David B. Clifford, MD; Scott Evans, PhD; Yijun Yang, ScD; Edward P. Acosta, PharmD; Karl Goodkin, MD, PhD; Karen Tashima, MD; David Simpson, MD; David Dorfman, PhD; Heather Ribaudo, PhD; Roy M. Gulick, MD, MPH; for the A5097s Study Team*
Trial ACTG A5097s.
Acknowledgments: The authors thank the participants who volunteered to participate in this study.
Grant Support: By AI 38858 (AIDS Clinical Trials Group Central Grant), AI 01781, AI 25859, AI 25868, AI 25879, AI 25897, AI 25903, AI 25915, AI 25924, AI 27658, AI 27659, AI 27660, AI 27661, AI 27664, AI 27668, AI 27670, AI 27673, AI 27675, AI 27767, AI 28697, AI 32775, AI 32782, AI 34832, AI 38855, AI 39156, AI 42848, AI 42851, AI 46339, AI 46370, AI 46376, AI 46381, AI 46386, AI 50410, AI 51966, RR00044, RR00046, RR00047, RR00052, RR00096, RR00865, RR 02635, and subcontracts from grant AI 38858 with the Virology Support Laboratories at the University of Alabama, the University of Colorado Health Sciences Center, the University of North Carolina, and Vanderbilt University and the Pharmacology Support Laboratories at the University of Alabama from the National Institute of Allergy and Infectious Diseases, and by the Neurologic AIDS Research Consortium Grant NS 32228, National Institute of Neurological Disorders and Stroke, National Institutes of Health.
Potential Conflicts of Interest:Honoraria: D.B. Clifford (Bristol-Myers Squibb, Boehringer-Ingelheim); K. Tashima (Bristol-Myers Squibb, GlaxoSmithKline); R.M. Gulick (Bristol-Myers Squibb); Grants received: D.B. Clifford (Neurogesix, Saviant Pharmaceuticals); K. Tashima (Bristol-Myers Squibb, GlaxoSmithKline); R.M. Gulick (Boehringer-Ingelheim); Consultancies: R.M. Gulick (Boehringer-Ingelheim, GlaxoSmithKline).
Author Contributions: Conception and design: D.B. Clifford, E.P. Acosta, K. Tashima, D. Simpson, D. Dorfman, R.M. Gulick.
Analysis and interpretation of the data: D.B. Clifford, S. Evans, Y. Yang, E.P. Acosta, K. Goodkin, K. Tashima, D. Dorfman, H. Ribaudo, R.M. Gulick.
Drafting of the article: D.B. Clifford, S. Evans, Y. Yang, E.P. Acosta, D. Simpson, H. Ribaudo.
Critical revision of the article for important intellectual content: D.B. Clifford, S. Evans, Y. Yang, E.P. Acosta, K. Goodkin, K. Tashima, D. Simpson, H. Ribaudo, R.M. Gulick.
Final approval of the article: D.B. Clifford, S. Evans, Y. Yang, E.P. Acosta, K. Goodkin, K. Tashima, D. Simpson, H. Ribaudo, R.M. Gulick.
Provision of study materials or patients: D.B. Clifford, K. Tashima, R.M. Gulick.
Statistical expertise: D.B. Clifford, S. Evans, Y. Yang, H. Ribaudo.
Obtaining of funding: D.B. Clifford.
Administrative, technical, or logistic support: D.B. Clifford.
Collection and assembly of data: D.B. Clifford, K. Tashima, R.M. Gulick.
Requests for Single Reprints: David B. Clifford, MD, Washington University School of Medicine, Box 8111, Neurology Department, 660 South Euclid Avenue, St. Louis, MO 63110.
Current Author Addresses: Dr. Clifford: Washington University School of Medicine, Box 8111, Neurology Department, 660 South Euclid Avenue, St. Louis, MO 63110.
Dr. Evans: CBAR/Harvard School of Public Health, FXB-513, 651 Huntington Avenue, Boston, MA 02115.
Drs. Yang and Ribaudo: SDAC/Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115.
Dr. Acosta: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1530 Third Avenue South, VH 116, Birmingham, AL 35294.
Dr. Goodkin: Department of Psychiatry and Neurology, University of Miami School of Medicine, 1400 Northwest 10th Avenue, 803-A, Miami, FL 33136.
Dr. Tashima: The Miriam Hospital, M-974112, 164 Summit Avenue, Providence, RI 02906.
Drs. Simpson and Dorfman: Department of Clinical Neurophysiology, Mount Sinai School of Medicine, P.O. Box 1052, New York, NY 10029.
Dr. Gulick: The Cornell Clinical Trials Unit, Box 566, 525 East 68th Street, New York, NY 10021.
Efavirenz is a commonly used antiretroviral drug that causes neurologic side effects in more than 50% of patients.
To characterize efavirenz-associated neurologic symptoms in a randomized, controlled study of initial antiretroviral treatment.
Substudy of a randomized, double-blind, controlled trial of combination antiretroviral regimens (A5095) that was performed between March 2001 and January 2002.
Multicenter academic clinical trial units.
HIV-infected patients who were initiating therapy in the context of a controlled trial.
Neuropsychological performance measures, including the Digit Symbol Substitution Test and the Trail Making Test (Parts A and B); symptom questionnaires; standardized assessments of sleep quality, anxiety, and depression; and efavirenz plasma concentrations.
Twenty of 303 (6.6%) enrolled participants prematurely discontinued the study. Neuropsychological performance improved in both groups over time without significant differences between patients who were receiving efavirenz and those who were not. The efavirenz group experienced more neurologic symptoms at week 1 (P < 0.001) but not at weeks 4, 12, or 24. A sleep index revealed that participants receiving efavirenz had more “bad dreams” during the first week of therapy (P = 0.038). No significant changes in anxiety or depressed mood were noted. Changes in efavirenz-associated neurologic symptoms were correlated to efavirenz plasma concentrations at week 1 but not at later time points. Twelve (6%) patients receiving efavirenz stopped taking the drug before the end of the study because of central nervous system symptoms.
Participant selection may have been biased in favor of patients with fewer psychiatric complications. The study design permitted substitution of a new drug in place of efavirenz in cases of treatment-limiting toxicity.
In a large controlled trial, efavirenz use was associated with neurologic symptoms distinct from depression and anxiety that began early in therapy but resolved by week 4. Improvement in neuropsychological performance was comparable in patients who were receiving efavirenz and those who were not.
*For members of the A5097s Study Team, see the Appendix.
Clifford DB, Evans S, Yang Y, Acosta EP, Goodkin K, Tashima K, et al. Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals. Ann Intern Med. 2005;143:714–721. doi: 10.7326/0003-4819-143-10-200511150-00008
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Published: Ann Intern Med. 2005;143(10):714-721.
HIV, Infectious Disease.
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