An update on neuropsychiatric adverse effects with second-generation integrase inhibitors and nonnucleoside reverse transcriptase inhibitors

Neuropsychiatric adverse effects (NPAE) associated with integrase strand transfer inhibitors (INSTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a growing concern, with higher rates in the real-world compared to phase III trials. This paper reviews the incidence, risk factors, and management of NPAE with second-generation INSTIs, INSTI/rilpivirine dual therapy, and doravirine.Recent cohort data confirm up to 8% NPAE-associated discontinuations for dolutegravir; NPAE with dolutegravir/rilpivirine therapy are higher than with dolutegravir alone, whereas bictegravir appears similar to dolutegravir. In contrast, NPAE with cabotegravir alone or with rilpivirine appears to be low. Doravirine has NPAE rates similar to rilpivirine and lower than efavirenz. Risk factors for NPAE include female gender, concurrent abacavir use, Sub-Saharan African descent, and age, whereas underlying psychiatric conditions do not appear to increase risk. Strategies to manage NPAE include changing administration time, therapeutic drug monitoring, or regimen modification including within-class INSTI changes. People experiencing NPAE with dolutegravir may tolerate bictegravir.Overall, mild to moderate NPAE are associated with INSTIs and newer NNRTIs. Rarely, more severe symptoms may occur and lead to treatment discontinuation. Clinicians should be aware of NPAE to identify and manage drug-related adverse effects.