Association Between Efavirenz as Initial Therapy for HIV-1 Infection and Increased Risk for Suicidal Ideation or Attempted or Completed Suicide

Context Postmarketing reports have suggested that efavirenz increases risk for suicide. Contribution In an analysis of data from 4 large, randomized trials in which patients with HIV were randomly assigned to either efavirenz-containing or efavirenz-free regimens for initial therapy, efavirenz was associated with a doubling of risk for suicidality (a composite of suicide, suicide attempt, and suicidal ideation). Caution The clinical trials were not specifically designed to investigate suicidality. Implication An increased risk for suicidality should be considered when choosing efavirenz as part of an initial antiretroviral regimen. The Editors Efavirenz is a preferred nonnucleoside reverse transcriptase inhibitor for treatment of HIV (14). Although efavirenz is generally safe and effective, it is associated with central nervous system side effects (58); prescribing information contains warnings of rare but serious psychiatric experiences, including suicide, but also notes that a causal relationship cannot be determined from postmarketing reports (5). Likewise, published cases and case series report suicidal thoughts or behavior with efavirenz (917). A literature review stated that clear evidence of association between efavirenz and suicide was not available and thus psychiatric history should not exclude patients from efavirenz treatment (18). Given the widespread use of efavirenz and uncertainty about its relationship to suicide, suicide attempt, or suicidal ideation, we report an AIDS Clinical Trials Group cross-protocol analysis of 4 studies in which participants were randomly assigned to an initial efavirenz-containing or efavirenz-free antiretroviral regimen. Our primary goal was to compare the hazard of suicidality between participants assigned to an efavirenz-containing versus efavirenz-free antiretroviral regimen for initial treatment of HIV-1, a potential safety issue not reported in the original studies. Supplement. Original Version (PDF) Methods Study Design and Participants Individual-level data from antiretroviral-naive participants with HIV-1 in AIDS Clinical Trials Group studies conducted from 2001 to 2010 that involved random assignment to an efavirenz-containing or efavirenz-free regimen were included in this prespecified retrospective cross-study analysis. Four studies met these criteria: A5095 (ClinicalTrials.gov: NCT00013520) (19, 20), A5142 (NCT00050895) (21), A5175 (NCT00084136) (22), and A5202 (NCT00118898) (23). Components of the antiretroviral regimen were randomly assigned, except for the nucleoside analogue choice in A5142. The studies varied by antiretroviral regimen and slightly by duration and eligibility criteria (Table 1); each study excluded participants with substantially abnormal baseline laboratory values. Histories of suicidal ideation or attempt were not exclusion criteria. Studies A5095 and A5202 enrolled participants in the United States and Puerto Rico; A5142 enrolled participants in the United States and South Africa; and A5175 enrolled participants from 9 countries in North and South America, Africa, and Asia. Table 1. Summary of Included Studies* Study protocols required reporting of signs, symptoms, or diagnoses at each visit, which were recorded with both open-text and data-entry codes. In A5175, diagnosis reporting instructions included specific codes for suicidality; the other studies used general psychiatric event codes (for example, psychiatric disorder, specify) plus open-text description. Each study required reporting of severe and life-threatening graded signs or symptoms per the Division of AIDS grading table (24), as well as any sign or symptom, regardless of grade, that led to change in study treatment; diagnoses were not graded. Further, study A5142 required report of all moderate signs or symptoms, and A5095 and A5202 required report of all moderate central nervous system symptoms. Site institutional review boards approved each study; participants provided written informed consent. Randomization Each study used permuted-block randomization; stratification factors and treatment groups are listed in Table 1. Efavirenz was formulated as one 600-mg pill given once daily, with three 200-mg pills given initially in A5095. Efavirenz assignment was open-label in A5142, A5175, and A5202 and was blinded and placebo-controlled in A5095 before a data safety monitoring board (DSMB) recommendation to unblind efavirenz. The DSMB released recommendations mid-study about inferior efficacy in the efavirenz-free group of A5095 (20 February 2003) and A5175 (23 May 2008), after which participants in the efavirenz-free groups were given the option to switch treatment (19, 22). Outcomes The primary outcome of this cross-study analysis was suicidality, defined as suicidal ideation or attempted or completed suicide and identified from signs, symptoms, diagnoses, adverse events, and death data via Medical Dictionary for Regulatory Activities, version 15.0. Prespecified Medical Dictionary for Regulatory Activities preferred terms were completed suicide, suicide attempt, intentional overdose, multiple drug overdose intentional, poisoning deliberate, suicidal ideation, suicidal behaviour, and depression suicidal. Attempted or completed suicide was a secondary outcome. Clinical investigators, blinded to treatment and previous adverse events, independently reviewed death data categorized as suicide, substance abuse, homicide, accident, unknown cause, or other cause (for example, infection, cancer, or organ failure); a secondary outcome included suicidality or fatal injury attributed to substance abuse, homicide, or accident. Covariates Each study protocol required report of prescription medication ongoing within 30 days before entry (denoted recent prestudy); prestudy psychoactive and antidepressant medications were identified from a medication list on the National Institute of Mental Health Web site (25). Psychiatric history was defined as any event in the Medical Dictionary for Regulatory Activities system organ class psychiatric disorders, and depression-related events were classified according to review of psychiatric events data by a psychologist. Prestudy psychiatric measures included psychiatric event history, recent psychoactive medication, depression-related event history, and recent antidepressant medication; presence of event history or prestudy medication was combined into 1 covariate. Additional a priori baseline covariates included geographic region, sex, race or ethnic group, age, pretreatment CD4 count, history of AIDS-defining event, and history of injection drug use (IDU); pretreatment HIV-1 RNA levels, body weight, and body mass index (BMI) at study entry were evaluated post hoc (Appendix Table 1). Analysis of race or ethnic group was limited to white, black, and Hispanic from the United States because of potential social and ethnic differences among countries and low frequencies in other groups and was self-reported and classified according to National Institutes of Health categories. Covariate misclassification was possible; for example, history of psychiatric events or IDU could have been undisclosed or underreported. Appendix Table 1. Baseline Characteristics* Data Synthesis and Statistical Analysis The primary analysis approach was intention-to-treat (ITT). Participant-level data were analyzed according to randomized treatment allocation, with follow-up from randomization to last on-study contact or death; all follow-up in A5095 and A5175 was censored after a DSMB recommendation related to the efavirenz comparison (denoted ITT DSMB). In a sensitivity analysis, follow-up included time from randomization to last on-study contact or death, regardless of DSMB recommendations (denoted ITT); deaths were summarized using the ITT approach. As-treated analyses excluded participants who never started treatment and included follow-up from treatment initiation through the earliest of the following: discontinuation of the assigned efavirenz-containing or efavirenz-free strategy plus 28 days for washout, discontinuation of all antiretroviral therapy plus 28 days, or last on-study contact (denoted as-treated). A sensitivity approach further censored as-treated follow-up at the time of DSMB recommendations (denoted as-treated DSMB). Antiretroviral modifications were allowed for reasons such as toxicity, virologic failure, or DSMB recommendations. Missing baseline data were rare (<1%); thus, covariate-adjusted analyses used a complete-case approach. Crude incidence rates were calculated as the number of cases per total person-years (PYs) at risk, presented as events per 1000 PYs. Incidence rate difference (IR) between treatment groups was quantified by a Mantel-Haenszel estimate, stratified by study, with a 95% CI computed using a rare events variance estimator (26). The primary end point, time to suicidality, is presented with cumulative incidence curves and compared between groups with a Gray test (27), stratified by study, with nonsuicide death considered a competing risk. Estimated efavirenz and baseline covariate associations were quantified by a hazard ratio (HR) from a Cox proportional hazards model, stratified by study. Modification of efavirenz association by covariates was evaluated with interaction terms. The Cox model proportional hazards assumption was evaluated with a piecewise constant hazard with time (24 weeks vs. >24 weeks) and with a log-transformed time variable. An incidence rate ratio for the efavirenz association was estimated from an exact Poisson model, stratified by study, to evaluate sensitivity of the Cox model to low event frequencies. Analyses were conducted 2-sided with a significance level of 0.05, without adjustment for multiplicity, in SAS, versions 9.2 or 9.3 (phreg, genmod) (SAS Institute, Cary, North Carolina), and in R, version 2.15. 1, competing risks package (cmprsk) (www.r-project.org). Role of the Funding Source The National Institute