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Efavirenz Linked to Suicide Risk at ID Week 2013

The NNRTI efavirenz (EFV) has been in clinical use since 1998 and serves as the anchor drug in some of the most effective antiretroviral therapy (ART) regimens. It has for many years been the only NNRTI granted preferred status in HIV treatment guidelines. The fixed-dose combination of EFV, tenofovir DF and emtricitabine is the most frequently prescribed ART regimen in developed countries. Its success came despite the frequent occurrence of central nervous system adverse effects that typically include transient dizziness, somnolence, vivid dreams and clouded mentation, although some patients experience persistent symptoms. Uncommonly, it can cause more severe acute symptoms such as hallucinations, behavioral or personality changes or psychosis. Controversy exists as to whether long-term EFV exacerbates depression. Suicidality has been reported in patients on EFV, but also occurs at an increased rate in the HIV-infected individuals not using EFV. To determine if EFV use is associated with an increased risk of suicidality, Mollan et al. collected all reports of suicidal ideation, suicide attempt or completed suicide among individuals participating in four ACTG trials that randomized patients to an EFV-containing or EFV-free ART. The analysis was large (EFV n=3241; EFV-free n=2091) and the two groups were well balanced for baseline characteristics that might affect suicide risk. There were 47 events (8.08/1,000 patient-years) in the EFV group and 15 events (3.66/1,000 patient-years) in the EFV-free group. A Cox proportional hazards model yielded a hazard ratio (HR) of 2.28 (95% CI 1.27-4.10, p=0.006) for suicidality. When only attempted and completed suicide was considered, there were 17 and 5 events in the EFV and EFV-free groups, respectively (HR 2.58, 95% CI 0.94-7.06, p=0.06). Combined deaths attributed to suicide, accident, substance abuse, homicide or unknown causes were increased in EFV recipients (HR 2.46, p=0.03) while deaths due to other causes were not. Factors significantly associated with suicidality were randomization to EFV, age <30, history of IDU and prior psychiatric history.

The findings of this study are bolstered by its size and randomized assignment to therapy. Limitations include lack of blinding in 3 or the 4 studies and lack of standardized reporting of suicidality. Although attempted or completed suicide was reported uncommonly in this study (less than 0.5% on EFV), EFV use appears to increase the risk 2-2.5-fold. Deaths due to suicide plus accidents, overdose or unknown causes appear to be increased, suggesting the possibility that some suicides may be misclassified or that EFV treatment may in other ways contribute to accidental deaths. Patients with a psychiatric history are at greatest risk. Alternative regimens should be considered in these cases. However, only one of the 5 regimens included in the EFV-free comparison group in this study is currently considered a guidelines preferred regimen. Other, simple, effective EFV-free regimens are now available. Analyses similar to this one should be conducted with these agents to assess the risk of suicidality.

Mollan K, Smurzynski M, Na L, 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). ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 670.

Source: Reporting from San Francisco for PRN News: David H Shepp, MD