Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program

We reported the efficacy and safety data for daclatasvir (DCV)-based all-oral antiviral therapy in patients treated in the Italian compassionate-use program. 275 patients were included (202 male-73.5%, mean age: 57.4 years, 62 HIV-coinfected, 94 with recurrence of hepatitis C post-OLT). Forty-nine patients (17.8%) had Child-Pugh B, Genotype(G) distribution was: G1a:72 patients (26.2%), G1b:137 (49.8%); G3:40 (14.5%) and G4:26 (9.5%). Patients received DCV with sofosbuvir(SOF) (n\u2009=\u2009221, 129 with ribavirin(RBV) or with simeprevir (SMV) or asunaprevir (ASU) (n\u2009=\u200954, 19 with RBV) for up to 24 weeks. Logistic regression was used to identify baseline characteristics associated with sustained virological response at week 12 post-treatment (SVR12). Liver function changes between baseline and follow up were assessed in 228 patients. 240 patients achieved SVR12 (87.3%), post transplant and HIV co-infected patients were equally distributed among SVR and no SVR (35% vs 34.3%; p\u2009=\u20090.56 and 24.2% vs 11.4%, p\u2009=\u20090.13, respectively). SVR rate was significantly higher with the combination DCV\u2009+\u2009SOF compared with DCV\u2009+\u2009SIM or ASU (93.2% vs 63.0%, p\u2009<\u20090.0001). Bilirubin value (OR: 0.69, CI95%: 0.54-0.87, p\u2009=\u20090.002) and regimen containing SOF (OR: 9.99, CI95%: 4.09-24.40; p\u2009<\u20090.001) were independently related with SVR. Mean albumin and bilirubin values significantly improved between baseline and follow-up week 12. DCV-based antiviral therapy was well tolerated and resulted in a high SVR when combined with SOF either in pre-transplant and in OLT patients and in "difficult to treat" HCV genotypes. Regimens containing DCV in combination with NS3 protease inhibitors obtained suboptimal results

Prevention of VTE in orthopedic surgery patients

<p>Venous thromboembolism (VTE) is defined as the obstruction, partial or complete, of one or more veins of deep circulation. It is a condition that can lead to a deterioration in his state of health until death, manifesting as deep vein thrombosis (DVT) or pulmonary embolism (PE). The major orthopedic surgery and the surgical oncology are frequently associated with thromboembolic complications, because of conditions that are often critical in these patients. It is estimated that in Italy DVT has an incidence that varies between 50 and 150 new cases per 100,000 population, while the prevalence would be between 2.5 and 5%. In the absence of thromboprophylaxis, the orthopedic surgery lead to a high increased risk of VTE. In elective hip replacement, in the absence of prophylaxis, the incidence of DVT and of fatal PE is about 50% and 2% respectively. In elective knee arthroplasty the risk of venous thromboembolic complications is even higher. It is estimated that 56.2% of the costs of prophylaxis with Low Molecular Weight Heparin (LMWH) in patients undergoing major orthopedic surgery are attributable to the cost of drugs (about € 200), followed (with 44.8%) by the cost of administration (approximately € 159). The average total cost/day was estimated at € 8 per patient. In Italy, it has been estimated an annual cost for new cases between 215 and 260 million €. The clinical advantages of the New Oral Anticoagulants (NOA) appear to be substantially clear, the major concern with regard to their reimbursement is therefore linked to the financial impact, due to the higher cost per day of the NOA compared with LMWH. To this end, it was built a model of budget impact, in the perspective of the Italian NHS, from the data related to cases of major surgical orthopedic procedures and a meta-analysis on the pivotal RCT, which aims to measure the differential effects in terms of prevention of VTE. The results show that the financial impact of the NOA in the prophylaxis of major orthopedic surgery is not particularly relevant. In fact, the major pharmaceutical costs that, at national level, amount to € 10.8 mil. (€ 15.2 mil. in the case of prolonged prophylaxis in knee operations) would be more than offset by savings in terms of fewer treatments of VTE, which is based on the assumption of more than 4,000 cases, up to about 6,600 in hypothesis best efficacy.</p><p><a href="http://dx.doi.org/10.7175/fe.v14i2S.881">http://dx.doi.org/10.7175/fe.v14i2S.881</a></p

Prevention of VTE in orthopedic surgery patients

Venous thromboembolism (VTE) is defined as the obstruction, partial or complete, of one or more veins of deep circulation. It is a condition that can lead to a deterioration in his state of health until death, manifesting as deep vein thrombosis (DVT) or pulmonary embolism (PE). The major orthopedic surgery and the surgical oncology are frequently associated with thromboembolic complications, because of conditions that are often critical in these patients. It is estimated that in Italy DVT has an incidence that varies between 50 and 150 new cases per 100,000 population, while the prevalence would be between 2.5 and 5%. In the absence of thromboprophylaxis, the orthopedic surgery lead to a high increased risk of VTE. In elective hip replacement, in the absence of prophylaxis, the incidence of DVT and of fatal PE is about 50% and 2% respectively. In elective knee arthroplasty the risk of venous thromboembolic complications is even higher. It is estimated that 56.2% of the costs of prophylaxis with Low Molecular Weight Heparin (LMWH) in patients undergoing major orthopedic surgery are attributable to the cost of drugs (about € 200), followed (with 44.8%) by the cost of administration (approximately € 159). The average total cost/day was estimated at € 8 per patient. In Italy, it has been estimated an annual cost for new cases between 215 and 260 million €. The clinical advantages of the New Oral Anticoagulants (NOA) appear to be substantially clear, the major concern with regard to their reimbursement is therefore linked to the financial impact, due to the higher cost per day of the NOA compared with LMWH. To this end, it was built a model of budget impact, in the perspective of the Italian NHS, from the data related to cases of major surgical orthopedic procedures and a meta-analysis on the pivotal RCT, which aims to measure the differential effects in terms of prevention of VTE. The results show that the financial impact of the NOA in the prophylaxis of major orthopedic surgery is not particularly relevant. In fact, the major pharmaceutical costs that, at national level, amount to € 10.8 mil. (€ 15.2 mil. in the case of prolonged prophylaxis in knee operations) would be more than offset by savings in terms of fewer treatments of VTE, which is based on the assumption of more than 4,000 cases, up to about 6,600 in hypothesis best efficacy

Effect of early treatment with polyvalent immunoglobulin on acute respiratory distress syndrome associated with SARS-CoV-2 infections (ICAR trial): study protocol for a randomized controlled trial

International audienceBackground: As of mid-June 2020, 7,500,000 people were infected with SARS-CoV-2 worldwide and 420,000 people died, mainly from coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). COVID-19-related ARDS is subject to a mortality rate of 50% and prolonged period of mechanical ventilation, with no specific pharmacological treatment currently available (Infection au nouveau Coronavirus (SARS-CoV-2), COVID-19, France et Monde. https://www.santepubliquefrance.fr/dossiers/coronavirus-covid-19). Because of its immunomodulatory action, we propose to evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) administration in patients developing COVID-19-related ARDS. Methods: The trial is a phase III double-blind, randomized, multicenter, parallel group, concurrent, controlled study in hospitalized participants with COVID-19 requiring mechanical ventilation using a sequential design. Participants in the treatment group will receive infusions of polyvalent immunoglobulin for 4 consecutive days, and the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration. The primary outcome is the number of ventilator-free days up to the 28th day. Secondary objectives are to evaluate the effect of IVIG on (1) organ failure according to the Sequential Organ Failure Assessment (SOFA) score at 14 and 28 days, (2) lung injury score at 14 and 28 days, (3) the occurrence of grade 3 or 4 adverse events of IVIG, (4) length of intensive care unit (ICU) stay, (5) length of hospital stay, (6) functional outcomes at day 90 defined by the activities of daily living and instrumental activities of the daily living scales, and (7) 90-day survival. One hundred thirty-eight subjects will be randomized in a 1:1 ratio to IVIG or placebo groups (69 in each group), considering 90% power, alpha level 0.05 (two sides), and 0.67 effect size level. Discussion: The ICAR trial investigates the effect of IVIG in COVID-19-related ARDS. We expect an increase in the survival rate and a reduction in the duration of mechanical ventilation, which is associated with significant morbidity. Trial registration: EudraCT 2020-001570-30. ClinicalTrials.gov NCT04350580. Registered on 17 April 2020

Etiology of intracerebral hemorrhage in children: cohort study, systematic review, and meta-analysis

International audienceOBJECTIVEUnderstanding the etiological spectrum of nontraumatic pediatric intracerebral hemorrhage (pICH) is key to the diagnostic workup and care pathway. The authors aimed to evaluate the etiological spectrum of diseases underlying pICH.METHODSChildren treated at the authors’ institution for a pICH were included in an inception cohort initiated in 2008 and retrospectively inclusive to 2000, which was analyzed in October 2019. They then conducted a systematic review of relevant articles in PubMed published between 1990 and 2019, identifying cohorts with pICH. Identified populations and patients from the authors’ cohort were pooled in a multicategory meta-analysis.RESULTSA total of 243 children with pICH were analyzed in the cohort study. The final primary diagnosis was an intracranial vascular lesion in 190 patients (78.2%), a complication of a cardiac disease in 17 (7.0%), and a coagulation disorder in 14 (5.8%). Hematological and cardiological etiologies were disproportionately more frequent in children younger than 2 years (p < 0.001). The systematic review identified 1309 children in 23 relevant records pooled in the meta-analysis. Overall, there was significant heterogeneity. The dominant etiology was vascular lesion, with an aggregate prevalence of 0.59 (95% CI 0.45–0.64; p < 0.001, Q = 302.8, I2 = 92%). In 18 studies reporting a detailed etiological spectrum, arteriovenous malformation was the dominant etiology (68.3% [95% CI 64.2%–70.9%] of all vascular causes), followed by cavernoma (15.7% [95% CI 13.0%–18.2%]).CONCLUSIONSThe most frequent etiology of pICH is brain arteriovenous malformation. The probability of an underlying vascular etiology increases with age, and, conversely, hematological and cardiac causes are dominant causes in children younger than 2 years

Etiology of intracerebral hemorrhage in children: cohort study, systematic review, and meta-analysis

International audienceOBJECTIVEUnderstanding the etiological spectrum of nontraumatic pediatric intracerebral hemorrhage (pICH) is key to the diagnostic workup and care pathway. The authors aimed to evaluate the etiological spectrum of diseases underlying pICH.METHODSChildren treated at the authors’ institution for a pICH were included in an inception cohort initiated in 2008 and retrospectively inclusive to 2000, which was analyzed in October 2019. They then conducted a systematic review of relevant articles in PubMed published between 1990 and 2019, identifying cohorts with pICH. Identified populations and patients from the authors’ cohort were pooled in a multicategory meta-analysis.RESULTSA total of 243 children with pICH were analyzed in the cohort study. The final primary diagnosis was an intracranial vascular lesion in 190 patients (78.2%), a complication of a cardiac disease in 17 (7.0%), and a coagulation disorder in 14 (5.8%). Hematological and cardiological etiologies were disproportionately more frequent in children younger than 2 years (p < 0.001). The systematic review identified 1309 children in 23 relevant records pooled in the meta-analysis. Overall, there was significant heterogeneity. The dominant etiology was vascular lesion, with an aggregate prevalence of 0.59 (95% CI 0.45–0.64; p < 0.001, Q = 302.8, I2 = 92%). In 18 studies reporting a detailed etiological spectrum, arteriovenous malformation was the dominant etiology (68.3% [95% CI 64.2%–70.9%] of all vascular causes), followed by cavernoma (15.7% [95% CI 13.0%–18.2%]).CONCLUSIONSThe most frequent etiology of pICH is brain arteriovenous malformation. The probability of an underlying vascular etiology increases with age, and, conversely, hematological and cardiac causes are dominant causes in children younger than 2 years

Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial

International audienceBackground: Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury.Methods: In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580.Findings: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089).Interpretation: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials. Findings: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0–8·0]) and the placebo group (0·0 [0·0–6·0]; difference estimate 0·0 [0·0–0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089).Interpretation: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials