Genetic Ancestry, Race, and Severity of Acutely Decompensated Cirrhosis in Latin America.

BACKGROUND & AIMS: Genetic ancestry or racial differences in health outcomes exist in diseases associated with systemic inflammation (eg, COVID-19). This study aimed to investigate the association of genetic ancestry and race with acute-on-chronic liver failure (ACLF), which is characterized by acute systemic inflammation, multi-organ failure, and high risk of short-term death. METHODS: This prospective cohort study analyzed a comprehensive set of data, including genetic ancestry and race among several others, in 1274 patients with acutely decompensated cirrhosis who were nonelectively admitted to 44 hospitals from 7 Latin American countries. RESULTS: Three hundred ninety-five patients (31.0%) had ACLF of any grade at enrollment. Patients with ACLF had a higher median percentage of Native American genetic ancestry and lower median percentage of European ancestry than patients without ACLF (22.6% vs 12.9% and 53.4% vs 59.6%, respectively). The median percentage of African genetic ancestry was low among patients with ACLF and among those without ACLF. In terms of race, a higher percentage of patients with ACLF than patients without ACLF were Native American and a lower percentage of patients with ACLF than patients without ACLF were European American or African American. In multivariable analyses that adjusted for differences in sociodemographic and clinical characteristics, the odds ratio for ACLF at enrollment was 1.08 (95% CI, 1.03-1.13) with Native American genetic ancestry and 2.57 (95% CI, 1.84-3.58) for Native American race vs European American race CONCLUSIONS: In a large cohort of Latin American patients with acutely decompensated cirrhosis, increasing percentages of Native American ancestry and Native American race were factors independently associated with ACLF at enrollment.

Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study.

BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 µg (TXR 140 ), CVC 150 mg (CVC), TXR 140 µg + CVC 150 mg (TXR 140 + CVC), or TXR 90 µg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Norfloxacin prophylaxis effect on multidrug resistance in patients with cirrhosis and bacterial infections.

It is unclear whether norfloxacin predisposes to infections by multidrug-resistant organisms (MDROs). We aimed to evaluate if patients with cirrhosis receiving norfloxacin prophylaxis at the time of the diagnosis of bacterial infections were more likely to present a multidrug-resistant isolate than those without prophylaxis. This is a cross-sectional study of hospitalized patients with cirrhosis and bacterial infections from Argentina and Uruguay (NCT03919032) from September 2018 to December 2020. The outcome variable was a multidrug-resistant bacterial infection. We used inverse probability of treatment weighting to estimate the odds ratio (OR) of norfloxacin on infection caused by MDROs considering potential confounders. Among the 472 patients from 28 centers, 53 (11%) were receiving norfloxacin at the time of the bacterial infection. Patients receiving norfloxacin had higher MELD-sodium, were more likely to have ascites or encephalopathy, to receive rifaximin, beta-blockers, and proton-pump inhibitors, to have a nosocomial or health-care-associated infection, prior bacterial infections, admissions to critical care units or invasive procedures, and to be admitted in a liver transplant center. In addition, we found that 13 (24.5%) patients with norfloxacin and 90 (21.5%) of those not receiving it presented infections caused by MDROs (adjusted OR 1.55; 95% CI: 0.60-4.03; p = 0.360). The use of norfloxacin prophylaxis at the time of the diagnosis of bacterial infections was not associated with multidrug resistance. These results help empiric antibiotic selection and reassure the current indication of norfloxacin prophylaxis in well-selected patients.Study registration number: NCT03919032.

Resistencia antimicrobiana y producción porcina de cría intensiva / Antimicrobial resistance and intensive swine production: mini review

Introducción: el impacto de la resistencia antimicrobiana (RAM) generará un aumento de las muertes relacionadas de 10 millones anuales hacia 2050. El 70% de la dispensación de antimicrobianos (ATB) se utiliza en la agroveterinaria y no en salud humana. Es fundamental conocer la portación de RAM en trabajadores de cría de animales y en los animales, para acciones tempranas de salud pública. Métodos: bajo metodología PRISMA se realizó la búsqueda bibliográfica en distintas fuentes disponibles hasta octubre de 2020. Se priorizaron revisiones sistemáticas, metanálisis, ensayos clínicos y estudios observacionales para determinar la RAM en trabajadores de cría de cerdos. De 990 artículos identificados se incluyeron 8 estudios. Resultados: la tasa de colonización por Staphylococcus aureus resistente a la meticilina (SAMR) en trabajadores fue mayor que la de la población general. La prevalencia de SAMR fue significativamente mayor en trabajadores en contacto directo con animales y los de granjas de cría intensiva con respecto a los de extensiva. En cerdos, la prevalencia de RAM en cría intensiva fue significativamente mayor que la de los de cría extensiva. También fue significativa la asociación entre el suministro de antibióticos en la cría intensiva y la presencia de RAM. Las granjas de más de 1250 cerdos presentaron mayor prevalencia de RAM (p < 0,001). El fenotipo de SAMR en cerdos, trabajadores y el ambiente fue el mismo. Conclusiones: existe evidencia de asociación entre la producción agrícola de cría intensiva y la RAM en cerdos y trabajadores. No se encontraron estudios de vigilancia epidemiológica en la Argentina en trabajadores de cría de animales. (AU)

Introduction: it is estimated that the impact of antimicrobial resistance (AMR) will generate an increase of 10 million deaths by 2050, being reflected to a greater extent in low-income countries. 70% of the annual use of antimicrobials is concentrated in agroveterinary but not in human health. Considering the presence of AMR in ranchers and agricultural workers is essential for early public health actions. Methods: using the PRISMA methodology, bibliography was searched in different sources until October 2020. Systematic reviews, meta-analyses, clinical trials and observational studies were prioritized to determine AMR in pig workers. Eight studies of the 990 found have been included. Results: the rate of colonization by methicillin-resistant Staphylococcus aureus (MRSA) in farming workers was higher than the general population. MRSA prevalence was significantly higher in workers who reported direct contact with animals. And also in those workers of intensive farms compared to those of extensive farms. The same situation is observed in swines, in which the prevalence of AMR in intensive farming was significantly higher than in extensive farming. The association between the supply of antibiotics in intensive farming workers and the presence of AMR was also significant. Farms with more than 1,250 swines had a higher prevalence of AMR (p<0.001). The MRSA phenotype found in swine, agricultural workers, and the environment was the same. Conclusions: there is scientific evidence of an association between agricultural production in intensive livestock farming and AMR in swine and farming workers. There aren't Argentine studies of epidemiological surveillance in farming workers. (AU)

Spontaneous bacterial peritonitis recurrence in patients with cirrhosis receiving secondary prophylaxis with norfloxacin.

OBJECTIVE: Few studies carried out more than 20 years ago have evaluated spontaneous bacterial peritonitis (SBP) recurrence in patients receiving secondary antibiotic prophylaxis. These studies reported a 1-year recurrence rate of 20-26%. Changes in the bacteriology of SBP over the last few years might have negative effects on secondary prophylaxis. Our primary aim was to estimate the incidence of SBP recurrence in patients with cirrhosis receiving secondary prophylaxis with norfloxacin and to explore the factors associated with SBP recurrence. PATIENTS AND METHODS: This was a retrospective cohort study of patients receiving norfloxacin for the secondary prophylaxis of SBP from 1 March 2003 to 31 March 2016. Follow-up was performed for 365 days after secondary prophylaxis was started. A competing risk analysis approach was used. RESULTS: A total of 115 patients were included. The prevalence of quinolone-resistant and multiresistant bacteria in the first episode of SBP among patients with culture-positive SBP was 70.96% [95% confidence interval (CI): 51.96-85.77%] and 12.90% (95% CI: 3.63-29.83%), respectively. The cumulative incidence of SBP recurrence was 28.53% (95% CI: 20.15-37.45%) after 365 days. Male patients showed an estimated subhazard ratio of SBP recurrence of 2.52 (95% CI: 1.07-5.91, P=0.034). No other risk factors for SBP recurrence were identified. The overall cumulative incidence of death after 365 days was 21.57% (95% CI: 14.14-30.04%), without significant differences among patients with or without SBP recurrence. CONCLUSION: Even though changes in the bacteriology of SBP occurred over time, its recurrence rate in patients receiving norfloxacin remains similar to what was reported in the initial studies.

Effectiveness and safety of original and generic sofosbuvir for the treatment of chronic hepatitis C: A real world study.

We report the first real-world prospective multicenter cohort study that evaluated the effectiveness and safety of original or generic sofosbuvir-based regimens in patients with chronic hepatitis C in Latin America. The main endpoints were assessment of sustained virological response and serious adverse events rates. A total of 321 patients with chronic hepatitis C treated with the following regimens were included: sofosbuvir plus daclatasvir for 12 (n = 34) or 24 (n = 135) weeks, sofosbuvir plus daclatasvir plus ribavirin for 12 (n = 84) or 24 (n = 56) weeks, or sofosbuvir plus ribavirin for 12 (n = 8) or 24 (n = 2) weeks. Patients received either original sofosbuvir (Sovaldi® , Gilead Sciences, n = 135) or generic sofosbuvir (Probirase® , Laboratorios RICHMOND, n = 184) which were randomly assigned by the National Ministry of Health. Overall, 292 (91%) patients had cirrhosis, 136 (42%) were treatment experienced, and 240 (75%) genotype 1. The overall sustained virological response was 90% (95% CI 86-93%); 91% (95% CI 84-95%) in patients who received Sovaldi® , and 89% (95% CI 84-93%) in patients who received Probirase® . Anemia was the most common adverse event and was reported in 52 (17%) patients. Bacterial infection, gastrointestinal bleeding, worsening of ascites or encephalopathy occurred in less than 5% of the patients. During the study, seven (2%) patients died, four of whom died of cirrhosis-related complications. In summary, we observed similar sustained virological response rates than prior studies, both in patients who received Sovaldi® or Probirase® . Serious adverse events were infrequent, in line with prior studies that included patients with cirrhosis treated with protease-inhibitor-free regimes.

Compartmentalization of hepatitis C virus variants in patients with hepatocellular carcinoma.

Chronic Hepatitis C Virus (HCV) infection is a major risk for hepatocellular carcinoma (HCC) development. HCV Core protein has been associated with the modulation of potentially oncogenic cellular processes and E2 protein has been useful in evolutive studies to analyze the diversity of HCV. Thus, the aim of this study was to evaluate HCV compartmentalization in tumoral, non-tumoral liver tissue and serum and to identify viral mutations potentially involved in carcinogenesis. Samples were obtained from four patients with HCC who underwent liver transplantation. Core and E2 were amplified, cloned and sequenced. Phylogenies and BaTS Test were performed to analyze viral compartmentalization and a signature sequence analysis was conducted by VESPA. The likelihood and Bayesian phylogenies showed a wide degree of compartmentalization in the different patients, ranging from total clustering to a more scattered pattern with small groups. Nevertheless, the association test showed compartmentalization for the three compartments and both viral regions tested in all the patients. Signature amino acid pattern supported the compartmentalization in three of the cases for E2 protein and in two of them for Core. Changes observed in Core included polymorphism R70Q/H previously associated with HCC. In conclusion, evidence of HCV compartmentalization in the liver of HCC patients was provided and further biological characterization of these variants may contribute to the understanding of carcinogenesis mediated by HCV infection. © 2016 Wiley Periodicals, Inc.

Hepatitis C virus infection in Argentina: Burden of chronic disease.

AIM: To estimate the progression of the hepatitis C virus (HCV) epidemic and measure the burden of HCV-related morbidity and mortality. METHODS: Age- and gender-defined cohorts were used to follow the viremic population in Argentina and estimate HCV incidence, prevalence, hepatic complications, and mortality. The relative impact of two scenarios on HCV-related outcomes was assessed: (1) increased sustained virologic response (SVR); and (2) increased SVR and treatment. RESULTS: Under scenario 1, SVR raised to 85%-95% in 2016. Compared to the base case scenario, there was a 0.3% reduction in prevalent cases and liver-related deaths by 2030. Given low treatment rates, cases of hepatocellular carcinoma and decompensated cirrhosis decreased < 1%, in contrast to the base case in 2030. Under scenario 2, the same increases in SVR were modeled, with gradual increases in the annual diagnosed and treated populations. This scenario decreased prevalent infections 45%, liver-related deaths 55%, liver cancer cases 60%, and decompensated cirrhosis 55%, as compared to the base case by 2030. CONCLUSION: In Argentina, cases of end stage liver disease and liver-related deaths due to HCV are still growing, while its prevalence is decreasing. Increasing in SVR rates is not enough, and increasing in the number of patients diagnosed and candidates for treatment is needed to reduce the HCV disease burden. Based on this scenario, strategies to increase diagnosis and treatment uptake must be developed to reduce HCV burden in Argentina.

Pre-treatment prediction of response to peginterferon plus ribavirin in chronic hepatitis C genotype 3.

AIM: To evaluate pre-treatment factors associated with sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 3 treated with peginterferon and ribavirin (RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index, steatosis, INFL3 polymorphism, pre-treatment HCV-RNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1 (± 1.8) wk. Overall, 58% (62/107) of the patients achieved an SVR and 42% (45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/mL (OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis (OR = 0.278, 95%CI: 0.113-0.684, P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥ 600000 UI/mL and advanced fibrosis, the probability of achieving an SVR was 29% (95%CI: 13.1-45.2). In patients with pre-treatment HCV-RNA < 600000 UI/mL and mild to moderate fibrosis, the probability of achieving an SVR was 81% (95%CI: 68.8-93.4). CONCLUSION: In patients with HCV genotype 3 infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agents-based regimes.

Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors.

BACKGROUND & AIMS: Robust clinical data evaluating fibrosis progression in hepatitis C virus (HCV) liver transplant patients receiving an mTOR inhibitor vs. calcineurin inhibitor (CNI) are lacking. To evaluate fibrosis progression in maintenance liver transplant patients receiving everolimus- or CNI-based immunosuppression. METHODS: In a randomised, multicentre, open-label study, 43 maintenance liver transplant patients with recurrent HCV infection were randomised to continue CNI-based immunosuppression or switch to everolimus. RESULTS: For patients with biopsy data at month 12, mean Ishak-Knodell fibrosis score at baseline was 2.6 ± 0.9 (n = 14) with everolimus vs. 1.9 ± 1.1 (n = 18) with CNI (P = 0.043), and 1.9 ± 1.2 vs. 2.2 ± 1.3 at month 12. Ishak-Knodell fibrosis score decreased from baseline to month 12 by a mean of -0.7 ± 1.1 with everolimus, but increased by 0.2 ± 1.2 with CNI (P = 0.046). No acute rejection or graft losses occurred up to month 12. Estimated GFR at month 12 was 65.6 ml/min/1.73 m² with everolimus and 62.2 ml/min/1.73 m² with CNI [mean difference 3.4 ml/min/1.73 m² compared to CNI control group, 95% CI -4.9, 11.8 ml/min/1.73 m², P = 0.411 (analysis of covariance adjusting for baseline GFR)]. Adverse events occurred in 95.5% of everolimus patients and 71.4% of CNI patients (serious adverse events 31.8% and 0.0%, respectively). Adverse events led to everolimus discontinuation in five patients (22.7%). CONCLUSIONS: This exploratory study suggests that conversion from CNI to everolimus reduces progression of liver fibrosis, and preserves renal function without jeopardising efficacy in liver transplant recipients with recurrent HCV, but is associated with a higher incidence of adverse events and serious adverse events. These preliminary findings merit examination in a larger trial.

Ultra-sensitive procalcitonin may help rule out bacterial infections in patients with cirrhosis.

BACKGROUND: Bacterial infections are frequent complications in patients with cirrhosis. Since they are associated with poor outcomes, antibiotics are frequently over-prescribed. Surrogate markers of bacterial infections, like procalcitonin, are needed to better discriminate between infected and not infected patients. AIMS: To evaluated the diagnostic accuracy of an ultra-sensitive procalcitonin assay for the diagnosis of bacterial infections in patients with cirrhosis. MATERIAL AND METHODS: In a single-center prospective study, we determined the basal levels of procalcitonin in 106 episodes of admissions to the emergency department in 84 cirrhotic patients. Patients were classified as infected or not infected by two independent hepatologists blinded to the procalcitonin result. RESULTS: The prevalence of bacterial infection was 28% (29 episodes). The median procalcitonin was significantly higher in the infected group than in the not infected group (0.45 vs. 0.061 ng/mL, p < 0.001). The diagnostic accuracy of procalcitonin for bacterial infection estimated by the ROC curve was 0.95 (CI: 95%, 0.91-0.99). When selecting a cutoff value of 0.098 ng/mL a sensitivity of 97% and a negative predictive value 98% were found. CONCLUSIONS: The use of an ultra-sensitive procalcitonin assay identifies patients with cirrhosis at very low risk of bacterial infections.

Efficacy and safety of long term entecavir in chronic hepatitis B treatment naïve patients in clinical practice.

BACKGROUND AND AIMS: Entecavir (ETV) is effective and safe in patients with chronic hepatitis B in the short term, but its long term efficacy and safety has not been established. MATERIAL AND METHODS: We evaluated HBV DNA clearance, HBeAg/antiHBe and HBsAg/antiHBs seroconversion rates in HBeAg-positive and negative NUC naïve HBV patients treated with ETV for more than 6 months, and predictors of response. RESULTS: A hundred and sixty nine consecutive patients were treated with ETV for a median of 181 weeks. 61% were HBeAg positive, 23% were cirrhotics, and mean HBV-DNA levels were 6,88 ± 1,74 log10 IU/mL. Overall, 156 (92%) patients became HBV DNA undetectable, 92 (88%) HBeAg positive and 64 (98%) HBeAg negative patients. Seventy four (71%) patients cleared HBeAg after a median of 48 weeks of treatment, 23 (14%) patients cleared HBsAg (19 HBeAg positive and 4 HBeAg negative, p 0.025) after a median of 96 weeks of treatment, and 22 (13%) patients developed protective titers of anti-HBs. At the end of the study, 35 (20%) patients had discontinued therapy: 33 HBeAg positive and 2 HBeAg negative; 9 of them (26%) developed virological relapse after a median of 48 weeks of stopping treatment. None of the patients had primary non response and one patient developed breakthrough. Two patients developed HCC, three underwent liver transplantation and 3 deaths were attributable to liver-related events. No serious adverse events were reported. CONCLUSION: Long term ETV treatment showed high virological response rates, and a favorable safety profile for NUC-naive HBeAg-positive and negative patients treated in clinical practice.

How to optimize current treatment of genotype 2 hepatitis C virus infection.

The standard of care (SOC) for hepatitis C virus (HCV) genotype 2 is pegylated interferon (PEG-IFN) plus ribavirin (RBV). Even though most patients can be cured with this therapy after 24 weeks, tailoring treatment can improve its safety and efficacy in special populations. Thus, shortening treatment together with a weight-based RBV dosing approach has been considered satisfactory in patients with positive predictors of response. With the development of the direct antiviral agents (DAAs), shorter, better tolerated and more efficient treatments for HCV genotype 2 will become available, including interferon-free regimens. Until these new treatments are released, the decision to treat patients with HCV genotype 2 with currently approved drugs or to wait for future options must be made, taking into account the stage of fibrosis.

HBV genotype F: natural history and treatment.

The analysis of the HBV genome revealed the existence of 10 genotypes, named A-J. Evidence of the influence of the different genotypes in the natural history and treatment response to nucleoside/nucleotide analogues or interferon-based regimens is scant. HBV genotype F is one of the most prevalent circulating genotypes in South America and the Arctic Circle. Since most of the available information on HBV is from Asia, the US and Europe, it reflects their predominant genotypes: A, B, C and D. To date, the evidence is not fully confirmed, but it appears that genotype F chronic hepatitis B is associated with a more aggressive course of liver disease, reflected by higher histological indexes, a higher risk of development of hepatocellular carcinoma and a higher rate of liver-related mortality. In terms of treatment response, the available data is, unfortunately, even more limited; however, what data is available suggests acceptable and similar response rates to pegylated interferon-α2a in genotype F compared to genotype A. Response rates to nucleoside/nucleotide analogues is not influenced by genotype. The review of this limited data sheds light on the necessity to conduct further studies in South America and the Arctic Circle in order to better understand the different aspects of HBV genotype F, especially in relation to treatment response.

Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease associated with insulin resistance and its metabolic consequences. Leukocyte mobilization, intrahepatic activation, and an exacerbated production of reactive oxygen species (ROS) and cytokines contribute to the development of NASH. Though alterations in peripheral blood (PB) T cell proportions and functionality remain unidentified, they might play a main role in NASH progression. We have compared the phenotype and Th1/Th2 commitment of peripheral immune cell reservoirs in adult patients and controls as well as the ability of neutrophils and monocytes to handle an ex vivo challenge. Also, we correlated those parameters with the main histological characteristics in NASH. Compared with controls, patients showed increased numbers of CD4(+) cells and both CD4(+) and CD8(+) CD45RO subsets together with a higher frequency of IFN-γ-producing CD4(+) and CD8(+) T cells. We also found a decreased number of CD4(+) and CD8(+) CD45RA subsets. The distinctive production of IFN-γ highlights the significance of the observed skewed frequencies of PB T cells. Whereas ROS production by monocytes from NASH patients did not differ from controls, circulating neutrophils displayed a particularly higher phorbol myristate acetate-induced production of ROS. A negative correlation between oxidative burst and fibrosis grade was observed. This study reveals the presence of a characteristic profile of peripheral immune cells in NASH. We also discuss the probable influence of obesity on some of our present findings.

Imatinib-induced fatal acute liver failure.

Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia (CML) in blast crisis, accelerated or chronic phase, and also for advanced gastrointestinal stromal tumors. Severe hepatic toxicity and three deaths from hepatic failure have been reported. We report the case of a 51-year-old woman who was admitted to our institution with severe acute hepatitis. She was diagnosed with CML and began treatment with imatinib mesylate at a dose of 400 mg/d. Five months after beginning treatment, she developed severe hepatitis associated with coagulopathy, and was admitted to our institution. She had been consuming acetaminophen 500-1000 mg/d after the onset of symptoms. She had a progressive increase in bilirubin level and a marked decrease of clotting factor V. Five days after admission, grade II encephalopathy developed and she was referred for liver transplantation. Her clinical condition progressively deteriorated, and 48 h after being referred for transplantation she suffered a cardiac arrest and died. This report adds concern about the possibility of imatinib-mesylate-induced hepatotoxicity and liver failure, particularly in the case of concomitant use with acetaminophen. Liver function tests should be carefully monitored during treatment and, with the appearance of any elevation of liver function tests, treatment should be discontinued.