A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease.

OBJECTIVE: Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. DATA SOURCES: Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. STUDY SELECTION AND DATA EXTRACTION: Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. DATA SYNTHESIS: The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. CONCLUSIONS: The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.

Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy.

In the phase 3 Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE), at 1 year, eliglustat was noninferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all 4 measures remained collectively stable (composite end point relative to baseline values) in ≥85% of patients as well as individually in ≥92%. Mean bone mineral density z scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well tolerated over 4 years; 4 (2.5%) patients withdrew because of adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years. This trial was registered at www.clinicaltrials.gov as #NCT00943111.

Direct antiviral therapy for treatment of hepatitis C: A real-world study from Brazil.

INTRODUCTION AND OBJECTIVES: Direct antiviral agents (DAAs) including sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM) and ombitasvir, paritaprevir and dasabuvir were introduced 2015 in Brazil for treatment of hepatitis C virus (HCV) infection. The aims of this study were to assess effectiveness and safety of HCV treatment with DAA in real-life world in a highly admixed population from Brazil. MATERIALS AND METHODS: All Brazilian reference centers for HCV treatment were invited to take part in a web-based registry, prospectively conducted by the Brazilian Society of Hepatology, to assess outcomes of HCV treatment in Brazil with DAAs. Data to be collected included demographics, disease severity and comorbidities, genotype (GT), viral load, DAA regimens, treatment side effects and sustained virological response (SVR). RESULTS: 3939 patients (60% males, mean age 58±10 years) throughout the country were evaluated. Most had advanced fibrosis or cirrhosis, GT1 and were treated with SOF/DCV or SOF/SIM. Overall SVR rates were higher than 95%. Subjects with decompensated cirrhosis, GT2 and GT3 have lower SVR rates of 85%, 90% and 91%, respectively. Cirrhosis and decompensated cirrhosis in GT1 and male sex and decompensated cirrhosis in GT3 were significantly associated with no SVR. Adverse events (AD) and serious AD occurred in 18% and 5% of those subjects, respectively, but less than 1% of patients required treatment discontinuation. CONCLUSION: SOF-based DAA regimens are effective and safe in the heterogeneous highly admixed Brazilian population and could remain an option for HCV treatment at least in low-income countries.

Neurocognitive impairment with hepatitis C and HIV co-infection in Southern Brazil.

Although cognitive impairment has been well documented in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) mono-infections, research on neurocognitive effects is limited in the context of HIV/HCV co-infection. The aims of this study were to explore the interplay between HIV and HCV infections in the expression of neurocognitive impairment (NCI), and to examine the differences in test performance between HIV/HCV co-infected and HIV or HCV mono-infected patients. A total of 128 participants from Southern Brazil underwent a comprehensive neuropsychological (NP) battery comprising 18 tests. Participants were grouped according to their serological status: HCV mono-infected (n = 20), HIV mono-infected (n = 48), HIV/HCV co-infected (n = 12), and HIV-/HCV-uninfected controls (n = 48). The frequencies of HIV subtypes B and C between the HIV mono-infected and HIV/HCV co-infected groups were comparable. There was greater prevalence of neuropsychological impairment among all three infection groups compared with the uninfected control group, but no statistically significant differences among mono- and co-infected groups were found. HCV infection was associated with cognitive deficits, independently of liver dysfunction. HCV infection did not show an additive effect on neurocognitive function among HIV+. NCI was independent of HCV RNA on peripheral blood, CSF, and hepatic injury. While we did not find additive global effect, in the present study, there was some evidence of additive HIV/HCV co-infection effects in speed of information processing, executive function, and verbal fluency domains when comparing the co-infected group with the other three groups. NP impairment was not dependent on HCV subtypes.

Effects of MASP2 haplotypes and MASP-2 levels in hepatitis C-infected patients.

Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are components of the lectin pathway, which activate the complement system after binding to the HCV structural proteins E1 and E2. We haplotyped 11 MASP2 polymorphisms in 103 HCV patients and 205 controls and measured MASP-2 levels in 67 HCV patients and 77 controls to better understand the role of MASP-2 in hepatitis C susceptibility and disease severity according to viral genotype and fibrosis levels. The haplotype block MASP2*ARDP was associated with protection against HCV infection (OR = 0.49, p = .044) and lower MASP-2 levels in controls (p = .021), while haplotype block AGTDVRC was significantly increased in patients (OR = 7.58, p = .003). MASP-2 levels were lower in patients than in controls (p < .001) and in patients with viral genotype 1 or 4 (poor responders to treatment) than genotype 3 (p = .022) and correlated inversely with the levels of alkaline phosphatase, especially in individuals with fibrosis 3 or 4 (R = -.7, p = .005). MASP2 gene polymorphisms modulate basal gene expression, which may influence the quality of complement response against HCV. MASP-2 levels decrease during chronic disease, independently of MASP2 genotypes, most probably due to consumption and attenuation mechanisms of viral origin and by the reduced liver function, the site of MASP-2 production.

THE EVALUATION OF INFLIXIMAB TROUGH LEVEL FAVORS MAINTENANCE THERAPY OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic diseases that result from the deregulation of the mucosal immune system of the gastrointestinal tract. The use of biological therapies, including infliximab (IFX), is one of the strategies to treat both CD and UC. The IFX treatment is monitored by complementary tests, namely: fecal calprotectin (FC); C-reactive protein (CRP); and endoscopic and cross-sectional imaging. Besides, serum IFX evaluation and antibody detection are also used. OBJECTIVE: To evaluate trough levels (TL) and antibodies in a population with inflammatory bowel (IBD) disease undergoing treatment with IFX, and the factors that might impact the treatment effectiveness. METHODS: Retrospective, cross-sectional study with patients with IBD that were assessed for TL and antibody (ATI) levels in a southern Brazilian hospital, from June 2014 to July 2016. RESULTS: The study assessed 55 patients (52.7% female) submitted to serum IFX and antibody evaluations (95 blood samples, 55 first test; 30 second test, and 10 as third testing. Forty-five (47.3%) cases were diagnosed with CD (81.8%), and ten with UC (18.2%). Serum levels were adequate in 30 samples (31.57%), subtherapeutic in 41 (43.15%), and supratherapeutic in 24 (25.26%). IFX dosages were optimized for 40 patients (42.10%), maintained for 31 (32.63%), and discontinued for 7 (7.60%). The intervals between infusions were shortened in 17.85% of the cases. In 55 tests (55.79%), the therapeutic approach was exclusively defined according to IFX and/or serum antibody levels. The assessment of patients one year later indicated that: the approach was maintained with IFX for thirty-eight patients (69.09%); the class of biological agent was changed for eight (14.54%); changes using the same class of biological agent occurred for two patients (3.63%); the medication was discontinued and not replaced for three patients (5.45%), and four patients (7.27%) were lost to follow-up. CONCLUSION: There were no differences in TL between groups with or without immunosuppressants, serum albumin (ALB), erythrocyte sedimentation rate (ESR), FC, CRP, and endoscopic and imaging examinations. Current therapeutic approach could be maintained for almost 70% of patients. Thus, serum and antibody levels are a useful tool in the follow-up of patients undergoing maintenance therapy and after treatment induction in patients with inflammatory bowel disease.

Cost-utility analysis of interferon-free treatments for patients with early-stage genotype 1 hepatitis C virus in Brazil.

INTRODUCTION: We conducted a cost-utility analysis of available interferon-free treatments for patients with early-stage genotype 1 chronic hepatitis C based on a Brazilian public health system perspective. METHODS: A Markov model was derived using a cohort of stage F0-F2 patients treated as recommended by the Brazilian national guidelines. RESULTS: Glecaprevir plus pibrentasvir was superior to all other treatments, followed by sofosbuvir plus velpatasvir. Sofosbuvir plus daclatasvir was identified as the least cost-effective option. CONCLUSIONS: The above findings were confirmed via probabilistic sensitivity analysis and the tested scenarios.

Liver involvement in patients with Gaucher disease types I and III.

BACKGROUND & AIMS: Gaucher disease (GD) is a multisystemic disease. Liver involvement in GD is not well characterised and ranges from hepatomegaly to cirrhosis and hepatocellular carcinoma. We aim to describe, and assess the effect of treatment, on the hepatic phenotype of a cohort of patients with GD types I and II. METHODS: Retrospective study based on the review of the medical files of the Gaucher Reference Centre of the Hospital de Clínicas de Porto Alegre, Brazil. Data from all GD types I and III patients seen at the centre since 2003 were analysed. Variables were compared as pre- ("baseline") and post-treatment ("follow-up"). RESULTS: Forty-two patients (types I: 39, III: 3; female: 22; median age: 35 y; enzyme replacement therapy: 37; substrate reduction therapy: 2; non-treated: 3; median time on treatment-MTT: 124 months) were included. Liver enzyme abnormalities, hepatomegaly, and steatosis at baseline were seen in 19/28 (68%), 28/42 (67%), and 3/38 patients (8%), respectively; at follow-up, 21/38 (55%), 15/38 (39%) and 15/38 (39%). MRI iron quantification showed overload in 7/8 patients (treated: 7; MTT: 55 months), being severe in 2/7 (treated: 2/2; MTT: 44.5 months). Eight patients had liver biopsy (treated: 6; MTT: 58 months), with fibrosis in 3 (treated: 1; time on treatment: 108 months) and steatohepatitis in 2 (treated: 2; time on treatment: 69 and 185 months). One patient developed hepatocellular carcinoma. CONCLUSIONS: GD is a heterogeneous disease that causes different patterns of liver damage even during treatment. Although treatment improves the hepatocellular damage, it is associated with an increased rate of steatosis. This study highlights the importance of a follow-up of liver integrity in these patients.

Haplotype specific-sequencing reveals MBL2 association with asymptomatic Plasmodium falciparum infection.

BACKGROUND: Mannose binding lectin (MBL) has an important role in the activation of the complement system and opsonization of pathogenic microorganisms. Frequent polymorphisms found in the MBL2 gene affect the concentration and functionality of the protein and are associated with enhanced susceptibility to severe malaria in African children. Most MBL2 typing strategies were designed to the analysis of selected variants, the significance of whole haplotypes is poorly known. In this work, a new typing strategy was developed and validated in an association analysis of MBL2 with adult asymptomatic infection. METHODS: MBL2 allele-specific fragments of 144 healthy Gabonese adults were amplified by using haplotype-specific sequencing (HSS), a new strategy that combines sequence-specific PCR and sequence-based typing. The Gabonese were investigated for the presence of Plasmodium falciparum parasitaemia by the amplification of parasite genes, immunochromatographic antigen detection and microscopic analysis. HSS results were also compared with a previously used real-time PCR (RT-PCR) method in 72 Euro-Brazilians. RESULTS: Fourteen polymorphisms were identified beside the commonly investigated promoter (H, L; X, Y; P, Q) and exon 1 (A, O; O = B, C or D) variants. The MBL2*LYPA/LYPA genotype was associated with the absence of asymptomatic infection (P = 0.017), whereas the MBL2*LYQC haplotype and YA/YO + YO/YO genotypes were associated with positive parasite counts in asymptomatic adults (P = 0.033 and 0.018, respectively). The associations were specific to LYPA (identical to the reference sequence Y16577) and LYQC (Y16578) and would not have been revealed by standard genotyping, as there was no association with LYPA and LYQC haplotypes carrying new polymorphisms defined by sequence-based typing. In contrast, HSS and RT-PCR produced very similar results in the less diverse European-derived population. CONCLUSION: In this work, a new typing strategy for a highly polymorphic gene was developed and validated focusing on the asymptomatic status of P. falciparum-infected adults. In populations with high nucleotide diversity, it allowed for the identification of associations with fine-scaled haplotypes that would not have been found using common typing techniques. In this preliminary study, MBL2 haplotypes or SNPs linked to them were found associated with susceptibility to infection and parasitaemia control of asymptomatic adults.

Liver damage in a patient with Gaucher's disease type 1 and alpha-1 antitrypsin deficiency: a potential epigenetic effect?

Gaucher's disease and alpha-1 antitrypsin deficiency are genetic diseases that can cause different kinds of liver damage, but are rarely associated with cirrhosis. Here, we describe the case of a patient with both diseases who presented with cirrhosis, followed by liver failure and death. Although the interaction between these two diseases remains unclear, we suspect the involvement of an epigenetic factor in the evolution of the aggressive liver disease.

Histological findings and NAFLD/NASH Status in liver biopsies of patients subjected to bariatric surgery

ABSTRACT Objective: To investigate nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hepatic fibrosis in biopsies of people with obesity who underwent bariatric surgery and examine the possible association of different variables with a diagnosis of NAFLD and NASH. Materials and methods: Epidemiological, clinical and laboratory data from 574 individuals with obesity of both genders seen by the same physician between 2003 and 2009 who had a liver biopsy during bariatric surgery were examined. Results: Of the 437 patients included, 39.8% had some degree of liver fibrosis, 95% had a histologic diagnosis of NAFLD, and the risk factors were age ≥ 28 years and Homeostatic Model Assessment (HOMA) ≥ 2.5 (p = 0.001 and p = 0.016, respectively). In the NAFLD group, NASH was present in 26% of patients and the associated factors were aspartate aminotransferase and alanine aminotransferase index (AST/ALT) > 1, high-density lipoprotein cholesterol (HDL-c) < 40 mg/dL, total cholesterol (TC) ≥ 200 mg/dL, gamma-glutamyl transferase (GGT) > 38 U/L and triglycerides (TG) levels > 150 mg/dL. The independent risk factors were low HDL-c, elevated AST/ALT and high TG. Conclusion: The variables associated with a diagnosis of NAFLD were HOMA ≥ 2.5 and age ≥ 28 years. NASH was associated with low HDL-c, high TG and AST/ALT ≤ 1.

EVALUATION OF PROGRESSION OF HEPATIC FIBROSIS IN A GROUP OF PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE ACCOMPANIED FOR 10 YEARS.

BACKGROUND: Non-alcoholic fatty liver disease has been progressively diagnosed in the general population as a consequence of the increased prevalence of obesity and type 2 diabetes mellitus, its main risk factors. It is characterized by accumulation of fat in the hepatocytes associated with lobular inflammation and balonization, which can lead to cirrhosis and hepatocarcinoma. Thus, a characterization and follow-up of a progression of the fibrosis level of these patients becomes important, being that the transient hepatic elastography is a reliable method for this evaluation with a measure of the kapa index. OBJECTIVE: To evaluate the progression of hepatic fibrosis through elastography in patients with non-alcoholic fatty liver disease. METHODS: Patients who had previously performed hepatic biopsy and noninvasive scores for non-alcoholic steatohepatitis (NASH) and fibrosis were included in the study. These same subjects were then submitted to current clinical evaluation, laboratory and liver elastography tests, defining the level of liver fibrosis, about 10 years after the first evaluation. RESULTS: Data were analyzed for 66 patients previously submitted to liver biopsy. Of these, 16 were not found, four could not participate because they were debilitated due to hepatic cirrhosis, two had died from an automobile accident and five from complications of cirrhosis of the liver. Therefore, of the 50 patients with a known history, 9 (18%) had died of cirrhosis or were unable to attend the examination because of their liver disease. The remaining population was predominantly female (61.5%), mean age of 63 years, being overweight, dyslipidemia (76.9%), disorders of the glycemic profile (76.9%), and metabolic syndrome (82.1%). Of the 39 cases evaluated, 35% had the same degree of fibrosis at the initial evaluation (biopsy) and at the current evaluation (elastography), 33% had an increase in the degree of fibrosis and another 30% had a decrease in the degree of fibrosis. Twenty-eight patients had NASH at baseline. Regarding these patients, it was observed in the current evaluation, that 25% remained stable in the degree of fibrosis, 39% progressed, and 35% regressed. CONCLUSION: Despite some limitations of our study, such as the small number of patients, and the use of two different methods of evaluation (biopsy and elastography), the data obtained allow us to conclude that of the 39 evaluated cases, 33% (13) presented progression of fibrosis and the total group of 50 patients, 42% had cirrhosis or died due to liver disease. The presence of NASH on hepatic biopsy did not prove to be, in our study, a predictive of the evolution of hepatic fibrosis in the patients.

A avaliação de níveis sérios de infliximabe favorece a manutenção do tratamento em pacientes com doença inflamatória intestinal / The evaluation of infliximab trough level favors maintenance therapy of patients with inflammatory bowel disease

ABSTRACT Background: Crohn's disease (CD) and ulcerative colitis (UC) are chronic diseases that result from the deregulation of the mucosal immune system of the gastrointestinal tract. The use of biological therapies, including infliximab (IFX), is one of the strategies to treat both CD and UC. The IFX treatment is monitored by complementary tests, namely: fecal calprotectin (FC); C-reactive protein (CRP); and endoscopic and cross-sectional imaging. Besides, serum IFX evaluation and antibody detection are also used. Objective: To evaluate trough levels (TL) and antibodies in a population with inflammatory bowel (IBD) disease undergoing treatment with IFX, and the factors that might impact the treatment effectiveness. Methods: Retrospective, cross-sectional study with patients with IBD that were assessed for TL and antibody (ATI) levels in a southern Brazilian hospital, from June 2014 to July 2016. Results: The study assessed 55 patients (52.7% female) submitted to serum IFX and antibody evaluations (95 blood samples, 55 first test; 30 second test, and 10 as third testing. Forty-five (47.3%) cases were diagnosed with CD (81.8%), and ten with UC (18.2%). Serum levels were adequate in 30 samples (31.57%), subtherapeutic in 41 (43.15%), and supratherapeutic in 24 (25.26%). IFX dosages were optimized for 40 patients (42.10%), maintained for 31 (32.63%), and discontinued for 7 (7.60%). The intervals between infusions were shortened in 17.85% of the cases. In 55 tests (55.79%), the therapeutic approach was exclusively defined according to IFX and/or serum antibody levels. The assessment of patients one year later indicated that: the approach was maintained with IFX for thirty-eight patients (69.09%); the class of biological agent was changed for eight (14.54%); changes using the same class of biological agent occurred for two patients (3.63%); the medication was discontinued and not replaced for three patients (5.45%), and four patients (7.27%) were lost to follow-up. Conclusion: There were no differences in TL between groups with or without immunosuppressants, serum albumin (ALB), erythrocyte sedimentation rate (ESR), FC, CRP, and endoscopic and imaging examinations. Current therapeutic approach could be maintained for almost 70% of patients. Thus, serum and antibody levels are a useful tool in the follow-up of patients undergoing maintenance therapy and after treatment induction in patients with inflammatory bowel disease.

RESUMO Contexto: A doença de Crohn e a colite ulcerativa são doenças crônicas nas quais existem desregulação do sistema imune da mucosa do trato gastrointestinal. Uma das terapias usadas no tratamento dessas doenças são as medicações biológicas, entre elas o Infliximabe. A monitorização do tratamento dos pacientes com Iinfliximabe é feita por exames complementares: calprotectina fecal, pesquisa de atividade inflamatória, exames endoscópicos e imagem. Utiliza-se, também a dosagem do nível sérico do Infliximabe e a pesquisa de anticorpos. Objetivo: Analisar uma população com doenças inflamatórias intestinais, em tratamento com Infliximabe, submetida a avaliação do nível sérico do Infliximabe e do anticorpo, além de possíveis fatores que possam alterar ou contribuir no tratamento. Métodos: Trata-se de estudo retrospectivo, transversal, realizado por meio da revisão dos prontuários dos pacientes com doença inflamatória intestinal, em um hospital sul-brasileiro, no período de junho de 2014 até julho de 2016, que foram submetidos a avaliação dos níveis séricos de Infliximabe e do anticorpo. Resultados: Foram incluídos 55 pacientes, submetidos a dosagem do Infliximabe e do anticorpo, totalizando 95 coletas sanguíneas. Destes, 55 realizaram uma primeira coleta, 30 tiveram uma segunda amostra coletada e 10 coletaram uma terceira vez. Vinte e nove pacientes eram do sexo feminino (52,7%) e vinte e seis do sexo masculino (43.2%). Quarenta e cinco (47,3%) casos tinham diagnóstico de doença de Crohn (81,8%) e 10 de colite ulcerativa (18,2%). Em relação ao nível sérico encontrou-se nível adequado em 30 coletas (31,57%), subterapêutico em 41 coletas (43,15%) e supraterapêutico em 24 coletas (25,26%). A prescrição foi otimizada em 40 (42,10%) casos, mantida em 31 (32,63%) pacientes, suspensa em 7 (7,60%) ou que o intervalo entre as infusões fosse aumentado (17,85%). Na análise geral, em 53 coletas (55,79%) a conduta foi definida em função exclusivamente da dosagem sérica do Infliximabe e/ou do anticorpo, já em relação, apenas a primeira coleta obteve-se 33 (60%) pacientes. Avaliando-se os pacientes um ano após, obteve-se: em 38 (69,09%) pacientes a conduta foi mantida com Infliximabe e, em 8 (14,54%) foi optado por troca de classe, em 2 (3,63%) foi optado por troca da medicação na mesma classe, em 3 (5,45%) pacientes a medicação foi suspensa e não foi substituída e, em 4 (7,27%), perdeu-se o seguimento. Conclusão: Não encontrou-se diferença entre os níveis de Infliximabe entre os grupos com ou sem imunossupressor, albumina sérica, velocidade de hemossedimentação, Calprotectina, Proteína C reativa, exames endoscópicos e exames de imagem. A conduta atual pode ser mantida em quase 70% dos pacientes. Concluindo, a dosagem do nível sérico e do anticorpo é ferramenta útil no acompanhamento dos pacientes em terapia de manutenção e após a indução de tratamento em pacientes com Doença Inflamatória Intestinal.

Effectiveness and tolerability of direct-acting antivirals for chronic hepatitis C patients in a Southern state of Brazil.

BACKGROUND: This study aimed to evaluate the clinical effectiveness in terms of sustained virological response and tolerability of available second generation direct-acting antivirals in Brazilian patients. METHODS: This was a retrospective observational study conducted in six centers in Southern Brazil. The sample comprised adult patients who were chronically infected with hepatitis C virus, regardless of virus genotype, fibrosis stage, or prior treatment. Statistical analysis was performed to compare the effectiveness among the treatments, and also to uncover the factors influencing the achievement of sustained virological response. RESULTS: A total of 296 patients were included in the study, with the majority receiving sofosbuvir with daclatasvir (59%) or sofosbuvir with simeprevir (26%). Overall sustained virological response rates were approximately 91.6%. For genotype 1, sofosbuvir with daclatasvir had an sustained virological response rate of approximately 95%, while the sustained virological response rate of sofosbuvir with simeprevir was 92%; this difference was statistically significant only for subtype 1b. The only treatment used for genotype 3 patients was sofosbuvir with daclatasvir, and lower rates of sustained virological response were observed for this group, compared to genotype 1 (84% versus 95%, p<0.05). Apart from this difference between genotypes, and a difference between patients who achieved rapid virologic response compared with those who did not, there were no other statistically significant factors associated with sustained virological response. CONCLUSIONS: The results point to the effectiveness of second-generation direct-acting antivirals in hepatitis C virus Brazilian patients, especially those with genotype 1. Furthermore, that patients with genotype 3 need more attention and adjustments in available treatment options.

Polymorphisms in the IFNAR1 gene in patients with chronic hepatitis C: outcome of combined IFN-alpha therapy.

AIMS: Interferon-alpha (IFN-alpha) alone or in combination with ribavirin has been used for the last decade in the treatment of chronic hepatitis C, although the achievement of a sustained virological response (SVR) has not been very satisfactory. The treatment outcome depends on viral genotypes and host genetic polymorphisms in genes involved in the IFN-alpha signaling cascade. In this paper, we investigated the distribution of two variants of the IFNAR1 gene, G17470C and L168V, in two patient groups having received IFN-alpha alone or in combination with ribavirin. METHODS: The analysis was performed using DNA sequencing of the relevant gene fragments. RESULTS AND CONCLUSIONS: This study suggests that when combination therapy with high dose IFN-alpha and ribavirin is administered, HCV genotypes and age rather than the IFNAR1 polymorphisms are the predictors of a sustained response.

Can FIB4 and NAFLD fibrosis scores help endocrinologists refer patients with non-alcoholic fat liver disease to a hepatologist?

OBJECTIVE: The objective of this study is to evaluate the performance of mathematical models used in non-invasive diagnosis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD) patients to determine when the patient needs to be referred to a hepatologist. SUBJECTS AND METHODS: Patients referred by endocrinologists to the liver outpatient departments in two hospitals in Curitiba, Brazil, over a 72-month period were analyzed. The results calculated using the APRI, FIB 4, FORNS and NAFLD Fibrosis Score non-invasive liver fibrosis assessment models were analyzed and compared with histological staging of this population. RESULTS: Sixty-seven patients with NAFLD were analyzed. Forty-two of them (62.68%) were female, mean age was 54.76 (±9.63) years, mean body mass index 31.42 (±5.64) and 59 (88.05%) of the 67 cases had glucose intolerance or diabetes. A diagnosis of steatohepatitis was made in 45 (76.27%) of the 59 biopsied patients, and advanced liver fibrosis (stages 3 and 4) was diagnosed in 18 (26.86%) of the 67 patients in the study population. The FIB 4 and NAFLD Fibrosis Score models had a high negative predictive value (93.48% and 93.61%, respectively) in patients with severe liver fibrosis (stages 3 and 4). CONCLUSION: In conclusion, use of the FIB 4 and NAFLD Fibrosis Score models in NAFLD patients allows a diagnosis of severe liver disease to be excluded.

Cost-utility analysis of interferon-free treatments for patients with early-stage genotype 1 hepatitis C virus in Brazil

Abstract INTRODUCTION We conducted a cost-utility analysis of available interferon-free treatments for patients with early-stage genotype 1 chronic hepatitis C based on a Brazilian public health system perspective. METHODS A Markov model was derived using a cohort of stage F0-F2 patients treated as recommended by the Brazilian national guidelines. RESULTS: Glecaprevir plus pibrentasvir was superior to all other treatments, followed by sofosbuvir plus velpatasvir. Sofosbuvir plus daclatasvir was identified as the least cost-effective option. CONCLUSIONS: The above findings were confirmed via probabilistic sensitivity analysis and the tested scenarios.

[The sustained response rates for chronic hepatitis C patients undergoing therapy with the several interferons and ribavarins supplied by Brazilians Health Ministry is comparable to those reported in the literature]. / A taxa de resposta sustentada da hepatite C crônica ao tratamento com os diversos interferons-alfa e ribavirinas distribuídos pelo governo brasileiro é semelhante à da literatura mundial.

BACKGROUND: The sustained response rates of chronic hepatitis C therapy to interferons alpha 2A and 2B associated to ribavirin are described as approximately 40%. Nevertheless, studies on the sustained response rates in a setting of frequent changes of type of interferon as well as of supplies of interferons and ribavirin are lacking. AIMS: To evaluate the prevalence of sustained response and to determine the predictors of response to chronic hepatitis C therapy, in a cohort of outpatients at Curitiba, PR, south Brazil, in a setting of heterogeneous therapy regarding type and supply of the medications. POPULATION AND METHODS: A cohort of 87 chronic hepatitis C patients submitted to therapy with interferon alpha 2 and ribavirin were followed from August 1999 to August 2002. The prevalence of sustained response and the influence of gender, age, genotype and severity of liver fibrosis in the response were evaluated. RESULTS: A sustained response prevalence of 32.1% was found, positively associated to genotypes 2 and 3. CONCLUSIONS: Despite the frequent changes on product type and/or procedence, the sustained response prevalence rate found in this study was similar to that described in the literature.

[Outcome of liver transplantation in patients with alcoholic liver disease]. / Resultados do transplante de fígado na doença hepática alcoólica.

BACKGROUND: Liver transplantation is accepted as effective therapeutic option for end-stage liver disease, including alcoholic liver disease AIM: To evaluate the outcome of liver transplantation for alcoholic liver disease in the Liver Transplantation Program at "Hospital de Clínicas" of the Federal University of Paraná, Curitiba, PR, Brazil. PATIENTS AND METHODS: It was performed a retrospective study of the patients who underwent liver transplantation for alcoholic end-stage liver disease between September 1991 and January 2001. The minimum abstinence period required was 6 months before liver transplantation. Identification of alcohol consumption after liver transplantation was determinated by information provided by patient or family and biochemical or histological anormalities. RESULTS: Twenty patients underwent liver transplantation for alcoholic liver disease in the study period, 95% (19/20) were men and the median age was 50 years (29-61 years). Seventy-five percent of the patients (15/20) had severe liver disfunction (Child C class) in the pre-transplant period. In six of them (30%) there was association with viral hepatitis and in one, with hepatocarcinoma. Median abstinence period before liver transplantation was 24 months, varying from 9 to 120 months. One-year and 3-year survival rate were 75% and 50%, respectively. The main complications were: acute cellular rejection (40%), chronic rejection (5%), hepatic artery thrombosis (15%), biliary complications (15%), bacterial or fungal infections (45%), cytomegalovirus infection (20%). Three patients returned to alcohol use after liver transplantation CONCLUSION: The survival of patients who received liver transplant for alcoholic cirrhosis are satisfactory. In the present study there was a small index of alcohol use after liver transplantation.

Avaliação da progressão da fibrose hepática em um grupo de pacientes com doença hepática gordurosa não alcoólica acompanhados por 10 anos / Evaluation of progression of hepatic fibrosis in a group of patients with non-alcoholic fatty liver disease accompanied for 10 years

ABSTRACT BACKGROUND: Non-alcoholic fatty liver disease has been progressively diagnosed in the general population as a consequence of the increased prevalence of obesity and type 2 diabetes mellitus, its main risk factors. It is characterized by accumulation of fat in the hepatocytes associated with lobular inflammation and balonization, which can lead to cirrhosis and hepatocarcinoma. Thus, a characterization and follow-up of a progression of the fibrosis level of these patients becomes important, being that the transient hepatic elastography is a reliable method for this evaluation with a measure of the kapa index. OBJECTIVE: To evaluate the progression of hepatic fibrosis through elastography in patients with non-alcoholic fatty liver disease. METHODS: Patients who had previously performed hepatic biopsy and noninvasive scores for non-alcoholic steatohepatitis (NASH) and fibrosis were included in the study. These same subjects were then submitted to current clinical evaluation, laboratory and liver elastography tests, defining the level of liver fibrosis, about 10 years after the first evaluation. RESULTS: Data were analyzed for 66 patients previously submitted to liver biopsy. Of these, 16 were not found, four could not participate because they were debilitated due to hepatic cirrhosis, two had died from an automobile accident and five from complications of cirrhosis of the liver. Therefore, of the 50 patients with a known history, 9 (18%) had died of cirrhosis or were unable to attend the examination because of their liver disease. The remaining population was predominantly female (61.5%), mean age of 63 years, being overweight, dyslipidemia (76.9%), disorders of the glycemic profile (76.9%), and metabolic syndrome (82.1%). Of the 39 cases evaluated, 35% had the same degree of fibrosis at the initial evaluation (biopsy) and at the current evaluation (elastography), 33% had an increase in the degree of fibrosis and another 30% had a decrease in the degree of fibrosis. Twenty-eight patients had NASH at baseline. Regarding these patients, it was observed in the current evaluation, that 25% remained stable in the degree of fibrosis, 39% progressed, and 35% regressed. CONCLUSION: Despite some limitations of our study, such as the small number of patients, and the use of two different methods of evaluation (biopsy and elastography), the data obtained allow us to conclude that of the 39 evaluated cases, 33% (13) presented progression of fibrosis and the total group of 50 patients, 42% had cirrhosis or died due to liver disease. The presence of NASH on hepatic biopsy did not prove to be, in our study, a predictive of the evolution of hepatic fibrosis in the patients.

RESUMO CONTEXTO: A doença hepática gordurosa não alcoólica vem sendo diagnosticada com frequência progressivamente maior na população geral, como consequência do aumento da prevalência da obesidade e do diabetes mellitus tipo 2, considerados seus principais fatores de risco. Caracteriza-se por acúmulo de gordura nos hepatócitos associada à inflamação lobular e balonização, podendo levar à cirrose e hepatocarcinoma. Desta forma, torna-se importante a caracterização e acompanhamento do nível de fibrose hepática destes pacientes, sendo que a elastografia hepática transitória, tem se mostrado um método confiável para esta avaliação com a medida do índice kapa. OBJETIVO: Avaliar a progressão da fibrose hepática através de elastografia em pacientes com doença hepática gordurosa não alcoólica. MÉTODOS: Foram incluídos no estudo pacientes que haviam realizado anteriormente biópsia hepática e cálculo de escores não invasivos para avaliação de esteato-hepatite não alcoólica (EHNA) e fibrose. Estes mesmos indivíduos foram então submetidos à avaliação clínica, laboratorial e exame de elastografia hepática atuais, definindo o nível de fibrose hepática, cerca de 10 anos após a primeira avaliação. RESULTADOS: Foram analisados dados relativos a 66 pacientes previamente submetidos a biópsia hepática. Destes, 16 não foram localizados, quatro não puderam participar por estarem incapacitados em função de cirrose hepática, dois haviam falecido por acidente automobilístico e cinco, por complicações de cirrose hepática. Portanto, do grupo de 50 pacientes com evolução conhecida, nove (18%) haviam falecido por cirrose ou estavam incapacitados de comparecer ao exame em função de sua doença hepática. A população restante era predominantemente do sexo feminino (61,5%), com idade média de 63 anos, apresentando sobrepeso, dislipidemia (76,9%), distúrbios do metabolismo glicêmico (76,9%) e síndrome metabólica (82,1%). Dos 39 casos avaliados, 35% tiveram o mesmo grau de fibrose na avaliação inicial (biópsia) e na avaliação atual (elastografia), 33% tiveram aumento no grau de fibrose e outros 30% tiveram diminuição no grau de fibrose. Vinte e oito pacientes apresentavam EHNA na avaliação inicial. Em relação a esses pacientes observou-se na avaliação atual que, 25% mantiveram-se estáveis no grau de fibrose, 39% progrediram e, 35% regrediram. CONCLUSÃO: Apesar de algumas limitações do nosso estudo, como o pequeno número de pacientes e o uso de dois métodos diferentes de avaliação (biópsia e elastografia), os dados obtidos nos permitem concluir que dos 39 casos avaliados, 33% apresentaram progressão da fibrose e do grupo total de 50 pacientes, 42% apresentam cirrose ou faleceram em decorrência de doença hepática. A presença de EHNA à biópsia hepática não se mostrou um dado capaz, no nosso estudo, de predizer a evolução da fibrose hepática nos pacientes.