Randomized Trial Evaluating the Neurotoxicity of Dolutegravir/Abacavir/Lamivudine and Its Reversibility After Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide: GESIDA 9016

Abstract

Background Despite evidence shown of dolutegravir-related neurotoxicity, which may be more common when combined with abacavir, its reversibility has not been explored in a clinical trial. Methods Randomized, multicentre, open-label, pilot-trial to evaluate the reversibility of patient-reported neuropsychiatric symptoms, developed or worsened on dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), in virologically suppressed patients switched to cobicistat-boosted-elvitegravir/emtricitabine/tenofovir-alafenamide (EVG/COBI/FTC/TAF). Participants were randomized to immediate switch (baseline) or to defer switch (week 4) and then, all completed 24 weeks of follow up on EVG/COBI/FTC/TAF. At each visit, participants completed Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression (HAD) scales and were interviewed about 11 neuropsychiatric symptoms potentially related with DTG through a questionnaire. At baseline and at the end of follow-up, they also performed neurocognitive testing. Our primary objective was to compare changes in neuropsychiatric symptoms and PSQI and HAD scales between arms at week 4. Secondary objectives were to evaluate changes in neuropsychiatric symptoms and PSQI and HAD scales at weeks 4, 12 and 24 after switching to EVG/COBI/FTC/TAF and in neurocognitive performance and MRI biomarkers at end of follow up. Results Thirty-eight participants were included. Study arms were similar at baseline. At week 4, neuropsychiatric symptoms and PSQI and HAD scores remained unchanged in participants receiving DTG/ABC/3TC while improved significantly in participants receiving EVG/COBI/FTC/TAF. These significant improvements were also observed at weeks 4, 12 and 24 after all participants switched to EVG/COBI/FTC/TAF. Also, global neurocognitive performance improved (NPZ-7) after switching to EVG/COBI/FTC/TAF. Conclusion Neuropsychiatric symptoms in patients on DTG/ABC/3TC could resolve or improve after switching to EVG/COBI/FTC/TAF.

Changes in Quality of Sleep, Mood, and Other Neuropsychiatric Symptoms After Switching Dolutegravir/Lamivudine/Abacavir to Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in a Randomized Study of People With Human Immunodeficiency Virus With Poor Sleep Quality: GESIDA 10418

“…In concordance with previous reports [ 3 , 5 , 8 ], we observed significant improvements but not complete reversibility of all the neuropsychiatric symptoms detected. This could be explained due to a relatively short period of observation (8 weeks) or due to the possibility that some of these disturbances, which are common among PWH and in the general population, could be unrelated to the medications; however, the chance of continued neurotoxicity from the new regimen cannot be completely ruled out.…”

“…Our results reinforced the association between the use of DTG and the presence of sleep disturbances and insomnia seen by Hill et al [ 7 ] in their metanalysis of DTG phase 3 clinical trials. In PWH reporting insomnia and neuropsychiatric adverse events, we confirmed the partial reversibility of those adverse events observed in several cohorts and in the DREAM trial after switching DTG/3TC/ABC to another regimen [ 2–6 , 8 ]. In addition, in people without insomnia, we show for the first time that switching DTG/3TC/ABC to another ART (DRV/COBI/FTC/TAF) was associated with a reduction in sleep disturbances, with an improvement in the quality of sleep.…”

“…Third, the study had a shorter follow-up than previous studies evaluating ART-related neurotoxicity. We do not know the long-term evolution of symptomatic changes observed after switching to DRV/COBI/FTC/TAF, and, based on the results of studies with a similar design but with a larger follow up [ 8 , 16–18 ], we do not expect long-term changes of tendency in symptomatic results.…”

“…In addition to the conventional procedures of HIV clinical trials, participants completed 3 patient-reported outcome (PRO) questionnaires at each visit: the PSQI, the Hospital Anxiety and Depression scale (HADS), and a neuropsychiatric symptoms score (defined as DETOX score) obtained by adding the severity grade (0, none; 1, mild; 2, moderate; and 3, severe) reported in the 11 neurological and psychiatric symptoms included in the US Division of AIDS table for grading the severity of adverse events [ 12 ]. The first 2 questionnaires have been validated for their use in PWH and can be widely used for assessing sleep and mood disturbances [ 13–15 ], whereas the third questionnaire has been used as a valid tool in several clinical trials to evaluate ART-related neurotoxicity [ 8 , 16 ].…”

“…A meta-analysis of randomized clinical trials reported a higher risk of developing insomnia with DTG (6.1%) than with other antiretrovirals (4.5%) [ 7 ]. In addition, a clinical trial designed to evaluate DTG/3TC/ABC neurotoxicity and its reversibility, which includes virologically suppress people with human immunodeficiency virus (PWH) reporting neuropsychiatric symptoms after starting DTG/3TC/ABC, revealed improvements in sleep, mood, and neuropsychiatric symptoms after switching from DTG/3TC/ABC to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) [ 8 ].…”