Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants

Abstract

Background: We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States.

Methods: Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates.

Results: Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication.

Conclusions: Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity.

Keywords: CYP2B6; HIV; efavirenz; pharmacogenetics; suicidality.

Figure 1.

Derivation of the study sample. Selection of the study population is shown among white, black, and Hispanic participants who were randomly assigned to an efavirenz-containing or nonefavirenz regimen in A5095, A5142, A5175, or A5202 and enrolled in the United States (US) or Puerto Rico. PC, principal component.

Figure 2.

Relative hazard of suicidality by genotype level among participants randomly assigned to efavirenz-containing regimens. Each incremental CYP2B6/CYP2A6 genotype level (levels 1–12) is known to be associated with progressively greater plasma efavirenz exposure. The estimated relative hazard of suicidality is shown overall and within each race/ethnicity group, for both exposed and on-treatment risk periods. Overall P values test reflect the main effect of genotype level; race/ethnicity P values, a statistical interaction between genotype level and race/ethnicity group. Hazard ratios were estimated from a weighted Cox model stratified by race/ethnicity; robust Wald confidence intervals (CIs) and P values are shown.

Figure 3.

Genotype level fit with a quadratic spline. CYP2B6/CYP2A6 genotype level was fit with a quadratic spline with 4 equally spaced knots at levels 2, 3, 4, and 6, as indicated by downward arrows. Each hash mark represents the participant’s observed genotype level (n = 1833); solid line, the estimated relative hazard; and dashed lines, pointwise 95% Wald-type confidence intervals from a weighted Cox model stratified by race/ethnicity group. This provides support for the assumption of a linear association with no apparent threshold effect. The unweighted result was similar and slightly closer to linear (data not shown).

Figure 4.

Cumulative probability of suicidality for each metabolizer group in on-treatment analysis, overall and by race/ethnicity. A, Estimated cumulative probability of suicidality for each metabolizer group is shown overall among all participants (A) and among white (B), black (C), and Hispanic (D) participants. Values for probability represent 1 minus the weighted Kaplan-Meier estimate; on-treatment analyses are shown. The unweighted number at risk is shown below each panel, and the number of suicidality events is provided in the key.