Katie R. Mollan, MS; Marlene Smurzynski, PhD; Joseph J. Eron, MD; Eric S. Daar, MD; Thomas B. Campbell, MD; Paul E. Sax, MD; Roy M. Gulick, MD; Lumine Na, MS; Lauren O'Keefe, BS; Kevin R. Robertson, PhD; Camlin Tierney, PhD
Presented in part at IDWeek 2013, Infectious Diseases Society of America, San Francisco, California, 2–6 October 2013.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.
Acknowledgments: The authors thank the study participants, investigators, and clinical research sites. They also thank James Hakim, MD (A5175 protocol co-chair; University of Zimbabwe College of Health Sciences, Harare, Zimbabwe), and Sharon Riddler, MD (University of Pittsburgh, Pittsburgh, Pennsylvania), and Richard Haubrich, MD (University of California, San Diego, San Diego, California) (A5142 protocol co-chairs). They also acknowledge Karin Klingman, MD, and Catherine Godfrey, MD (Division of AIDS medical officers; Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland); Heather Ribaudo, PhD (A5095 statistician, design and statistical advice); Michael Hughes, PhD; Meredith Warshaw, MA (statistical advice); Laura Smeaton, MS (A5175 statistician, statistical advice); Christina Lalama, MS (A5095 statistician, database advice); and Andrew Ellingson, MPH (antiretroviral database programming) (Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts). In addition, the authors thank Terri Corbelli, RHIT; Michele Daneau, CPC-A, CMBS; Lucinda Phillips, MS, RN; Lynn Strusa, AAS (Medical Dictionary for Regulatory Activities coding); Ann Walawander, MA, CCRP; Amy Mirand, PhD; Laurie Myers, MS; David Rusin, MT; Apsara Nair, MS (data management; Frontier Science & Technology Research Foundation, Amherst, New York); and Sarah Yosief, AB (literature search assistance; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina).
Grant Support: By award U01AI068636 (National Institute of Allergy and Infectious Diseases), along with the previous grant for the AIDS Clinical Trials Group Central Group (AI38858) and the AIDS Clinical Trials Group Statistical and Data Management Center grant (AI68634). The study was also supported in part by the General Clinical Research Center Units, funded by the National Center for Research Resources: UL1-RR024996 (Weill Cornell Clinical and Translational Science Center), AI-69419 (Weill Cornell AIDS Clinical Trials Unit), K24 AI-51966, and P30 AI50410 (University of North Carolina at Chapel Hill Center for AIDS Research). Abbott Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline provided study medications.
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0293.
Reproducible Research Statement: Study protocol and data set: Available through written agreement with the AIDS Clinical Trials Group and the Division of AIDS, National Institute of Allergy and Infectious Diseases (https://actgnetwork.org/contact-us). Statistical code: Available from Ms. Mollan (University of North Carolina at Chapel Hill, 3126 McGavran-Greenberg Hall, CB 7420, Chapel Hill, NC 27599).
Requests for Single Reprints: Camlin Tierney, PhD, Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115.
Current Author Addresses: Ms. Mollan: University of North Carolina at Chapel Hill, 3126 McGavran-Greenberg Hall, CB 7420, Chapel Hill, NC 27599.
Dr. Smurzynski: Department of Epidemiology and Biostatistics, George Washington University Milken Institute School of Public Health, 950 New Hampshire Avenue Northwest, Suite 500, Washington, DC 20052.
Dr. Eron: University of North Carolina AIDS Clinical Trials Unit, 130 Mason Farm Road, Suite 2100, Bioinformatics Building, Chapel Hill, NC 27599.
Dr. Daar: Harbor–University of California, Los Angeles Medical Center CRS, 1124 West Carson Street, Building N-24, Torrance, CA 90502.
Dr. Campbell: Division of Infectious Diseases, University of Colorado, Mail Stop B-168, Room P15-11001, 12700 East 19th Avenue, Aurora, CO 80045.
Dr. Sax: Brigham and Women's Hospital, Division of Infectious Disease, 75 Francis Street, PBB-A-4, Boston, MA 02115.
Dr. Gulick: Division of Infectious Diseases, Cornell Clinical Trials Unit, Cornell University, Box 125, 1300 York Avenue, New York, NY 10065.
Ms. Na and Dr. Tierney: Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115.
Ms. O'Keefe: Division of Biostatistics, University of Minnesota, Mayo Building, 420 Delaware Street Southeast, Minneapolis, MN 55455.
Dr. Robertson: University of North Carolina, Physician's Office Building, 170 Manning Drive, Chapel Hill, NC 27599.
Author Contributions: Conception and design: K.R. Mollan, M. Smurzynski, J.J. Eron, E.S. Daar, P.E. Sax, R.M. Gulick, K.R. Robertson, C. Tierney.
Analysis and interpretation of the data: K.R. Mollan, M. Smurzynski, J.J. Eron, E.S. Daar, T.B. Campbell, P.E. Sax, R.M. Gulick, L. Na, L. O'Keefe, K.R. Robertson, C. Tierney.
Drafting of the article: K.R. Mollan, M. Smurzynski, T.B. Campbell, P.E. Sax, K.R. Robertson, C. Tierney.
Critical revision of the article for important intellectual content: K.R. Mollan, M. Smurzynski, J.J. Eron, E.S. Daar, T.B. Campbell, P.E. Sax, R.M. Gulick, K.R. Robertson, C. Tierney.
Final approval of the article: K.R. Mollan, M. Smurzynski, J.J. Eron, E.S. Daar, T.B. Campbell, P.E. Sax, R.M. Gulick, L. Na, L. O'Keefe, K.R. Robertson, C. Tierney.
Provision of study materials or patients: J.J. Eron, E.S. Daar, T.B. Campbell, P.E. Sax, R.M. Gulick.
Statistical expertise: K.R. Mollan, L. Na, C. Tierney.
Obtaining of funding: J.J. Eron, E.S. Daar, T.B. Campbell, P.E. Sax, R.M. Gulick.
Administrative, technical, or logistic support: K.R. Mollan, L. O'Keefe, C. Tierney.
Collection and assembly of data: K.R. Mollan, E.S. Daar, T.B. Campbell, P.E. Sax, L. O'Keefe, K.R. Robertson.
Mollan K., Smurzynski M., Eron J., Daar E., Campbell T., Sax P., Gulick R., Na L., O'Keefe L., Robertson K., Tierney C.; Association Between Efavirenz as Initial Therapy for HIV-1 Infection and Increased Risk for Suicidal Ideation or Attempted or Completed Suicide: An Analysis of Trial Data. Ann Intern Med. 2014;161:1-10. doi: 10.7326/M14-0293
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Published: Ann Intern Med. 2014;161(1):1-10.
This article has been corrected. The original version (PDF) is appended to this article as a Supplement.
The relationship between efavirenz use and suicidality is not well-defined.
To compare time to suicidality with efavirenz-containing versus efavirenz-free antiretroviral regimens for initial treatment of HIV.
Participant-level data were analyzed from 4 AIDS Clinical Trials Group, antiretroviral-naive studies conducted from 2001 to 2010. Within each study, participants were randomly assigned to an efavirenz-containing (n = 3241) or efavirenz-free (n = 2091) regimen. (ClinicalTrials.gov: NCT00013520 [A5095], NCT00050895 [A5142], NCT00084136 [A5175], and NCT00118898 [A5202])
AIDS Clinical Trials Group sites; 74% of participants enrolled in the United States.
Efavirenz versus efavirenz-free regimens.
Suicidality was defined as suicidal ideation or attempted or completed suicide. Groups were compared with a hazard ratio and 95% CI estimated from a Cox model, stratified by study.
Seventy-three percent of participants were men, the median age was 37 years, and 32% had documented psychiatric history or received psychoactive medication within 30 days before entering the study. Median follow-up was 96 weeks. Suicidality incidence per 1000 person-years was 8.08 (47 events) in the efavirenz group and 3.66 (15 events) in the efavirenz-free group (hazard ratio, 2.28 [95% CI, 1.27 to 4.10]; P = 0.006). Incidence of attempted or completed suicide was 2.90 (17 events) and 1.22 (5 events) in the efavirenz and efavirenz-free groups, respectively (hazard ratio, 2.58 [CI, 0.94 to 7.06]; P = 0.065). Eight suicides in the efavirenz group and 1 in the efavirenz-free group were reported.
There was not a standardized questionnaire about suicidal ideation or attempt. Efavirenz was open-label in 3 of 4 studies.
Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a 2-fold increased hazard of suicidality compared with a regimen without efavirenz.
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