Safety of TNF-blocking agents in rheumatic patients with serology suggesting past hepatitis B state: results from a cohort of 21 patients

INTRODUCTION: Reactivation of hepatitis B virus (HBV) infection in patients with past infection has been described in 5% to 10% of individuals undergoing immunosuppressive therapies. No data are available to date on the outcome of patients treated by tumour necrosis factor-alpha (TNFα) inhibitors for chronic arthritis with a serological pattern of past HBV infection. The aim of our study was to monitor HBV markers in HBV surface antigen (HBsAg)-negative/anti-HBcAb-positive patients treated with a TNFα inhibitor for inflammatory arthritides. METHODS: Twenty-one HBsAg-negative/anti-HBcAb-positive patients were included. HBV serological patterns were compared with those determined before starting TNFα inhibitors. Serum HBV DNA testing by polymerase chain reaction was additionally performed. Spearman correlation analysis was used and P < 0.05 was chosen as the significance threshold. RESULTS: Before starting therapy, mean anti-HBsAb titre was 725 IU/L, no patient had an anti-HBsAb titre <10 IU/L, and 18 patients had an anti-HBsAb >100 IU/L. At a mean time of 27.2 months following therapy introduction, mean anti-HBsAb titre was 675 IU/L and anti-HBsAb titre remained >100 IU/L in 17 patients. There was a strong correlation between the first and second anti-HBsAb titres (r = 0.98, P = 0.013). Moreover, no patient had an anti-HBsAb titre below 10 IU/L or HBV reactivation (HBsAg seroreversion or positive HBV DNA detection). However, the anti-HBsAb titre decreased by more than 30% in 6 patients. The mean anti-HBsAb titre at baseline was significantly lower (P = 0.006) and the mean duration of anti-TNFα therapy, although non-significant (P = 0.09), was longer in these six patients as compared to patients without a decrease in anti-HBsAb titre. CONCLUSIONS: Anti-TNFα treatments are likely to be safe in patients with past hepatitis B serological pattern. However, the significant decrease of anti-HBsAb titre observed in a proportion of patients deserves HBV virological follow-up in these patients, especially in those with a low anti-HBsAb titre at baseline

Autochthonous Infections with Hepatitis E Virus Genotype 4, France

During January–March 2011, diagnoses of hepatitis E virus (HEV) infection increased in Marseille University hospitals in southeastern France. HEV genotype 4, which is described almost exclusively in Asia, was recovered from 2 persons who ate uncooked pork liver sausage. Genetic sequences were 96.7% identical to those recently described in swine in Europe

Peri-operative risk factors of chronic kidney disease after liver transplantation

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Endogenous Ethanol and Triglyceride Production by Gut Pichia kudriavzevii, Candida albicans and Candida glabrata Yeasts in Non-Alcoholic Steatohepatitis

International audienceNonalcoholic steatohepatitis (NASH) increases with fructose consumption and metabolic syndrome and has been recently linked with endogenous ethanol production, notably by high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn). Candida yeasts are the main causes of auto-brewery syndromes but have been neglected in NASH. Here, the fecal ethanol and microbial content of 10 cases and 10 controls were compared. Ethanol was measured by gas chromatography-mass spectrometry. Species identification was performed by MALDI-TOF MS, and triglyceride production was assessed by a colorimetric enzymatic assay. The fecal ethanol concentration was four times higher in patients with NASH (median [interquartile range]: 0.13 [0.05–1.43] vs. 0.034 [0.008–0.57], p = 0.037). Yeasts were isolated from almost all cases but not from controls (9/10 vs. 0/10, p = 0.0001). Pichia kudriavzevii was the most frequent (four patients), while Candida glabrata, Candida albicans, and Galactomyces geotrichum were identified in two cases each. The concentration of ethanol produced by yeasts was 10 times higher than that produced by bacteria (median, 3.36 [0.49–5.60] vs. 0.32 [0.009–0.43], p = 0.0029). Using a 10% D-fructose restricted medium, we showed that NASH-associated yeasts transformed fructose in ethanol. Unexpectedly, yeasts isolated from NASH patients produced a substantial amount of triglycerides. Pichia kudriavzevii strains produced the maximal ethanol and triglyceride levels in vitro. Our preliminary human descriptive and in vitro experimental results suggest that yeasts have been neglected. In addition to K. pneumoniae, gut Pichia and Candida yeasts could be linked with NASH pathophysiology in a species- and strain-specific manner through fructose-dependent endogenous alcohol and triglyceride production

Treatment of autochthonous acute hepatitis E with short-term ribavirin: a multicenter retrospective study

International audienceBackground & aims: Hepatitis E virus (HEV) genotypes 3 and 4 cause sporadic cases of infection in developed countries. Being elderly and having an underlying liver disease are the main risk factors for death in this population. Chronic infection has been described in immunocompromised patients. Ribavirin is now the antiviral treatment of choice in solid-organ-transplant recipients with chronic HEV infection. We hypothesized that early short-term treatment of acute HEV infection may be useful for patients with risk factors or undergoing chemotherapy.Methods: Between July 2010 and January 2014, 21 patients diagnosed with acute HEV infection were treated with ribavirin, at 600-800 mg/day for up to 3 months. All serum samples were positive for HEV RNA.Results: Nine patients were treated for severe hepatitis. Six patients were aged >70 years. Four patients were receiving an immunosuppressive therapy for an autoimmune disease and two patients were undergoing chemotherapy for a malignancy. Two patients received a fixed-dose regimen. For all other patients, ribavirin was stopped when HEV became undetectable in the serum. The median duration of ribavirin treatment was 26 days. Two patients developed severe anaemia. Two patients with encephalopathy died. One patient relapsed transiently. All patients were cleared of HEV and regained normalized liver-enzyme levels. Immunosuppressive treatment and chemotherapy could be resumed.Conclusions: Treatment of acute HEV infection using ribavirin seems safe and effective. Short-term treatment tailored to viraemia may be the best regimen for this indication

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with -Mutated Hepatocellular Carcinoma.

Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with -mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with -mutant unresectable or metastatic HCC. Eligible patients with mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Of 1,318 patients screened, 59 (4.4%) had a mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in (63.0%), (48.1%), and β-catenin (; 37.0%). Prospective testing for family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of -mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored.