Objective and Subjective Improvement of Cognition After Discontinuing Efavirenz in Asymptomatic Patients: A Randomized Controlled Trial

Abstract

Background: Efavirenz is well known for its clinical cognitive side effects. Even asymptomatic patients who switch for other reasons than neurocognitive complaints have reported a subjective improvement in cognitive functioning after discontinuing efavirenz. The aim of this study was to assess the effect on cognition of switching Atripla (TDF/FTC/EFV) to Eviplera (TDF/FTC/RPV), hypothesizing an improvement when discontinuing efavirenz. Setting: A randomized controlled design with a highly comparable comparator drug was used to minimize bias and to differentiate drug versus learning effects. An extensive sensitive neuropsychological assessment (NPA) was used to detect subtle changes. Methods: Virologically suppressed, cognitively asymptomatic male HIV-infected patients on Atripla were included and randomized (2:1) to switch to Eviplera (switch group) or continue on Atripla (control group) for 12 weeks. At baseline and week 12, patients underwent an extensive NPA. Results: Fourteen control and 34 switch subjects completed the study. There were no differences at baseline. Group analysis demonstrated a significantly better improvement for the switch group on the domains attention (P = 0.041) and speed of information processing (P = 0.014). Normative comparison analyses showed that 5 of the 34 patients who switched (15%) improved on NPA score as compared to the control group. Interestingly, subjective improvement after discontinuing efavirenz made 74% of the switch group chose for a regime without efavirenz after study completion. Conclusions: Switching from Atripla to Eviplera resulted in objective cognitive improvement on the group level in cognitively asymptomatic patients. Discrepancies in objective and subjective cognitive complaints make it challenging to identify patients who would benefit from discontinuing efavirenz.

Cognitive and Neurologic Rehabilitation Strategies for Central Nervous System HIV Infection

“…Other cART optimisation strategies include a switch from regimes that have been associated with poor neurocognitive performance, particularly efavirenz. Neuropsychological symptoms, and in some cases objective neuropsychological dysfunction, have been noted as side effects of using efavirenz in cART regimes [15], and switching from efavirenz-containing regimes has been associated with improved well-being but not always cognitive benefit in formal testing [37].…”

“…Poorly controlled cardiovascular risk factors such as diabetes or hypertension are associated with poorer cognitive outcomes in PLWH [36][37][38][39]. Studies in improved management of those diseases have shown mixed results in improving cognition [42].…”

High efavirenz levels but not neurofilament light plasma levels are associated with poor neurocognitive functioning in asymptomatic HIV patients

“…This study is a sub-analysis of the ESCAPE trial (Effect of SwitChing AtriPla to Eviplera on neurocognitive and emotional functioning) which was previously published (Hakkers et al 2019 ). In short, this randomised controlled trial included neurologically asymptomatic, stable (i.e.…”

“…Even in patients without clinically manifested cognitive complaints (cognitively asymptomatic patients), a negative effect of efavirenz on cognition has been shown (Robertson et al 2010). In the ESCAPE study, we found that discontinuing efavirenz led to an objective improvement in neurocognitive functioning in a group of asymptomatic people with HIV (Hakkers et al 2019). However, efavirenz remains a popular choice in antiretroviral therapy, mainly in resource-limited settings, mainly because is it part of Atripla, a single-tablet regime that is relatively cheap and has a convenient once a day dosage.…”

High-content analysis and Kinetic Image Cytometry identify toxic and epigenotoxic effects of HIV antiretrovirals on human iPSC-neurons and primary neural precursor cells

“…For example, cART leads to reduced Myelin Basic Protein in the prefrontal cortex of HAND subjects 19 , and HIV+ subjects that withdraw from cART demonstrate improved cognition 20 . EFV (NNRTI) is linked neuropsychiatric effects (e.g., nightmares, dizziness, depression) and cognitive impairment [21][22][23] . Dolutegravir (DTG) is also linked to neuropsychiatric effects (sleep disturbance, depression) [24][25][26][27] .…”