Cardiovascular Disease Risk in a Cohort of Virologically Suppressed People Living with HIV Switching to Doravirine: Preliminary Data from the Real Life

Iannone, Valentina; Farinacci, Damiano; D’Angelillo, Anna; Dusina, Alex; Lamanna, Francesco; Passerotto, Rosanna; Baldin, Gianmaria; Visconti, Elena; Tamburrini, Enrica; Borghetti, Alberto; Giambenedetto, Simona Di; Ciccullo, Arturo

doi:10.1089/aid.2022.0050

Cited by 7 publications

(7 citation statements)

References 9 publications

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“…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: 95%

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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Section: Discussionmentioning

confidence: 95%

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

Zizioli

Ferretti

Tiecco

et al. 2023

IJMS

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“…In a retrospective cohort of 40 virologically suppressed PLWHIV switched to a regimen with doravirine plus two NRTIs, a significant decrease in median values of total cholesterol, LDL cholesterol and triglycerides were reported, in association with a reduction in median predicted 10-years risk of cardiovascular disease. 15…”

Section: Discussionmentioning

confidence: 99%

“…14 In a retrospective cohort of 40 virologically suppressed PLWHIV switched to a regimen with doravirine plus two NRTIs, a significant decrease in median values of total cholesterol, LDL cholesterol and triglycerides were reported, in association with a reduction in median predicted 10-years risk of cardiovascular disease. 15 The coformulation of doravirine with tenofovir disoproxil fumarate (TDF) and lamivudine in a single-tablet regimen raised some concerns following the documented risk of renal toxicity and treatment discontinuation associated with TDF exposure. However, studies in healthy volunteers and PLWHIV have shown that concomitant administration of doravirine had no significant effects on the pharmacokinetics of tenofovir from TDF, suggesting a lower potential risk of renal toxicity of the DOR/3TC/TDF combination.…”

Section: Discussionmentioning

confidence: 99%

Doravirine/lamivudine/tenofovir disoproxil fumarate in virologically suppressed people living with HIV: A real-life experience

et al. 2023

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Background Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) showing high efficacy and tolerability in both naïve and experienced people living with HIV (PLWHIV) in randomized trials, but scarce data are available to date from the real-life experience. Methods We performed an observational, retrospective study of PLWHIV on suppressive antiretroviral therapy who switched to a daily single-tablet regimen containing doravirine 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg. Results As a whole, 62 suppressed patients (51 men, median age, 51.7 years; median CD4 T+ lymphocyte count, 577 cells/mm3) were enrolled. After 12 months, 58 (93.5%) patients showed HIV RNA <20 copies/mL and reasons for treatment failure were virological failure in one case, missing data in one case, and adverse events in two cases. At month 12, a significant decrease in median serum level of triglycerides (median change −61.2 mg/dL; p = .009) and total cholesterol (median change −38.4 mg/dL; p = .021) was reported, while a not significant median weight increase was registered (+0.55 kg). Conclusions In our study, simplification to a single-tablet regimen of doravirine/lamivudine/tenofovir disoproxil fumarate in virologically suppressed PLWHIV was effective and showed a good tolerability profile, in association with a significant improvement in serum lipid levels.

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“…Doravirine has beneficial metabolic profiles and can reduce the risk of CVD. Studies have demonstrated decreases in total cholesterol, LDL cholesterol, and triglycerides after switching to doravirine from different regimens [ 123 ]. In contrast, PIs are generally considered to have unfavorable effects in terms of cardiovascular risk.…”

Section: Modifiable Cvd Risk Factors In Plwhmentioning

confidence: 99%

Human Immunodeficiency Virus as a Risk Factor for Cardiovascular Disease

Lembas,

Załęski,

Peller

et al. 2023

Cardiovasc Toxicol

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The developments in HIV treatments have increased the life expectancy of people living with HIV (PLWH), a situation that makes cardiovascular disease (CVD) in that population as relevant as ever. PLWH are at increased risk of CVD, and our understanding of the underlying mechanisms is continually increasing. HIV infection is associated with elevated levels of multiple proinflammatory molecules, including IL-6, IL-1β, VCAM-1, ICAM-1, TNF-α, TGF-β, osteopontin, sCD14, hs-CRP, and D-dimer. Other currently examined mechanisms include CD4 + lymphocyte depletion, increased intestinal permeability, microbial translocation, and altered cholesterol metabolism. Antiretroviral therapy (ART) leads to decreases in the concentrations of the majority of proinflammatory molecules, although most remain higher than in the general population. Moreover, adverse effects of ART also play an important role in increased CVD risk, especially in the era of rapid advancement of new therapeutical options. Nevertheless, it is currently believed that HIV plays a more significant role in the development of metabolic syndromes than treatment-associated factors. PLWH being more prone to develop CVD is also due to the higher prevalence of smoking and chronic coinfections with viruses such as HCV and HBV. For these reasons, it is crucial to consider HIV a possible causal factor in CVD occurrence, especially among young patients or individuals without common CVD risk factors.

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Cardiovascular Disease Risk in a Cohort of Virologically Suppressed People Living with HIV Switching to Doravirine: Preliminary Data from the Real Life

Cited by 7 publications

References 9 publications

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

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

Doravirine/lamivudine/tenofovir disoproxil fumarate in virologically suppressed people living with HIV: A real-life experience

Human Immunodeficiency Virus as a Risk Factor for Cardiovascular Disease

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