BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR SYSTEMIC TREATMENT OF HEPATOCELLULAR CARCINOMA.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

Atualização das Recomendações da Sociedade Brasileira de Hepatologia para o Tratamento Sistêmico do Carcinoma Hepatocelular / Brazilian society of hepatology updated recommendations for systemic treatment of hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

RESUMO O carcinoma hepatocelular (CHC) é uma das principais causas de mortalidade relacionada a câncer no Brasil e no mundo. A Sociedade Brasileira de Hepatologia (SBH) publicou em 2020 a atualização das recomendações da SBH para o diagnóstico e tratamento do CHC. Desde então, novas evidências científicas sobre o tratamento sistêmico do CHC foram relatadas na literatura médica, incluindo novos medicamentos aprovados que não estavam disponíveis na época do último consenso, levando a diretoria da SBH a promover uma reunião monotemática on-line para discutir e rever as recomendações sobre o tratamento sistêmico do CHC. Um grupo de experts foi convidado para realizar uma revisão sistemática da literatura e apresentar uma atualização, baseada em evidências científicas, sobre cada tópico relacionado ao tratamento sistêmico e a apresentar os dados e recomendações resumidas durante a reunião. Todos os painelistas se reuniram para discutir os tópicos e elaborar as recomendações atualizadas. O presente documento é a versão final do manuscrito revisado, contendo as recomendações da SBH, e seu objetivo é auxiliar os profissionais de saúde, formuladores de políticas e planejadores no Brasil e na América Latina na tomada de decisões sobre o tratamento sistêmico de pacientes com CHC.

Treatment of Hepatitis C with Direct-Acting Antivirals does not Induce Significant Arrhythmias

Abstract Background Chronic Hepatitis C (CHC) therapy with direct-acting antivirals (DAAs) has high efficacy and safety, but some cases of bradyarrhythmias have been described. Objective To evaluate heart rhythm disorders during DAA treatments. Methods Forty-eight patients with CHC (mean 61 years of age; 56% males; 73% HCV genotype 1) were evaluated before and during treatment with DAAs, analyzed by a resting 12-lead ECG [PR, QRS, and QT corrected (QTc) intervals measured] and a 24-h-Holter system, to evaluate the heart rate (HR) and the occurrence of arrhythmias. The Student's t-test or the Wilcoxon-Mann-Whitney test for continuous, independent variables were performed with a statistically significant p-value < 0.05. Results The electrocardiographic parameters before and during treatment were: PR interval (147.2 ± 15.6 vs 144.9 ± 15.6 ms; p = 0.21), QTc interval (427 ± 22.3 vs 421.7 ± 25.3 ms; p = 0.24), minimum HR (52.7 ± 8.4 vs 53.2 ± 8.5 bpm; p = 0.49), median HR (74.2 ± 10.4 vs 75.2 ± 9 bpm; p = 0.83), and maximum HR (117.4 ± 16.8 vs 117.9 ± 16.3 bpm; p = 0.25). These parameters proved to be similar among 11 beta-blockers or 22 ribavirin users. During treatment, the 21 cirrhotic patients presented significantly lower median HRs (72.1 ± 9.0 vs 77.9 ± 8.2 bpm; p = 0.02) and maximum HRs (108.9 ± 15.2 vs. 125.1 ± 13.2 bpm, p < 0.0001) through a 24-h-Holter monitoring than the patients without cirrhosis. No clinically relevant arrhythmias were detected. Conclusion DAAs do not significantly influence heart rate or induce significant cardiac arrhythmias in patients with CHC.

A real-life study on the impact of direct-acting antivirals in the treatment of chronic hepatitis C in liver transplant recipients at two university centers in Northeastern Brazil.

The efficacy of direct-acting antivirals (DAAs) in the treatment of chronic hepatitis C (CHC) in liver transplant recipients is poorly understood, and several factors, including immunosuppression, drug interactions, elevated viraemia, and intolerance to ribavirin (RBV), can reduce cure rates. We conducted a real-life study on liver transplant recipients with CHC treated with a combination of sofosbuvir (SOF) and daclatasvir (DCV) or simeprevir (SIM), with or without RBV, followed-up for 12 to 24 weeks. The treatment effectiveness was assessed by determining the sustained virological response (SVR) rates at 12 or 24 weeks after the treatment cessation. Eighty-four patients were evaluated, with a mean age of 63.4 ± 7.4 years, HCV genotype 1 being the most prevalent (63.1%). Nineteen patients (22.7%) had mild fibrosis (METAVIR < F2) and 41 (48.8%) significant fibrosis (METAVIR ≥ F2). The average time between liver transplantation and the start of treatment was 4 years (2.1-6.6 years). The SOF + DCV regimen was used in 58 patients (69%). RBV in combination with DAAs was used in seven patients (8.3%). SVR was achieved in 82 patients (97.6%), and few relevant adverse events could be attributed to DAA therapy, including a patient who stopped treatment due to a headache. There was a significant reduction in ALT, AST, GGT and FA levels, or the APRI index after 4 weeks of treatment, which remained until 12/24 weeks post-treatment. DAA treatment of CHC in liver-transplanted patients achieved a high SVR rate and resulted in the normalization of serum levels of liver enzymes.

Exuberant bullous vasculitis associated with SARS-CoV-2 infection.

We described a case of exuberant cutaneous small-vessel vasculitis in a 27-year-old male with mild CoVID-19 in Brazil. The patient presented painful purpuric papules and vesicobullous lesions with hemorrhagic content located in the larger amount in the lower limbs and, to a lesser extent in the region of the back and upper limbs, saving palms and soles of the feet. Influenza-like syndrome with anosmia and ageusia was reported seven days before the skin lesions. A real-time reverse transcription polymerase chain reaction was positive on a nasopharyngeal swab for SARS-CoV-2. Histopathological study showed leukocytoclastic cutaneous vasculitis affecting small vessels and microthrombi occluding some vessels. The patient presented an improvement in skin lesions by the fifth day of prednisone therapy. This case highlights the importance of the SARS-CoV-2 test in investigating the etiology of cutaneous vasculitis during this pandemic.

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

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

Factors associated with the choice of a second specialty among internal medicine residency graduates / Fatores associados à escolha da segunda especialidade entre concluintes da residência em clínica médica

Abstract: Introduction: After the residency in Internal Medicine, most graduates choose to undergo a new selection process to obtain a second specialty. The phenomenon of early specialization is encouraged as early as in the undergraduate course. Despite this, the demand for general practitioners is growing. Objective: To investigate the factors that lead the newly graduated clinician to undertake a new residency. Method: This is a cross-sectional study that analyzes the responses of Internal Medicine residency graduates from the state of Pernambuco in 2020, through a questionnaire available online by Google Forms, containing questions about social aspects, undergraduate medical course, Medical Residency and intentions for the future career. Results: There were 81 responses of the 104 possible participants (77.88%). Most of these were female (66.67%), graduated from public universities (69.14%) and had already started the Internal Medicine residency shortly after graduation (50.62%). Regarding the specialty choice, 51.85% answered they had decided in the second year of residency, and 80.25% stated that they had undergone the selection process for the second specialty shortly after completing the Internal Medicine residency. The most often chosen career was Cardiology (20%). The factors most often associated with the choice of specialty were, according to the means on the Likert scale, "work in an outpatient setting", "long-term patient follow-up", and "more contact with patients". Conclusion: As far as it could be investigated in the literature, this was the first Brazilian study on specialty choices after the Internal Medicine residency. It was possible to identify the most important reasons for choosing a second specialty among the graduates of this Medical Residency program in Pernambuco in 2020. More studies are needed to establish correlations between the factors of choice with the chosen specialty.

Resumo: Introdução: Após a residência em clínica médica, a maioria dos concluintes opta por se submeter a um novo processo seletivo para obter uma segunda especialidade. O fenômeno da especialização precoce é incentivado já na graduação. Apesar disso, a demanda por médicos generalistas está em crescimento. Objetivo: Este estudo teve como objetivo investigar os fatores que levam o clínico recém-formado a realizar uma nova residência. Método: Trata-se de um estudo transversal que analisou as respostas dos concluintes do Programa de Residência Médica em Clínica Médica (PRM-CM) realizado em 2020 no estado de Pernambuco. Os concluintes do PRM-CM, por meio de um questionário disponibilizado de forma on-line pelo Google Forms, responderam a perguntas sobre aspectos sociais, a graduação, a residência médica e intenções para a carreira futura. Resultado: Dos 104 participantes possíveis, houve 81 respostas (77,88%). Desse total final, 66,67% eram do sexo feminino, 69,14% tinham se graduado em universidades públicas, e 50,62% já haviam iniciado o PRM-CM logo após a graduação. Quanto à escolha de especialidade, 51,85% responderam ter decidido no segundo ano de residência, e 80,25% afirmaram ter se submetido ao processo seletivo para a segunda especialidade logo após o PRM-CM. A carreira mais escolhida foi cardiologia (20%). Os fatores mais associados à escolha de especialidade foram, de acordo com as médias na escala de Likert, "trabalho em ambiente ambulatorial", "acompanhamento de pacientes por longo período" e "mais contato com pacientes". Conclusão: Até onde se pôde investigar na literatura, este é o primeiro estudo brasileiro a abordar as escolhas de especialidade após o PRM-CM. Foi possível identificar os motivos mais importantes para escolher uma segunda especialidade entre os concluintes desse PRM em Pernambuco, em 2020. Mais estudos são necessários para tecer correlações entre os fatores de escolha com a especialidade escolhida.

Anti-rod and ring antibodies in patients with chronic hepatitis C using direct-acting antivirals.

Anti-rods and rings (anti-RR) antibody induction is related to the combination of interferon and ribavirin in the treatment of hepatitis C virus (HCV) infection. If the main factor leading to this autoimmune reaction is the combination of these drugs, is not well known, but in vitro studies shows that ribavirin alone can induce rods and rings structures. New direct-acting antivirals (DAAs) permit HCV treatment without needing interferon but may be associated with ribavirin in the most difficult-to-treat patients. The aim of this study is to evaluate the occurrence of anti-RR in patients with chronic HCV infection, before and after 12 weeks of treatment with DAAs, with and without ribavirin. From Jun 2016 to Oct 2017, 52 HCV-infected patients were screened for anti-RR before and after DAA therapy, including sofosbuvir, daclatasvir, simeprevir, and ribavirin. Serum samples were analyzed using indirect immunofluorescence. The anti-RR was present in 11 (21%) of the 52 patients (51.9% male and mean age of 59.1 years) before using DAAs. All of them had been previously treated and previous exposed to interferon/ribavirin, with exposure time to ribavirin associated with the presence of anti-RR. After 12 weeks of DAA treatment, 3 patients (5.7%) developed the antibody in low titers, and two of them (66%) were interferon/ribavirin experienced. Only one of the 29 naïve patients (3.44%) developed anti-RR during the current treatment. Anti-RR was present in patients previously treated with interferon/ribavirin and can emerge after DAA treatment probably at a lower frequency than after interferon/ribavirin treatment.

Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation.

Liver transplantation is the best treatment option for cirrhotic patients with early-stage hepatocellular carcinoma, but it faces the problem of scarcity of donors and the risk of tumor recurrence, which affects between 15% and 20% of the cases, despite the use of restrictive criteria. The risk of recurrence depends on a number of factors, related to the tumor, the patient, and the treatment, which are discussed in this review. Some of these factors are already well established, such as the histopathological characteristics of the tumor, Alpha-fetoprotein (AFP) levels, and waiting time. Other factors related to the biological behavior of the tumor and treatment should be recognized because they can be used in the refinement of the selection criteria of transplant candidates and in an attempt to reduce recurrence. This review also discusses the clinical presentation of recurrence and its prognosis, contributing to the identification of a subgroup of patients who may have better survival, if they are timely identified and treated. Development of recurrence after the first year, with AFP levels ≤ 100 ng/mL, and single site capable of locoregional therapy are associated with better survival after recurrence.

Long-term persistence of anti-rods and rings antibodies in patients with chronic hepatitis C after antiviral treatment.

Anti-rods and rings (anti-RR) antibodies are related to hepatitis C virus (HCV) in patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). Only RBV induces rods/rings structures in vitro; but in vivo, the antibody appearance is related to the combination of these drugs, because data about patients using just one of these drugs alone is missing. Some studies suggest disappearance of these antibodies over time. The aim of this study was to describe the occurrence of anti-RR in patients with chronic hepatitis C treatment-naïve or previously PEG-IFN/RBV-experienced, evaluating the persistence of anti-RR antibodies long after PEG-IFN/RBV treatment. From 2016 to 2017, 70 HCV-infected patients were screened for anti-RR using indirect immunofluorescence. Demographic and clinical data about previous treatments against HCV were assessed. Thirty-four patients (49%) had been previously treated with PEG-IFN/RBV and the average time since they had received the last antiviral treatment was 85.4 months. Anti-RR seropositivity was detected in 16 patients (23%), and all of these had used PEG-IFN/RBV (corresponding to 47% of experienced patients). Previous antiviral treatment and previous exposure time to RBV were associated with anti-RR positivity. Median time elapsed since last treatment was similar between anti-RR-positive and anti-RR-negative patients. Anti-RR seropositivity was not observed in treatment-naïve patients, but was detected in almost half of patients previously treated with PEG-IFN and RBV, even after a long period without exposure to these drugs. This antibody was related to extended prior exposure to ribavirin.

Schistosomal liver fibrosis and hepatocellular carcinoma - case series of patients submitted to liver transplantation

ABSTRACT Schistosomiasis affects approximately 207 million people in 76 countries. The association between hepatocellular carcinoma and Schistosoma mansoni infection has been investigated. Studies using animal models suggest that the parasite may accelerate the oncogenic process when combined with other factors, such as hepatitis C virus infection or exposure to a carcinogen. Herein, we report a case series of six hepatocellular carcinoma patients from Northeast Brazil, with negative serology for both hepatitis B and C virus, submitted to liver transplantation, whose explant showed evidence of schistosomal liver fibrosis. Since all patients enrolled in this study were submitted to liver transplantation, we were able to access the whole explanted liver and perform histopathological analysis, which is often not possible in other situations. Although 50% of them showed signs of liver failure, no cirrhosis or any liver disease other than schistosomal fibrosis had been detected. These uncommon findings suggest that Schistosoma mansoni infection might predispose to hepatocellular carcinoma development, regardless of the absence of other risk factors.

Schistosomal liver fibrosis and hepatocellular carcinoma - case series of patients submitted to liver transplantation.

Schistosomiasis affects approximately 207 million people in 76 countries. The association between hepatocellular carcinoma and Schistosoma mansoni infection has been investigated. Studies using animal models suggest that the parasite may accelerate the oncogenic process when combined with other factors, such as hepatitis C virus infection or exposure to a carcinogen. Herein, we report a case series of six hepatocellular carcinoma patients from Northeast Brazil, with negative serology for both hepatitis B and C virus, submitted to liver transplantation, whose explant showed evidence of schistosomal liver fibrosis. Since all patients enrolled in this study were submitted to liver transplantation, we were able to access the whole explanted liver and perform histopathological analysis, which is often not possible in other situations. Although 50% of them showed signs of liver failure, no cirrhosis or any liver disease other than schistosomal fibrosis had been detected. These uncommon findings suggest that Schistosoma mansoni infection might predispose to hepatocellular carcinoma development, regardless of the absence of other risk factors.