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Background: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with coronavirus disease 2019 (COVID-19) who received remdesivir plus standard of care (SoC) compared with SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases., Methods: This post hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19. Any first AE that occurred between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves, and Kaplan-Meier estimates were calculated for event rates., Results: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (hazard ratio [HR], 1.0; 95% confidence interval [CI], .7-1.5; P = .98), even when serious and nonserious cardiac AEs were evaluated separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between the two groups in the occurrence of cardiac AE subclasses, including arrhythmic events (HR, 1.1; 95% CI, .7-1.7; P = .68)., Conclusions: Remdesivir treatment was not associated with an increased risk of cardiac AEs compared with control in patients hospitalized with moderate or severe COVID-19. These results are consistent with other randomized, controlled trials and meta-analyses. Clinical Trials Registration. NCT04315948; EudraCT 2020-000936-23., Competing Interests: Potential conflicts of interest. D. C. reports an human immunodeficiency virus grant from Janssen and lecture fees from Pfizer, outside the submitted work. F. M. reports grants and consulting fees from Pharmatheus, grants from Sanofi, and consulting fees from Ipsen, outside the submitted work. M. H. reports grants from the Belgian Center for Knowledge, the Fonds Erasme-COVID-Université Libre de Bruxelles, and the EU-Horizon programme, for the submitted work; support for attending meetings from Pfizer, MSD and Gilead, Pharmamar; support for participation on an advisory board for therapeutics on COVID-19 (DisCoVeRy trial); support for leadership for the Belgian guidelines on therapeutics for COVID-19; acting as president for the Belgian Society of Clinical Microbiology and Infectious Diseases; and payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Gilead, GKS, INSMED, and Shionogi. J. P. reports lecture fees from Gilead and MSD; support for attending meetings from Gilead, Eumedica, and Merck Sharp & Dohme, outside the submitted work. C. B. reports participation on a DSMB for 4Living Biotech and consulting fees from Da Volterra and Mylan Pharmaceuticals, outside the submitted work. R. G. reports consulting fees from Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankvo; lecture fees from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, and Daiichi Sankvo; support for attending meetings from Roche, Amgen, Janssen, AstraZeneca, Novartis, Merck Sharp & Dohme, Celgene, Gilead, Bristol Myers Squibb, AbbVie, and Daiichi Sankvo; participation on a DSMB for Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankyo; research grants from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, and Daiichi Sankyo; and stock or stock options from Novo Nordisk, Lilly. J.-A. P. reports consulting fees from Pfizer, Merck Sharp & Dohme, Janssen-Cilag, and AOP Orphan Pharmaceuticals; lecture fees from Cepheid, Pfizer, and Gilead; and support for attending meetings from Pfizer and Gilead. C. A. reports lecture fees from Insmed, GSK, Moderna, AstraZeneca, and Chiesi; grants or contracts from FEDER funding; support for attending meetings from Home perf; a leadership or fiduciary role as president of the Scientific Council of the French Respiratory Society; and serving as a member of the French ANRS-MIE for COVID and member of the COVID Group of the French Public Health High Council. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background & Aims: In France, bulevirtide (BLV) became available in September 2019 through an early access program to treat patients with HDV. The aim of this analysis was to evaluate the efficacy and safety of BLV in patients with HIV and HDV coinfection., Methods: Patients received BLV 2 mg ± pegylated interferon-α (pegIFNα) according to the physician's decision. The primary endpoint (per-protocol analysis) was the virological response rate at Week 48, defined as the proportion of patients with undetectable serum HDV RNA or a HDV RNA decline >2 log 10 IU/ml from baseline., Results: The characteristics of the 38 patients were as follows: 28 male, mean age 47.7 years, and mean baseline HDV RNA viral load 5.7 ± 1.2 log 10 IU/ml. Median HIV viral load and mean CD4 count were 32 (30-65) copies/ml and 566 ± 307/mm 3 , respectively. Eight patients stopped treatment before Week 48. At Week 48, 10 of 19 patients (52.6%) in the 2 mg BLV group and five of seven patients (71.4%) in the 2 mg BLV + pegIFNɑ group had reached virological response (no HDV RNA available in four patients). At Week 48, seven of 19 patients in the 2 mg BLV group and three of six patients in the 2 mg BLV + pegIFNɑ group had a combined response (virological response and normal alanine aminotransferase level)., Conclusions: Adults living with HIV coinfected with HDV can be treated by BLV with a virological response in more than 50% of patients. The combination of BLV and pegIFNɑ showed a strong virological response., Impact and Implications: Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug-drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug-drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug-drug interaction is reported., (© 2024 The Author(s).)

Background & Aims: Bulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with pegylated-interferon (Peg-IFN) are unknown., Methods: We used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks., Results: The efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (>2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7-95.0]), compared with 56.1% (95% PI = [46.4-66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5-13.2]) with bulevirtide compared with 18.8% (95% PI = [11.6-29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks of treatment, the rates of viral cure could be 42.1% (95% PI = [33.3-52.6]) with bulevirtide and 66.7% (95% PI = [56.5-76.8]) with bulevirtide + Peg-IFN., Conclusions: In this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment., Impact and Implications: Bulevirtide has been approved for chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of Peg-IFN and bulevirtide in patients with CHD. Clinical trials are now warranted to confirm those predictions., Competing Interests: JG has received research funding and has consulted with Hoffman-LaRoche. SB, EG, and AG have received research funding from Eurobio Scientific. VdL received consulting fees from Gilead, AbbVie, BMS, GSK, Escopics, Alfasigma, Janssen, Orphalan, NovoNordisk, AstraZeneca. JMP has served as an advisor or speaker for Abbott, Abbvie, Gilead, and GSK. The other authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Objectives: The clinical profile and outcomes of patients with Coronavirus Disease 2019 (COVID-19) who require veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or veno-arterial-venous extracorporeal membrane oxygenation (VAV-ECMO) are poorly understood. We aimed to describe the characteristics and outcomes of these patients and to identify predictors of both favourable and unfavourable outcomes., Methods: ECMOSARS is a multicentre, prospective, nationwide French registry enrolling patients who require veno-venous extracorporeal membrane oxygenation (ECMO)/VA-ECMO in the context of COVID-19 infection (652 patients at 41 centres). We focused on 47 patients supported with VA- or VAV-ECMO for refractory cardiogenic shock., Results: The median age was 49. Fourteen percent of patients had a prior diagnosis of heart failure. The most common aetiologies of cardiogenic shock were acute pulmonary embolism (30%), myocarditis (28%) and acute coronary syndrome (4%). Extracorporeal cardiopulmonary resuscitation (E-CPR) occurred in 38%. In-hospital survival was 28% in the whole cohort, and 43% when E-CPR patients were excluded. ECMO cannulation was associated with significant improvements in pH and FiO2 on day 1, but non-survivors showed significantly more severe acidosis and higher FiO2 than survivors at this point (P = 0.030 and P = 0.006). Other factors associated with death were greater age (P = 0.02), higher body mass index (P = 0.03), E-CPR (P = 0.001), non-myocarditis aetiology (P = 0.02), higher serum lactates (P = 0.004), epinephrine (but not noradrenaline) use before initiation of ECMO (P = 0.003), haemorrhagic complications (P = 0.001), greater transfusion requirements (P = 0.001) and more severe Survival after Veno-Arterial ECMO (SAVE) and Sonographic Assessment of Intravascular Fluid Estimate (SAFE) scores (P = 0.01 and P = 0.03)., Conclusions: We report the largest focused analysis of VA- and VAV-ECMO recipients in COVID-19. Although relatively rare, the need for temporary mechanical circulatory support in these patients is associated with poor prognosis. However, VA-ECMO remains a viable solution to rescue carefully selected patients. We identified factors associated with poor prognosis and suggest that E-CPR is not a reasonable indication for VA-ECMO in this population., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Setting: Health measures taken during the pandemic deeply modified the clinical research practices. At the same time, the demand for the results of the COVID-19 trials was urgent. Thus, the objective of this article is to share Inserm's experience in ensuring quality control in clinical trials in this challenging context., Objectives: DisCoVeRy is a phase III randomized study that aimed at evaluating the safety and efficacy of 4 therapeutic strategies in hospitalized COVID-19 adult patients. Between March, 22nd 2020 and January, 20th 2021, 1309 patients were included. In order to guarantee the best quality of data, the Sponsor had to adapt to the current sanitary measures and to their impact on clinical research activity, notably by adapting Monitoring Plan objectives, involving the research departments of the participating hospitals and a network of clinical research assistants (CRAs)., Results: Overall, 97 CRAs were involved and performed 909 monitoring visits. The monitoring of 100% of critical data for all patients included in the analysis was achieved, and despite of the pandemic context, a conform consent was recovered for more than 99% of patients. Results of the study were published in May and September 2021., Discussion/conclusion: The main monitoring objective was met thanks to the mobilization of considerable personnel resources, within a very tight time frame and external hurdles. There is a need for further reflection to adapt the lessons learned from this experience to the context of routine practice and to improve the response of French academic research during a future epidemic., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CFL, VT, ADI, VPS, NM, ADE, AM, FM, DB and FA have nothing to disclose. CB has received consulting fees from MYLAN and Da Volterra and participated on a DSMB for 4Living Biotech. MH has received funding from The Belgian Centre for Knowledge (KCE), the Fonds-Erasme-COVID-19-Université Libre de Bruxelles and an EU-Horizon 2020 grant, payement or honoraria for lectures from Pfizer, Gilead and INSM, support for attending meetings and/or travel from Pfizer and Gilead, participated on a DSMB for Gilead and is President of the Belgian Society of Infectious Diseases and Clinical Microbiology and expert for Belgian Taskforce on COVID therapeutics. The institution employing AF, CD, HE, JS, SCC, MD and SLM received support from the French government, the European Commission, the Region Ile de France, Gilead Sciences, Inc., Sanofi, Merck group and AbbVie for the DisCoVeRy study., (Copyright © 2023. Published by Elsevier Inc.)

The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-β1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: In neurovascular treatment planning, endovascular devices to manage complex intracranial aneurysms requiring intervention are often selected based on conventional measurements and interventional neuroradiologist experience. A recently developed technology allows a patient-specific 3D-printed model to mimic the navigation experience. The goal of this study was to assess the effect of pre-procedure 3D simulation on procedural and clinical outcomes for wide-neck aneurysm embolization., Materials & Methods: In this unblinded, non-randomized, prospective, multicenter study conducted from November 18 through December 20, patients with complex intracranial aneurysms (neck > 4 mm or ratio < 2 1 ) were treated by WEB or flow diverter stents (FDS). The primary endpoint was concordance between simulation and procedure, 3D-printed model accuracy as well as embolization outcomes including complications, procedure times, and radiation dose were also assessed. Secondary endpoint was to compare versus a retrospective WEB cohort., Results: Twenty-one patients were treated, 76% of cases by WEB and 24% by FDS. Concordance between post-simulation and real procedure efficiency was 0.85 [0.69 - 1.00] for size device selection and 0.93 [0.79 - 1.00] for wall-apposition/aneurysm neck closure. Geometrical accuracy of the 3D-printed model showed a mean absolute shift of 0.11 mm. Two complications without major clinical impact were reported with a post-operative mRS similar to pre-procedure mRS for all patients., Conclusions: Rehearsal using accurate 3D-printed patient-specific aneurysm models enabled optimization of embolization strategy, resulting in reduced procedure duration and cumulative fluoroscopy time which translated to reduced radiation exposure compared to procedures performed without simulation., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Introduction: Hepatitis C virus (HCV) may recur after liver transplantation (LT) in the severe form of fibrosing cholestatic hepatitis (FCH). The prognosis dramatically improved by the use of direct acting antivirals (DAAs). The aim of the present study was to describe the change in histological features of FCH after virological eradication., Methods: From the ANRS CUPILT cohort we included 17 patients who presented FCH and at least two graft biopsies, one before DAA-treatment and one after. A single expert pathologist, blinded for clinical outcome, retrospectively confirmed the diagnosis of FCH and progression of fibrosis., Results: Diagnosis of FCH was made after a median [IQR] 6.0 [3.1-11.8] months after LT, and the median interval between diagnosis and onset of treatment was 1.2 [0.7-6.1] months. The rate of viral eradication was 94.1%. The median delay between the pre-treatment and the treatment biopsies was 12.5 [11.1-20.0] months. Between the end of treatment and the second biopsy, the delay was 5.3 [0.6-7.4] months. Fibrosis stage worsened in 10 patients (58.8%); 6 patients had cirrhosis (35.3%). Chronic rejection appeared in 4 (23.5%) patients., Conclusion: Our results suggest that, despite viral eradication in patients presenting FCH after LT, fibrosis progression was observed in half of patients. This should encourage monitoring fibrosis progression despite HCV cure., (Copyright © 2022. Published by Elsevier Masson SAS.)

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Good clinical practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. Before the start of a clinical trial, investigators commit to perform the research in accordance with GCPs, regulatory dispositions and protocol. The sponsors are responsible for investigators' selection and for controlling their skills. Whereas industrial sponsors systematically require a certificate of GCP training, academic sponsors seem to be less demanding. We have carried out two surveys between April and June 2018. A first questionnaire was sent to the 40 French academic directions of clinical research and innovation in order to determine their requirements about the GCP training of the investigators participating in their trials. The second questionnaire was transmitted to physicians of the "Bretagne recherche clinique hospitalière network": Rennes, Saint-Malo, Saint-Brieuc, Vannes, Lorient and Pontivy hospitals, in order to determine the GCP certification rate, and their needs in terms of clinical research training. Twenty-eight (70%) directions of clinical research answered the first survey, among which 18 (64%) required systematically the investigators' GCP certification in case of category 1 interventional studies. This rate decreased for category 2 (50%) and non-interventional category 3 (18%) studies. A total of 345 physicians answered the second survey, among which 263 (76%) had already been clinical trial investigators. However, only 29% of all physicians and 54% of those who had been principal investigator were certified for GCP training. These results support the need for large campaigns of GCP training in public hospitals., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Aims: Monitoring risk-based approaches in clinical trials are encouraged by regulatory guidance. However, the impact of a targeted source data verification (SDV) on data-management (DM) workload and on final data quality needs to be addressed., Methods: MONITORING was a prospective study aiming at comparing full SDV (100% of data verified for all patients) and targeted SDV (only key data verified for all patients) followed by the same DM program (detecting missing data and checking consistency) on final data quality, global workload and staffing costs., Results: In all, 137 008 data including 18 124 key data were collected for 126 patients from 6 clinical trials. Compared to the final database obtained using the full SDV monitoring process, the final database obtained using the targeted SDV monitoring process had a residual error rate of 1.47% (95% confidence interval, 1.41-1.53%) on overall data and 0.78% (95% confidence interval, 0.65-0.91%) on key data. There were nearly 4 times more queries per study with targeted SDV than with full SDV (mean ± standard deviation: 132 ± 101 vs 34 ± 26; P = .03). For a handling time of 15 minutes per query, the global workload of the targeted SDV monitoring strategy remained below that of the full SDV monitoring strategy. From 25 minutes per query it was above, increasing progressively to represent a 50% increase for 45 minutes per query., Conclusion: Targeted SDV monitoring is accompanied by increased workload for DM, which allows to obtain a small proportion of remaining errors on key data (<1%), but may substantially increase trial costs., (© 2019 The British Pharmacological Society.)

Purpose: Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse., Methods: Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays., Results: Sixty-seven mainly male patients (79%) were included, with a mean age of 57 years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4 weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30-2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (p = 0.02) and lower haemoglobin during direct-acting antiviral treatment (p = 0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range., Conclusion: Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels., Trial Registration: NCT01944527.

Beyond the application of legal requirements, clinical trials must have a permanent approach of quality control. The clinical investigation centers (CICs) are academic structures of clinical research certified by the French National institute of health and medical research (Inserm) and whose functioning relies on recommendations of good practice. It is important to accompany this standardization of practices by the implementation of a quality management system. This article presents the process that enabled the CIC of Rennes to become certified ISO 9001 by French standards association (Afnor) certification in May, 2016. The application of the fundamental principles of the standard ISO 9001 in the domain of clinical research is approached. The problem of the perimeter for the certification and the related process mapping are exposed. The activities of methodology, management and analysis of clinical studies were chosen for the initial certification of the CIC of Rennes. The perspectives for the extension of the perimeter of certification are also approached at the end of article., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Sofosbuvir (SOF) combined with nonstructural protein 5A (NS5A) inhibitors has demonstrated its efficacy in treating a recurrence of hepatitis C virus (HCV) after liver transplantation (LT). However, the duration of treatment and need for ribavirin (RBV) remain unclear in this population. Our aim was to determine whether LT recipients could be treated with an SOF + NS5A inhibitor-based regimen without RBV for 12 weeks post-LT. Between October 2013 and December 2015, 699 LT recipients experiencing an HCV recurrence were enrolled in the multicenter ANRS CO23 CUPILT cohort. We selected patients receiving SOF and NS5A inhibitor ± RBV and followed for at least 12 weeks after treatment discontinuation. The primary efficacy endpoint was a sustained virological response 12 weeks after the end of treatment (SVR12). Among these 699 patients, 512 fulfilled the inclusion criteria. Their main characteristics were: 70.1% genotype 1, 18.2% genotype 3, 21.1% cirrhosis, and 34.4% previously treated patients. We identified four groups of patients according to their treatment and duration: SOF + NS5A without RBV for 12 (156 patients) or 24 (239 patients) weeks; SOF + NS5A + RBV for 12 (47 patients) or 24 (70 patients) weeks. SVR12 values reached 94.9%, 97.9%, 95.7%, and 92.9%, respectively (P = 0.14). Only 20 patients experienced a treatment failure. Under multivariate analysis, factors such as fibrosis stage, previous treatment, HCV genotype, and baseline HCV viral load did not influence SVR12 rates in the four groups (P = 0.21). Hematological adverse events (AEs) were more common in the RBV group: anemia (P < 0.0001) and blood transfusion (P = 0.0001)., Conclusion: SOF + NS5A inhibitors without RBV for 12 weeks constituted reliable therapy for recurrent HCV post-LT with an excellent SVR12 whatever the fibrosis stage, HCV genotype, and previous HCV treatment. (Hepatology 2018; 00:000-000)., (© 2018 by the American Association for the Study of Liver Diseases.)

Background: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable., Aim: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time., Methods: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles., Results: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m 2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m 2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73)., Conclusion: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients., (© 2018 John Wiley & Sons Ltd.)

Background: A recurrence of hepatitis C virus (HCV) after liver transplantation affects survival in human immunodeficiency virus (HIV)/HCV coinfected patients. This study assessed the efficacy and safety of sofosbuvir (SOF)-based regimens in HIV/HCV coinfected patients after liver transplantation., Methods: Twenty-nine HIV/HCV coinfected transplanted patients receiving tacrolimus-, cyclosporine-, or everolimus-based immunosuppressive therapy were enrolled in the Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation cohort. Their antiviral treatment combined SOF, daclatasvir with or without ribavirin (n = 10/n = 6), or SOF, ledipasvir with or without ribavirin (n = 2/n = 11)., Results: The median delay between liver transplantation and treatment initiation was 37.5 months (interquartile range [IQR], 14.4-99.2). The breakdown of HCV genotypes was G1, 22 patients (75.9%); G3, 3 patients (10.3%); and G4, 4 patients (13.8%). The treatment indications were HCV recurrence (≥ F1 n = 23) or fibrosing cholestatic hepatitis (n = 6). Before starting SOF, the HCV viral load and CD4 count were 6.7 log10 IU/mL (IQR, 5.9-7.2) and 342 cells/mm (IQR, 172-483), respectively. At week 4, the HCV viral load was less than 15 IU/mL in 12 (42.9%) patients. The overall sustained virological response 12 was 96.6%. No significant drug-drug interactions were observed., Conclusions: SOF-based treatment regimens produced excellent results in HIV/HCV coinfected patients after liver transplantation, suggesting an important change in their prognosis.

Hepatitis C virus (HCV) infection is associated with reduced patient survival following combined liver-kidney transplantation (LKT). The aim of this study was to assess the efficacy and safety of second-generation direct-acting antivirals (DAAs) in this difficult-to-treat population. The ANRS CO23 "Compassionate use of Protease Inhibitors in Viral C Liver Transplantation" (CUPILT) study is a prospective cohort including transplant recipients with recurrent HCV infection treated with DAAs. The present work focused on recipients with recurrent infection following LKT. The study population included 23 patients. All patients received at least one NS5B inhibitor (sofosbuvir) in their antiviral regimen an average of 90 months after LKT. Ninety-six percent of recipients achieved a sustained virological response (SVR) at week 12 (SVR12). In terms of tolerance, 39% of recipients presented with at least one serious adverse event. None of the patients experienced acute rejection during therapy and there were no deaths during follow-up. The glomerular filtration rate (GFR) decreased significantly from baseline to the end of therapy. However, this study did not show that the decline in GFR persisted over time or that it was directly related to DAAs. The DAA-based regimen is well tolerated with excellent results in terms of efficacy. It will become the gold standard for the treatment of recurrent HCV following LKT., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background & Aims: HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy., Methods: From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective multicentre France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) Compassionate use of Protease Inhibitors in viral C Liver Transplantation cohort. We selected 137 patients with an HCV recurrence receiving SOF and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy were at the investigator's discretion. The primary efficacy end point was a sustained virological response (SVR) 12weeks after the end of treatment., Results: The SVR rate 12weeks after completing treatment was 96% under the intention-to treat analysis and 99% when excluding non-virological failures. Only two patients experienced a virological failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more cases in the ribavirin group (56% vs. 18%; p<0.0001). A slight but significant reduction in creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs., Conclusions: Treatment with SOF plus DCV was associated with a high SVR12 and low rates of serious adverse events among liver recipients with HCV recurrence., Lay Summary: The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct-acting antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per cent of recipients were cured. The safety profile of this combination seemed to be good, especially no relevant drug-drug interaction with immunosuppressive drugs., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) can rapidly lead to liver graft cirrhosis and, therefore, graft failure and retransplantation or death. The aim of the present study was to assess efficacy and tolerance of sofosbuvir (SOF)-based regimens for the treatment of HCV recurrence in patients with severe fibrosis after LT. The Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation (CULPIT) study is a prospective multicenter cohort including patients with HCV recurrence following LT treated with second generation direct antivirals. The present study focused on patients included between October 2013 and November 2014 and diagnosed with HCV recurrence and liver graft extensive fibrosis (METAVIR F3/F4). A SOF-based regimen was administered to 125 patients fulfilling inclusion criteria. The median delay from LT was 95.9 ± 69.6 months. The characteristics of patients were as follows: mean age, 59.4 ± 9.0 years; 78.4% male; infected by HCV genotype 1: 78.2%, mean HCV RNA: 6.1 ± 1.0 log10 IU/mL. Eighty patients had failed previous post-LT antiviral therapy (64.0%) including triple therapy with first generation protease inhibitors in 19 (15.2%) patients. The main combination regimen was SOF/daclatasvir (73.6%). Ribavirin was used in 60 patients. Sustained virological response 12 weeks after treatment was 92.8% (on an intention-to-treat basis); 7 patients with virological failure were observed. Serious adverse events occurred in 25.6% of the patients during antiviral treatment. During antiviral treatment and follow-up, 3 patients were retransplanted and 4 patients died. In conclusion, SOF-based antiviral treatment shows very promising results in patients with HCV recurrence and severe fibrosis after LT. Liver Transplantation 22 1367-1378 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Background & Aims: Fibrosing cholestatic hepatitis (FCH) is a life-threatening disorder that develops in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation. Until recently, therapeutic options have been limited. We evaluated the efficacy and safety of sofosbuvir- and daclatasvir-based regimens., Methods: We analyzed data from 23 patients with FCH who participated in a prospective cohort study in France and Belgium of the effects of antiviral agents in patients with recurrence of HCV infection after liver transplantation, from October 2013 through April 2014. Most of the patients had genotype 1 infections that had not responded to previous treatment; 4 patients also were infected with human immunodeficiency virus. Eight patients (37%) had ascites and 15 patients (65%) had bilirubin levels greater than 100 mmol/L; their median serum level of HCV RNA was 7 log IU/mL. The median time between transplantation and treatment initiation was 5 months. Subjects were given either sofosbuvir and daclatasvir (n = 15) or sofosbuvir and ribavirin (n = 8) for 24 weeks. The primary outcome was complete clinical response (survival without re-transplantation, bilirubin level <34 μmol/L, and no ascites or hepatic encephalopathy 36 weeks after treatment began)., Results: All patients survived, without re-transplantation, until week 36. Rapid and dramatic improvements in clinical status were observed. The patients' median bilirubin concentration decreased from 122 μmol/L at baseline to a normal value at week 12 of treatment. Twenty-two patients (96%) had a complete clinical response at week 36. Despite the low rate of rapid virologic response, 22 patients (96%) achieved a sustained virologic response at week 12. The only relapse of HCV infection occurred in a patient with human immunodeficiency virus infection who received sofosbuvir and ribavirin. Tolerance was satisfactory, with no grade 3 or 4 adverse events related to sofosbuvir or daclatasvir and no significant interactions among drugs., Conclusions: Sofosbuvir therapy with daclatasvir or ribavirin leads to major clinical improvement and high rates of sustained virologic response at week 12 in most patients with recurrence of HCV infection and FCH after liver transplantation. ClinicalTrial.gov no: NCT01944527., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)