To report the first case of severe hypoglycaemia episodes related to voriconazole, involving neither over dosage nor any identified interaction with hypoglycaemic drugs. A 51-year-old man developed faints without loss of consciousness, with sweating in the morning for 3-4 days and low blood glucose, about 1 month after initiating voriconazole therapy. Hypoglycaemia was diagnosed and the patient required permanent intravenous glucose solutions for 8 days after voriconazole was stopped, after which glycaemia remained normal. A hyperinsulinaemia peak was observed, which disappeared when glycaemia normalized. Hypoglycaemia is known as a less common adverse event resulting from high voriconazole concentration and hepatic dysfunction. The mechanism of hypoglycaemia may be linked to insulinemia as its serum values are similar to glycaemia. Voriconazole may induce hypoglycaemia in patients without over dosage nor drug interaction.
Abstract Transjugular intrahepatic portosystemic shunt (TIPS) has become essential in the treatment or prevention of portal hypertension‐related complications. In the early 1990s, the primary indication was refractory bleeding. It is now proposed for the treatment of ascites for the prevention of bleeding and in patients with vascular diseases of the liver. Thus, there are a growing number of patients being treated with TIPS all over the world. The broadening of indications, the involvement of multiple stakeholders, the need for an accurate selection, the positioning in relation to transplantation and the lack of standardization in pre‐therapeutic assessment, in the procedure itself and in the follow‐up have led the board of the French Association for the Study of the Liver to establish recommendations.
Background: Bulevirtide (BLV) received EMA approval for treatment of chronic compensated hepatitis due to Delta virus (HDV) infection, however real-life data in large cohorts of patients with cirrhosis are lacking. Methods: Consecutive HDV patients with compensated cirrhosis starting BLV 2 mg/day since September 2019 were included in a retrospective multicenter real-life European study. Patients’ characteristics before and during BLV treatment were collected. Virological, biochemical, combined responses, adverse events and liver-related events (HCC, decompensation, liver transplant) were assessed. Findings: 176 patients with HDV compensated cirrhosis receiving BLV monotherapy for a median of 48 (8-96) weeks were included: at BLV start, age was 50 (19-82) years, 59% men, ALT 77 (23-1,074) U/L, liver stiffness measurement (LSM) 18.4 (6.4-75.0) kPa, platelets 89 (17-330) x 103/mm3, 55% with esophageal varices, 12% with previous ascites, 9% HIV-positive, 91% on NUC, median HDV RNA 5.4 (1.2-8.5) Log IU/mL, HBsAg 3.7 (0.8-4.5) Log IU/mL. Virological, biochemical and combined responses were observed in 50%, 69%, 61%, 77%, and 58%, 67%, 58%, 63% and 31%, 50%, 45%, 58% patients at week (W)24, W48, W72 and W96, respectively. Serum Bile acid levels increased in most patients but only 11% reported mild and transient pruritus. One patient discontinued BLV due to a grade 3 maculopapular rash; 4 patients were lost to follow-up and 3 discontinued due to virologic non-response. The W96 cumulative risk of de-novo HCC and decompensation was 4.4% (95% CI 1-9%) and 2.4% (95% CI 1-5%), respectively. Six (3%) patients underwent liver transplantation (n=4 for HCC, n=2 for decompensation). The overall cumulative survival rate was 93% (95% CI 88-98%) at W96. Interpretation: BLV 2 mg/day monotherapy up to 96 weeks was safe and effective in patients with HDV-related compensated cirrhosis. Virological and clinical responses increased over time. The risk of decompensation was low.Funding: This work was supported in part by grants from “Ricerca Corrente RC2021/105-01”, ItalianMinistry of Health and Gilead Sciences (IN-IT-589-6246).Declaration of Interest: Elisabetta Degasperi: Advisory Board: AbbVie, Roche; Speaking and teaching: Gilead, Intercept, AbbVie; Travel Grant: Abbvie, Intercept Gilead; Research grant: Gilead Stanislas Pol: Consulting and lecturing fees from Gilead, MSD, Abbvie, Biotest, Shinogui, Viiv, LFB and grants from Bristol-Myers Squibb, Gilead, Roche and MSD George Papatheodoridis: Advisor/lecturer:Abbvie, Albireo, Amgen, Dicerna, Genesis, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche and Takeda; Research grants: Abbvie, Gilead and Takeda. Victor De Ledinghen: Advisory board and Speaking: Gilead Mathias Jachs: Speaking: Gilead Thomas Reiberger: Speaker and/or consultant and/or advisory board member speaking honoraria from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Roche, Siemens, and W. L. Gore & Associates; Travel support from AbbVie, Boehringer-Ingelheim, Gilead, and Roche; Grants/research support from AbbVie, Boehringer-Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens, and W. L. Gore & Associates Maurizia Brunetto: Speakers Bureau: AbbVie, Gilead, EISAI-MSD; Advisory: AbbVie, Gilead, Janssen, AstraZeneca Heiner Wedemeyer: Grants from Abbvie, Biotest, Gilead, Merck/MSD, Roche; consulting fees from Abbvie, Aligos, Altimmune, Biotest, BMS, BTG, Dicerna, Enanta, Gilead, Janssen, Merck/MSD, MYR GmbH, Roche, Vir Biotechnology; Speaker for Abbvie, Biotest, Gilead, Merck/MSD Christopher Dietz-Fricke: Grant and travel support by Gilead George Papatheodoridis: Advisor/Consultant/Lecturer: Abbvie, Albireo, Amgen, Astellas, Elpen, Genesis, Gilead, GlaxoSmithKline, Janssen, Ipsen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Takeda; Grants: Abbvie, Gilead, Takeda Fabien Zoulim: consultant for Aligos, Assembly, Evotec, GSK; speaker for Gilead; research grants: Assembly, Beam, Blue Jay, Janssen Pietro Lampertico: Roche Pharma/Diagnostics, Gilead Sciences, Gsk, Abbvie, Janssen, Myr, Eiger, Antios, Aligos, Vir, Grifols, Altona, Roboscreen Other authors have nothing to discloseEthical Approval: Patients gave their informed consent to provide clinical and virological data for the study, which was approved by the local IRB of the coordinating center (Comitato Etico Area 2 Milano, Italy) and conformed to the Helsinki Declaration.
The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear.To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone.Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019.Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147).The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days.Among 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, -4.7% [95% CI, -14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% [95% CI, -23.0% to -0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group).In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis.ClinicalTrials.gov Identifier: NCT02281929.
Background: Anastomotic biliary stricture (ABS) remains the most frequent complication after liver transplantation (LT). This study aimed to identify new anastomotic biliary stricture risk factors, with a specific focus on postoperative events. Additionally, ABS management and impact on patient and graft survival were assessed. Methods: All consecutive patients who underwent LT with duct-to-duct anastomosis between 2010 and 2019 were included. All patients who died within 90 days after LT due to non-ABS-related causes were excluded. Results: Among 240 patients, 65 (27.1%) developed ABS after a median time of 142 days (range, 13-1265). Median follow-up was 49 months (7-126). Upon multivariable analysis, donor BMI (OR=0.509, p = 0.037), post-LT CMV primoinfection (OR = 5.244, p < 0.001) or reactivation (OR = 2.421, p = 0.015) and the occurrence of post-LT anastomotic biliary fistula (OR = 2.691, p = 0.021) were associated with ABS. Anastomotic technical difficulty did not independently impact the risk of ABS (OR = 1.923, p = 0.051). First-line ABS treatment was systematically endoscopic (100%), and required a median of 2 (range, 1-11) procedures per patient. Repeat LT was not required in patients developing ABS. The occurrence of ABS was not associated with overall patient survival (p = 0.912) nor graft survival (p = 0.521). Conclusion: The risk of developing ABS after LT seems driven by the occurrence of postoperative events such as CMV infection and anastomotic fistula. In this regard, the role of CMV prophylaxis warrants further investigations.
We report the case of a 49-Year-old-man with primary sclerosis cholangitis (PSC) and ulcerative colitis who developed two acute episodes of pseudo-angiocholitis. Both episodes were triggered by septic hepatitis translocated from ulcerative colonic adenocarcinoma. The biliary MRI did not show any signs of lithiasis or cholangiocarcinoma. cholangiocarcinoma, intra-hepatic lithiasis and colonic cancer are potential diagnoses in patients with PSC who develop angiocholitis.
The bacterial epidemiology of bacterascites and spontaneous bacterial peritonitis is evolving. Four hundred and eleven strains isolated from ascites in cirrhotic patients from 5 French hospitals were isolated in 2006 and 2007. Of these, 114 were definitely associated with spontaneous bacterial peritonitis. The proportion of Gram-positive and Gram-negative agents was quite similar, even after excluding coagulase-negative staphylococci, or when considering only definite spontaneous bacterial peritonitis or community-acquired strains. Staphylococci and Escherichia coli were the most frequent pathogens, but enterococci were also involved in nearly 15% of the cases. Among the E. coli, 28% were intermediate or resistant to amoxicillin+clavulanate, 5.3% expressed cephalosporinases or extended beta-lactamases and 17.3% were intermediate or resistant to fluoroquinolones. Resistance to methicillin was observed in 27% of Staphylococcus aureus. Cefotaxime and amoxicillin-clavulanate remained the most effective 'single' agents, however on less than 70% of isolates. Some combinations (such as cefotaxime+amoxicillin) extended coverage to a further 15% of strains. Since inadequate empiric antibiotic therapy is associated with increased mortality, these combinations may be of great interest as first-line treatment, even though they may also lead to the development of antimicrobial resistance. Repeated epidemiological surveys and new clinical trials are thus needed.
The role of endotoxemia related to intestinal bacterial translocation in worsening liver disease is the subject of many studies, but its impact on cirrhosis mortality has not been well evaluated. In this study, 3-hydroxymyristate (3-HM) (specific lipid of lipopolysaccharides) was directly quantified by an innovative patented assay with the aim of assessing the impact on cirrhosis mortality. The 3-HM concentration was measured in 593 patients with alcoholic or viral cirrhosis in stable clinical condition. A Cox hazards regression model was used to evaluate association between 3-HM and its fractions bound or nor bound to lipoprotein and the mortality. The 3-HM concentration was increased in patients with more severe cirrhosis (p<0.001). After 5 years of follow-up, 271 (45.7%) patients had died. In multivariate analysis, high level of 3HM was strongly associated with high risk of death in patients with Child-Pugh A cirrhosis (Hazard ratio (HR)Tertile3vsTertile1(T3vsT1)=3.86, confidence interval to 95% (CI 95%) 1.66-6.04, p-trend<0.001), as well as the 3-HM fraction bound to lipoprotein (HR T3vsT1=2.32, CI 95% 1.31-4.13, p-trend=0.005), and not bound to lipoprotein (HR T3vsT1=2.86, CI 95% 1.61-5.08, p-trend<0.001). Such association did not exist in Child-Pugh B or C patients. In patients without liver complication before inclusion, 3-HM concentration was associated with the occurrence of at least one complication of cirrhosis (p<0.001) as occurrence of ascites (p=0.001) and encephalopathy (p=0.008) but not with gastrointestinal bleeding (p=0.56).
