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. (HCC cancerrelated cancer worldwide (SBH 202 then time singletopic single professionals policymakers, policymakers policy makers, makers policy-makers decisionmaking decision making 20 2

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. (CHC mundo (SBH 202 então médica consenso online on line atualizadas revisado saúde 20 2

RESUMO CONTEXTO: A infecção pelo vírus da hepatite C (HCV) é uma das principais causas de hepatite C crônica e provoca implicações graves para pacientes, familiares e sistema de saúde. OBJETIVO: Os objetivos deste estudo foram: analisar a gravidade da fibrose hepática, comorbidades e complicações da hepatite C; examinar a qualidade de vida relacionada à saúde (QVRS), a perda de produtividade e o uso de recursos e custos no sistema público por pacientes brasileiros com hepatite C crônica, genótipo tipo 1. MÉTODOS: Foi realizado um estudo transversal, multicêntrico em pacientes com hepatite C crônica genótipo-1 para avaliar a carga da doença no sistema público de saúde brasileiro entre novembro de 2014 e março de 2015. Os pacientes foram submetidos a uma elastografia hepática transitória (FibroScan) para avaliar a fibrose e a uma entrevista composta por um questionário desenvolvido para o estudo e cinco questionários padronizados: EQ-5D-3L, HCV-PRO, e WPAI:HepC. RESULTADOS: Foram recrutados 313 pacientes. A amostra foi composta predominantemente por mulheres (50,8%), caucasianos/brancos (55,9%) e indivíduos empregados (39,9%). A média de idade foi 56 (DP=10,4) anos. Em média, os pacientes com HCV esperaram 40,6 (DP=49,6) meses entre o diagnóstico e o primeiro tratamento. Ademais, 42,8% dos pacientes que realizaram o FibroScan tinham cirrose; a comorbidade mais frequente foi doença cardiovascular (62,6%) e a complicação mais comum as varizes esofágicas (54,5%). Os resultados também mostraram que “dor e desconforto” foi a dimensão de QVRS mais afetada (55,0% dos pacientes relataram alguns problemas) e que a média do escore do HCV-PRO foi 69,1 (DP=24,2). Em relação à perda de produtividade, o componente do WPAI:HepC mais afetado foi atividade diária (23,5%) e entre os pacientes empregados, presenteísmo foi mais frequente do que absenteísmo (18,5% vs 6,5%). Os custos diretos médicos totais com essa amostra foi de 12.305,72USD por paciente em um período de dois anos; o tratamento medicamentoso representou 95% desse total. CONCLUSÃO Esse estudo mostrou a maioria dos pacientes possui cirrose, apresenta alta prevalência de doenças cardiometabolicas e varizes esofágicas, QVRS reduzida principalmente em termos de dor/desconforto e dano na produtividade, especialmente presenteísmo. Adicionalmente, nós demonstramos que o HCV impõe uma carga econômica no sistema de saúde brasileiro e que os medicamentos correspondem à maioria dos custos.

ABSTRACT BACKGROUND: Infection by hepatitis C virus is one of the leading causes of chronic hepatitis C and cause severe burden for patients, families and the health care system. OBJECTIVE: The aims of this research were to assess the severity of liver fibrosis, comorbidities and complications of hepatitis C virus; to examine health-related quality of life (HRQoL), productivity loss and resource use and costs in a sample of Brazilian chronic hepatitis C, genotype 1, patients. METHODS: This was a cross-sectional multicenter study performed in genotype-1 chronic hepatitis C patients to assess disease burden in the Brazilian public health care system between November 2014 and March 2015. Patients were submitted to a liver transient elastography (FibroScan) to assess liver fibrosis and answered an interview composed by a questionnaire specifically developed for the study and three standardized questionnaires: EQ-5D-3L, HCV-PRO and WPAI:HepC. RESULTS: There were 313 subjects enrolled, with predominance of women (50.8%), caucasian/white (55.9%) and employed individuals (39.9%). Mean age was 56 (SD=10.4) years old. Moreover, 42.8% of patients who underwent FibroScan were cirrhotic; the most frequent comorbidity was cardiovascular disease (62.6%) and the most frequent complication was esophageal varices (54.5%). The results also showed that “pain and discomfort” was the most affected HRQoL dimension (55.0% of patients reported some problems) and that the mean HCV-PRO overall score was 69.1 (SD=24.2). Regarding productivity loss, the most affected WPAI:HepC component was daily activity (23.5%) and among employed patients, presenteeism was more frequent than absenteeism (18.5% vs 6.5%). The direct medical costs in this chronic hepatitis C sample was 12,305.72USD per patient in the 2 years study period; drug treatment costs represented 95.9% of this total. CONCLUSION: This study showed that most patients are cirrhotic, present high prevalence of cardiometabolic diseases and esophageal varices, reduced HRQoL mainly in terms of pain/discomfort, and work productivity impairment, especially presenteeism. Additionally, we demonstrated that hepatitis C virus imposes an economic burden on Brazilian Health Care System and that most of this cost is due to drug treatment.

Resumo Mariposa-oriental (Grapholita molesta) é a praga mais importante de pomares de maçã no Brasil. Por muitos anos, o inseticida foi a única ferramenta usada como controle. O objetivo deste trabalho foi caracterizar o manejo dos pomares por meio da Avaliação de Impacto Ambiental da Inovação Tecnológica Agropecuária (AMBITEC-AGRO) e relacionar com o status da resistência de populações de G. molesta nos pomares de maçã, por bioensaios toxicológicos e atividades enzimáticas de glutatione S-transferase (GST), esterases (a-ß EST) e acetilcolinesterase (AChE). A estratégia fitossanitária adotada por quatro pomares de maçã no Sul do Brasil foi analisada em: Vacaria (população RS), Fraiburgo (população SC1), São Joaquim (população SC2) e Porto Amazonas (população PR). As populações foram criadas em laboratório para bioensaios com clorpirifós, carbaril, deltametrina e tebufenozide. A mortalidade larval foi avaliada durante sete dias. A atividade das enzimas GST, a-ßEST e AChE foi realizada com larvas de terceiro e quarto instares. O resultado indicou que as populações coletadas em Vacaria, Fraiburgo e São Joaquim mostraram tolerância ao carbaril e ao clorpirifós, enquanto em Porto Amazonas se mostraram mais suscetíveis. As populações de SC2 e PR foram mais tolerantes à deltametrina, enquanto que nenhuma foi tolerante a tebufenozide. A população RS foi a que apresentou maior atividade para AChE, GST e a-EST. Os resultados deste estudo podem sugerir que o sistema AMBITEC-AGRO foi um método adequado para avaliar as atividades fitossanitárias de um pomar de maçã e relacioná-lo ao estado de resistência das populações de G. molesta.

Abstract Oriental fruit moth (Grapholita molesta) is the most important pest of apple orchards in Brazil. For many years, insecticides have been the only tool used for its control. The aim of this work was to characterize the management of apple orchards by the system for Assessment of Environment Impact of Agricultural Technology Innovations (AMBITEC-AGRO) and to relate it with the resistance status of G. molesta populations. Insecticide resistance was estimated by toxicology and enzymatic activities of glutathione S-transferase (GST), esterases (a-ß EST), and acetylcholinesterase (AChE). The phytosanitary strategies adopted by the four apple production orchards in southern Brazil were analyzed in: Vacaria (RS population), Fraiburgo (SC1 population), São Joaquim (SC2 population), and Porto Amazonas (PR population). Oriental fruit moth field populations were reared in laboratory for bioassays with chlorpyriphos, carbaryl, deltamethrin, and tebufenozide insecticides and were compared with a reference susceptible population. Larval mortality rates were recorded for seven days. GST, a-ß EST, and AChE assays were performed with third- and fourth-instar larvae. Results indicated that oriental fruit moth populations collected in Vacaria, Fraiburgo, and São Joaquim showed tolerance to carbaryl and chlorpyriphos, whereas the population collected in Porto Amazonas was more susceptible. SC2 and PR populations were more tolerant to deltamethrin, while RS and SC1 populations were more susceptible. No population was tolerant to tebufenozide. RS population showed the highest activity for AChE, GST, and a-EST. The findings of this study suggest that the AMBITEC-AGRO system was a suitable method to evaluate the phytosanitary activity of apple orchards and to relate it to the resistance status of G. molesta populations.

Objective: Patients with chronic hepatitis C (CHC) have a poorer quality of life than those with other chronic liver diseases. However, some of the factors that determine health-related quality of life (HRQOL) in these patients, such as the degree of liver fibrosis, are still controversial. Therefore, the aim of the present study was to investigate the impact of CHC on HRQOL by conducting clinical, psychiatric, and sociodemographic evaluations. Methods: One hundred and twenty-four consecutive patients attending a referral center for hepatitis were evaluated using the Mini-International Neuropsychiatry Interview, the Hamilton Depression Rating Scale, the Hospital Anxiety and Depression Scale, and the Medical Outcomes Study 36-Item Short-Form Health Survey. Multiple linear regression analyses were used to quantify independent associations between HRQOL and the clinical, psychiatric, and sociodemographic variables of interest. Results: Reduced HRQOL was independently associated with major depressive disorder (MDD) and with elevated levels of alanine aminotransferase, but was not associated with hepatic cirrhosis. Conclusions: MDD rather than the grade of liver fibrosis was strongly associated with HRQOL impairment in patients with CHC. These findings highlight that, in patients with CHC, the psychological effects of the disease deserve more attention and the implementation of integrated medical, psychiatric, and psychological care may be helpful.

Sequence variation among different hepatitis C virus (HCV) isolates has adaptive significance and reflects the modes and intensities of selection mechanisms operating on the virus. In this work, we sought to investigate using classical population genetics parameters, the genetic variability of HCV genotype 1 using the 5' UTR and NS5A regions from treatment non-responding and responding groups of patients. Both regions showed low genetic varia-bility and the 5' UTR showed neutral deviation. No differences were observed in the nonsynonymous/synonymous nucleotide substitution ratio among groups for NS5A. The analysis of molecular variance test of the 5' UTR region showed an 11.94% variation among groups. Phylogenetic analysis showed no correlation between sequence variations and therapeutic responses.

The use of medicinal plants by the general population is an old and still widespread practice, which makes studies of their genotoxicity essential. Psidium guajava L. and Achillea millefolium L. are examples of plants commonly used in popular medicine. P. guajava L. is indicated for diarrhea and also as an antiseptic, while A. millefolium L. is indicated as an analgesic, antispasmodic, digestive, diuretic, antiseptic, astringent, emollient, wound healer and hemorrhoid medication. The aim of this study was to determine the effects of the infusions of these two plant species on chromosomes and the cell cycle. Leaves from the plants were used to prepare infusions, in the same manner as teas, but at two different concentrations. Allium cepa L. root-tip cells (P. guajava L. - 2.62 and 26.2 mg/mL, and A. millefolium L. - 3.5 and 35.0 mg/mL) and Wistar rat bone marrow cells (P. guajava L. - 2.62 and 26.2 mg/100g body weight, and A. millefolium L. - 3.5 and 35.0 mg/100g body weight) were used as in vivo plant and animal test systems, respectively. Human peripheral blood lymphocytes (P. guajava L. - 0.262 and 2.62 mg/mL culture medium, and A. millefolium L. - 0.35 and 3.5 mg/mL culture medium) were used as in vitro test system. The P. guajava L. infusion at the higher concentration caused a statistically significant inhibition of cellular division in the onion root-tip cells, not observed in onion root-tip cells treated with A. millefolium L. No statistically significant alterations were found, as compared to untreated controls, in either the cell cycle or the number of chromosome alterations, after treatments with either plant, in rat cells or in cultured human lymphocytes. These results regarding the cytotoxicity and mutagenicity of these plants provide valuable information about the safety of using them as therapeutic agents.

Medicinal plants are widely used to treat various diseases, and in Brazil the plants Maytenus ilicifolia Mart. and Bauhinia candicans Benth are commonly used in popular medicine. However, there are a large number of compounds in plants which can produce alterations in genetic material, and this study was conducted to investigate any possible mutagenic and cytotoxic effects that M. ilicifolia and B. candicans infusions may have on the cell cycle and chromosomes. Infusions were prepared with in natura leaves to give two concentrations of infusions, one at the concentration normally used by the population in general and the other at 10 times this value (i.e. 3.5 and 35 mg/mL for M. ilicifolia and 0.465 and 4.65 mg/mL for B. candicans). Onion (Allium cepa L.) root-tip cells (RTC) and Wistar rat bone-marrow cells (BMC) were used as test systems in in vivo assays. The M. ilicifolia infusions at both concentrations, and the B. candicans infusion at the lower concentration, had no statistically significant depressive mitotic effect on RTC. A statistically significant depressive mitotic effect on RTC was found with the more concentrated (4.65 mg/mL) B. candicans infusion as compared with a negative control. In BMC, infusions of B. candicans and M. ilicifolia produced no statistically significant increase in the number of chromosome alterations or rates of cell division as compared to controls. The significance of these findings are discussed in the light of the use of these plants as therapeutic agents.