Real-world discontinuations due to neuropsychiatric symptoms in people living with HIV treated with second-generation integrase inhibitors: a systematic review

Pérez‐Valero, Ignacio; Corona, Diana; Martínez, Natàlia; López-Cavanillas, María; Lluis, Carla; Luque, Isabel

doi:10.1080/14787210.2023.2203914

Cited by 8 publications

(2 citation statements)

References 87 publications

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“…However, in our assay DTG did not evoke synaptic changes. Discontinuation rates due to neuropsychiatric symptoms are generally elevated in DTG-containing regimens relative to those containing BIC ( Pérez-Valero et al, 2023 ) which produced robust synapse loss in our assay. Thus, the automated synapse loss assay does not capture all mechanisms that lead to adverse neuropsychiatric symptoms and the induction of synapse loss was not uniform across drugs within a given class.…”

Section: Discussionmentioning

confidence: 93%

Antiretroviral drugs from multiple classes induce loss of excitatory synapses between hippocampal neurons in culture

McMullan,

Gansemer,

Thayer

2024

Front. Pharmacol.

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Introduction: Antiretroviral (ARV) drugs have improved prognoses for people living with HIV. However, HIV-associated neurocognitive disorders (HAND) persist despite undetectable viral loads. Some ARVs have been linked to neuropsychiatric effects that may contribute to HAND. Synapse loss correlates with cognitive decline in HAND and synaptic deficits may contribute to the neuropsychiatric effects of ARV drugs.Methods: Using an automated high content assay, rat hippocampal neurons in culture expressing PSD95-eGFP to label glutamatergic synapses and mCherry to fill neuronal structures were imaged before and after treatment with 25 clinically used ARVs.Results and Discussion: At a concentration of 10 μM the protease inhibitors nelfinavir and saquinavir, the non-nucleoside reverse transcriptase inhibitors etravirine and the 8-OH metabolite of efavirenz, the integrase inhibitor bictegravir, and the capsid inhibitor lenacapavir produced synaptic toxicity. Only lenacapavir produced synapse loss at the nanomolar concentrations estimated free in the plasma, although all 4 ARV drugs induced synapse loss at Cmax. Evaluation of combination therapies did not reveal synergistic synaptic toxicity. Synapse loss developed fully by 24 h and persisted for at least 3 days. Bictegravir-induced synapse loss required activation of voltage-gated Ca2+ channels and bictegravir, etravirine, and lenacapavir produced synapse loss by an excitotoxic mechanism. These results indicate that select ARV drugs might contribute to neuropsychiatric effects in combination with drugs that bind serum proteins or in disease states in which synaptic function is altered. The high content imaging assay used here provides an efficient means to evaluate new drugs and drug combinations for potential CNS toxicity.

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Section: Discussionmentioning

confidence: 93%

Antiretroviral drugs from multiple classes induce loss of excitatory synapses between hippocampal neurons in culture

McMullan,

Gansemer,

Thayer

2024

Front. Pharmacol.

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“…These findings are different from those reported in clinical trials [6,7,11,12,15,16,[39][40][41], previous observational studies [10,[43][44][45], and real-life cohorts [36,37], which showed that neuropsychiatric adverse events (NPAEs) and gastrointestinal toxicity were the main cause of discontinuation of INIs. In a meta-analysis, Pérez-Valero et al reported that TD due to NPAEs was higher for DTG-based regimens than for TAF/FTC/BIC [46]. However, the evidence of TAF/FTC/BIC versus DTG/3TC discontinuation in relation to neuropsychiatric symptoms is inconsistent [32,35,47].…”

Section: Discussionmentioning

confidence: 99%

Dolutegravir/Lamivudine versus Tenofovir Alafenamide/Emtricitabine/Bictegravir as a Switch Strategy in a Real-Life Cohort of Virogically Suppressed People Living with HIV

De Socio,

Tordi,

Altobelli

et al. 2023

JCM

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Background: The aim of the study is to evaluate the effectiveness, safety, and tolerability of a two-drug regimen (2-DR) dolutegravir/lamivudine (DTG/3TC) versus a three-drug regimen (3-DR) tenofovir alafenamide/emtricitabine/bictegravir (TAF/FTC/BIC) in a real-life cohort of HIV-1 virologically suppressed treatment-experienced (TE) people living with HIV (PLWH). Methods: This was a single-center, retrospective, observational study analyzing adult TE PLWH who started the 2-DR or 3-DR between January 2018 and January 2023. All PLWH with a viral load (VL) <50 copies/mL at the time of switching, and a follow-up of more than 6 months or interruption of treatment at any time, were included. Results: A total of 324 PLWH were included; of these, 110 (34%) were on the 2-DR and 214 (66%) were on the 3-DR. Most patients remained on therapy in both groups (93.6% 2-DR versus 90.2% 3-DR) and, at the last control, 99.1% achieved VL < 50 copies/mL with the 2-DR versus 97.2% with the 3-DR (p = 0.260). No virological failures occurred in either group. Adverse events occurred in a few cases: four (3.6%) in the 2-DR group and five (2.3%) in the 3-DR group (p = 0.500). The median follow-up-time was 19.6 months for the 2-DR and 27.5 months for the 3-DR. Conclusion: Our study shows a similar effectiveness and safety profile in virologically suppressed PLWH switching to DTG/3TC or TAF/FTC/BIC.

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Therapeutic Considerations in HIV-Associated Neurocognitive Disorders (HAND)

Adelsberg,

Kolson

2024

Neuroimmune Pharmacology and Therapeutics

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Real-world discontinuations due to neuropsychiatric symptoms in people living with HIV treated with second-generation integrase inhibitors: a systematic review

Cited by 8 publications

References 87 publications

Antiretroviral drugs from multiple classes induce loss of excitatory synapses between hippocampal neurons in culture

Antiretroviral drugs from multiple classes induce loss of excitatory synapses between hippocampal neurons in culture

Dolutegravir/Lamivudine versus Tenofovir Alafenamide/Emtricitabine/Bictegravir as a Switch Strategy in a Real-Life Cohort of Virogically Suppressed People Living with HIV

Therapeutic Considerations in HIV-Associated Neurocognitive Disorders (HAND)

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