultures, CD4⁺ cell counts, and clinical evaluations for AIDS-defining illnesses and bacterial infections were done every 8 weeks. Plasma HIV-1 RNA levels were measured at 16-week intervals.

Results: During follow-up (median, 16 months), 2 cases of M. avium complex infection were reported among the 321 patients assigned to placebo (incidence rate, 0.5 event per 100 person-years [95% CI, 0.06 to 1.83 events per 100 person-years]) compared with no cases among the 322 patients assigned to azithromycin (CI, 0 to 0.92 events per 100 person-years), resulting in a treatment difference of 0.5 event per 100 person-years (CI, –0.20 to 1.21 events per 100 person-years) for placebo versus azithromycin. Both cases were atypical in that M. avium complex was localized to the vertebral spine. Patients receiving azithromycin were more likely than those receiving placebo to discontinue treatment with the study drug permanently because of adverse events (8% vs. 2%; hazard ratio, 0.24 [CI, 0.10 to 0.57]).

Conclusions: Prophylaxis against Mycobacterium avium complex can safely be withdrawn or withheld in adults with HIV infection who experience increases in CD4⁺ cell count while receiving antiretroviral therapy.

Author and Article Information

for the AIDS Clinical Trials Group 362 Study Team
From University of California Los Angeles, Los Angeles, California; Harvard School of Public Health, Boston, Massachusetts; Ohio State University, Columbus, Ohio; University of Rochester Medical Center, Rochester, New York; Northwestern University Medical School; Duke University Medical Center, Durham, North Carolina; National Institutes of Health, Bethesda, Maryland; Johns Hopkins University, Baltimore, Maryland; Pfizer, Inc., New York, New York; University of Colorado Health Sciences Center, Denver, Colorado; Case Western Reserve University, Cleveland, Ohio; University of California, San Francisco, San Francisco, California; and University of California, San Diego, San Diego, California.

Presented in part at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, 26–29 September 1999, and the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, California, 30 January–2 February 2000.

Grant Support: By the AIDS Clinical Trials Group and National Institute of Allergy and Infectious Diseases and in part by Pfizer, Inc.

Requests for Single Reprints: Judith S. Currier, MD, MSc, University of California, Los Angeles, 10833 LeConte Avenue, Room BH-412, Los Angeles, CA 90095; e-mail, jscurrier{at}mednet.ucla.edu.

Current Author Addresses: Dr. Currier: University of California, Los Angeles, CARE Center, 10833 LeConte Avenue, Room BH-412 CHS, Los Angeles, CA 90095.

Dr. Williams: Statistical and Data Analysis Center, Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115.

Dr. Koletar: Ohio State University Hospitals, Doan Hall, N-115, 410 West 10th Avenue, Columbus, OH 43210.

Dr. Cohn: Infectious Diseases Unit, University of Rochester Medical Center, 601 Elmwood Avenue, Box 689, Rochester, NY 14642.

Dr. Murphy: Northwestern University Medical School, Passavant Pavilion, Room 828, 303 East Superior Street, Chicago, IL 60611.

Dr. Heald: Duke University Medical Center, Box 3284, Durham, NC 27710.

Dr. Hafner: Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Room 5107, 6700-B Rockledge Drive, MSC 7620, Bethesda, MD 20892-7620.

Dr. Bassily: Statistical and Data Analysis Center, Harvard School of Public Health, COMP RAC Section, FXB Building, Room 614, 651 Huntington Avenue, Boston, MA 02115.

Dr. Lederman: Johns Hopkins Hospital, CMSC 1102, 600 North Wolfe Street, Baltimore, MD 21287.

Dr. Knirsch: Pfizer, Inc., 235 East 42nd Street, Mailstop 235/14/5, New York, NY 10017.

Dr. Benson: University of Colorado Health Sciences Center, Division of Infectious Diseases, 4200 East Ninth Avenue, Box B-196, Denver, CO 80262.

Dr. Valdez: Division of Infectious Diseases, Case Western Reserve University, 2061 Cornell Road, Room 301B, Cleveland, OH 44106.

Dr. Aberg: AIDS Clinical Trials Unit, Washington University School of Medicine, 4511 Forest Park Boulevard, Suite 304, St. Louis, MO 63108.

Dr. McCutchan: Treatment Center, University of California San Diego, 2760 Fifth Avenue, Suite 300, San Diego, CA 92103.

Author Contributions: Conception and design: J.S. Currier, P.L. Williams, S.L. Koletar, S.E. Cohn, R.L. Murphy, A.E. Heald, R. Hafner, H.M. Lederman, J.A. McCutchan.

Analysis and interpretation of the data: J.S. Currier, P.L. Williams, S.L. Koletar, S.E. Cohn, R.L. Murphy, A.E. Heald, E.L. Bassily, H.M. Lederman, C. Knirsch, C.A. Benson, H. Valdez, J.A. McCutchan.

Drafting of the article: J.S. Currier, P.L. Williams, S.E. Cohn, H.M. Lederman, C.A. Benson, J.A. Aberg, J.A. McCutchan.

Critical revision of the article for important intellectual content: J.S. Currier, P.L. Williams, S.L. Koletar, R.L. Murphy, A.E. Heald, R. Hafner, E.L. Bassily, C. Knirsch, C.A. Benson, H. Valdez, J.A. Aberg, J.A. McCutchan.

Final approval of the article: J.S. Currier, P.L. Williams, S.L. Koletar, S.E. Cohn, R.L. Murphy, A.E. Heald, R. Hafner, H.M. Lederman, C. Knirsch, C.A. Benson, H. Valdez, J.A. Aberg, J.A. McCutchan.

Provision of study materials or patients: J.S. Currier, S.L. Koletar, S.E. Cohn, R.L. Murphy, A.E. Heald, C. Knirsch, C.A. Benson, H. Valdez, J.A. Aberg.

Statistical expertise: P.L. Williams, E.L. Bassily.

Obtaining of funding: C.A. Benson, J.A. McCutchan.

Administrative, technical, or logistic support: J.S. Currier, C. Knirsch, C.A. Benson.

Collection and assembly of data: J.S. Currier, E.L. Bassily, H. Valdez.