Hazard of Suicidality in Patients Randomly Assigned to Efavirenz for Initial Treatment of HIV-1: a Cross-Study Analysis Conducted by the AIDS Clinical Trials Group (ACTG)

Background: Efavirenz (EFV) is widely used for the treatment of HIV, but there is some uncertainty regarding its relationship to suicidality.  Here we examine the effect of initial treatment with an EFV-containing versus EFV-free regimen on the risk of suicidality.

Methods:   Data from four ACTG studies (A5095, A5142, A5175, A5202) of antiretroviral-naïve participants enrolled from 2001-2007 were included. Participants in each trial were randomized to EFV-containing or EFV-free (protease inhibitor or 3-nucleoside) regimens; assignment to EFV was open label in 3 of the 4 trials.  Suicidality was defined as suicidal ideation, attempted or completed suicide and was derived from signs, symptoms, diagnoses and death data. The primary analysis included follow-up from randomization through last study contact or data safety and monitoring board (DSMB) recommendations to stop an EFV-free arm for virologic inferiority (A5095 and A5175). As-treated analyses censored follow-up at the earlier of DSMB recommendations, EFV-strategy cross-over or treatment discontinuation plus 28 days. EFV versus EFV-free groups were compared with a cause-specific hazard ratio (HR) with a 95% confidence interval (CI) estimated from a Cox model stratified by study.

Results:   5332 participants (EFV: 3241, EFV-free: 2091) had median follow-up of 150 weeks. A majority (74%) enrolled in the United States, 73% were men, median age was 37 years, and 32% had a pre-study psychiatric event or were taking psychoactive medication in the 30 days prior to entry. Baseline characteristics were balanced by randomization. Suicidality incidence per 1000 person-years was 8.08 (47 events) in the EFV group and 3.66 (15 events) in the EFV-free group, HR: 2.28 (95% CI: 1.27, 4.10, p=0.006), with no evidence of a differential effect by clinical trial (p>0.9). Incidence of attempted/completed suicide was 2.90 (17 events) and 1.22 (5 events) in the EFV and EFV-free groups, respectively, HR: 2.58 (95% CI: 0.94, 7.06, p=0.065).

Conclusion:   Initial treatment with an EFV-containing regimen was associated with a two-fold increase in the hazard of suicidality compared to a regimen without EFV. HIV-infected patients treated with EFV should be carefully monitored for suicide risk.

Katie Mollan, MS^1,2, Marlene Smurzynski, MSPH, PhD^2,3, Lumine Na, MS², Kevin Robertson, PhD⁴, Thomas Campbell, MD⁵, Paul Sax, MD, FIDSA⁶, Eric Daar, MD⁷, Joseph Eron, MD⁴, Roy Gulick, MD, FIDSA⁸, Lauren O’keefe, BS² and Camlin Tierney, Ph.D.², (1)University of North Carolina at Chapel Hill, Chapel Hill, NC, (2)Harvard School of Public Health, Boston, MA, (3)School of Public Health and Health Services, George Washington University, Washington, DC, (4)University of North Carolina At Chapel Hill, Chapel Hill, NC, (5)University of Colorado Denver, Aurora, CO, (6)Division Of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA, (7)Los Angeles Biomedical Research Institute At Harbor-UCLA Medical Center, Torrance, CA, (8)Weill Cornell Medical College, New York, NY

Disclosures:

1. Mollan, Gilead: Collaborator, Research support
2. Smurzynski, None
   L. Na, None
   K. Robertson, viiv: Consultant, Consulting fee
   abbott: Consultant, Consulting fee

   T. Campbell, Gilead: Scientific Advisor, Consulting fee

   P. Sax, BMS: Investigator and Scientific Advisor, Grant recipient and Salary
   Gilead: Investigator and Scientific Advisor, Research grant and Salary
   Janssen: Scientific Advisor, Salary
   Merck: Scientific Advisor, Salary
   GSK: Investigator and Scientific Advisor, Grant recipient and Salary

   E. Daar, Abbott: Research Contractor, Grant recipient
   Bristol Myers Squibb: Consultant, Consulting fee
   Gilead: Consultant and Investigator, Consulting fee and Grant recipient
   Janssen: Consultant, Consulting fee
   Merck: Consultant and Investigator, Consulting fee and Grant recipient
   ViiV: Consultant and Grant Investigator, Consulting fee and Grant recipient

   J. Eron, BMS: Consultant, Consulting fee and Grant recipient
   Merck: Consultant, Consulting fee
   Gilead: Consultant, Consulting fee
   GSK/ViiV: Consultant, Consulting fee and Grant recipient
   Janssen: Consultant, Consulting fee

   R. Gulick, None
   L. O’keefe, None
   C. Tierney, Tibotec: I am a member of a Data Monitoring Committee for a hepatitis C drug, fee for Data Monitoring Committee Membership

Haber: Dr. Sibel Bolukçu

https://idsa.confex.com/idsa/2013/webprogram/Paper40032.html