No Evidence Found That Efavirenz Use Increases Depression in HIV Antiretroviral Therapy

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The researchers believe this study is the first to detect a statistically significant, unexpected inverse association between efavirenz use and depression.

In people with HIV in Uganda, researchers found no evidence that use of efavirenz as a first-line antiretroviral therapy (ART) increased the risk for depression or suicidal ideation compared with nevirapine use, according to research published in the Annals of Internal Medicine.1

To estimate the association between efavirenz and depression/suicidal ideation in people with HIV in Uganda — a population in which data is limited —  researchers conducted a prospective observational cohort study ( identifier: NCT01596322).

A total of 694 adults with HIV (median age 33 years; median pretreatment CD4+ count, 1.8×109 cells/L) were enrolled at the start of ART and were observed every 3 to 4 months from 2005 to 2015.

The main measurement of interest was time-varying efavirenz use, defined as use during the 7 days before a study visit and in 60 or more of the 90 days before a study visit, compared with nevirapine use. Self-reported outcomes included depression, defined as a mean score >1.75 on the Hopkins Symptom Checklist depression subscale, and suicidal ideation. Multivariable-adjusted generalized estimating equations (GEE) logistic regression, Cox proportional hazards regression, and marginal structural models were used to estimate the association between efavirenz use and the risk for depression and suicidal ideation.

The 694 participants contributed a total of 1200 person-years of observation (460 person-years receiving efavirenz). The researchers found no baseline differences in depression or suicidal ideation between patients ever exposed to efavirenz and those never exposed to efavirenz and receiving nevirapine (P >.80 for both). Of 305 participants ever-exposed to efavirenz, 61 (20.0%) had depression and 19 (6.2%) had suicidal ideation on at least 1 follow-up visit, compared with 125 (32.1%) and 47 (12.1%) respectively of the 389 who received nevirapine.

In adjusted GEE models, efavirenz use was associated with decreased odds of depression compared with nevirapine use (adjusted odds ratio [aOR], 0.62; 95% CI, 0.40-0.96) and was not significantly associated with suicidal ideation (aOR, 0.61; 95% CI, 0.30-1.25]). Similar estimates were found in time-to-event and marginal structural models.

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Primary study limitations included nonrandom assignment to treatment, and substantial differences between the efavirenz and nevirapine groups.

“In summary, we believe our study is the first to detect a statistically significant, unexpected inverse association between efavirenz use and depression,” the researchers concluded. “These data offer preliminary evidence of possible regional differences in efavirenz tolerability.”

The researchers noted that further research is needed to confirm these results, to establish consistency in other subpopulations, and to determine possible genetic or environmental factors that might account for regional differences in efavirenz tolerability. The ADVANCE study ( NCT03122262) is randomly assigning patients in South Africa to receive either efavirenz- or dolutegravir-based ART regimens with a focus on safety and tolerability.2


  1. Chang JL, Tsai AC, Musinguzi N, et al. Depression and suicidal ideation among HIV-infected adults receiving efavirenz versus nevirapine in Uganda: a prospective cohort study [published online June 26, 2018]. Ann Intern Med. doi:10.7326/M17-2252
  2. Venter WDF, Clayden P, Serenata C; OPTIMIZE Consortium. The ADVANCE study: a groundbreaking trial to evaluate a candidate universal antiretroviral regimen. Curr Opin HIV AIDS. 2017;12:351-4. doi:10.1097/COH.0000000000000389