Alejandro Arenas-Pinto1, Birgit Grund2, Shweta Sharma3, Esteban Martinez4, Nathan Cummins5, Julie Fox6, Karin L Klingman7, Dalibor Sedlacek8, Simon Collins9, Patricia M Flynn10, William M Chasanov11, Eynat Kedem12, Christine Katlama13, Juan Sierra-Madero14, Claudia Afonso15, Pim Brouwers7, David A Cooper16. 1. Medical Research Council Clinical Trials Unit, University College London, United Kingdom. 2. School of Statistics, Minneapolis. 3. Division of Biostatistics, University of Minnesota, Minneapolis. 4. Hospital Clinic, Barcelona, Spain. 5. Mayo Clinic, Rochester, Minnesota. 6. Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom. 7. Division of AIDS, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, Maryland. 8. University Hospital Plzen, Czech Republic. 9. HIV i-Base, London, United Kingdom. 10. St. Jude Children's Research Hospital, Memphis, Tennessee. 11. Cooper University Hospital, Camden, New Jersey. 12. Clinical Immunology Unit, Rambam Health Care Center, Haifa, Israel. 13. Hospitalier Pitié-Salpétrière, Paris, France. 14. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, México. 15. Hospital de Santa Maria, Lisbon, Portugal. 16. The Kirby Institute, University of New South Wales, Sydney, Australia.
Abstract
Background: Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods: The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results:Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions: Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.
RCT Entities:
Background: Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods: The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results: Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions: Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.
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