Risk of Suicidal Behavior With Use of Efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial

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.

Figure 1.

Kaplan-Meier estimates of the cumulative percent of participants with suicidal or self-injurious behavior in the deferred antiretroviral therapy (ART) group prior to any ART use, within subgroups by pre-specified ART type (efavirenz [EFV] versus other ART). Follow-up is censored at ART initiation. The difference between the curves (P < .001) indicates that participants who were pre-specified EFV-containing regimens had a lower a-priori risk of suicidal behavior compared with those pre-specified other ART. Abbreviations: ART, antiretroviral therapy; EFV, efavirenz; NRTI, nucleoside reverse transcriptase inhibitor PY, person-years.

Figure 2.

Study design for investigating associations between efavirenz and suicidal behavior. Abbreviations: ART, antiretroviral therapy; EFV, efavirenz; HIV, human immunodeficiency virus; HR, hazard ratio; NRTI, nucleoside reverse transcriptase inhibitor; START, Strategic Timing of Antiretroviral Treatment.

Figure 3.

Antiretroviral therapy (ART) and efavirenz (EFV) use in the immediate and deferred ART groups, within subgroups by pre-specified ART type. A, Percent of participants using ART and EFV. B, Percent of follow-up time during which ART and EFV were used. Abbreviations: ART, antiretroviral therapy; Def., deferred; EFV, efavirenz; Imm., immediate; NRTI, nucleoside reverse transcriptase inhibitor.

Figure 4.

Kaplan-Meier estimates of the cumulative percent of participants with suicidal or self-injurious behavior, within subgroups by pre-specified antiretroviral therapy (ART) type. In the deferred ART group, follow-up is censored at ART initiation. A, Kaplan-Meier estimates for participants who were pre-specified efavirenz (EFV)-containing ART regimens. In the immediate ART group, follow-up time is started at EFV initiation, excluding 116 (6.6%) participants who never initiated EFV. B, Kaplan-Meier estimates for participants whose pre-specified regimen did not contain EFV. In the immediate group, follow-up time is started at ART initiation, excluding 32 participants who never initiated ART or whose first regimen contained EFV; for the 31 participants who started EFV, follow-up is censored at EFV start. Abbreviations: ART, antiretroviral therapy; Def., deferred; EFV, efavirenz; Imm., immediate; NRTI, nucleoside reverse transcriptase inhibitor.