Suicide Risk with Efavirenz Evident in Controlled Comparison

August 28, 2018
Kenneth Bender, PharmD, MA

Results of an analysis indicate suicidal behavior occurred more often in patients taking an efavirenz-based treatment for HIV than in a control group that had not started treatment.

Alejandro Arenas-Pinto, MBBS, MSc, PhD

The risk of suicidal behavior in patients with HIV who were taking efavirenz (Sustiva, Bristol-Myers Squibb) based treatment was higher than in a control group of patients with HIV who had not started antiretroviral treatment (ART), according to an analysis of data from the Strategic Timing of Antiretroviral Treatment (START) trial.

Alejandro Arenas-Pinto, MBBS, MSc, PhD, Medical Research Council Clinical Trials Unit, University College London, United Kingdom, and colleagues used controlled trial data to reconcile the difference in findings from case reports and a meta-analysis of 4 trials which included ART-naïve patients that showed increased suicidal behavior in patients receiving efavirenz-based ART, and observational, cohort studies which did not make that association.

"Observational studies that compare [efavirenz] use to other ART are unreliable," Arena-Pinto and colleagues argued in their article. "However... efavirenz is often avoided for patients with elevated risk of suicidal behavior, resulting in higher a priori risk of suicidal behavior in the other ART group."

Arena-Pinto and colleagues chose to analyze data from the START randomized, controlled trial because it was of sufficient size and duration to power the comparison of suicidal and self-injurious behaviors and identify the possible influence of psychiatric diagnosis in appropriate control groups.

A total of 4684 participants at 215 sites in 35 countries were enrolled in the START trial, which ran from 2009 through 2013. For the trial, treatment-naïve patients who were HIV-positive with CD4+ cell counts of >500 cells/µL were randomized to either start ART immediately or defer treatment until counts dropped to <350 cells/µL (>1 year for most) or AIDS developed. The ART regimens were derived from those in the US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents.

To avoid direct comparisons being confounded by differences in a priori risk, the investigators used a series of intention-to-treat comparisons of the incidence of suicidal behavior in the immediate versus the deferred ART groups overall, and separately within the deferred and immediate treatment groups among patients on efavirenz- and non-efavirenz-based ART. There were not sufficient numbers of patients receiving particular non-efavirenz treatments to directly compare individual regimens.

Suicidal behavior was not found to be statistically different between immediate and deferred ART treatment groups overall. The event was reported in 28 participants receiving immediate ART, and 25 in the deferred ART groups over the mean follow-up of 3.8 years, for rates of 0.39 and 0.34 per 100 person-years, respectively.

In those receiving an efavirenz-based regimen (n = 3515), suicidal behavior was reported in 19 participants with immediate treatment and 12 with deferred treatment, hazard ratio (HR) 1.38 (95% Confidence Interval [CI] 0.7-2.9). Across non- efavirenz-based ART, there were 9 events in the immediate treatment groups, compared with 13 in those with deferred treatment, HR 0.74 (CI 0.3-1.7).

Although event rates were estimated without adjustment for baseline characteristics, the analysis was stratified for having history of psychiatric diagnosis (n = 271), which was found to be associated with an increased risk of suicidal behavior in both efavirenz and non-efavirenz immediate treatment groups. In those receiving efavirenz-based treatment, the risk was also increased in those with a baseline history of heavy alcohol use and recreational drug use.

The investigators concluded that ART-naïve participants had an increased risk of suicidal behavior on ART with efavirenz, based on the comparison of those who were immediately started on efavirenz-based regimens to those whose treatment was deferred. This was contrasted with the absence of increased risk in the comparisons between immediate and deferred treatments across all groups, and with non-efavirenz-based regimens.

"Although most treatment guidelines across the world, including the World Health Organization guidelines for treatment of HIV, no longer recommend using efavirenz as first-line treatment, it will probably remain as an important therapeutic tool in a number of situations and regions," Arenas-Pinto told MD Magazine®. "Therefore, targeted [mental health] screening protocols for patients being considered for efavirenz-based combinations might be manageable, even in resource-limited settings."

"At a very minimum, if efavirenz is prescribed, patients must be made aware of the potential risk and advised on low mood-related symptoms," he concluded.

The study, “Risk of Suicidal Behavior With Use of Efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial,” is published in Clinical Infectious Diseases.