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To achieve WHO's goal of eliminating hepatitis C virus (HCV), innovative strategies must be designed to diagnose and treat more patients. Therefore, we aimed to describe an implementation strategy to identify patients with HCV who were lost to follow-up (LTFU) and offer them re-linkage to HCV care. We conducted an implementation study utilizing a strategy to contact patients with HCV who were not under regular follow-up in 13 countries from Latin America. Patients with HCV were identified by the international classification of diseases (ICD-9/10) or equivalent. Medical records were then reviewed to confirm the diagnosis of chronic HCV infection defined by anti-HCV+ and detectable HCV-RNA. Identified patients who were not under follow-up by a liver specialist were contacted by telephone or email, and offered a medical reevaluation. A total of 10,364 patients were classified to have HCV. After reviewing their medical charts, 1349 (13%) had undetectable HCV-RNA or were wrongly coded. Overall, 9015 (86.9%) individuals were identified with chronic HCV infection. A total of 5096 (56.5%) patients were under routine HCV care and 3919 (43.5%) had been LTFU. We were able to contact 1617 (41.3%) of the 3919 patients who were LTFU at the primary medical institution, of which 427 (26.4%) were cured at a different institutions or were dead. Of the remaining patients, 906 (76.1%) were candidates for retrieval. In our cohort, about one out of four patients with chronic HCV who were LTFU were candidates to receive treatment. This strategy has the potential to be effective, accessible and significantly impacts on the HCV care cascade.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease in which anti-mitochondrial antibodies (AMA) are the diagnostic hallmark. Whether AMA-negative PBC patients represent a different phenotype of disease is highly debated. The purpose of our study was to compare AMA-positive and AMA-negative PBC patients in a large non-white admixed Brazilian cohort. The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian PBC patients, stratifying data according to AMA status. A total of 464 subjects (95.4% females, mean age 56 ± 5 years) with PBC were included. Three hundred and eighty-four (83%) subjects were AMA-positive, whereas 80 (17%) had AMA-negative PBC. Subjects with AMA-negative PBC were significantly younger (52.2 ± 14 vs. 59.6 ± 11 years, p = 0.001) and had their first symptom at an earlier age (43.2 ± 13 vs. 49.5 ± 12 years, p = 0.005). Frequency of type 2 diabetes was significantly increased in subjects with AMA-negative PBC (22.5% vs. 12.2%, p = 0.03). Lower IgM (272.2 ± 183 vs. 383.2 ± 378 mg/dL, p = 0.01) and triglycerides (107.6 ± 59.8 vs.129.3 ± 75.7 mg/dL, p = 0.025) and higher bilirubin (3.8 ± 13.5 vs. 1.8 ± 3.4 mg/dL, p = 0.02) levels were also observed in this subgroup. Response to ursodeoxycholic acid varied from 40.5 to 63.3% in AMA-positive and 34 to 62.3% in AMA-negative individuals, according to different response criteria. Outcomes such as development of liver-related complications, death and requirement for liver transplantation were similar in both groups. AMA-negative PBC patients are similar to their AMA-positive counterparts with subtle differences observed in clinical and laboratory features.

The Latin American Association for the Study of the Liver (Asociación Latinoamericana para el Estudio del Hígado; ALEH) represents liver professionals in Latin America with the mission of promoting liver health and quality patient care by advancing the science and practice of hepatology and contributing to the development of a regional health policy framework. Fatty liver disease associated with metabolic dysfunction is of specific concern in the ALEH region, where its prevalence is one of the highest globally, second only to the Middle East. A recent consensus from an international panel recommended a new definition of fatty liver disease associated with metabolic dysfunction, including a shift in name from non-alcoholic fatty liver disease (NAFLD) to metabolic-associated fatty liver disease (MAFLD), and adoption of a set of positive criteria to diagnose the disease, independent of alcohol intake or other liver diseases. Given, the importance of this proposal, ALEH invited leading members of regional nations to come to a consensus on it from a local perspective. We reached a consensus to endorse the proposal that the disease should be renamed as MAFLD and that the disease should be diagnosed by the proposed simple and easily applicable criteria. We expect that this change in nosology will result in improvements in disease awareness and in advances in scientific, economic, public health, political, and regulatory aspects of the disease.

Introduction: Liver stiffness measurement (LSM) is a widely used non-invasive test to assess the stage of liver fibrosis in chronic liver diseases, particularly in HCV but its clinical usefulness after viral elimination is uncertain. Objectives: To identify the course of liver fibrosis by LSM 3 years after viral elimination in patients with HCV and its association with clinically relevant outcomes: progression to advanced liver fibrosis/cirrhosis (≥F3) in those with F14.5 KPa respectively) prior to treatment and at 6 months, 1, 2 and 3 years after cure. Results: The course of changes in LSM are depicted in figure1. There was no progression to F≥3 in any of the patients at stages F0-1, F2. Among patients with F≥3, 23 patients developed decompensation (1 F3, 2 F3/F4 and 20 F4) and 9 developed HCC (all F4). Probability of decompensation is lower in patients in whom LSM decreases at 6 months, while it is higher in those in whom LSM increases, however CI are large (Table). Conclusion: While in patients with F0-1, F2 prior to antiviral therapy, there is no need to follow LSM as progression does not occur, LSM should be continued in those with F3/F4 or F4 (>12.5 kPa). Changes in LSM at 6 months can help determine probability of outcomes but larger studies combining other parameters are necessary to improve predictive value.

Introduction: Primary biliary cholangitis (PBC) diagnosis is based on international criteria, which requires two of the following: (i) elevated alkaline phosphatase (AP), (ii) anti-mitochondrial antibody (AMA) and (iii) liver biopsy (BX) suggestive of PBC. It is still unclear if patients diagnosed by different criteria combinations present peculiarities, especially in highly-admixed populations. Objectives: To investigate if patients diagnosed with PBC by different combinations of validated criteria present clinical or laboratory particularities. Methods: The Brazilian Cholestasis Study Group database was reviewed to compare clinical, biochemical and histological characteristics of PBC between four groups diagnosed by: (1) AP ≥2x upper limit of normality (ULN) + presence of AMA, (2) AP ≥2x ULN + BX suggestive of PBC, (3) presence of AMA + BX suggestive of PBC and (4) all criteria. Results: 482 patients with PBC were included (Table 1). Group-1 presented with higher levels of IgG, lower frequency of arterial hypertension (AH) and lower response to ursodeoxycholic acid (UDCA), while Group-2 had lower: age at diagnosis and HDL-C levels. Group-3 had higher: age at diagnosis, frequency of neoplasms, AH and response to UDCA; and lower: frequency of pruritus and jaundice, levels of aminotransferases, GGT and bilirubin, advanced liver disease and esophageal varices. Group-4 showed higher frequency of symptoms at presentation, especially pruritus. Conclusion: PBC patients diagnosed by different combinations of established criteria may present singular features that can possibly impact in disease presentation and progression.

BACKGROUND Hepatitis C virus (HCV) treatment has undergone major changes in recent years. Previous interferon-based therapies have been replaced by oral direct-acting antivirals (DAA) regimens, with high sustained virologic response (SVR) rates, and a lower incidence of adverse events (AEs). AIM To evaluate the efficacy and safety of DAAs for HCV treatment in subjects from two tertiary university centers in Brazil. METHODS This is a multicenter retrospective cohort study of 532 patients with chronic hepatitis C (CHC), undergoing treatment with interferon-free regimens from November 2015 to November 2019. The therapeutic regimen was defined by the current Brazilian guidelines for HCV management at the time of treatment. Demographic, anthropometric, clinical, and laboratory variables were evaluated. SVRs were assessed at 12 to 24 wk after therapy by intention-to-treat (ITT), and modified ITT (m-ITT) analysis. AEs and serious adverse events (SAEs) were registered. In the statistical analysis, a P value of < 0.05 was considered significant. RESULTS The mean age was 56.88 years, with 415 (78.5%) being HCV genotype 1, followed by genotype 3 (20.1%). Moreover, 306 (57.5%) subjects had cirrhosis, and a third of them had decompensated cirrhosis. Sofosbuvir (SOF) plus daclatasvir ± ribavirin was the most frequently used treatment (66.9%), followed by SOF plus simeprevir (21.2%). The overall ITT SVR was 92.6% (493/532), while the m-ITT SVR was 96.8% (493/509). Variables associated with treatment failure via ITT evaluation were hepatic encephalopathy (OR: 4.320; 95%CI: 1.920-9.721, P = 0.0004), presence of esophageal varices (OR: 2.381; 95%CI: 1.137-4.988, P = 0.0215), previous portal hypertensive bleeding (OR: 2.756; 95%CI: 1.173-6.471, P = 0.02), higher model for end-stage liver disease scores (OR: 1.143, 95%CI: 1.060–1.233, P = 0.0005), lower serum albumin levels (OR: 0.528, 95%CI: 0.322-0.867, P = 0.0115), higher serum creatinine (OR: 1.117, 95%CI: 1.056-1.312, P = 0.0033), and international normalized ratio (INR) levels (OR: 5.542, 95%CI: 2.023-15.182, P = 0.0009). AEs were reported in 41.1% (211/514) of patients, and SAEs in 3.7%. The female gender, higher body mass index, esophageal varices, higher INR values, and longer treatment duration were independently associated with AE occurrence. CONCLUSION Treatment with oral DAAs attains a high SVR rate, with fewer SAEs in a real-life cohort of subjects with CHC, from two tertiary university centers in Brazil.

Made available in DSpace on 2021-06-25T15:08:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 AbbVie 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-naive Brazilian adults without cirrhosis or with compensated cirrhosis. Patients and methods: EXPEDITION-3 was a Phase 3, open-label, multicenter study in treatment-naive 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-nave Brazilian patients with hepatitis C infection without cirrhosis and with compensated cirrhosis. (C) 2020 Published by Elsevier Espafia, S.L.U. on behalf of Fundacion Clinica Medica Sur, A.C. This is an open access article under the CC BY-NC-ND license. Hosp Dia, Ave Dr Arnaldo,165, Sao Paulo, Brazil Ramiro Barcelos 2350,CPC Sala,21216, Porto Alegre, RS, Brazil AbbVie Inc, N Chicago, IL USA Inst Infectol Campinas, Rua Dr Quirino,524,Sala 72, Campinas, Brazil Univ Fed Rio Grande do Sul, Sch Med, GI Liver Div, Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil Rua Santa Cruz,81, Sao Paulo, Brazil Rua Diogo Faria,816 Vila Clementino, Sao Paulo, Brazil Univ Sao Paulo, Sch Med, Div Gastroenterol & Hepatol, Ave Eneas Carvalho Aguiar,255 Bloco B 4 Andar, Sao Paulo, Brazil Rua Conego Xavier,276 Amb Infectol, Sao Paulo, Brazil Univ Sao Paulo, Fac Med Ribeirao Preto, Hosp Clin, Unidade Pesquisa Clin, Campus Univ S-N,Bloco G Subsolo 2, Ribeirao Preto, Brazil Univ Fed Maranhao, Clin Hosp Univ, Ctr Pesquisa, Rua Almirante Tamandare,01 Ctr, Sao Luis, Maranhao, Brazil Hosp Ernesto Dornelles, Ave Ipiranga 1801,7 Andar, Porto Alegre, RS, Brazil Ave Mandacaru,1590, Maringa, Parana, Brazil UNESP, Campus Botucatu,Rua Prof Dr Armanda Alves,S-N, Botucatu, SP, Brazil Outclin 5, Marechal Campos Ave 1355, Vitoria, ES, Brazil UNESP, Campus Botucatu,Rua Prof Dr Armanda Alves,S-N, Botucatu, SP, Brazil

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) is an uncommon cause of liver disease presenting with a wide range of phenotypes and disease severity, acute hepatitis mimicking viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity ranges from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified in predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies are assessing the real prevalence and incidence of hepatotoxicity in the general population. DILI registries represent useful networks used for the study of liver toxicity, aimed at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not carry out population-based studies, they may provide important data related to the prevalence of DILI, and also may be useful to compare features from different countries. With the support of the Spanish Registry of Hepatotoxicity, our Latin American Registry (LATINDILI) was created in 2011, and more than 350 DILI patients have been recruited to date. This position paper describes the more frequent drugs and herbs-induced DILI in Latin America, mainly focusing on several features of responsible medicaments. Also, we highlighted the most critical points on the management of hepatotoxicity in general and those based on findings from our Latin American experience in particular.

Background Despite the growing body of knowledge about TM6SF2 and PNPLA3 polymorphisms in non-alcoholic fatty liver disease, their influence in the spectrum of HCV liver disease is not yet fully defined. Besides that, admixed populations, such as Brazilians, were not included in most of the studies. Methods This cross-sectional study enrolled 365 treatment-naïve patients with HCV and 134 healthy individuals. TM6SF2 (rs58542926 c.499C > T) and PNPLA3 (rs738409 c.444C > G) polymorphisms were evaluated regarding their association with clinical and laboratory data, histological liver steatosis and fibrosis, and with components of the metabolic syndrome. Results In HCV subjects, the frequencies of TM6SF2 CC and CT + TT were 89% and 11%, while PNPLA3 frequencies of CC and CG + GG were 51.4% and 48.6%. In the univariate logistic regression analysis, the TM6SF2 CT + TT genotype in HCV was associated with significant liver fibrosis (p = 0.047; OR 1.953; 95% CI 1.009–3.788). In comparison to the CT + TT genotype, the TM6SF2 CC genotype in HCV was associated with older age (p = 0.002), higher frequency of arterial hypertension (p = 0.032), obesity (p = 0.030), metabolic syndrome (p = 0.014) and lower total cholesterol levels (p = 0.036). The PNPLA3 GG subjects had lower body mass index than CG/ CC individuals (p = 0.047). None of the polymorphisms, or their combinations, was independently associated with hepatic steatosis or fibrosis. On the other hand, older age, lower serum levels of total cholesterol, and higher serum levels of alanine aminotransferase and alkaline phosphatase were associated with liver fibrosis in the multivariate logistic regression analysis. Conclusion In this evaluation of an admixed HCV population, neither TM6SF2 nor PNPLA3 polymorphisms were independently associated with hepatic steatosis or fibrosis. Other factors seem more influential than these specific polymorphisms in isolation. More studies are warranted to clarify the role of the TM6SF2 and PNPLA3 polymorphisms in Brazilians with HCV.

Chronic hepatitis B is an important health problem that can progress to cirrhosis and complications such as hepatocellular carcinoma. There is approximately 290 million of people with chronic hepatitis B virus (HBV) infection worldwide, however only 10% of patients are currently identified.Most part of Brazil is considered of low prevalence of HBV infection but there are some regions with higher frequency of carriers. Unfortunately, many infected patients are not yet identified nor evaluated for treatment.The Brazilian Society of Infectious Diseases (SBI) and the Brazilian Society of Hepatology worked together to elaborate a guideline for diagnosis and treatment of hepatitis B. The document includes information regarding the population to be tested, diagnostic tools, indications of treatment, therapeutic schemes and also how to handle HBV infection in specific situations (pregnancy, children, immunosuppression, etc).Delta infection is also part of the guideline, since it is an important infection in some parts of the country.

Introduction and objectives: Little is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population. Material and methods: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC. Results: 562 patients (95% females, mean age 51 ± 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 ± 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates.Conclusions: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization.

Introduction and aim: Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an open-label multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection. Materials and methods: All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA

Background Despite the growing body of knowledge about TM6SF2 and PNPLA3 polymorphisms in non-alcoholic fatty liver disease, their influence in the spectrum of HCV liver disease is not yet fully defined. Besides that, admixed populations, such as Brazilians, were not included in most of the studies. Objectives Describe the prevalence of these polymorphisms in Brazilians with chronic hepatitis C, and to assess their association with liver fibrosis and other components of the metabolic syndrome. Methods This cross-sectional study enrolled 365 treatment-naive patients with HCV and 134 healthy individuals. TM6SF2 (rs58542926 c.499C>T) and PNPLA3 (rs738409 c.444C>G) polymorphisms were evaluated regarding their association with clinical and laboratory data, histological liver steatosis and fibrosis, and with components of the metabolic syndrome. Results In HCV subjects, the frequencies of TM6SF2 CC and CT + TT were 89% and 11%, while PNPLA3 frequencies of CC and CG + GG were 51.4% and 48.6%. In the univariate logistic regression analysis, the TM6SF2 CT + TT genotype in HCV was associated with significant liver fibrosis (p = 0.047; OR:1.953; 95% CI:1.009-3.788) however it was not confirmed by multivariate analysis. In comparison to the CT + TT genotype, the TM6SF2 CC genotype in HCV was associated higher frequency of arterial hypertension (p = 0.032), obesity (p = 0.030), metabolic syndrome (p = 0.014) and lower total cholesterol levels (p=0.036). The PNPLA3 GG subjects had lower body mass index than CG/ CC individuals (p = 0.047). None of the polymorphisms, or their combinations, was independently associated with hepatic steatosis. Conclusion In this evaluation of an admixed HCV population, neither TM6SF2 nor PNPLA3 polymorphisms were independently associated with hepatic steatosis or fibrosis.

Background: Co-infection with hepatitis A or B viruses may aggravate liver injury in hepatitis C virus (HCV) infected patients. However, few studies have assessed hepatitis E virus (HEV) and HCV coinfection. Aim: Our goal was to assess the prevalence and impact of HEV infection among Brazilian patients with chronic hepatitis C virus. Methods: This cross-sectional study included adult patients with chronic HCV infection, naïve to antiviral therapy. Prospectively and consecutively recruited from January 2013 to March 2016. 181 patients were enrolled and HEV serology and PCR were performed for all patients. Results: Seropositivity for anti-HEV IgG was detected in 22 (12.0%) and for anti-HEV IgM in 3 (1.6%) patients. HEV RNA was inconclusive in 9 (4.9%) and undetectable in the remaining cases. HEV serology positive cases had more severe liver disease, characterized by liver fibrosis ≥3 vs ≤2 (p

Introduction: Choosing wisely (CW) initiative aims to improve daily practice supported by evidence avoiding unnecessary medical tests, procedures, and treatments. This philosophy is of utmost importance in managing viral hepatitis (VH), increasingly carried out by primary care physicians. Objective: To propose evidence-based CW recommendations in VH. Methods: The Brazilian Society of Hepatology (SBH) selected a panel of experts in VH who selected evidence-based CW recommendations, which were subsequently scrutinized and ranked by all members of SBH using a web-based approach. Results: Eight recommendations were chosen in order of importance, including 1) Do not order anti-HCV testing after achieving sustained virological response; 2) Do not request serial HCV viral load to evaluate HCV progression, 3) Do not add ribavirin to direct-acting antivirals in non-cirrhotic, naïve HCV patients; 4) Do not screen for hepatocellular carcinoma in HCV patients with none to moderate fibrosis; 5) Do not request anti-HBs after HBV vaccination, except for children born to HBV-infected mothers, hemodialysis patients, healthcare professionals, sexual contacts of chronic HBV carriers, HIV-positive persons and immunocompromised individuals (hematopoietic stem-cell transplant recipients or persons receiving chemotherapy); 6) Do not order complete HBV serology for screening HBV infection; 7) Do not order complete HBV serology for evaluation of acute hepatitis B; 8) Do not treat chronic hepatitis B based on a single ALT and viral load results, except in cirrhotic patients. Conclusion: These recommendations defined by SBH may help general practitioners adopt a more rational and cost-effective approach to handling VH cases in Brazil.

Introduction: Little is known about primary biliary cholangitis (PBC) in Latin America, where this disease is thought to be rare. Objectives: To analyze clinical and biochemical features of Brazilian PBC patients. Methods: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical and laboratory features from PBC patients. Results: 562 patients with PBC were included; 80 (14.2%) had overlapping syndrome with autoimmune hepatitis and were excluded. Most subjects were middle-aged women (95%; mean age 51 ± 11 years) with classical symptoms of pruritus and/or fatigue (65%) and jaundice (22%). Mean time to diagnosis was 2.5 years. Prevalence of antimitochondrial (AMA) and antinuclear antibodies was 82.8% and 72.1%, respectively. Concurrent autoimmune diseases occurred in 18.9%, mainly Hashimoto's thyroiditis and Sjogren syndrome. Celiac disease was diagnosed in 1:80 (1.2%). Osteopenia and osteoporosis were demonstrated in 42% and 26%, respectively. Liver pathology at diagnosis was available for 326 patients (67.6%). One third of them had advanced PBC. After a mean follow-up of 6.2 ± 5.3 years, 32% of the subjects had clinical, laboratory or imaging evidence of cirrhosis. Requirement for liver transplantation and liver-related deaths were reported in 6.6% and 3.2% of the patients, respectively. Hepatocarcinoma was diagnosed in 1.9% of the subjects. Conclusion: A higher predominance of PBC among females, compared to other populations, was observed, while AMA positivity was lower. Concurrent autoimmune, celiac and bone diseases are common and should be adequately screened. Prolonged time to diagnosis and high prevalence of advanced liver disease might reflect difficulties in health care access in Brazil.

Background Lysosomal acid lipase deficiency (LAL-D) is a rare genetic disease associated with lipid metabolism deregulation leading to atherosclerosis, dyslipidemia, and hepatic steatosis, with potential progression to cirrhosis. Investigation of LAL-D in patients with chronic liver disease is not routinely performed in most centers. Aim The aim of this study was to evaluate whether it is worthwhile to investigate LAL-D in patients with liver disease of unknown etiology, and if there is any particular population that this search should be focused. Methods This was a multicenter cross-sectional study in 295 patients followed with presumed cryptogenic liver disease from four tertiary centers in Brazil. Clinical, demographic and laboratory data from participants were assessed, with the exclusion of all known causes of liver disease. All patients were submitted to the investigation of LAL enzyme activity. The exams were collected on dried blood spot (DBS). Results A total of 135 patients were included in the study. Three patients (2.22%) presented values of LAL below the reference limit, compatible with LAL-D. The mean age of these patients was 43.9±10.1 years, of which 2 were females. The mean BMI was 24.3±0.7 and mean serum glycemia was 89.7±3.2 mg/dL. The mean serum HDL and triglycerides were 21.7±3.2 mg/dL and 206.7±25.5 mg/dL, respectively. Conclusion Despite being a rare disease, also in our study population, LAL-D investigation may be considered in those individuals without overweight with reduced serum HDL and elevated triglycerides levels and chronic liver disease of unknown etiology.

Introduction: Hepatitis B virus (HBV) vaccination is regarded as the most effective method for the prevention and control of HBV infection. Studies showed a reduced HBV vaccine response between patients with chronic hepatitis C (HCV), but studies exploring HBV vaccine efficacy in this population have equivocal results. Objectives: To evaluate HBV vaccine response in patients with HCV submitted to two different (20 µg vs 40 µg in 0, 1 and 6 months) anti-HBV vaccine schemes and administer the 4th additional dose in non-responders as well as assess the maintenance of seroprotectors titers. Methods: This randomized controlled trial included 141 HCV who received double dose (40ug) or standard dose (20ug) and 70 healthy volunteers who received standard dose (20ug) at 0, 1 and 6 months. Anti-HBs titers were measured at 1 month after last dose. Vaccine response was defined by anti-HBs ≥10 U/L. Non-responders received the fourth dose according to the group that were previously randomized. Multivariate regression was modeled as a logistic regression. Results: 128 completed the study. Median age 51 years, 61% female, 52% White, 40% F2-3, and 75% GT1, median 6 log10 HCV RNA. Overall seroconversion rate was 76.7% (n=60) in double dose and 73.5% (n=68) in standard dose, compared to 91.2% in controls (n=68). 23 patients received the fourth dose; 7 seroconverted (30.4%) and seroconversion rate for double and standard doses were 42.9% and 11.1%, respectively (p=0.18). Controlling for confounders, only older age (p

Background Chronic hepatitis C virus (HCV) infection is associated with impairment of cognitive function and mood disorders. Our aim was to evaluate the impact of sustained virological response (SVR) on cognitive function and mood disorders. Method A prospective exploratory one arm study was conducted. Adult clinically compensated HVC patients were consecutively recruited before treatment with interferon and ribavirin for 24 to 48 weeks, according to HCV genotype. Clinical, neurocognitive and mood assessments using the PRIME-MD and BDI instruments were performed at baseline, right after half of the expected treatment has been reached and 6 months after the end of antiviral treatment. Exclusion criteria were the use of illicit psychotropic substances, mental confusion, hepatic encephalopathy, hepatocellular carcinoma, severe anemia, untreated hypothyroidism, Addison syndrome and major depression before treatment. Results Thirty six patients were enrolled and 21 completed HCV treatment (n = 16 with SVR and n = 5 without). Regardless of the viral clearance at the end of treatment, there was a significant improvement in the immediate verbal episodic memory (p = 0.010), delayed verbal episodic memory (p = 0.007), selective attention (p

Introduction and aim: Hepatitis C is a key challenge to public health in Brazil. The objective of this paper was to describe the Brazilian strategy for hepatitis C to meet the 2030 elimination goal proposed by World Health Organization (WHO). Methods: A mathematical modeling approach was used to estimate the current HCV-infected Brazilian population, and to evaluate the relative costs of two different scenarios to address HCV disease burden in Brazil: (1) if no further changes are made to the HCV treatment program in Brazil; (2) where the WHO targets for 2030 elimination are met through diagnosis and treatment efforts peaking before 2024. Results: An anti-HCV prevalence of 0.53% was calculated for the total population. It was estimated that the number of HCV-RNA+ individuals in Brazil in 2017 was 632,000 (0.31% of the population). Scale-up of treatment and diagnosis over time will be necessary in order to achieve WHO targets beginning in 2018. Direct costs (diagnostic, treatment and healthcare costs) are projected to increase significantly during the scale-up of treatment and diagnosis in the initial years of the intervention scenario, but then fall below the base case on an annual basis by 2025–2036, once HCV is eliminated, due to health sectors savings from the prevention of HCV liver-related morbidity and mortality. Conclusion: Achieving the WHO targets is technically feasible in Brazil with a scale-up of treatment and diagnosis over time, beginning in 2018. However, elimination of hepatitis C requires policy changes to substantially scale-up prevention, screening and treatment of HCV, together with public health advocacy to raise awareness among affected populations and healthcare providers. Keywords: Hepatitis C, Hepatitis C elimination, Hepatitis C disease burden, Brazil

Hepatitis E Virus (HEV) is an infection known worldwide for its asymptomatic and self-limited course in most cases. Some cases progressing to chronicity have been described in immunosuppressed patients, especially in recipients of solid organ transplants. We evaluated laboratory parameters of HEV infection (HEV RNA, anti-HEV IgM and anti-HEV IgG) through enzyme-linked immunosorbent assay (Elisa), confirmed by immunoblotting, in a cohort of 294 patients who received liver transplants at the HCFMUSP (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo). Laboratory and demographic data were collected from the entirety of the transplanted population. Hepatic biopsies of 122 patients transplanted due liver failure secondary to hepatitis C (HCV), with or without serological or molecular markers of HEV, were analyzed according to METAVIR score. Out of 24 (8.2%) patients tested positive for anti-HEV IgG, six (2%) were positive for anti-HEV IgM and 17 (5.8%) for HEV RNA. Of the patients transplanted because of HCV infection, 95 (77.8%) had received treatment including ribavirin for at least six months before blood sample collection. Among patients transplanted due to HCV cirrhosis who tested positive for anti-HEV IgG, only three (37.5%) showed fibrosis beyond stage 2, while five (41.7%) of the HEV RNA-positive patients had liver fibrosis beyond stage 2. Overall, the prevalence of HEV in the post-hepatic transplant scenario appears to be low, and, at least histologically, seemingly not harmful. We conclude that, although some studies reported a risk of HEV chronification, patients who had their livers transplanted due to HCV and showed serological or molecular markers of HEV did not have higher levels of fibrosis compared to patients who showed no indications of HEV infection at the time of the analysis.

Background: A 2-year roadmap study was conducted to evaluate the efficacy and safety of tenofovir intensification at Week 24 in patients with chronic hepatitis B (CHB) receiving telbivudine. Scope: A prospective multicenter study was conducted in treatment-naive patients with hepatitis B e antigen (HBeAg)- positive CHB. All patients received telbivudine (600 mg/day) until Week 24. Thereafter, patients with detectable hepatitis B virus (HBV) DNA (≥300 copies/mL) were administered tenofovir (300 mg/day) plus telbivudine, and patients with undetectable HBV DNA continued telbivudine monotherapy until Week 104. The primary endpoint was the proportion of patients with undetectable HBV DNA (

Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.

PubMed: 29599078, 2-s2.0-85044540918, Background: The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment. Methods: In this modelling study, we used a Delphi process that included a literature review in PubMed and Embase, followed by interviews with experts, to quantify the historical epidemiology of HBV infection. We then used a dynamic HBV transmission and progression model to estimate the country-level and regional-level prevalence of HBsAg in 2016 and the effect of prophylaxis and treatment on disease burden. Findings: We developed models for 120 countries, 78 of which were populated with data approved by experts. Using these models, we estimated that the global prevalence of HBsAg in 2016 was 3·9% (95% uncertainty interval [UI] 3·4–4·6), corresponding to 291 992 000 (251 513 000–341 114 000) infections. Of these infections, around 29 million (10%) were diagnosed, and only 4·8 million (5%) of 94 million individuals eligible for treatment actually received antiviral therapy. Around 1·8 (1·6–2·2) million infections were in children aged 5 years, with a prevalence of 1·4% (1·2–1·6). We estimated that 87% of infants had received the three-dose HBV vaccination in the first year of life, 46% had received timely birth-dose vaccination, and 13% had received hepatitis B immunoglobulin along with the full vaccination regimen. Less than 1% of mothers with a high viral load had received antiviral therapy to reduce mother-to-child transmission. Interpretation: Our estimate of HBV prevalence in 2016 differs from previous studies, potentially because we took into account the effect of infant prophylaxis and early childhood vaccination, as well as changing prevalence over time. Although some regions are well on their way to meeting prophylaxis and prevalence targets, all regions must substantially scale-up access to diagnosis and treatment to meet the global targets. Funding: John C Martin Foundation. © 2018 Elsevier Ltd, H28-kansei-ippan-001 National Academy of Sciences, NAS Novartis Roche World Health Organization, WHO Gilead Sciences Alnylam Pharmaceuticals AbbVie Meso Scale Diagnostics, MSD British Microcirculation Society, BMS Japan Society for the Promotion of Science, JSPS: 17H03589 Ministry of Health, Labour and Welfare, MHLW Vetenskapsrådet, VR Siemens Universiteit Antwerpen OLL-683801, DR-S, IGa, SB, SMB, CE, KM, HMN, KP, KR-S, SR, JDS, and HR report grants from John C Martin Foundation, during the conduct of the study, and grants from Gilead Sciences, AbbVie, WHO, National Academy of Sciences, Intercept Pharmaceuticals, and Boehringer Ingelheim, outside the submitted work. MHN reports grants and personal fees from Bristol-Myers Squibb (BMS), Gilead Sciences, and Janssen, and personal fees from Novartis, Anylam, and Dynavax, outside the submitted work. PVD acts as chief and principal investigator for vaccine trials done on behalf of the University of Antwerp, Belgium, for which the University obtains research grants from vaccine manufacturers; speaker's fees for presentations on vaccines are paid directly to an educational fund held by the University of Antwerp, and PVD receives no personal remuneration for this work. ACA reports personal fees from Mylan Pharmaceuticals, outside the submitted work. JEA reports fees paid to his hospital for participation on the advisory boards of Gilead Sciences, ViiV Healthcare, BMS, Janssen, and AbbVie, and grants from BMS, Merck Sharp & Dohme (MSD), AbbVie, and ViiV Healthcare, outside the submitted work. TB reports grants, personal fees, and non-financial support from AbbVie and Gilead Sciences; grants and personal fees from BMS, Janssen, Roche, MSD, and Sequana Medical; and personal fees from Bayer, Vertex, Tibotec, Intercept, Sirtex, and Alexion, outside the submitted work. PB reports grants and personal fees from AbbVie, Gilead Sciences, and MSD, outside the submitted work. MBr reports personal fees from BMS, Gilead Sciences, and Janssen, and grants from BMS, outside the submitted work. HLYC reports personal fees from Gilead Sciences, BMS, AbbVie, Roche, MedImmune, and Intellia, outside the submitted work. PBC reports grants from AbbVie, Gilead Sciences, and MSD, outside the submitted work. VC reports personal fees from AbbVie, BMS, Gilead Sciences, and MSD, and grants from BMS, outside the submitted work. MCor reports personal fees from AbbVie, BMS, Boehringer Ingelheim, Biogen Idec, Falk Foundation, Gilead Sciences, Janssen, MSD, Roche Diagnostics, Roche Pharma, and Siemens, outside the submitted work. SD and PJ report personal fees and non-financial support from AbbVie and Gilead Sciences, and personal fees from MSD, outside the submitted work. MHE-S is an advisory board member for Perspectum Diagnostics, and reports grants and non-financial support from Gilead Sciences, and non-financial support from AbbVie and Quadri Pharma, outside the submitted work. RF reports grants, personal fees, and non-financial support from Roche and Gilead Sciences, and personal fees and non-financial support from BMS, outside the submitted work. GBG reports grants and personal fees from Gilead Sciences, outside the submitted work. JG-S reports grants and personal fees from Gilead Sciences, and personal fees from MSD, Abbvie, Janssen, and BMS, outside the submitted work. JGer reports grants and personal fees from AbbVie, Gilead Sciences, Janssen, MSD, BMS, and ViiV Healthcare, outside the submitted work. RG reports grants from New South Wales Ministry of Health and provided project advice regarding viral hepatitis treatment to Gilead Sciences, outside the submitted work. AHa reports unrestricted grants from AbbVie, MSD, Gilead Sciences, BMS, and Novartis, and non-financial support from Gilead Sciences, outside the submitted work; he was also on advisory boards for AbbVie, Gilead Sciences, and BMS. CH reports personal fees from AbbVie, BMS, Gilead Sciences, Janssen, and MSD, outside the submitted work. JJ reports personal fees and non-financial support from Gilead Sciences and AbbVie, and personal fees from Roche and BMS, outside the submitted work. MK reports grants from Roche, Siemens, Hologic, and Boerhinger Ingleheim, outside the submitted work. JVL reports grants and personal fees from Gilead Sciences and personal fees from Cepheid, outside the submitted work. MMan reports personal fees from Roche, BMS, GlaxoSmithKline, Aevi Genomic Medicine, ENYO Pharma, and CureVac, and grants and personal fees from Gilead Sciences and Novartis, outside the submitted work. SMau reports personal fees and non-financial support from Gilead Sciences and BMS, outside the submitted work. CM reports grants and personal fees from AbbVie, Gilead Sciences, and BMS; personal fees from MSD; and grants from Roche, outside the submitted work. BM reports grants and personal fees from Gilead Sciences and personal fees from AbbVie, MSD, BMS, Bayer, Intercept, and Sigma-Tau, during the conduct of the study. FN reports personal fees and non-financial support from Gilead Sciences, during the conduct of the study. AR reports grants and personal fees from AbbVie, Gilead, and MSD, and personal fees form BMS, Celgene, Janssen, Intercept, and Lupin, outside the submitted work. HWR reports grants and personal fees from AbbVie, BMS, Boehringer Ingelheim, ENYO Pharma, Gilead Sciences, Janssen, MSD, PRA Health Sciences, Regulus, and Roche; personal fees from Alnylam and R-Pharm; and grants from Replicor, outside the submitted work. LRR reports grants from the Center for Clinical and Translational Science and the Swedish Research Council (Ghana), during the conduct of the study. LRR also reports grants from Gilead Sciences, BTG, Ariad, and Wako, outside the submitted work, and was a consultant and advisory board member for Wako, Medscape, Axis, OncLive, Bayer, Tavec, and Grail. SDR has served as an advisory board member and speaker for Gilead Sciences, AbbVie, and MSD. OS has served as a consultant and on advisory boards for MSD; received research grants from AbbVie, BMS, MSD, Boehringer Ingelheim, R-Pharm, and Hepatera; and served as a speaker for Abbott, AbbVie, BMS, Gilead Sciences, Janssen, MSD, and R-Pharm. JFS-A reports personal fees from AbbVie and grants from Gilead Sciences and Janssen, outside the submitted work. CSa reports personal fees from Gilead Sciences and BMS, outside the submitted work. PS reports grants and personal fees from Gilead Sciences, AbbVie, and BMS, and personal fees from Intercept, outside the submitted work. CSt has consulted with and served on advisory boards for Gilead Sciences, AbbVie, and MSD. VSy reports grants and personal fees from Gilead Sciences, personal fees and non-financial support from AbbVie, and personal fees from Janssen, outside the submitted work. KT reports grants and personal fees from AbbVie, Gilead Sciences, and BMS; personal fees from MSD and Alfa Wasserman; and grants from Janssen, outside the submitted work. AJvdM reports grants and personal fees from Gilead Sciences and personal fees from AbbVie, outside the submitted work. IW reports personal fees from AbbVie, Gilead Sciences, Janssen, Marcyrl, Mylan, Onxio, and Pharco, outside the submitted work. NW reports personal fees paid to her department from AbbVie, BMS, Gilead Sciences, and MSD, outside the submitted work. VWW reports personal fees from Gilead Sciences, BMS, and MSD, outside the submitted work. M-FY was a speaker or advisory board member for AbbVie, BMS, Gilead Sciences, Roche, GlaxoSmithKline, Fujirebio, Biocartis, and MSD, outside the submitted work. SZ reports consultancy and lecture fees from AbbVie, Gilead Sciences, and MSD, and consultancy fees from Intercept, outside the submitted work. All other authors declare no competing interests., This study was funded by the John C Martin Foundation through the Polaris Observatory. We thank the Research on Hepatitis group (H28-kansei-ippan-001 and H25-kanen-ippan-010; led by JT), funded by the Ministry of Health, Labour and Welfare of Japan, for their provision of country-level data for Japan, and Örebro County Council for providing ALF grants (OLL-683801) to A-SD, which allowed collection of country-level data for Sweden.

Despite recent advances in therapy for chronic hepatitis C (CHC), the disease caused by genotype 3 virus (GEN3) is still considered a treatment challenge in certain patient subgroups. The aim of this retrospective study was to evaluate the effectiveness and safety of the peginterferon (Peg-IFN) and ribavirin (RBV) combination treatment for GEN3/CHC patients, and to evaluate sustained virological response (SVR) indicators and early treatment interruption due to serious adverse events (SAE). This was a retrospective observational study of GEN3/CHC patients, co-infected or not by HIV and treated with Peg-IFN/RBV in nine Brazilian healthcare centers. The study sample included 184 GEN3/CHC patients; 70 (38%) were co-infected with HIV. The overall SVR rate was 57.1% (95% CI 50-64). Among co-infected and mono-infected patients, the SVR rate was 51.4% (36/70) and 60.5% (69/114), respectively (p=0.241). Thirty-four (18.5%) patients experienced SAE and interrupted treatment. SVR was negatively associated with the use of Peg-IFN alpha 2b (PR 0.75; 95% CI 0.58-0.99; p=0.045) and to early treatment interruption due to SAE (PR 0.36; 95% CI 0.20-0.68; p=0.001). Early treatment interruption due to SAE was associated with age (PR 1.06; 95% CI 1.02-1.10; p

WOS: 000426979400014, PubMed ID: 28404132, Background The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of-and expansion on-the 2014 analysis, which reported 80 million (95% CI 64-103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1.0% (95% uncertainty interval 0.8-1.1) in 2015, corresponding to 71.1 million (62.5-79.4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections., John C Martin Foundation, John C Martin Foundation.

Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Immunoparasitologia. Salvador, BA, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil / Instituto Butantan. Imunologia Viral. Sao Paulo, SP, Brasil Several new direct-acting antiviral (DAA) drugs are in development for chronic hepatitis C viral (HCV) infection, and NS3-NS4A serine protease and the NS5B RNA-dependent RNA polymerase have been the major targets. HCV variants displaying drug-resistant phenotypes have been observed both in vitro and during clinical trials. Our aim was to characterize amino acid changes at positions previously associated with resistance in protease (NS3) and polymerase (NS5B) regions from treatment-naïve HCV patients infected with genotypes 1a, 1b and 3a. All 1383 NS3 protease sequences (genotype 1a = 680, 1b = 498 and 3a = 205) and 806 NS5B polymerase sequences (genotypes 1a = 471, 1b = 329, 3a = 6) were collected from Los Alamos databank. Genotype 3a protease sequences showed the typical low-level resistance mutation V36L. NS3 sequences from other genotypes presented mutations on positions 36, 39, 41, 43, 54, 80, 109, 155 and 168 in a frequency lower than 2%, except for the mutation Q80R found in 35% of genotype 1a isolates. Polymerase sequences from genotype 3a patients showed five typical mutations: L419I, I424V, I482L, V499A and S556G. Two positions presented high polymorphism in the NS5B region from genotype 1a (V499A) and genotype 1b (C316N) subjects. Our results demonstrated a natural profile of genotype 3a that can be associated with the pre-existence of HCV variants resistant to first-generation protease inhibitors and to non-nucleoside polymerase inhibitors. Likewise, genotype 1b isolates and genotype 1a sequences exhibited pre-existing mutations associated with resistance to Palm II and Thumb I polymerase inhibitors, respectively.

Background. The epidemiology and clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in South America are not well known. Brazil is a largest country in this part of the world and the present study aimed to contribute with this information. Methods. This descriptive study included patients from medical centers around Brazil, who had diagnosis of NAFLD. They were selected from chart review and also prospectively in Hepatology out-clinics. Patients with history of alcohol intake and others liver diseases were excluded. Histological diagnosis included: steatosis or steatohepatitis (steatosis, ballooning of hepatocytes or fibrosis). The criteria to perform a liver biopsy was ALT or AST > 1.5 x normal levels. Results. A total of 1280 patients from 16 Brazilian centers and all five regions were included. The mean age was 49.68 ± 13.59 years; 53.3% were males and 85% were asymptomatic. Hyperlipidemia was observed in 66.8% cases, obesity in 44.7%, overweight in 44.4%, diabetes in 22.7%, and toxins exposure in 10%. Metabolic syndrome was observed in 41.3% cases. Elevated levels of ALT, AST and GGT were observed in 55.8%, 42.2% and 63.1% cases, respectively. Liver biopsy performed in 437 cases showed: isolate steatosis in 42% cases, steatohepatitis in 58% and 27% of them also presented fibrosis. Cirrhosis was observed in 15.4% and hepatocellular carcinoma in 0.7%. Conclusions. NAFLD in Brazil is more frequent in asymptomatic males; steatohepatitis with fibrosis and cirrhosis were a significant diagnosis. The genetic predisposition and lifestyle should be influenced in the spectrum; however these findings deserve a future investigation.

Background: Prolonged use of lamivudine in patients coinfected with HIV and hepatitis B virus (HBV) leads to an increasing risk of lamivudine resistance in both diseases. We investigated the addition of entecavir, a potent inhibitor of HBV polymerase, to lamivudine-containing highly active antiretroviral therapy (HAART) in patients who experienced rebound in HBV viremia while maintaining suppression of plasma HIV RNA less than 400 copies/ml. Methods: Sixty-eight patients were randomized to entecavir 1 mg (n=51) or placebo (n = 17) once daily for 24 weeks; 65 patients continued the study with entecavir for an additional 24 weeks. Lamivudine-containing HAART was continued throughout. Results: At week 24, the mean HBV DNA in entecavir-treated patients was 5.52 log 10 -copies/ml versus 9.27 log 10 copies/ml for placebo, and atweek48, it was 4.79 log 10 copies/ ml versus 5.63 log 10 copies/ml, respectively. The mean HBV DNA change from baseline for entecavir was -3.65 log 10 copies/ml (versus + 0.11 for placebo, P < 0.0001) and alanine aminotransferase normalization in 34% of patients (versus 8% for placebo, P = 0.08). At48 weeks, mean change in H BV DNA reached -4.20 log 10 copies/ml in patients who received entecavir for the entire 48 weeks. The frequency of adverse events with entecavir and placebo was comparable. Through 48 weeks, no clinically relevant changes in HIV viremia or CD4 cell counts were identified. Conclusion: In this study, entecavir was associated with rapid, clinically significant reductions in HBV DNA, with maintenance of HIV viremia suppression, in HIV/HBV coinfected patients with HBV viremia while on lamivudine treatment.

Introduction: The mechanisms by which severe cholestatic hepatitis develops after liver transplantation are not fully understood. Reports on immunohistochemical distribution of hepatitis C virus (HCV) antigens are still scarce, but recently, HCV immunostaining was suggested for early diagnosis of cholestatic forms of recurrent hepatitis C in liver grafts. After purification, Rb246 pab anticore (aa1-68) yielded specific, granular cytoplasmic staining in hepatocytes. Signal amplification through the Envision-Alkaline Phosphatase System avoided endogenous biotin and peroxidase. Aims/Methods: Rb246 was applied to liver samples of explants of 12 transplant recipients, six with the most severe form of post-transplantation recurrence, severe cholestatic hepatitis (group 1) and six with mild recurrence (group 2). We also assessed immuno-reactivity at two time-points post-transplantation (median 4 and 22 months) in both groups. HCV-core Ag was semiquantified from 0 to 3+ in each time point. Serum HCV-RNA was also measured on the different time points by branched DNA. Results: In the early post-transplant time point, one patient had a mild staining (1+), two patients had a moderate staining (2+) and the other three had no staining in group 1, compared with five patients with no staining (0) and one patient with mild staining (1+) in group 2. Late post-transplant liver samples were available in nine patients, and two out of four samples in group 1 showed a mild staining, compared with no staining patients in five patients in group 2. Strikingly, on the explant samples, HCV immunostaining was strongly positive in group 1, and mildly positive in group 2. Two out of five samples showed 3+ staining, and three samples showed 2+ staining in group 1; two out of five samples showed no staining, two samples showed 1+ staining and one sample showed 2+ staining in group 2. Serum HCV-RNA was significantly higher in group 1, on both time-points post-transplantation. HCV-core Ag was not directly associated with serum HCV-RNA on the different time points. Conclusion: These preliminary results suggest that strong HCV immunostaining in the explant is predictive of more severe disease recurrence.

OBJETIVO: O objetivo deste estudo foi estimar o padrão de tratamento, a utilização de recursos e os gastos para cada estágio da HCVB, no ambiente do Sistema Único de Saúde (SUS) do Brasil, no ano 2005. MÉTODOS: Foi desenvolvido painel Delphi de especialistas para obter informação sobre o padrão de tratamento da HCVB no Brasil. Os dados foram coletados com dez médicos especialistas em hepatologia e doenças infecciosas. A valoração dos recursos foi obtida predominantemente das tabelas de pagamentos do Sistema Único de Saúde e tabelas de preços de medicamentos. As estimativas de custo tiveram a perspectiva do pagador público. Os dados foram analisados estatisticamente pelo programa SPSS 12.0 para Windows. RESULTADOS: Os gastos estimados dos pacientes foram separados em cada estágio da HCVB. O gasto estimado anual por paciente foi: R$ 980,89 para hepatite B crônica, sem cirrose e sem tratamento antiviral; R$ 1.243,17 para cirrose compensada sem tratamento antiviral; R$ 22.022,61 para cirrose descompensada; R$ 4.764,95 para o carcinoma hepatocelular; e R$ 87.372,60 para o transplante hepático. CONCLUSÃO: Os gastos estimados com procedimentos e medicamentos, excluindo antivirais, representaram os principais componentes do gasto da HCVB. Neste modelo, os gastos aumentam dramaticamente nos estágios mais avançados, sugerindo que retardar a progressão da doença poderá reduzir o gasto no longo prazo. BACKGROUD: Chronic Hepatitis B Virus (CHBV) is a disease that places a large financial burden on healthcare systems and society. OBJECTIVE: The aim of this study was to estimate patient management patterns, and associated medical resource utilization and expenses, for each of the four stages of chronic HBV infection in the public unified healthcare system settings, in 2005. METHODS. An expert panel comprised of ten physicians, leading specialists in hepathology and infectious diseases, was convened to obtain information regarding management of CHBV patients in Brazil. Expense inputs were mainly obtained from government fee schedules and pharmaceutical price tables. Costs were estimated under the perspective of the public health system. Data were analyzed using Windows SPSS version 12.0. RESULTS: Estimated patient expenses were calculated for the four stages of CHBV infection. The estimated annual expenses per patient were: R$ 980.89 (US$ 392) for chronic hepatitis B with no cirrhosis and without antiviral therapy; R$ 1,243.17 (US$ 496) for compensated cirrhosis without antiviral therapy; R$ 22,022.61 (US$ 8809) for decompensated cirrhosis; R$ 4,764.95 (US$ 1,905) for hepatocellular carcinoma; and R$ 87,372.60 (US$ 34,948) for liver transplant. CONCLUSION: Estimated expenses associated with drugs and procedures represented the main components of the expenses of CHBV infection. In this model, expenses increase dramatically as the disease progresses to more advanced stages, suggesting that over the long term delaying progression may reduce costs.

Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a (40KD) plus ribavirin has given an overall sustained virological response of 18% in F3/F4 previous nonresponder US patients. We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients. Federal University of São Paulo Santa Casa de Misericórdia Gastroenterology Service Federal University of Pará Federal University of Juiz de Fora São Paulo University Medical School of Ribeirão Preto Emílio Ribas Institute Federal University of Minas Gerais Medical School of São José do Rio Preto Federal University of Alagoas Federal University of Santa Catarina Federal University of Bahia Tropical Medicine Fundation Oswaldo Cruz Hospital Federal University of Paraíba Roche UNIFESP, EPM, São Paulo SciELO

Background/Aims: To evaluate whether interferon treatment failure/relapse is related to changes in hepatitis C virus quasispecies complexity (number of variants) or diversity (genetic relatedness of variants). Methods: We analyzed hypervariable region heterogeneity in hepatitis C virus-infected patients by heteroduplex mobility assay and by phylogenetic analysis of sequenced clones. Sera from 11 patients were tested. Response was defined biochemically and virologically. Patients were treated with 3 or 6 MIU interferon for 6 months and followed up for 6 months. Four patients were non-responders, four were transient responders and three untreated patients served as controls. Three time points were studied for the non-responders (preinterferon, end of interferon, end of 6 months of follow-up), two for the transient responders (pre-interferon and post follow-up) and two for the controls (1 year apart). A total of 260 clones were examined by heteroduplex mobility assay and 144 clones were sequenced. Results: A linear correlation between heteroduplex mobility and nucleotide substitutions was observed, validating this method for assessment of quasispecies diversity. Although complexity at each time point was similar in all groups, diversity increased significantly with interferon treatment. The percentage of new variants in follow up was significantly higher in non-responders than in controls. These new variants exhibited a greater change in heteroduplex mobility, a higher percentage of changes in amino acids in non-responders compared to controls and were found to cluster separately from pretreatment variants when analyzed phylogenetically. These changes were less marked in transient responders. Conclusions: These mutations may allow hepatitis C virus to escape antiviral effects of interferon therapy.

An assay for the detection of antibody against the second envelope (E2) protein of GB virus type C (GBV-C) has been developed. Early reports suggested that this antibody was a marker of viral clearance, yet it is unknown whether anti-E2 is protective against further GBV-C infection. The primary aims were to determine (1) if posttransplantation immunosuppression alters the prevalence of anti-E2; and (2) if anti-E2 positivity pretransplantation protects against acquisition of GBV-C infection posttransplantation. Fifty-four recipients who underwent orthotopic liver transplantation for end-stage liver disease of nonviral etiologies were tested for GBV-C RNA using a PCR-based assay and anti-E2 antibodies by an enzyme-linked immunoassay. Anti-E2 was present in 35% and in 46% of patients pre- and posttransplantation, respectively. Anti-E2 positivity pretransplantation was strongly associated with anti-E2 positivity after transplantation (P < 0.001); 83% of patients with anti-E2 prior to transplantation remained anti-E2-positive after transplantation. A negative association between presence of GBV-C viremia and presence of anti-E2 was found in all patients tested either prior to or following transplantation (P=0.03). Acquisition of GBV-C infection was significantly lower in patients who were anti-E2-positive prior to transplantation (2/13) compared to those who were anti-E2-negative (12/26) (P=0.05). It is concluded that immunosuppression does not reduce the prevalence of anti-E2 after transplantation in those who are seroreactive prior to transplantation. Anti-E2 appears to be a neutralizing antibody whose presence at the time of liver transplantation protects against acquisition of GBV-C infection in the peritransplantation period.

HCV is a common cause of chronic liver disease, accounting annually for 8000 to 10,000 deaths resulting from liver-related complications. As such, HCV is an important indication for liver transplantation, representing a major financial burden to the health care system in the United States (from $150 million to $300 million annually). HCV has a worldwide prevalence of 5% to 15% in transplant recipients, causing a relatively indolent course of infection, the clinical impact of which usually is not seen until more than 5 years after transplantation. 40 Recurrence of HCV after liver transplantation is nearly universal; thus, HCV infection, modified by immunosuppression, has the potential to affect both graft and patient survival. Because of prior parenteral exposure, HCV infection is present in other potential organ recipients (kidneys, hearts, and bone marrow), and, hence, also may play an important role in post-transplantation morbidity in these groups. Finally, transplantation is a risk factor for acquiring HCV infection, either through the donor organ or through transfused blood products, which in turn, can contribute to liver-related morbidity and mortality in the post-transplantation period. In this review we will focus on the spectrum of HCV infection in organ transplantation, with particular emphasis on liver and kidney transplant recipients. Diagnosis, natural history of disease, and current options for treatment are outlined. This information will guide us to make rational choices regarding transplantation of anti-HCV-positive patients and utilization of anti-HCV–positive donors.

Background and Aims: The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. Methods: A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (

Roche Produtos Quimicos e Farmaceuticos Introduction. A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care (pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after 24 weeks of treatment with conventional interferon plus ribavirin. Material and methods. Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (401(D) 180 pg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). Results. The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 IU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6-72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. Conclusion. Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting. Univ Sao Paulo, Sch Med, BR-05403000 Sao Paulo, Brazil Inst Infectol Emilio Ribas, Sao Paulo, Brazil Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil Fed Univ Hlth Sci Porto Alegre, Porto Alegre, RS, Brazil State Univ Botucatu, Botucatu, SP, Brazil Pontificia Univ Catolica Campinas, Campinas, SP, Brazil Univ Fed Bahia, Salvador, BA, Brazil Indiana Univ, Indiana, PA USA Univ Fed Sao Paulo, Sao Paulo, Brazil Univ Fed Pernambuco, Recife, PE, Brazil Santa Casa de Misericordia de Goiania, Goiania, Go, Brazil Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil Hosp Alemao Oswaldo Cruz, Sao Paulo, Brazil Roche Prod Quim & Farmaceut, Sao Paulo, Brazil Univ Fed Sao Paulo, Sao Paulo, Brazil Web of Science

A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown.The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years).Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse.In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.