Resilience and Life Expectations of Perinatally HIV-1 Infected Adolescents in France

International audienceBackground: Resilience of perinatally HIV-infected youth in European countries is poorly studied. Life satisfaction and expectations for adulthood are rarely examined.Objective: This cross-sectional, descriptive study of a French cohort of 54 perinatally HIV-infected adolescents raised in France (age 14-20 years) aimed to (1) evaluate their psychosocial adjustment, (2) identify their expectations for adulthood and (3) delineate risk and protective factors associated with mental health, life satisfaction, and HIV-1 viral load level.Method: Medical evaluation, psychological semi-structured interview, and self-report questionnaires were used.Results: All the adolescents had been receiving Highly Active Anti-Retroviral Therapy (HAART) for 9 to 11 years and 2/3 were healthy with controlled viral load (<50 copies/mL). The majority had medium to high levels of life satisfaction. They viewed HIV as having only minor impact on their current daily life and had positive expectations for adulthood. However, 46% exhibited psychiatric symptomatology. Multivariable analysis showed that having a deceased parent and current worries about HIV were substantial risk factors for psychiatric symptoms. Having two living parents and being satisfied with life were protective factors for mental health. Good quality of caregiver-adolescent relationships and high life satisfaction were significant protective factors for controlled viral load.Conclusion: These data indicate psychosocial resilience among perinatally HIV-1 infected adolescents with 10 years of HAART treatment. These findings demonstrate the influence of life satisfaction, parent’s life status and quality of caregiver-adolescent relationships on resilience and health outcomes in these patients. We conclude that healthcare providers should attend to these factors

Evaluation of Hydroxychloroquine Blood Concentrations and Effects in Childhood-Onset Systemic Lupus Erythematosus

International audienceBackground: Hydroxychloroquine (HCQ) is an antimalarial agent given to patients with systemic lupus erythematosus (SLE) as first-line therapy. It alleviates childhood-onset systemic lupus erythematosus cSLE skin and musculoskeletal disease, decreasing disease activity and flares. HCQ concentration–effect relationships in children remains unknown. This study aimed to investigate the pharmacokinetics of HCQ and possible concentration–effect relationships. Methods: HCQ blood concentrations and effects were obtained during clinical follow-up on different occasions. cSLE flares were defined using the SLE Disease Activity Index (SLEDAI); flare was denoted by a SLEDAI score > 6. Blood concentration was measured using high-performance liquid chromatography with fluorometric detection. Statistical analysis was performed using a nonlinear mixed-effect approach with the Monolix software. Results: A total of 168 blood samples were obtained from 55 pediatric patients. HCQ apparent blood clearance (CL/F) was dependent on patients’ bodyweight and platelet count. Patients with active cSLE had a lower mean blood HCQ concentration compared with inactive cSLE patients (536 ± 294 vs. 758 ± 490 ng/mL, p = 5 × 10−6). Among patients with HCQ blood concentration ≥ 750 ng/mL, 87.6% had inactive cSLE. Moreover, HCQ blood concentration was a significant predictor of disease status. Conclusion: We developed the first HCQ blood concentration–effect relationship for cSLE associated with active or non-active disease status. A prospective randomized study is necessary to confirm these results. View Full-Tex

P-glycoprotein influences urinary excretion of aldosterone in healthy individuals

International audienceObjectivesP-glycoprotein (P-gp), the product of the ABCB1 gene, is involved in the transport of aldosterone and cortisol in adrenal cells in vitro but its physiological role in humans remains controversial. Our objective was to test the influence of P-gp polymorphisms on aldosterone.MethodsWe evaluated plasma aldosterone concentration (PAC), urinary aldosterone, and blood pressure in a cohort of white normotensive men at baseline on diets unrestricted for sodium and potassium and after a 5-day treatment with 500 mg b.i.d. clarithromycin, a P-gp inhibitor. Included were 20 homozygous wild-type (P-gp0), 20 heterozygous (P-gp1), and 20 individuals with combined 2677G>T/A-3435C>T loss-of-function polymorphism of the ABCB1 gene (P-gp2).ResultsAt baseline, PAC, urinary aldosterone, urinary free cortisol to urine creatinine ratios, and blood pressure did not differ in the three genotypes. After clarithromycin administration, the urinary aldosterone to creatinine ratio increased by an average of 30% in the entire cohort (P < 0.001, n = 60). Increases were pronounced in P-gp1 (+40%; P = 0.014) and P-gp2 individuals (+50%; P = 0.020) but lesser and were NS in P-gp0 individuals (+10%; P = 0.259). PAC also increased from baseline after clarithromycin treatment in all individuals (+19%, P = 0.050); however, the increase in PAC was NS when the three genotypes were analyzed separately.ConclusionIn our experimental conditions, the interaction between P-gp inhibition and the ABCB1 genotype, suggests that aldosterone is indeed a physiological endogenous substrate of P-gp in humans and that P-gp interferes with the net equilibrium between aldosterone secretion and elimination processes in humans.Clinical Trial Registration-URL http//www.clinicaltrials.gov. Unique identifier NCT01627665

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system modeling and assessing inter-individual variability

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Evaluation of the effects on the QT-interval of 4 artemisinin-based combination therapies with a correction-free and heart rate-free method

Abstract Several antimalarial drugs are known to prolong ventricular repolarization as evidenced by QT/QTc interval prolongation. This can lead to Torsades de Pointes, a potentially lethal ventricular arrhythmia. Whether this is the case with artemisinin-based combination therapies (ACTs) remains uncertain. Assessment of the extent of QTc prolongation with antimalarials is hampered by important variations of heart rate during malaria crises and previous studies have reported highly variable values of QTc prolongations with ACTs. We assessed QTc prolongation with four ACTs, using high quality ECG recording and measurement techniques, during the first episode of malaria in 2,091 African patients enrolled in the WANECAM study which also monitored clinical safety. Using an original and robust method of QTc assessment, independent from heart rate changes and from the method of QT correction, we were able to accurately assess the extent of mean maximum QTc prolongation with the four ACTs tested. There was no evidence of proarrhythmia with any treatment during the study although dihydroartemisinin-piperaquine, artesunate-amodiaquine and artemether-lumefantrine significantly prolonged QTc. The extent of prolongation of ventricular repolarization can be accurately assessed in studies where heart rate changes impede QTc assessment

Deep learning analysis of ECG for risk prediction of drug-induced arrhythmias and diagnosis of long QT syndrome

International audienceAims: Congenital (cLQTS) or drug-induced (diLQTS) long-QT syndromes can cause Torsadede-Pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy for identification of drugs at high-risk of TdP relies on measuring the QT-interval corrected for heart rate (QTc) on ECG. However, QTc has a low positive predictive value. Methods: We used convolutional-neural-network (CNN) models to quantify ECG alterations induced by sotalol, an IKr-blocker associated with TdP, aiming to provide new tools (CNN-models) to enhance prediction of diTdP and diagnosis of cLQTS. Tested CNN-models used single or multiple 10sec recordings/patient using 8 leads or single leads in various cohorts: 1029 healthy subjects before and after sotalol intake (n=14135 ECGs); 487 cLQTS patients (n=1083 ECGs: 560 type 1, 456 type 2, 67 type 3); 48 patients with diTdP (n=1105 ECGs, with 147 obtained within 48hours of a diTdP episode). Results: CNN-models outperformed models using QTc to identify exposure to sotalol (ROC-AUC=0.98 vs. 0.72,p≤0.001). CNN-models had higher ROC-AUC using multiple vs. single 10s-ECG (p≤0.001). Performances were comparable for 8-lead vs. single lead models. CNN-models predicting sotalol exposure also accurately detected presence and type of cLQTS vs. healthy controls, particularly for cLQT2 (AUC-ROC=0.9), and were greatest shortly after a diTdP event and declining over time(p≤0.001), after controlling for QTc and intake of culprit drugs. ECG segment analysis identified the J-Tpeak interval as the best discriminator of sotalol intake. Conclusion: CNN-models applied to ECGs outperform QTc measurements to identify exposure to drugs altering the QT-interval, congenital LQTS, and are greatest shortly after a diTdP episode

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations

International audienceBACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship