Abstract
ObjectiveTo assess the potential association of selected antiretrovirals (ARVs), including efavirenz, with suicidality.DesignRetrospective analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS), by performing a Multi-Item Gamma Poisson Shrinker (MGPS) disproportionality analysis.MethodsMGPS disproportionality analysis, a technique to identify associations between drugs and adverse events, was performed using cumulative data from the FAERS database collected up to August 2012. This method yields an Empirical Bayesian Geometric Mean score and corresponding 90% confidence interval (EB05, EB95). EB05 scores ≥2 were pre-defined as a signal for a potential drug-event association. The FAERS database includes spontaneous adverse-event reports from consumers and healthcare professionals. All FAERS reports of suicidality (including suicidal ideation, suicide attempt and completed suicide or a composite of these) in patients taking efavirenz (as single agent or in fixed-dose combination), atazanavir, darunavir, etravirine, nevirapine and raltegravir were identified. A number of parallel analyses were performed to assess the validity of the methodology: fluoxetine and sertraline, antidepressants with a known association with suicidality, and raltegravir, an ARV with rhabdomyolysis and myopathy listed as “uncommon” events in the US-prescribing information.ResultsA total of 29,856 adverse event reports were identified among patients receiving efavirenz, atazanavir, darunavir, etravirine, nevirapine and raltegravir, of which 457 were reports of suicidality events. EB05 scores observed for the composite suicidality term for efavirenz (EB05=0.796), and other ARVs (EB05=0.279–0.368), were below the pre-defined threshold. Fluoxetine and sertraline gave EB05 scores for suicidality >2. Raltegravir gave EB05 scores >2 for myopathy and rhabdomyolysis.ConclusionsThe pre-determined threshold for signals for suicidality, including suicidal ideation, suicide attempt, completed suicide and a composite suicidality endpoint, was not exceeded for efavirenz and other ARVs in this analysis. Efavirenz has been associated with suicidality in clinical trials. Further studies that adjust for confounding factors are needed to better understand any potential association with ARVs and suicidality.
Highlights
Efavirenz is a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in combination with other antiretrovirals (ARVs)
A pooled analysis of four AIDS Clinical Trial Group (ACTG) studies, which included 5332 subjects, identified an increased risk of suicidality in efavirenz-containing regimens compared to regimens containing atazanavir, atazanavir/ritonavir, lopinavir/ ritonavir and zidovudine/lamivudine/abacavir [5]
Disproportionality scores (EB05) for suicidality observed for efavirenz were below the threshold of 2
Summary
Efavirenz is a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in combination with other antiretrovirals (ARVs). Rare but serious psychiatric adverse events, including severe depression, suicidal ideation, nonfatal suicide attempts and completed suicide, have been reported in clinical trials and in post-marketing surveillance among patients taking efavirenz [1Á4]. The Food and Drug Administration Adverse Event Reporting System (FAERS, formerly AERS) is a database set up to support the FDA’s post-marketing surveillance programme by recording adverse events spontaneously reported by consumers and healthcare professionals to the FDA or manufacturers [6]. As there is no measure of the total number of patients exposed to a particular drug in a spontaneously reported adverse event database, it is not possible to estimate the rate of adverse events. Drug-event pair disproportionality analysis is a method to identify potential signals for drug-associated adverse events using spontaneous adverse event reporting surveillance databases [7Á9]. Simple methods for disproportionality analysis can be utilized, but when the number of events is small, large estimates with wide confidence
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