Efavirenz is associated with higher suicide risk in meta-analysis of four ACTG studies

Efavirenz is one of the most widely used antiretroviral drugs despite a side effect profile that includes anxiety, mood changes, sleep disturbance, depression and serious psychiatric adverse events including suicide ideation and suicide. A new analysis supports these concerns.

In a presentation at IDWeek, Katie Mollan and colleagues analysed retrospective data from four independent investigator-led ACTG trials (A5095, A5142, A5175, A5202) to look for reports of suicidal thinking or behavior from 2001–2007. Each ACTG trial was randomised to either efavirenz or a non-efavirenz containing arm (three were PI-based and one was triple nucleoside) in antiretroviral naïve subjects. Three out of four of the trials efavirenz were open label.

This analysis included 5332 participants (3241 efavirenz, 2091 efavirenz-free) with a median follow-up of 150 weeks. Approximately 74% of participants were enrolled in US sites and 73% were men. The median age was 37 years (IQR 30, 43) and 32% reported a pre-psychiatric diagnosis or were prescribed a psychoactive medication 30 days prior to study entry. Less than 10% had injected drugs.

In the primary analysis, there were 47 suicide events in the efavirenz arm compared to 15 in the no efavirenz group (8.08 vs 3.66 per 1000 person-years) with a hazard ratio (HR) of 2.28 (95% CI 1.27 to 4.10, p=0.006). Completed or attempted suicide was also higher in the efavirenz group with 17 vs 5 events (2.90 versus 1.22 per 1000 person-years; HR 2.58; 95% CI 0.94 to 7.06, p=0.065), but this was not statistically significant. An intent-to treat analysis showed stronger significance finding 27 vs 7 attempted suicides (HR 2.61; 95% CI:1.1 to 5.9, p=0.03). Similar results were seen in ITT and as treated analyses.

In multivariate analysis, four risks found to be associated with suicide were use of efavirenz (HR 2.15; 95% CI: 1.20 to 3.87, p=0.01), under 30 years of age versus 45 or older (HR 2.82, 95% CI 1.25 to 6.34, p=0.04), injection drug use history (HR 2.18; 95% CI 1.11 to 4.30, p=0.02) and having a psychiatric history or psychoactive drug use: HR 3.90 (95% CI 2.23 to 6.82, p< 0.001). When assessing for risk in the countries studied, the US was higher (HR 2.32, 95% CI 1.23 to 4.38) compared to other countries (HR 2.02, 95% CI 0.43 to 9.53).

These results showed that use of efavirenz approximately doubled the risk of suicide with a number needed to harm (NNH) risk over one year of 217 for suicidal thought or behaviour and of 538 for attempted or completed suicide.

Despite concluding that the overall risk of suicide was low in this analysis, the authors urge that people treated with efavirenz be monitored for suicide risk.

Comment

This is an important analysis given that relatively rare events are unlikely to have statistical significance in smaller studies. This was a large study with three years follow up. The results should prompt a larger analysis from other randomised ACTG studies.

Although suicidal ideation is unlikely to be reported and confounding only allows reporting an association, analyses of suicides and efavirenz use in cohort studies, including D:A:D, might be important given their large patient numbers and length of follow up.

Mollan K et al. 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). IDWeek 2013. 2-6 October 2013, San Francisco. Abstract 670.
https://idsa.confex.com/idsa/2013/webprogram/Paper40032.html