Higher Rates of Neuropsychiatric Adverse Events Leading to Dolutegravir Discontinuation in Women and Older Patients

C Hoffmann; T Welz; M Sabranski; M Kolb; E Wolf; H-J Stellbrink; C Wyen


HIV Medicine. 2017;18(1):56-63. 

In This Article

Abstract and Introduction


Objectives Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among the most frequently used antiretroviral agents. However, recent reports have raised concerns about potential neurotoxicity.

Methods We performed a retrospective analysis of a cohort of HIV-infected patients who had initiated an INSTI in two large German out-patient clinics between 2007 and 2016. We compared discontinuation rates because of adverse events (AEs) within 2 years of starting treatment with dolutegravir, raltegravir or elvitegravir/cobicistat. We also evaluated factors associated with dolutegravir discontinuation.

Results A total of 1950 INSTI-based therapies were initiated in 1704 patients eligible for analysis within the observation period. The estimated rates of any AE and of neuropsychiatric AEs leading to discontinuation within 12 months were 7.6% and 5.6%, respectively, for dolutegravir (n = 985), 7.6% and 0.7%, respectively, for elvitegravir (n = 287), and 3.3% and 1.9%, respectively, for raltegravir (n = 678). Neuropsychiatric AEs leading to dolutegravir discontinuation were observed more frequently in women [hazard ratio (HR) 2.64; 95% confidence interval (CI) 1.23–5.65; P = 0.012], in patients older than 60 years (HR: 2.86; 95% CI: 1.42–5.77; P = 0.003) and in human leucocyte antigen (HLA)-B*5701-negative patients who initiated abacavir at the same time (HR: 2.42; 95% CI: 1.38–4.24; P = 0.002).

Conclusions In this large cohort, the rate of discontinuation of dolutegravir because of neuropsychiatric adverse events was significantly higher than for other INSTIs, at almost 6% within 12 months. Despite the limitations of this retrospective study, the almost three-fold higher discontinuation rates observed amongst women and older patients underscore the need for further investigation, especially in patient populations usually underrepresented in clinical trials.


Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) developed by ViiV Healthcare (Brentford, Greater London, UK). Dolutegravir showed a high antiviral potency and a good safety profile in four large randomized clinical trials (RCTs) in treatment-naïve patients and in one RCT in treatment-experienced patients. Among 1579 trial subjects, only 2% experienced an adverse event (AE) leading to discontinuation.[1,3,10,11,15] Dolutegravir has an improved pharmacokinetic and resistance profile compared with the other INSTIs, with the higher resistance barrier probably attributable to prolonged binding with integrase complexes.[5] In addition to its excellent efficacy, dolutegravir has a low interaction potential and is available in two different once-daily formulations, including a single-tablet regimen (STR) co-formulated with abacavir and lamivudine. Consequently, since its approval in 2014, dolutegravir has rapidly gained an important place in the management of HIV infection. However, in recent months, a small case series[6] and a report from a Dutch cohort study[14] have raised concerns about the safety of dolutegravir in real-life settings, especially with regard to neuropsychiatric AEs. This led us to review data on INSTI use in our own cohort with a specific focus on neuropsychiatric AEs leading to INSTI discontinuation.