Doravirine/lamivudine/tenofovir disoproxil fumarate-induced hypertriglyceridemia in a newly diagnosed AIDS patient

Barchi, Virginia; Rindi, Lorenzo Vittorio; Iannazzo, Roberta; Massa, Barbara; Simone, G.; Andreoni, Massimo; Sarmati, Loredana; Iannetta, Marco

doi:10.1097/qad.0000000000003370

Cited by 2 publications

(3 citation statements)

References 9 publications

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“…Conversely, in this study, no accumulation of lipids was observed in the embryo liver until 144 hpf after DOR exposure, suggesting that DOR, at therapeutic concentrations, would not likely exert profound deleterious effects on lipid metabolism in the liver, in contrast to the effects exerted by EFV [49]. Also, we did not observe further gross alterations in neutral lipid distribution in the DOR-treated embryos, in agreement with the previous observation in that in clinical trials, DOR-based regimens have demonstrated to possess a superior lipid profile compared with the EFV-based regimens [25][26][27], although greater weight increase at 48 weeks after DOR treatment has been observed [36][37][38][39]. Currently, there are several ongoing trials that have been aimed to verify whether people living with HIV who had a significant weight gain after starting an INSTI regimen could improve their metabolic and cardiovascular health (loss weight, waist circumference, and fat and lean mass body composition) within about 1 year if they switch to a regimen containing DOR [54].…”

Section: Discussionsupporting

confidence: 91%

“…Hypertriglyceridemia (500-1000 mg/dL) has been reported as a rare side effect in patients treated with DOR in the same trials (accounting for 0.3-0.6% of patients). Very few post marketing or real-life studies on DOR safety have been published, with most of them showing a favorable metabolic impact of the DOR-based regimens with improvements in the cardiovascular risk parameters [36][37][38][39]. Hepatic safety was also confirmed in these real-life studies [38].…”

Section: Discussionmentioning

confidence: 93%

“…Currently, there are several ongoing trials that have been aimed to verify whether people living with HIV who had a significant weight gain after starting an INSTI regimen could improve their metabolic and cardiovascular health (loss weight, waist circumference, and fat and lean mass body composition) within about 1 year if they switch to a regimen containing DOR [54]. Nonetheless, very few studies on DOR safety have been published [36][37][38][39], but most of them show a favorable metabolic impact of these DOR-based regimens. Our results further confirm those observations in humans.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Efavirenz and Doravirine Developmental Toxicity in an Embryo Animal Model

Zizioli

Ferretti

Tiecco

et al. 2023

IJMS

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In the past, one of the most widely used non-nucleoside reverse transcriptase inhibitors (NNRTI) in first-line antiretroviral therapy (ART) of HIV infection was efavirenz (EFV), which is already used as a cost-effective treatment in developing countries due to its efficacy, tolerability, and availability. However, EFV also demonstrates several adverse effects, like hepatotoxicity, altered lipid profile, neuropsychological symptoms, and behavioral effects in children after in utero exposure. In 2018, another NNRTI, doravirine (DOR), was approved due to its similar efficacy but better safety profile. Preclinical safety studies demonstrated that DOR is not genotoxic and exhibits no developmental toxicity or effects on fertility in rats. Zebrafish (Danio rerio) embryos have been widely accepted as a vertebrate model for pharmacological and developmental studies. We used zebrafish embryos as an in vivo model to investigate the developmental toxicity of DOR compared to EFV. After exposure of the embryos to the drugs from the gastrula stage up to different developmental stages (30 embryos for each arm, in three independent experiments), we assessed their survival, morphology, hatching rate, apoptosis in the developing head, locomotion behavior, vasculature development, and neutral lipid distribution. Overall, DOR showed a better safety profile than EFV in our model. Therapeutic and supra-therapeutic doses of DOR induced very low mortality [survival rates: 92, 90, 88, 88, and 81% at 1, 5, 10, 25, and 50 μM, respectively, at 24 h post fecundation (hpf), and 88, 85, 88, 89, and 75% at the same doses, respectively, at 48 hpf] and mild morphological alterations compared to EFV exposure also in the sub-therapeutic ranges (survival rates: 80, 77, 69, 63, and 44% at 1, 5, 10, 25, and 50 μM, respectively, at 24 hpf and 72, 70, 63, 52, and 0% at the same doses, respectively, at 48 hpf). Further, DOR only slightly affected the hatching rate at supra-therapeutic doses (97, 98, 96, 87, and 83% at 1, 5, 10, 25, and 50 μM, respectively, at 72 hpf), while EFV already strongly reduced hatching at sub-therapeutic doses (83, 49, 11, 0, and 0% at 1, 5, 10, 25, and 50 μM, respectively, at the same time endpoint). Both DOR at therapeutic doses and most severely EFV at sub-therapeutic doses enhanced apoptosis in the developing head during crucial phases of embryo neurodevelopment and perturbed the locomotor behavior. Furthermore, EFV strongly affected angiogenesis and disturbed neutral lipid homeostasis even at sub-therapeutic doses compared to DOR at therapeutic concentrations. Our findings in zebrafish embryos add further data confirming the higher safety of DOR with respect to EFV regarding embryo development, neurogenesis, angiogenesis, and lipid metabolism. Further studies are needed to explore the molecular mechanisms underlying the better pharmacological safety profile of DOR, and further human studies are required to confirm these results in the zebrafish animal model.

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