Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice

Povar-Echeverría, Marina; Comet-Bernad, Macarena; Gasso-Sánchez, Amalia; Ger-Buil, Adriana; Navarro-Aznarez, Herminia; Martínez‐Álvarez, Rosa; Arazo-Garcés, Piedad

doi:10.1016/j.eimce.2020.02.009

Cited by 15 publications

(14 citation statements)

References 18 publications

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“…Most of the adverse drug reactions were neuropsychiatric complications (e.g., insomnia, which is a class effect of INSTIs 32 ), but the effect was usually mild, generally tolerable, and rarely led to discontinuation. 32 We observed a slight rise in serum creatinine from baseline to week 12, but no significant change from week 12 to week 24.…”

Section: Resultsmentioning

confidence: 99%

“…23,31 Taken together, these findings support the use of DTG for maintaining virological suppression due to its potency and high genetic barrier. [3][4][5][6][7]15,16,21,30 Most of the adverse drug reactions were neuropsychiatric complications (e.g., insomnia, which is a class effect of INSTIs 32 ), but the effect was usually mild, generally tolerable, and rarely led to discontinuation. 32 We observed a slight rise in serum creatinine from baseline to week 12, but no significant change from week 12 to week 24.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7]15,16,21,30 Most of the adverse drug reactions were neuropsychiatric complications (e.g., insomnia, which is a class effect of INSTIs 32 ), but the effect was usually mild, generally tolerable, and rarely led to discontinuation. 32 We observed a slight rise in serum creatinine from baseline to week 12, but no significant change from week 12 to week 24. This could most likely be explained by a non-pathogenic tubular blockade of creatinine secretion through OCT2 inhibition rather than a decline in glomerular filtration rate.…”

Section: Discussionmentioning

confidence: 99%

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Virological outcomes and metabolic effects after switching from ritonavir-boosted protease inhibitors to a dolutegravir-based regimen in virologically suppressed patients living with HIV

et al. 2022

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Background A ritonavir-boosted protease inhibitor (PI)-based antiretroviral therapy (ART) regimen can cause abnormal lipid levels and increased incidence of cardiovascular disease. Switching to a dolutegravir (DTG)-based regimen has been shown to improve blood lipid levels, but data in the Thai population are limited. Method A prospective cohort study was conducted at Srinagarind Hospital between April 28, 2021, and April 30, 2022. Patients were eligible if they (1) were over 18 years of age, 2) had received a ritonavir-boosted PI-based regimen for at least three months, and 3) had documented plasma HIV RNA levels below 50 copies/mL within six months before the enrollment. All eligible patients included in the study switched from a ritonavir-boosted PI-based ART regimen to a DTG-based regimen. The primary outcome was changes in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 24. Results Forty-six eligible patients were enrolled, 71.7% of whom were male, with a mean age of 49.4 years. Mean body weight was 62.7 kg and body mass index (BMI) was 22.86 kg/m2. The majority of patients had been on a regimen of boosted atazanavir (ATV/r; 60.9%), followed by boosted lopinavir (LPV/r; 37.0%). Six patients were withdrawn from the study. At week 24 after switching to DTG, LDL-C was significantly lower than at baseline, with a difference of −15.1 mg/dL (95% confidence interval [CI; −23.3 to −6.8]; p-value < 0.001), as were total cholesterol and triglycerides, with differences of −22.1 mg/dL (95% CI [−33.3 to −10.8]; p-value <0.001) and −67.7 mg/dL, (95% CI [−88.3 to −47.0]; p-value 0.001), respectively. There were no significant changes in body weight (0.51 kg; 95% CI [−0.37 to 1.38]; p-value 0.251) or BMI (0.17 kg/m2; 95% CI [−0.14 to 0.48]; p-value 0.284) from baseline to week 24. In addition, 39 of 40 patients (97.5%) maintained virological suppression (HIV RNA <50 copies/mL), with only one patient (2.5%) developing virological failure. Three grade 3 adverse events were observed. Conclusion Switching from a boosted PI-based ART regimen to a DTG-based regimen in people living with HIV/AIDS who had attained prior virological suppression resulted in a significant reduction in total cholesterol, LDL-C, and triglyceride levels, but did not increase the patient’s body weight at 24 weeks of follow-up. Furthermore, the DTG-based regimen was also highly effective in maintaining virological suppression. Trial Registration Thai Clinical Trials Registry, TCTR20210625004.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Virological outcomes and metabolic effects after switching from ritonavir-boosted protease inhibitors to a dolutegravir-based regimen in virologically suppressed patients living with HIV

et al. 2022

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“…INSTI based cART are the current preferred first line clinical regimen in most clinical settings. DTG, an INSTI with the highest CPE score (4) is associated with various neuropsychiatric side effects and a relative high discontinuation rate in the clinic ( Cailhol et al, 2017 ; Povar-Echeverría et al, 2021 ). Therefore, we focused on investigating the potential DTG-mediated toxicity in various BBB models.…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral drugs efavirenz, dolutegravir and bictegravir dysregulate blood-brain barrier integrity and function

2023

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The implementation of combined antiretroviral therapy (cART) significantly reduces the mortality associated with human immunodeficiency virus (HIV) infection. However, complications such as HIV-associated neurocognitive disorders (HAND) remain a major health concern. We hypothesized that the toxicity of antiretroviral drugs (ARVs) may contribute to the pathogenesis of HAND in addition to cerebral viral infection. To address this question, we evaluated the impact of HIV integrase strand transfer inhibitors (dolutegravir and bictegravir), and a non-nucleoside reverse transcriptase inhibitor (efavirenz) on the integrity and permeability of various human and mouse blood-brain barrier (BBB) models, in vitro, ex vivo and in vivo. We observed a significant downregulation of tight junction proteins (TJP1/Tjp1, OCLN/Ocln and CLDN5/Cldn5), upregulation of proinflammatory cytokines (IL6/Il6, IL8/Il8, IL1β/Il1β) and NOS2/Nos2, and alteration of membrane-associated transporters (ABCB1/Abcb1a, ABCG2/Abcg2 and SLC2A1/Slc2a1) mRNA expression, in vitro, in human (hCMEC/D3) and primary cultures of mouse microvascular endothelial cells, and ex vivo in isolated mouse brain capillaries treated with efavirenz, dolutegravir, and/or bictegravir. We also observed a significant increase in BBB permeability in vivo following treatment with the selected ARVs in mice applying NaF permeability assay. Taken together, these results suggest that clinically recommended integrase strand transfer inhibitors such as dolutegravir may exacerbate HIV-associated cerebrovascular pathology, which may contribute to the associated short-term neuropsychiatric side effects and the high incidence of mild forms of HAND reported in the clinical setting.

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“…Finally, among integrase inhibitors (INSTIs), dolutegravir (DTG) is one of the preferred agents in first-line ART and switch strategies. However, observational data highlighted a certain rate of neurological and psychiatric disorders occurring in the course of treatment [ 14 ], owing to drug discontinuation in the variable frequency of PLWH [ 15 , 16 , 17 , 18 , 19 , 20 ], up to a maximum of 9.9% in a single Dutch study [ 21 ]. For other INSTIs such as raltegravir (RAL) and elvitegravir (EVG), the incidence of CNS toxicity reports seems lower in the literature [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Reversibility of Central Nervous System Adverse Events in Course of Art

Taramasso

Orofino

Ricci

et al. 2022

Viruses

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The purpose of this study is to evaluate the frequency of central nervous system adverse events (CNS-AE) on dolutegravir (DTG) and non-DTG containing ART, and their reversibility, in the observational prospective SCOLTA cohort. Factors associated with CNS-AE were estimated using a Cox proportional-hazards model. 4939 people living with HIV (PLWH) were enrolled in DTG (n = 1179) and non-DTG (n = 3760) cohorts. Sixty-six SNC-AE leading to ART discontinuation were reported, 39/1179 (3.3%) in DTG and 27/3760 (0.7%) in non-DTG cohort. PLWH naïve to ART, with higher CD4 + T count and with psychiatric disorders were more likely to develop a CNS-AE. The risk was lower in non-DTG than DTG-cohort (aHR 0.33, 95% CI 0.19–0.55, p < 0.0001). One-year follow-up was available for 63/66 PLWH with CNS-AE. AE resolution was reported in 35/39 and 23/24 cases in DTG and non-DTG cohorts, respectively. The probability of AE reversibility was not different based on ART class, sex, ethnicity, CDC stage, or baseline psychiatric disorder. At the same time, a lower rate of event resolution was found in PLWH older than 50 years (p = 0.017). In conclusion, CNS-AE leading to ART discontinuation was more frequent in DTG than non-DTG treated PLWH. Most CNS-AE resolved after ART switch, similarly in both DTG and non-DTG cohorts.

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Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice

Cited by 15 publications

References 18 publications

Virological outcomes and metabolic effects after switching from ritonavir-boosted protease inhibitors to a dolutegravir-based regimen in virologically suppressed patients living with HIV

Virological outcomes and metabolic effects after switching from ritonavir-boosted protease inhibitors to a dolutegravir-based regimen in virologically suppressed patients living with HIV

Antiretroviral drugs efavirenz, dolutegravir and bictegravir dysregulate blood-brain barrier integrity and function

Reversibility of Central Nervous System Adverse Events in Course of Art

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