Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

Geographic disparities in access to liver transplant for advanced cirrhosis: Time to ring the alarm!

Decompensated cirrhosis and hepatocellular cancer are major risk factors for mortality worldwide. Liver transplantation (LT), both live-donor LT or deceased-donor LT, are lifesaving, but there are several barriers toward equitable access. These barriers are exacerbated in the setting of critical illness or acute-on-chronic liver failure. Rates of LT vary widely worldwide but are lowest in lower-income countries owing to lack of resources, infrastructure, late disease presentation, and limited donor awareness. A recent experience by the Chronic Liver Disease Evolution and Registry for Events and Decompensation consortium defined these barriers toward LT as critical in determining overall survival in hospitalized cirrhosis patients. A major focus should be on appropriate, affordable, and early cirrhosis and hepatocellular cancer care to prevent the need for LT. Live-donor LT is predominant across Asian countries, whereas deceased-donor LT is more common in Western countries; both approaches have unique challenges that add to the access disparities. There are many challenges toward equitable access but uniform definitions of acute-on-chronic liver failure, improving transplant expertise, enhancing availability of resources and encouraging knowledge between centers, and preventing disease progression are critical to reduce LT disparities.

Muscle fibre morphometric analysis (MusMA) correlates with muscle function and cardiovascular risk prognosis.

Morphometry of striated muscle fibres is critical for monitoring muscle health and function. Here, we evaluated functional parameters of skeletal and cardiac striated muscle in two experimental models using the Morphometric Analysis of Muscle Fibre tool (MusMA). The collagen-induced arthritis model was used to evaluate the function of skeletal striated muscle and the non-alcoholic fatty liver disease model was used for cardiac striated muscle analysis. After euthanasia, we used haeamatoxylin and eosin stained sections of skeletal and cardiac muscle to perform muscle fibre segmentation and morphometric analysis. Morphometric analysis classified muscle fibres into six subpopulations: normal, regular hypertrophic, irregular hypertrophic, irregular, irregular atrophic and regular atrophic. The percentage of atrophic fibres was associated with lower walking speed (p = 0.009) and lower body weight (p = 0.026), respectively. Fibres categorized as normal were associated with maximum grip strength (p < 0.001) and higher march speed (p < 0.001). In the evaluation of cardiac striated muscle fibres, the percentage of normal cardiomyocytes negatively correlated with cardiovascular risk markers such as the presence of abdominal adipose tissue (p = .003), miR-33a expression (p = .001) and the expression of miR-126 (p = .042) Furthermore, the percentage of atrophic cardiomyocytes correlated significantly with the Castelli risk index II (p = .014). MusMA is a simple and objective tool that allows the screening of striated muscle fibre morphometry, which can complement the diagnosis of muscle diseases while providing functional and prognostic information in basic and clinical research.

Changes in the gut microbiota of rats after exposure to the fungicide Mancozeb.

Mancozeb is a fungicide commonly used in pest control programs, especially to protect vineyards. Its toxicity has already been evidenced in several studies. However, its influence on the composition and diversity of the gut microbiota remains unknown. In this work, the adverse impact of Mancozeb on the intestinal microbiota was investigated using a rodent model. Adult male Sprague Dawley rats were randomized into three groups: Control (standard diet), MZ1 (Mancozeb dose: 250 mg/kg bw/day), and MZ2 (Mancozeb dose: 500 mg/kg bw/day). After 12 weeks of experiment, animals were euthanized, and feces present in the intestine were collected. After fecal DNA extraction, the V4 region of the 16S rRNA gene was amplified followed by sequencing in an Ion S5™ System. Alpha and beta diversity analysis showed significant differences between Control and Mancozeb groups (MZ1 e MZ2), but no difference between MZ1 and MZ2 was observed. Seven genera significantly increased in abundance following Mancozeb exposure, while five genera decreased. Co-occurrence analyses revealed that the topological properties of the microbial networks, which can be used to infer co-occurrence interaction patterns among microorganisms, were significantly lower in both groups exposed to Mancozeb when compared to Control. In addition, 23 differentially abundant microbial metabolic pathways were identified in Mancozeb-treated groups mainly related to a change in energy metabolism, LPS biosynthesis, and nucleotide biosynthesis. In conclusion, the exposure to Mancozeb presented side effects by changing the composition of the microbiota in rats, increasing bacterial diversity regardless of the dose used, reducing the interaction patterns of the microbial communities, and changing microbial metabolic pathways.

Gut mycobiota changes in liver diseases: A systematic review.

Intestinal fungi play an important role in the health-disease process. We observed that in liver diseases, fungal infections lead to high mortality. In this review, we were able to gather and evaluate the available scientific evidence on intestinal mycobiota and liver diseases. We searched PubMed and Embase, using a combination of several entry terms. Only studies in adults ≥ 18 years old with liver disease and published after 2010 were included. We observed that individuals with liver disease have an altered intestinal mycobioma, which accompanies the progression of these diseases. In cirrhotic patients, there are a high number of Candida sp. strains, especially Candida albicans. In early chronic liver disease, there is an increase in alpha diversity at the expense of Candida sp. and conversely, in advanced liver disease, there is a negative correlation between alpha diversity and model for end-stage liver disease score. On the other hand, patients with non-alcoholic fatty liver disease demonstrate greater diversity compared to controls. Our study concluded that the evidence on the subject is sparse, with few studies and a lack of standardization of outcome measures and reporting, and it was not possible to perform a meta-analysis capable of synthesizing relevant parameters of the human mycobiotic profile. However, certain fungal genera such as Candida play an important role in the context of liver disease and that adults with liver disease have a distinct gut mycobiotic profile from healthy controls.

In people with end-stage liver disease, there is a high mortality from fungal infections. In this context, the genus Candida plays an important role in the context of liver disease, and adults with liver disease have a distinct gut mycobiota profile from healthy controls.

HLA-G 3'UTR haplotype analyses in HCV infection and HCV-derived cirrhosis, hepatocellular carcinoma and fibrosis.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune-related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G (HLA-G) gene codes for an immunomodulatory protein known to be expressed in the maternal-foetal interface and in immune-privileged tissues. The HLA-G 3' untranslated region (3'UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA-G 3'UTR with susceptibility to viral infections, but other polymorphic variants in the HLA-G 3'UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA-G 3'UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR-1, UTR-2 and UTR-3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA-G expression can be involved in HCV infection susceptibility.

New FIB-4 and NFS cutoffs to guide sequential non-invasive assessment of liver fibrosis by magnetic resonance elastography in NAFLD.

INTRODUCTION AND OBJECTIVES: Liver fibrosis is an important prognosis marker in non-alcoholic fatty liver disease (NAFLD). Biopsy has been considered the gold-standard method for measuring liver fibrosis; however, it is an invasive procedure. Non-invasive diagnostic tools have been developed, such as clinical scores and magnetic resonance elastography (MRE), which is the most accurate non-invasive method to determine liver fibrosis. Thus, the aim was to determine the NAFLD Fibrosis Score (NFS) and the Fibrosis-4 Score (FIB-4) cut-off points that best identify NAFLD patients at risk for developing liver fibrosis. PATIENTS AND METHODS: Single-center cross-sectional study with prospective recruitment of NAFLD (training-cohort) and MAFLD (validation-cohort) patients undergoing MRE. The NFS and the FIB-4 cut-off points that best-differentiated patients with fibrosis, using the MRE as the standard method, were determined. RESULTS: Two cohorts were analyzed, a training cohort that included the initial 183 patients with NAFLD and a validation cohort that included 289 patients. In the training cohort, 60.1% had mild steatosis and 11.5% had liver fibrosis ≥ F1 by MRE. ROC curves were developed for FIB-4 and NFS, and the cut-off points chosen were 1.505 (sensitivity=85% and specificity=86%) for FIB-4 and -0.835 (sensitivity=100% and specificity=70%) for NFS, showing greater specificity than the cut-off points currently used (51% and 76%, respectively). The two cohorts exhibited similar characteristics and similar sensitivity and specificity results for the chosen cut-off points. CONCLUSIONS: This study has shown cut-off points with greater specificity and excellent sensitivity to guide the indication for further liver evaluation by MRE in NAFLD patients.

Oral 24-week probiotics supplementation did not decrease cardiovascular risk markers in patients with biopsy proven NASH: A double-blind placebo-controlled randomized study.

INTRODUCTION AND OBJECTIVES: Cardiovascular disease (CVD) is the major cause of death in non-alcoholic fatty liver disease (NAFLD), a clinical condition without any approved pharmacological therapy. Probiotics are often indicated for the disease, but their results are controversial in part due to the poor quality of studies. Thus, we investigated the impact of 24-week probiotics supplementation on cardiovascular risk (CVR) in biopsy-proven non-alcoholic steatohepatitis (NASH) patients. PATIENTS AND METHODS: Double-blind, placebo-controlled, single-center study (NCT03467282), adult NASH, randomized for 24 weeks daily sachets of probiotic mix (109CFU of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus paracasei and Bifidobacterium lactis) or placebo. Clinical scores (atherogenic indexes, atherosclerotic cardiovascular disease-ASCVD and systematic coronary risk evaluation-SCORE), biochemistry, miR-122, miR-33a, plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), were determined before and after the intervention. RESULTS: Forty-six patients were enrolled (23 received probiotics and 23 placebo), with a mean age of 51.7 years, most of them females and whites. Clinical and demographic features were similar between the groups at the baseline. The Median NAFLD activity score was 4.13 in both groups. Fibrosis was mild in most patients (15.2% and 65.2% F0 and F1, respectively). Treatment did not promote any clinically significant changes in body mass index or laboratory, including lipid and glucose profile. High CVR patients through atherogenic indexes decreased from baseline in both groups, as well as PAI-1 and miR-122 levels, although there was no difference between probiotics and placebo. CONCLUSIONS: A 24-week probiotic mix administration was not superior to placebo in reducing CVR markers in patients with NASH.

Chronic exposure to ethanol alters the expression of miR-155, miR-122 and miR-217 in alcoholic liver disease in an adult zebrafish model.

AIM: The aim of this study was to evaluate the hepatic and circulating expression of miR-155, miR-122 and miR-217 in a model of chronic exposure to ethanol in adult zebrafish. METHODS: Wild-type adult zebrafish were divided into two groups (n = 281): an EG (exposed to 0.5% v/v Ethanol in aquarium water) and a CG (without ethanol). After 28 days the animals were euthanized, followed by histopathological analysis, quantification of lipids, triglycerides and inflammatory cytokines in liver tissue. miR-155, miR-122 and miR-217 gene expression was quantified in liver tissue and serum. RESULTS: We observed hepatic lesions and increased accumulation of hepatic lipids in the EG. The expression of il-1ß was higher in the EG, but there were no differences in il-10 and tnf-α between groups. In the liver, expression of miR-122 and miR-155 was higher in the EG. The circulating expression of miR-155 and miR-217 was significantly higher in the EG. CONCLUSION: Chronic exposure to ethanol in zebrafish leads to altered hepatic and circulating expression of miR-155, miR-122 and miR-217. This confirms its potential as a biomarker and therapeutic target.

Sinusoidal obstruction syndrome secondary the intake of Senecio brasiliensis: A case report.

Hepatic sinusoidal obstruction syndrome (HSOS) is a hepatic vascular disease histologically characterized by edema, necrosis, detachment of endothelial cells in small sinusoidal hepatic and interlobular veins and intrahepatic congestion, which leads to portal hypertension and liver dysfunction. In the Western world, most HSOS cases are associated with myeloablative pretreatment in a hematopoietic stem cell transplantation setting. Here we report a case of a 54 years old female patient, otherwise healthy, with no history of alcoholic ingestion, who presented with jaundice and signs of portal hypertension, including ascites and bilateral pleural effusion. She had no history of liver disease and denied any other risk factor for liver injury, except Senecio brasiliensis ingestion as a tea, prescribed as a therapy for menopause. Acute viral hepatitis and thrombosis of the portal system were excluded in complementary investigation, as well as sepsis, metastatic malignancy and other liver diseases, setting a RUCAM score of 6. Computed tomography demonstrated a diffuse liver parenchymal heterogeneity (in mosaic) and an extensive portosystemic collateral venous circulation, in the absence of any noticeable venous obstruction. HSOS diagnosis was confirmed through a liver biopsy. During the following-up period, patient developed refractory pleural effusion, requiring hemodialysis. Right before starting anticoagulation, she presented with abdominal pain and distention, with findings compatible of mesenteric ischemia by computed tomography. A laparotomy was performed, showing an 80cm segment of small bowel ischemia, and resection was done. She died one day after as a result from a septic shock refractory to treatment. The presented case was related to oral intake of S. brasiliensis, a plant containing pyrrolidine alkaloids, which are one of the main causes of HSOS in the East, highlighting the risk of liver injury with herbs intake.

Efficacy and safety of glecaprevir/pibrentasvir in treatment-naïve adults with chronic hepatitis C virus genotypes 1-6 in Brazil.

INTRODUCTION AND OBJECTIVES: Glecaprevir/pibrentasvir is a highly effective and well tolerated treatment for hepatitis C infection. Brazilian patients were not included in the original development studies for glecaprevir/pibrentasvir. This study aimed to assess safety and efficacy of glecaprevir/pibrentasvir in treatment-naïve Brazilian adults without cirrhosis or with compensated cirrhosis. PATIENTS AND METHODS: EXPEDITION-3 was a Phase 3, open-label, multicenter study in treatment-naïve Brazilian adults with hepatitis C infection genotype 1-6. Patients without cirrhosis (F2 or F3) or with compensated cirrhosis (F4) received 8 or 12 weeks of glecaprevir/pibrentasvir, respectively. The primary efficacy endpoint was the rate of sustained virologic response at post-treatment Week 12. Secondary endpoints were on-treatment virologic failure and relapse rates. Baseline polymorphisms were assessed in NS3 and NS5A. Adverse events and laboratory abnormalities were monitored. RESULTS: 100 patients were enrolled, 75 received 8 weeks of treatment and 25 received 12 weeks; all patients completed treatment. Overall sustained virologic response at post-treatment Week 12 rate was high (98.0%; 98/100; 95% confidence interval: 93.0-99.4) and remained high regardless of baseline viral or host factors, including demographics, hepatitis C virus RNA levels, polymorphisms in NS3 and/or NS5A, genotype, and relevant comorbidities. 55% of patients reported ≥1 adverse event, the most common being headache (18.0%). Four patients reported serious adverse events; none were considered drug related or led to study drug discontinuation. No hepatic decompensations were observed. CONCLUSIONS: Glecaprevir/pibrentasvir was effective and well tolerated in treatment-naïve Brazilian patients with hepatitis C infection without cirrhosis and with compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03219216.

Evaluation of drug-induced liver injury as etiology for acute liver failure in Brazil.

INTRODUCTION AND OBJECTIVES: Little is known about the etiology of acute liver failure (ALF) in Latin America. The objective of this paper is to investigate the main etiologies of ALF in Brazil, including Drug Induced Liver Injury (DILI) using stringent causality criteria. PATIENTS OR MATERIAL AND METHODS: All the cases of individuals who underwent liver transplantation (LT) in 12 centers in Brazil for ALF were reviewed. When DILI was stated as the cause of ALF, causality criteria were applied on site by the main investigator in order to rule out other etiologies. RESULTS: 325 individuals had ALF mainly for unknown reasons (34%), DILI (27%) and AIH (18%). Reassessment of the 89 cases of DILI, using stringent causality criteria, revealed that in only 42 subjects could DILI be confirmed as the cause of ALF. Acetaminophen (APAP) toxicity (n = 3) or DILI due to herbal and dietary supplements (HDS) (n = 2) were not commonly observed. CONCLUSIONS: Undetermined etiology and DILI are the main causes of ALF in Brazil. However, APAP toxicity and DILI due to HDS are mostly uncommon.

Hepatoprotective Effect of Probiotic Lactobacillus rhamnosus GG Through the Modulation of Gut Permeability and Inflammasomes in a Model of Alcoholic Liver Disease in Zebrafish.

Objective: Alcoholic liver disease (ALD) is among the leading causes of death from liver disease. Among the factors involved in its pathogenesis are inflammation and increased intestinal permeability. The aim of this study was to assess the effect of Lactobacillus rhamnosus GG (LGG) on hepatic lipid accumulation, activation of inflammasomes, and gut permeability markers in experimental model of ALD with zebrafish.Methods: An experiment was conducted to assess the effective LGG dose capable of promoting intestinal colonization. Animals were divided into three groups (n = 64/group): ethanol group (E), ethanol + probiotic group (EP), and control group (C). Groups E and EP were exposed to 0.5% ethanol concentration for 28 days. At the end of this period, animals were euthanized, and livers were collected for Oil Red staining and assessment of the inflammasome system. Intestines were collected for evaluation of gut permeability markers.Results: The dose of 1.55 × 106 UFC LGG/fish/d promoted intestinal colonization. Group EP presented lower hepatic lipid accumulation, lower il-1ß expression, and higher cldn15a expression when compared to group E.Conclusions: Supplementation with LGG was protective for hepatic steatosis in ALD model. In addition, LGG influenced the modulation of the inflammatory response and markers of gut permeability, improving the gut barrier structure.

Diagnostic performance of three non-invasive fibrosis scores (Hepamet, FIB-4, NAFLD fibrosis score) in NAFLD patients from a mixed Latin American population.

INTRODUCTION AND AIMS: Several non-invasive scoring systems have been developed and validated worldwide to predict the risk of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). However, information about the performance of these systems in Latin American populations is scarce. Our aim was to evaluate the performance of the Hepamet Fibrosis Score, Fibrosis-4 (FIB-4) and the NAFLD Fibrosis Score (NFS) in a mixed Latin American group of NAFLD patients. METHODS: Clinical, laboratory and liver biopsy data collected from 379 biopsy-proven NAFLD patients from Latin American tertiary health centers were reviewed. Histological fibrosis stages were classified using the Kleiner score. Accuracy was determined, and new fibrosis score thresholds were calculated to better compare the performances of non-invasive tests and to explore their usefulness in excluding fibrosis. RESULTS: The distribution of fibrosis stages among the sample population was as follows: F0 (45%), F1 (27%), F2 (8%), F3 (16%) and F4 (4%). Using modified thresholds, the areas under the ROC curves (AUROC) for Hepamet and FIB-4 (0.73 and 0.74, respectively) to detect significant fibrosis were higher than that of NFS (0.58). However, the AUROCs of the three scores were not significantly different in advanced fibrosis and cirrhosis. To exclude fibrosis, we calculated lower cutoffs than standard thresholds for Hepamet, FIB-4 and NFS with similar performances. CONCLUSION: Thresholds of non-invasive fibrosis scores (Hepamet, FIB-4 and NFS) can be modified to maximize diagnostic accuracy in Latin American patients with NAFLD.

Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future.

Anaphylaxis preceded by erythema multiforme with sorafenib: First case report.

A 63-year-old female patient with recent diagnosis of hepatitis C and cirrhosis and no other comorbidities, on no medications, was found to have Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma and began systemic therapy with sorafenib 400mg twice daily. Five days after starting treatment, the patient went to an emergency department with pruritic, target-shaped, erythematous papules compatible with erythema multiforme, painful oral aphthous ulcers, and fever. Sorafenib was suspended and the patient underwent oral corticosteroid treatment for 5 days, showing significant improvement of the lesions. One month after discharge, the patient was reassessed at an outpatient clinic. As she was asymptomatic and had no skin lesions, sorafenib was resumed at a lower dose (200mg daily). Three hours after ingesting a single dose of sorafenib, the patient experienced chills, fever, rash, angioedema and stridor. She immediately sought the emergency department and was diagnosed with anaphylaxis. The patient received intravenous corticosteroid therapy, which improved her respiratory and cutaneous symptoms in 72h. Sorafenib was permanently suspended, and regorafenib could not be prescribed as second-line therapy. This is the first description of anaphylaxis to sorafenib.

Chromosomal instability and cytotoxicity induced by ribavirin: comparative analysis in cell lines with different drug-metabolizing profiles.

Ribavirin is an important component of the treatment for hepatitis C virus (HCV) infection and, in combination with the new direct-acting antiviral (DAA) agents, comprises the major current therapeutic regimens. This study evaluated the cytotoxicity and chromosomal instability induced by ribavirin using the in vitro cytokinesis-block micronucleus cytome (CBMN-Cyt) assay in two cell lines with different expression levels of drug-metabolizing enzymes: human hepatocellular carcinoma cells (HepG2) and Chinese hamster ovary (CHO-K1) cells. HepG2 cells were treated with nine concentrations (from 15.3 µg/ml to 3.9 mg/ml) and CHO-K1 cells were exposed to eight concentrations (from 15.3 µg/ml to 1.9 mg/ml) of ribavirin for 24 h. Ribavirin inhibited cell proliferation in both cell lines, but at different concentrations: 3.9 mg/ml in HepG2 and 244.2 µg/ml in CHO-K1 cells. No significant differences were observed regarding aspects of cell death in HepG2 and CHO-K1 cells, reflecting the absence of cytotoxic effects associated to ribavirin. Ribavirin did not increase the frequency of nucleoplasmic bridges (NPBs) and nuclear bud (NBUD). However, when compared to the negative control, a significant increase in micronuclei (MNi) frequency was observed in both cell lines. However, chromosomal instability was induced by higher concentrations of ribavirin in HepG2 cells (from 61.1 to 976.8 µg/ml), compared with CHO-K1 cells (15.3 and 30.5 µg/ml). These results demonstrate the potential of ribavirin to promote chromosomal instability, and suggest that cells with different expressions of drug-metabolizing enzymes show different susceptibility to ribavirin effects.

Sorafenib for Advanced Hepatocellular Carcinoma: A Real-Life Experience.

INTRODUCTION: Sorafenib (SOR) has proved to be effective in patients with advanced hepatocellular carcinoma (HCC), since overall survival was higher in phase III clinical trials; however, disease progression can occur. OBJECTIVES: The study aimed to describe real-life experience in advanced HCC treatment with SOR at a university hospital in Brazil and to estimate the number of patients with indication of second-line therapy. METHODS: This is a retrospective study that included cases of HCC with prescription of SOR based on real-life practice between 2011 and 2016. Demographic, clinical, and laboratory data were collected. RESULTS: From 572 patients with HCC, SOR was prescribed in 103 cases. From them, 62.1% were classified as Child-Pugh (CP)-A, 54.4% as Barcelona Clinic Liver Cancer (BCLC)-C, and 74 (71.8%) started treatment. Overall survival was 25.5 (95% CI 17.0-34.1) months and 1-year survival was greater in patients who received SOR than in non-treated (88.7 vs. 44.4%, p < 0.001). There was no difference in survival between BCLC-B and C (p = 0.405), as well as CP-A and B (p = 0.919). In 21.6% of the patients, a second-line therapy with regorafenib was indicated. CONCLUSION: In this real-life study, SOR significantly increased the survival rate by 1 year in patients with advanced HCC regardless of BCLC staging and CP score. Second-line therapy would be indicated in 21.6% of cases.