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

Abstract

Background: The relationship between efavirenz use and suicidality is not well-defined.

Objective: To compare time to suicidality with efavirenz-containing versus efavirenz-free antiretroviral regimens for initial treatment of HIV.

Design: 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]).

Setting: AIDS Clinical Trials Group sites; 74% of participants enrolled in the United States.

Patients: Antiretroviral-naive participants.

Intervention: Efavirenz versus efavirenz-free regimens.

Measurements: 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.

Results: 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.

Limitation: There was not a standardized questionnaire about suicidal ideation or attempt. Efavirenz was open-label in 3 of 4 studies.

Conclusion: Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a 2-fold increased hazard of suicidality compared with a regimen without efavirenz.

Primary funding source: National Institutes of Health.

Appendix Figure 1. Cumulative incidence of attempted or completed suicide and non-suicide death

Appendix Figure 1A (Attempted or completed suicide ITT DSMB) Appendix Figure 1B (Attempted or completed suicide ITT) Cumulative incidence of attempted or completed suicide is presented on the left, and cumulative incidence of death attributed to causes other than reported suicide (competing risk) is presented on the right. Range of y-axis is limited to 0 through 0.10. Gray's test was stratified by study. Panel A: follow-up was censored after data safety monitoring board recommendations pertaining to the efavirenz comparisons, Panel B: intention-to-treat approach, including follow-up from randomization to last on-study contact.

Appendix Figure 1. Cumulative incidence of attempted or completed suicide and non-suicide death

Appendix Figure 1A (Attempted or completed suicide ITT DSMB) Appendix Figure 1B (Attempted or completed suicide ITT) Cumulative incidence of attempted or completed suicide is presented on the left, and cumulative incidence of death attributed to causes other than reported suicide (competing risk) is presented on the right. Range of y-axis is limited to 0 through 0.10. Gray's test was stratified by study. Panel A: follow-up was censored after data safety monitoring board recommendations pertaining to the efavirenz comparisons, Panel B: intention-to-treat approach, including follow-up from randomization to last on-study contact.

Figure 1. Cumulative incidence of suicidality and non-suicide death

Figure 1A (Suicidality ITT DSMB) Figure 1B (Suicidality ITT) Cumulative incidence of suicidal ideation, attempted, or completed suicide (suicidality) is presented on the left, and cumulative incidence of death attributed to causes other than reported suicide (competing risk) is presented on the right. Range of y-axis is limited to 0 through 0.10. Gray's test was stratified by study. Panel A: follow-up was censored after data safety monitoring board recommendations pertaining to the efavirenz comparisons, Panel B: intention-to-treat approach, including follow-up from randomization to last on-study contact.

Figure 1. Cumulative incidence of suicidality and non-suicide death

Figure 1A (Suicidality ITT DSMB) Figure 1B (Suicidality ITT) Cumulative incidence of suicidal ideation, attempted, or completed suicide (suicidality) is presented on the left, and cumulative incidence of death attributed to causes other than reported suicide (competing risk) is presented on the right. Range of y-axis is limited to 0 through 0.10. Gray's test was stratified by study. Panel A: follow-up was censored after data safety monitoring board recommendations pertaining to the efavirenz comparisons, Panel B: intention-to-treat approach, including follow-up from randomization to last on-study contact.

Figure 2. Association between efavirenz and the hazard of suicidality

DSMB= data safety monitoring board, IR=crude incidence rate, PY=person-years, CI=confidence interval. Univariate estimated hazard ratios were quantified from a Cox model with a Wald CI and p-value, stratified by study, and are plotted on a logarithm scale. Panel A: follow-up was censored after data safety monitoring board recommendations pertaining to the efavirenz comparisons, Panel B: intention-to-treat approach, including follow-up from randomization to last on-study contact. *p-value for efavirenz association, p-values for interaction with efavirenz are presented for study and region