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Brief Report: Efficacy and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Females Living With HIV: An Integrated Analysis of 5 Trials.
Orkin, C, Ajana, F, Kityo, C, Koenig, E, Natukunda, E, Gandhi-Patel, B, Wang, H, Liu, Y, Wei, X, White, K, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(4):393-398
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BACKGROUND We characterized the efficacy and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in a broad population of pediatric/adolescent/adult/elderly females living with HIV (FWH). SETTING Integrated analysis. METHODS Available data from 5 trials were integrated. Week 48 virologic suppression (HIV-1 RNA <50 copies/mL), resistance, adverse events (AEs), and laboratory parameters were assessed. RESULTS Three hundred and seventy-three FWH [304 virologically suppressed; 69 antiretroviral therapy (ART)-naive] received B/F/TAF [data from comparator regimens available for 306 individuals (236 virologically suppressed and 70 ART-naive participants)]. Virologic suppression rates with B/F/TAF at week 48 were high regardless of age in participants virologically suppressed at baseline (≥95%) and in ART-naive participants (≥87%). Virologic suppression rates were similar in B/F/TAF and comparator regimens (both virologically suppressed and ART-naive groups). Treatment-emergent resistance was not detected in the B/F/TAF group. AEs considered related to study drugs were experienced by 9.2% (B/F/TAF) and 5.5% (comparator regimen) of virologically suppressed participants and 15.9% (B/F/TAF) and 31.4% (comparator regimen) of ART-naive participants. For virologically suppressed and ART-naive FWH combined, only 1 of the 373 B/F/TAF-treated and 2 of the 306 comparator-regimen participants discontinued because of AEs (none were bone/renal/hepatic AEs); grade 3/4 AEs were experienced by 5.1% (B/F/TAF) and 7.8% (comparator regimen); and grade 3/4 elevation of low-density lipoprotein/total cholesterol occurred in 2.7%/0.3% (B/F/TAF) and 5.9%/2.0% (comparator regimen). At week 48, median changes from baseline estimated glomerular filtration rate in adults were <5 mL/min; results were similar in B/F/TAF and comparator-regimen groups. CONCLUSION B/F/TAF treatment was effective and well tolerated over 48 weeks, confirming B/F/TAF as an option for a broad population of FWH.
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Brief Report: Improvement in Metabolic Health Parameters at Week 48 After Switching From a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen to the 2-Drug Regimen of Dolutegravir/Lamivudine: The TANGO Study.
van Wyk, J, Ait-Khaled, M, Santos, J, Scholten, S, Wohlfeiler, M, Ajana, F, Jones, B, Nascimento, MC, Tenorio, AR, Smith, DE, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(2):794-800
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BACKGROUND In TANGO, switching to dolutegravir/lamivudine was noninferior at 48 weeks to continuing 3-/4-drug tenofovir alafenamide-based regimens in virologically suppressed individuals with HIV-1. Antiretroviral agents have been associated with weight gain and metabolic complications. SETTING One hundred thirty-four centers; 10 countries. METHODS We assessed weight; fasting lipids, glucose, and insulin; and prevalence of insulin resistance and metabolic syndrome at baseline and week 48 in TANGO participant subgroups by boosting agent use in baseline regimens (boosted and unboosted). RESULTS In each treatment group, 74% of participants used boosted regimens at baseline. In boosted and unboosted subgroups, weight and fasting glucose changes at week 48 were small and similar between treatment groups. Overall and in the boosted subgroup, greater decreases from baseline were observed with dolutegravir/lamivudine in fasting total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), total cholesterol/high-density lipoprotein cholesterol ratio (overall, P = 0.017; boosted, P = 0.007), and insulin (boosted, P = 0.005). Prevalence of HOMA-IR ≥2 was significantly lower at week 48 with dolutegravir/lamivudine overall [adjusted odds ratio (aOR), 0.59; 95% confidence interval (CI), 0.40 to 0.87; P = 0.008] and in the boosted subgroup [aOR, 0.56; 95% CI, 0.36 to 0.88; P = 0.012] but not in the unboosted subgroup [aOR, 0.70; 95% CI, 0.31 to 1.58; P = 0.396]. Prevalence of metabolic syndrome at week 48 was low and consistent between treatment groups overall, with differences trending to favor dolutegravir/lamivudine in the unboosted subgroup [aOR, 0.41; 95% CI, 0.15 to 1.09; P = 0.075]. CONCLUSION Generally, switching from 3-/4-drug tenofovir alafenamide-based regimens to dolutegravir/lamivudine improved metabolic parameters, particularly when switching from boosted regimens. Because of smaller sample size in the unboosted subgroup, results warrant further investigation.
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A Scoping Review of Alternative Anticoagulation Strategies for Hemodialysis Patients with a Mechanical Heart Valve.
Thomson, BKA, Pilkey, NG, Monteith, B, Holden, RM
American journal of nephrology. 2021;(10-11):861-870
Abstract
INTRODUCTION Patients with end-stage renal disease (ESRD) have high rates of cardiac valvulopathy but can develop contraindications for vitamin K antagonist (VKA) therapy. We explored the evidence for alternative anticoagulation strategies in patients with ESRD with a contraindication for VKA therapy. METHODS A scoping review was completed, searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Conference abstracts from inception to March 30, 2021. The study population was patients with ESRD who were on VKA therapy and developed a contraindication to VKA therapy use. All data regarding studies, patient characteristics, anticoagulation strategy, and clinical outcomes were summarized. RESULTS Twenty-three articles met inclusion criteria. These articles included 57 patients. Contraindications to VKA therapy included calcific uremic arteriolopathy (CUA) (n = 55) and warfarin-induced skin necrosis (n = 2). All studies were either case reports or case series. There were 10 anticoagulation strategies identified. Continuation of VKA therapy was associated with increased death and decreased rates of CUA resolution (80.0% and 10.0%, respectively), compared to apixaban (24.0% and 70.8%), subcutaneous (SC) low-molecular-weight heparin (LMWH) (14.3%, 85.7%), and SC unfractionated heparin (0.0%, 100.0%). While only 5 patient cases were reported with mechanical heart valves, SC LMWH use has been reported in this context with good outcomes. CONCLUSIONS In patients with ESRD who develop a contraindication to VKA therapy, several alternative anticoagulation strategies have been reported with superior outcomes to VKA continuation. While outcomes appear superior to continuation of VKA therapy, more data are required before definitive recommendations can be made for the patient with ESRD and a mechanical heart valve.
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Increased bleeding events with the addition of apixaban to the dual anti-platelet regimen for the treatment of patients with acute coronary syndrome: A meta-analysis.
Jin, J, Zhuo, X, Xiao, M, Jiang, Z, Chen, L, Devi Shamloll, Y
Medicine. 2021;(12):e25185
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BACKGROUND Dual anti-platelet therapy (DAPT) with aspirin and clopidogrel has been the mainstay of treatment for patients with acute coronary syndrome (ACS). However, the recurrence of thrombotic events, potential aspirin and clopidogrel hypo-responsiveness, and other limitations of DAPT have led to the development of newer oral anti-thrombotic drugs. Apixaban, a new non-vitamin K antagonist, has been approved for use. In this meta-analysis, we aimed to compare the bleeding outcomes observed with the addition of apixaban to DAPT for the treatment of patients with ACS. METHODS Online databases including EMBASE, Cochrane Central, http://www.ClinicalTrials.gov, MEDLINE and Web of Science were searched for English based publications comparing the use of apixaban added to DAPT for the treatment of patients with ACS. Different categories of bleeding events and cardiovascular outcomes were assessed. The analysis was carried out by the RevMan software version 5.4. Odds ratios (OR) with 95% confidence intervals (CI) were used to represent the data following analysis. RESULTS This research analysis consisted of 4 trials with a total number of 9010 participants. Thrombolysis in myocardial infarction (TIMI) defined major bleeding (OR: 2.45, 95% CI: 1.45-4.12; P = .0008), TIMI defined minor bleeding (OR: 3.12, 95% CI: 1.71-5.70; P = .0002), International society of thrombosis and hemostasis (ISTH) major bleeding (OR: 2.49, 95% CI: 1.80-3.45; P = .00001) and Global Use of Strategies to Open Occluded Arteries (GUSTO) defined severe bleeding (OR: 3.00, 95% CI: 1.56-5.78; P = .01) were significantly increased with the addition of apixaban to DAPT versus DAPT alone in these patients with ACS. However fatal bleeding (OR: 10.96, 95% CI: 0.61-198.3; P = .11) was not significantly different. CONCLUSIONS Addition of the novel oral anticoagulant apixaban to the DAPT regimen significantly increased bleeding and therefore did not show any beneficial effect in these patients with ACS. However, due to the extremely limited data, we apparently have to rely on future larger studies to confirm this hypothesis.
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TMS-EEG signatures of glutamatergic neurotransmission in human cortex.
Belardinelli, P, König, F, Liang, C, Premoli, I, Desideri, D, Müller-Dahlhaus, F, Gordon, PC, Zipser, C, Zrenner, C, Ziemann, U
Scientific reports. 2021;(1):8159
Abstract
Neuronal activity in the brain reflects an excitation-inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. Here, we tested the effects of a single oral dose of two anti-glutamatergic drugs (dextromethorphan, an NMDA receptor antagonist; perampanel, an AMPA receptor antagonist) and an L-type voltage-gated calcium channel blocker (nimodipine) on transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) potentials (TEPs) and TMS-induced oscillations (TIOs) in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled crossover design. Single-pulse TMS was delivered to the hand area of left primary motor cortex. Dextromethorphan increased the amplitude of the N45 TEP, while it had no effect on TIOs. Perampanel reduced the amplitude of the P60 TEP in the non-stimulated hemisphere, and increased TIOs in the beta-frequency band in the stimulated sensorimotor cortex, and in the alpha-frequency band in midline parietal channels. Nimodipine and placebo had no effect on TEPs and TIOs. The TEP results extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA receptor-mediated glutamatergic excitation. In contrast, AMPA receptor-mediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations. This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation-inhibition balance.
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Characteristics of patients receiving extended treatment after incident venous thromboembolism.
Albertsen, IE, Jensen, M, Abdelgawwad, K, Søgaard, M, Larsen, TB, Nielsen, PB
Basic & clinical pharmacology & toxicology. 2021;(4):332-342
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Given high recurrence risk after venous thromboembolism (VTE), guidelines recommend extended dose rivaroxaban (10 mg OD) or apixaban (2.5 mg BID) to be considered after 6 months of initial treatment. This study aimed to provide insight into clinical practice regarding the use of extended preventive treatment and to describe duration of the initial treatment. Linkage of nationwide health registers identified all in- and outpatients with VTE from April 2017 through 2018. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated adjusting for other VTE-related factors. The study included 6030 patients with VTE. Among rivaroxaban users, 2.2% (n = 113) received the extended 10-mg dose after mean 9.4 (SD 3.1) months of standard treatment. For apixaban, 4.7% (n = 40) received extended 2.5-mg dose after mean 8.0 months (SD 3.9). After adjustments, incident pulmonary embolism (HR 1.81 95% CI 1.12;2.91) and trauma/fracture (HR 1.42 95% CI 0.46;4.43) were associated with switching to extended dose, whereas patients with unprovoked VTE were less likely to receive the extended dose (HR 0.68 95% CI 0.30;1.55). Less than 3% of patients with incident VTE received extended treatment after initial standard treatment. Even though international guidelines suggest that the risk-benefit balance is in favour of extended VTE treatment, this was yet to be translated into clinical practice as of 2018. Studies using contemporary data are warranted to investigate routine clinical practice of extended treatment for VTE recurrence.
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Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection: a theoretical perspective.
Hamidi, SH, Kadamboor Veethil, S, Hamidi, SH
Pharmacological reports : PR. 2021;(3):712-727
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. DRUG SUGGESTION Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. CONCLUSION The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.
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Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa.
Chandiwana, NC, Chersich, M, Venter, WDF, Akpomiemie, G, Hill, A, Simmons, B, Lockman, S, Serenata, CM, Fairlie, L, Moorhouse, MA
AIDS (London, England). 2021;(2):205-211
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OBJECTIVE Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir. DESIGN We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial. METHODS We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/l) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1053 treatment-naïve participants were randomized to initiate tenofovir-alafenamide/emtricitabine + dolutegravir (TAF/FTC + DTG), tenofovir-disoproxil-fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV). RESULTS Analysis includes 406 females, mean age 31.5 years and baseline CD4+ cell count 356 cells/μl. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC + DTG arm (+4.0 ± 8.1 nmol/l), while folate concentrations decreased slightly in the TDF/FTC + DTG arm (-1.8 ± 8.9 nmol/l) and decreased in the TDF/FTC/EFV arm (-5.9 ± 8.1 nmol/l). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (P < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ± 7.1 nmol/l in the TAF/FTC + DTG arm and 2.3 ± 8.4 nmol/l in the TDF/FTC + DTG arm, but decreased by -3.3 ± 8.1 with TDF/FTC/EFV arm. CONCLUSION Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the EFV arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.
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Factors Influencing the Selection of Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Patients With Non-Valvular Atrial Fibrillation.
Park, S, Je, NK
Journal of cardiovascular pharmacology and therapeutics. 2021;(6):656-664
Abstract
BACKGROUND Major atrial fibrillation (AF) guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over warfarin, except in rare clinical circumstances based on 4 randomized controlled trials comparing each NOAC with warfarin. We aimed to investigate the current NOAC prescription behaviors in alignment with the recent clinical evidence available. METHOD We conducted a cross-sectional analysis of NOAC-using patients with non-valvular atrial fibrillation (NVAF) who were aged ≥65 years on the index date (July 1, 2018) based on nationwide claims data. The types of NOACs being taken were analyzed using chi-squared tests, and factors influencing NOAC selection were identified using multinomial logistic regression analysis. RESULTS A total of 6,061 patients were included. Among the 4 NOACs, rivaroxaban was the most used NOAC. Patients aged ≥75 years (odds ratio [OR] = 1.270, confidence interval [CI] = 1.089-1.450) and women (OR = 1.148, CI = 1.011-1.284) were more likely to use apixaban relative to rivaroxaban. Patients with prior stroke/transient ischemic attack/thromboembolism had higher odds of using dabigatran (OR = 1.508, CI = 1.312-1.704) and apixaban (OR = 1.186, CI = 1.026-1.346). Patients with renal disease had higher odds of using apixaban (OR = 1.466, 95% CI = 1.238-1.693). These findings are consistent with the efficacy and safety profiles reported in pivotal trials and observational studies comparing individual NOACs. CONCLUSION Among the 4 NOACs, rivaroxaban was the most commonly used NOAC. Apixaban was preferred for patients aged ≥75 years, females, and patients with renal disease.
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Educational Impact on Apixaban Adherence in Atrial Fibrillation (the AEGEAN STUDY): A Randomized Clinical Trial.
Montalescot, G, Brotons, C, Cosyns, B, Crijns, HJ, D'Angelo, A, Drouet, L, Eberli, F, Lane, DA, Besse, B, Chan, A, et al
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(1):61-71
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INTRODUCTION Adherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring. OBJECTIVE We assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF). METHODS Patients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks. RESULTS In total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3-89.7), 85.2% (95% CI 81.5-88.2), and 87.8% (95% CI 83.4-91.1). Serious adverse events were similar across groups. CONCLUSION High implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits. CLINICAL TRIAL REGISTRATION This study is registered at ClinicalTrials.gov [NCT01884350].