Increased Dolutegravir Peak Concentrations in People Living With Human Immunodeficiency Virus Aged 60 and Over, and Analysis of Sleep Quality and Cognition

Elliot, Emilie R; Wang, Xinzhu; Singh, Suveer; Simmons, Bryony; Vera, Jaime H.; Miller, R F; Fitzpatrick, Colin; Moyle, Graeme; McClure, Myra O.; Boffito, Marta

doi:10.1093/cid/ciy426

Cited by 56 publications

(40 citation statements)

References 34 publications

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“…Ral-Age study [57•] reported that switching to a RAL-containing regimen in PLWH over 60 years old showed a statistically significant reduction of median values of triglycerides (p = 0.0001) as well as of cholesterol at 36 months of follow-up (p = 0.0023). Significantly increased dosages of DTG were found in patients 9 60 years [26], potentially explaining reported association between age and DTG NP effects.…”

Section: Aging Patientsmentioning

confidence: 80%

“…Moreover, some authors found risk factors associated with NP side effects with DTG, with higher risk among women, those aged 60 years and more and those who started abacavir (ABC) at the same time as DTG vs those who did not [11,23,26]. Some data on therapeutic drug monitoring suggest that morning dosing or reducing dosage of DTG could reduce the NP effects [26,27].…”

Section: Neuropsychiatric Symptomsmentioning

confidence: 99%

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Update on Adverse Effects of HIV Integrase Inhibitors

Kołakowska

Maresca

Collins

et al. 2019

Curr Treat Options Infect Dis

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Keywords HIV integrase inhibitors I Drug-related side effects and adverse reactions I Raltegravir I Elvitegravir I Dolutegravir Abstract Purpose of review The goal of this paper is to provide an up-to-date review of adverse events related to the class of integrase strand transfer inhibitors (INSTIs), which became the class of choice in few years. We sought answers specifically to issues pertaining to neuropsychiatric adverse events, as well as weight gain, which were the two most important categories of adverse events raised in recent studies based on real-life experience. The primary focus of this paper is on adults with a brief summary on pregnant women and children/adolescents. Recent findings Dolutegravir (DTG) bears the heaviest burden of neuropsychiatric side effects. Weight gain was reported with all INSTIs, although there are methodological caveats in the analyses and the findings need to be interpreted with caution. Moreover, due to recent findings on neural tube defects in infants exposed to dolutegravir during their peri-conception period, its use is not recommended for women of childbearing age without proper birth control method, while raltegravir remains the only drug which may be prescribed without caution. Given the importance of cognitive and metabolic comorbidities in people living with HIV in regard to their quality of life, future research needs to focus on long-term effects of INSTIs in relation to these adverse events. Pharmacogenetics seems to be a promising tool. Safety during pregnancy is also another important issue to further clarify. Summary INSTIs are a generally well-tolerated class of antiretrovirals (ARV), and has a

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Section: Aging Patientsmentioning

confidence: 80%

Section: Neuropsychiatric Symptomsmentioning

confidence: 99%

Update on Adverse Effects of HIV Integrase Inhibitors

Kołakowska

Maresca

Collins

et al. 2019

Curr Treat Options Infect Dis

View full text Add to dashboard Cite

show abstract

“…This would suggest an association between dolutegravir C max , rather than AUC or C min , and sleep disorders. A study prospectively designed to ascertain the association between dolutegravir pharmacokinetics and sleep quality found no sleep impairment with higher dolutegravir C max . Not surprisingly, this study dosed dolutegravir in the morning to allow for steady‐state pharmacokinetic measurements.…”

Section: Discussionmentioning

confidence: 79%

“…However, unexpectedly, sleep or cognition changes did not correlate with pharmacokinetics in these older subjects [26]. Higher drug concentrations are universally reported in older people, with a 25% dolutegravir C max increase in people ≥ 60 years old, but increased rates of NPAEs have only been seen in some series [20,25,39]. In agreement with all these data and other series, we did not identify higher dolutegravir-related NPAE rates in older people, a group under-represented in RCTs [43].…”

Section: Discussionmentioning

confidence: 86%

“…Older people (> 60 years old) have significantly higher dolutegravir plasma C max levels (but not C 24 , AUC 0–24 (area under the curve) or t 1/2 ) . There is disagreement over whether this higher dolutegravir exposure correlates with NPAEs . In addition, in a single‐arm trial using a double dose of dolutegravir (100 mg daily instead of 50 mg) the safety profile was similar, suggesting a lack of association between NPAEs and dolutegravir plasma exposure .…”

Section: Introductionmentioning

confidence: 99%

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Discontinuation of dolutegravir, elvitegravir/cobicistat and raltegravir because of toxicity in a prospective cohort

et al. 2019

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Objectives The aim of the study was to assess the rates of discontinuation of integrase inhibitor regimens because of any neuropsychiatric adverse event (NPAE) and the factors associated with discontinuation. Methods A population‐based, prospective, multicentre cohort study was carried out. Treatment‐naïve subjects starting therapy with a regimen containing integrase inhibitors, or those switching to such a regimen, with plasma HIV‐1 RNA < 50 HIV‐1 RNA copies/mL in 14 hospitals in Catalonia or the Balearic Islands (Spain) were included in the study. Every discontinuation because of adverse events (AEs) was double‐checked directly with treating physicians. Multivariable Cox models identified factors correlated with discontinuation. Results A total of 4165 subjects (37% treatment‐naïve) started regimens containing dolutegravir (n = 1650; 91% with abacavir), raltegravir (n = 930) or elvitegravir/cobicistat (n = 1585). There were no significant differences among regimens in the rate of discontinuation because of any AE. Rates of discontinuation because of NPAEs were low but higher for dolutegravir/abacavir/lamivudine [2.1%; 2.9 (95% confidence interval (CI) 2.0, 4.2) discontinuations/100 patients/year] versus elvitegravir/cobicistat (0.5%; 0.8 (95% CI 0.3, 1.5) discontinuations/100 patients/year], with significant differences among centres for dolutegravir/abacavir/lamivudine and NPAEs (P = 0.003). We identified an association of female gender and lower CD4 count with increased risk of discontinuation because of any AE [Incidence ratio (IR) 2.3 (95% CI 1.4, 4.0) and 1.8 (95% CI 1.1, 2.8), respectively]. Female gender, age > 60 years and abacavir use were not associated with NPAE discontinuations. NPAEs were commonly grade 1–2, and had been present before and improved after drug withdrawal. Conclusions In this large prospective cohort study, patients receiving dolutegravir, raltegravir or elvitegravir/cobicistat did not show significant differences in the rate of discontinuation because of any toxicity. The rate of discontinuations because of NPAEs was low, but was significantly higher for dolutegravir than for elvitegravir/cobicistat, with significant differences among centres, suggesting that greater predisposition to believe that a given adverse event is caused by a given drug of some treating physicians might play a role in the discordance seen between cohorts.

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Development and validation of an HPLC method for quantification of dolutegravir in human plasma

Li,

Fu,

et al. 2023

Biomedical Chromatography

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Dolutegravir (DTG) has been the first‐line drug in many human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) guidelines for the treatment of naïve and experienced HIV‐infected individuals, which calls for cost‐effective and convenient methods for quantitative detection of DTG in human plasma for pharmacokinetic studies and patient adherence evaluation. Here, an HPLC–ultraviolet method in combination with liquid–liquid extraction with isocratic elution was developed for the first time. The analysis was performed on a CLC‐ODS column (6 mm internal diameter × 15 cm, 5 μm) using a mixture of acetonitrile and phosphate buffer (40:60, v/v) as the mobile phase at the flow rate of 1 mL/min. Using triamcinolone as the internal standard, 100 μL of plasma sample was extracted by methyl tert‐butyl ether, followed by evaporating under nitrogen stream, re‐dissolving with 100 μL mobile phase, and injection of 20–40 μL of supernatant into the chromatographic system. The linearity of DTG was good in the range of 0.05–10 μg/mL (r = 0.9995), and the inter‐ and intra‐day variabilities were 0.4%–4.3% (n = 10) and 1.2%–6.2% (n = 10) for the lower limit of quantification, low‐, medium‐, and high‐concentration quality control samples (0.05, 0.1, 0.8, and 8 μg/mL), respectively, while the methodological and extraction recoveries were 98.0%–103.0% (n = 20) and 65.2%–75.7% (n = 3), respectively. This method was successfully applied to analyze DTG plasma concentration in 84 Chinese patients with HIV.

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Increased Dolutegravir Peak Concentrations in People Living With Human Immunodeficiency Virus Aged 60 and Over, and Analysis of Sleep Quality and Cognition

Abstract: DTG Cmax was significantly higher in older PLWH. Our data provides clinicians with key information on the safety of prescribing DTG in older PLWH.

Cited by 56 publications

References 34 publications

Update on Adverse Effects of HIV Integrase Inhibitors

Update on Adverse Effects of HIV Integrase Inhibitors

Discontinuation of dolutegravir, elvitegravir/cobicistat and raltegravir because of toxicity in a prospective cohort

Development and validation of an HPLC method for quantification of dolutegravir in human plasma

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