Reported rates of neuropsychiatric adverse events (NPAEs) leading to Dolutegravir (DTG) discontinuation in clinical routine have been markedly higher than seen in randomized trials (RCTs), in particular in female and in older pts. It has been speculated that this may be due to higher background rates of psychiatric conditions in HIV+ pts and/or elevated plasma drug levels in specific populations.
In this single center study, charts of all HIV+ pts who had initiated DTG outside RCTs were evaluated for depressive disorders or other neuropsychiatric diagnoses (ICD-10-CM, Diagnosis Codes F01-F99). In addition, DTG plasma levels from frozen samples collected at various time points after drug intake of pts discontinuing DTG due to NPAEs were measured by liquid chromatography coupled with tandem mass spectrometry (LC−MS/MS). Levels were compared with levels of a control group of pts with a comparable age and gender distribution who had continued DTG containing regimens for at least one year without reported neuropsychiatric problems.
In total, 861 pts (768 males, median age 47.1 years) had initiated DTG outside RCTs since 2014, among them 151 treatment-naïve and 710 treatment-experienced pts. There were 155 pts (18.0%) with depressive disorders and 55 pts (6.4%) with other neuropsychiatric diagnoses. After a median follow-up of 19.6 months, 54/861 pts (6.3%) had discontinued DTG due to NPAEs, mainly sleep disorders (74%), dizzyness (52%), and paraesthesia (33%). NPAEs leading to discontinuation were observed more frequently in women (hazard ratio [HR] 2.31; 95% confidence interval [CI] 1.12-4.74, p=0.03), in patients older than 60 years (HR 2.14; 95% CI 1.10-4.18, p=0.025), but not in patients with depressive disorders (HR 1.00; 95% CI 0.54-1.88, p=0.952) or other neuropsychiatric diagnoses (HR 0.93; 95% CI 0.29-3.00, p=0.896). In 37 patients who had discontinued DTG due to NPAEs of whom stored samples were available, population plasma drug levels of DTG including peak levels did not differ substantially from control pts who did not discontinue DTG due to NPAEs.
In this large cohort of HIV+ patients exposed to DTG in clinical routine, discontinuation due to NPAEs was around 6 %. Drug discontinuation was not associated with a pre-existing or prevalent depression or with other neuropsychiatric diagnoses, but with female sex and older age. The effect of DTG plasma exposure on the occurrence of NPAEs appears to be limited.