Lipoproteína de alta densidade e hipertensão arterial sistêmica estão associados à atividade necroinflamatória hepática em pacientes com hepatite C crônica / High-density lipoprotein cholesterol and systemic arterial hypertension are associated with hepatic necroinflammatory activity in patients with chronic hepatitis c

ABSTRACT Background: Approximately 71 million people are chronically infected with hepatitis C virus (HCV) worldwide. A significant number of these individuals will develop liver cirrhosis and/or hepatocellular carcinoma. Beyond the liver, there is a sizeable body of scientific evidence linking cardiovascular disease and chronic hepatitis C (CHC); however, the biological mechanisms behind the concurrence of these conditions have not been completely clarified yet. Objective: To evaluate associations between hepatic histology, clinical comorbidities and lipid profile in patients with CHC. To investigate associations between liver histology and demographic, nutritional, biochemical and virological parameters. Methods: Eight-five patients with CHC prospectively underwent hepatic biopsy. Liver fragments were obtained from each patient by percutaneous route using a Menghini needle. Fibrosis was evaluated according to the METAVIR scoring system, as follows: F0, no fibrosis; F1, fibrous portal expansion; F2, fibrous portal widening with few septa; F3, bridging fibrosis with architectural distortion; and F4, liver cirrhosis. The activity was classified based on the degree of lymphocyte infiltration and hepatocyte necrosis, from A0 to A3. The diagnosis of liver disease was based on clinical, biochemical, histological, and radiological methods. The data were analyzed by logistic regression models. Results: This cross-sectional study included 85 outpatients followed at the tertiary care ambulatory centre with a mean age of 57.2±10.7 years and 45 (52.9%) were females. There were 10 patients with cirrhosis. Patients with a METAVIR F3-F4 were significantly older (P=0.02) and had higher levels of ALT (P=0.0006), AST (P<0.0001), γ-GT (P=0.03) and bilirubin (P=0.001) and higher prothrombin time than patients with F0-F2 score. Albumin levels (P=0.01) were significantly lower in METAVIR F3-F4. Age (OR=1.09; 95%CI=1.02-1.16; P=0.02), steatosis (OR=4.03; 95%CI=1.05-15.45; P=0.04) and high-density lipoprotein cholesterol (HDL-C) <60 mg/dL (OR=7.67; 95%CI=1.71-34.49; P=0.008) were independently associated with fibrosis. Hypertension (OR=6.36; 95%CI=1.31-30.85; P=0.02) and HDL-C <60 mg/dL (OR=9.85; 95%CI=2.35-41.39; P=0.002) were independently associated with necroinflammatory activity. Hypertension (OR=6.94; 95%CI=1.92-25.05; P=0.003) and HDL-C <60 mg/dL (OR=3.94; 95%CI=1.27-12.3; P=0.02) were associated with interface inflammatory activity. Triglycerides (TG ≥150 mg/dL) remained associated with lobular inflammatory activity. Conclusion: cholesterol levels <60 mg/dL were independently associated with necroinflammatory activity in chronic hepatitis C. Patients with hypertension are at an increased risk of developing necroinflammatory activity.

RESUMO Contexto: Aproximadamente 71 milhões de pessoas estão infectadas pelo vírus da hepatite C em todo o mundo. Um número significativo desses indivíduos desenvolverá cirrose hepática e/ou carcinoma hepatocelular. Além do fígado, há evidências científicas que associam doenças cardiovasculares e hepatite C crônica; no entanto, os mecanismos biológicos implicados na ocorrência dessas condições ainda não foram completamente esclarecidos. Objetivo: Avaliar a associação entre histologia hepática, comorbidades clínicas e perfil lipídico em pacientes com hepatite C crônica. Investigar associações entre histologia hepática e parâmetros demográficos, nutricionais, bioquímicos e virológicos. Métodos: Oitenta e cinco pacientes com hepatite C crônica foram prospectivamente submetidos à biópsia hepática. Biópsias hepáticas foram obtidas de cada paciente por via percutânea com agulha de Menghini. A fibrose foi avaliada de acordo com o sistema de pontuação METAVIR, como segue: F0, sem fibrose; F1, expansão portal fibrosa; F2, alargamento portal fibroso com poucos septos; F3, fibrose em ponte com distorção arquitetônica; e F4, cirrose hepática. A atividade foi classificada com base no grau de infiltração de linfócitos e necrose de hepatócitos, de A0 a A3. O diagnóstico da doença hepática foi baseado em métodos clínicos, bioquímicos, histológicos e radiológicos. Os dados foram analisados por modelos de regressão logística. Resultados: Neste estudo transversal, realizado em um ambulatório do hospital universitário, foram incluídos 85 pacientes que tinham média de idade de 57,2±10,7 anos, sendo 45 (52,9%) do sexo feminino. Havia 10 pacientes com cirrose. Os pacientes com METAVIR F3-F4 eram significativamente mais velhos (P=0,02) e tinham níveis mais elevados de ALT (P=0,0006), AST (P<0,0001), γ-GT (P=0,03) e bilirrubina (P=0,001) e, maior tempo de protrombina do que pacientes com escore F0-F2. Os níveis de albumina (P=0,01) foram significativamente mais baixos naqueles classificados como METAVIR F3-F4. Idade (OR=1,09; IC95%=1,02-1,16; P=0,02), esteatose (OR=4,03; IC95%=1,05-15,45; P=0,04) e HDL-C <60 mg/dL (OR=7,67; 95%IC=1,71-34,49; P=0,008) foram independentemente associados à fibrose. Hipertensão (OR=6,36; IC95%=1,31-30,85; P=0,02) e HDL-C <60 mg/dL (OR=9,85; IC95%=2,35-41,39; P=0,002) foram independentemente associados à atividade necroinflamatória. Hipertensão (OR=6,94; IC 95%=1,92-25,05; P=0,003) e HDL-C <60 mg/dL (OR=3,94; IC95%=1,27-12,3; P=0,02) foram associados à atividade inflamatória de interface. Os triglicerídeos (TG >150 mg/dL) permaneceram associados à atividade inflamatória lobular. Conclusão: Níveis de coleterol HDL <60 mg/dL foram independentemente associados à atividade necroinflamatória na hepatite C crônica. Pacientes com hipertensão têm risco aumentado de desenvolver atividade necroinflamatória.

Diagnostic value of novel hepatic fibrosis markers in assessing cirrhosis in patients with chronic hepatitis C / 中华肝脏病杂志

Objective: To investigate the efficacy of chitinase-3-like protein 1 (CHI3L1) and Golgi protein 73 (GP73) in the diagnosis of cirrhosis and the dynamic changes of CHI3L1 and GP73 after HCV clearance in patients with chronic hepatitis C (CHC) treated with direct-acting antiviral drugs (DAAs). The comparison of continuous variables of normal distribution were statistically analyzed by ANOVA and t-test. The comparison of continuous variables of non-normal distribution were statistically analyzed by rank sum test. The categorical variables were statistically analyzed by Fisher's exact test and χ(2) test. Correlation analysis was performed using Spearman correlation analysis. Methods: Data of 105 patients with CHC diagnosed from January 2017 to December 2019 were collected. The receiver operating characteristic curve (ROC curve) was plotted to study the efficacy of serum CHI3L1 and GP73 for the diagnosis of cirrhosis. Friedman test was used to compare CHI3L1 and GP73 change characteristics. Results: The areas under the ROC curve for CHI3L1 and GP73 in the diagnosis of cirrhosis at baseline were 0.939 and 0.839, respectively. Serum levels of CHI3L1 and GP73 in the DAAs group decreased significantly at the end of treatment compared with baseline [123.79 (60.25, 178.80) ng/ml vs. 118.20 (47.68, 151.36) ng/ml, P = 0.001; 105.73 (85.05, 130.69) ng/ml vs. 95.52 (69.52, 118.97) ng/ml, P = 0.001]. Serum CHI3L1 and GP73 in the pegylated interferon combined with ribavirin (PR) group were significantly lower at the end of 24 weeks of treatment than the baseline [89.15 (39.15, 149.74) ng/ml vs. 69.98 (20.52, 71.96) ng/ml, P < 0.05; 85.07 (60.07, 121) ng/ml vs. 54.17 (29.17, 78.65) ng/ml, P < 0.05]. Conclusion: CHI3L1 and GP73 are sensitive serological markers that can be used to monitor the fibrosis prognosis in CHC patients during treatment and after obtaining a sustained virological response. Serum CHI3L1 and GP73 levels in the DAAs group decreased earlier than those in the PR group, and the serum CHI3L1 levels in the untreated group increased compared with the baseline at about two years of follow-up.

Prevalence of chronic hepatitis C and liver function impairment in Taixi Region in 2018 - 2021 / 公共卫生与预防医学

Objective To analyze the prevalence trend of chronic hepatitis C and liver function impairment in Taixi area from 2018 to 2021, and to provide theoretical basis for preventing liver function impairment in hepatitis C patients in Taixi area. Methods The data of hepatitis C cases reported in Taixi were downloaded from the infectious disease reporting Information management system of Chinese Center for Disease Control and Prevention, and the epidemiological characteristics of hepatitis C were analyzed by descriptive epidemiological methods. The clinical data including gender, age, place of residence, smoking history, drinking history, therapeutic drugs, genotyping and other clinical data were collected from HIS system of the hospital. Patients were divided into liver function injury group and control group according to whether they had liver function injury. Univariate analysis and logistic regression were used to analyze the factors of liver function injury in hepatitis C patients in Taixi area. Results Among the 550 cases reported from 2018 to 2021, there were no deaths, including 292 males and 258 females. The male cases were more than the female cases, and the average age was (53.47±5.74) years old. There was no significant difference in the composition of male and female cases among different age groups (χ2=1.472,P>0.05). From 2018 to 2021, the proportion of patients aged 40 to 59 was significantly higher than that of patients aged 20 to 39 and ≥60. The occupation composition was mainly farmers, accounting for 44.36% (244/550), and 287 cases (52.18%) lived mainly in rural areas. From 2018 to 2021, 129 (23.45%) of 550 patients with hepatitis C had liver function injury. ALT, AST and GGT values in the liver function injury group were significantly higher than those in the control group (P5%, genotype 1b and high load of HCV-RNA were independent risk factors for liver function impairment in hepatitis C patients in Taixi area (P<0.05). Conclusion The incidence of hepatitis C was high in Taixi area from 2018 to 2021, and patients with CD4+CD25+Treg<5%, genotype 1b and high load of HCV-RNA had a high risk of liver function impairment. Therefore, active treatment should be carried out to reduce the occurrence of liver function injury.

C-reactive protein to lymphocyte count ratio is a promising novel marker in hepatitis C infection: the clear hep-c study

SUMMARY OBJECTIVE: Chronic hepatitis C (CHC) is one of the most important health problems affecting the significant rate of world population and it may lead to cirrhosis and hepatocellular carcinoma. C-reactive protein to lymphocyte count ratio (CLR) is used in estimating inflammatory burden. Therefore, this study aimed to compare CLR values between CHC patients and healthy controls and between CHC patients with and without fibrosis. METHODS: Patients with CHC infection who visited outpatient and inpatient internal medicine clinics of our institution between January 2021 and December 2021 were enrolled to this retrospective study. CLR of the patients with CHC and healthy controls were compared. We further compared CLR of CHC patients with and without fibrosis. RESULTS: Median CLR of CHC and control subjects was 2.61 (5.13%) and 0.31 (0.37%), respectively. CLR of the CHC group was significantly increased compared to the CLR of the controls (p<0.001). There was a significant positive correlation between CLR and APRI score (r=0.15, p=0.04). The sensitivity and specificity of CLR in determining CHC above 0.58% level were 84% and 82%, respectively (AUC: 0.884, p<0.001, 95%CI 0.84-0.93). In subgroup analysis, CLR was 3.97 (6.6%) for CHC patients with fibrosis and 1.7 (4.4%) for CHC subjects without fibrosis (p=0.001). CONCLUSION: Increased CLR in patients with CHC may be an alarming finding of liver fibrosis, as CLR is associated with both CHC and hepatic fibrosis.

A rare case report of acute acalculous cholecystitis in active chronic hepatitis C virus infection

Acute acalculous cholecystitis (AAC) is an inflammation of gallbladder with absence of gall stones or bile sludge. Daily cases reported about 90-95% of the acute cholecystitis present with gall stone, while only 5-15% occur without gall stones obstruction.AAC is reported associated with Epstein bar virus infection, hepatitis B virus and hepatitis A virus. Hepatitis C-induced AAC cases still rare. This case report presents a 49-years-old female patient with epigastric pain, nausea, yellowish sclera, tea urine color, pale stool and there was a history of the patient's husband with hepatitis C. On physical examination there was epigastric and right hypochondriac pain, and positive murphy sign. There was leukocytosis, hyperbilirubinemia and an increase in SGPT (1.360 U/L) and SGOT (1.720 U/L). Antibodies to HCV were positive. Abdominal ultrasonography showed cholecystitis with no biliary duct dilatation and no parenchymal liver disease appearance The patient was diagnosed with acute chronic hepatitis C and cholecystitis. Pathophysiology of hepatitis C induced AAC is not fully understood, but is thought to be due to complexes immune, directly infect gallbladder and proximal biliary epithelial cells uncontrolled, increased portal/septal myofibroblasts activity and inflammation. The presence of AAC with an increase in serum levels of SGOT and SGPT 5-10 times the normal limit should be suspected due to acute hepatitis viral infection. Further research still needs to be done to determine the relationship between hepatitis C and the incidence of AAC.

Efficacy and safety of using DAAs to treatment the special populations with chronic hepatitis C / 中国热带医学

@#Abstract:Chronic hepatitis C (CHC) is a global health problem, which is prevalent all over the world. China is a low epidemic area. Hepatitis C virus (HCV) is mainly transmitted through blood, and nowadays, intravenous drug addicts are the key population for the prevention and treatment of hepatitis C. HCV has multiple genotypes and gene subtypes, and the distribution of these genotypes and gene subtypes varies significantly among the regions of the world. Nowadays, the treatment of hepatitis C has entered the era of direct-acting antiviral agents, which have high efficacy and safety in the general population. However, when special populations use direct-acting antiviral agents to treatment hepatitis C, we don't know how its efficacy and safety will be. The special populations include children, adolescents, drug users, HCV/HBV co-infected patients, HCV/HIV co-infected patients, and patients who have comorbidity of HCV and chronic kidney disease. This review will discuss the efficacy and safety of using direct-acting antiviral agents to treat hepatitis C in these special populations.

Changes of serum uric acid levels in patients with chronic hepatitis C after using direct antiviral agents therapy / 中华肝脏病杂志

Objective: To observe the changes of serum uric acid levels and clinical characteristic in patients with chronic hepatitis C combined with hyperuricemia after direct antiviral agents (DAA) therapy. Methods: A prospective cohort study was used to investigate the risk of hyperuricemia in patients with chronic hepatitis C who received DAA treatment to obtain sustained virological response. The changes and factors influencing serum uric acid levels after 12 weeks of DAA treatment were observed. Comparisons between groups were performed using χ (2) test or Fisher's exact test, analysis of variance, Student's t test, or the non-parametric Mann-Whitney U test. Serum uric acid (SUA) changes, liver and kidney function indexes before and after treatment were compared by repeated measurement and paired t-test. Uric acid reduction was defined as a decrease in SUA from baseline at 12 weeks after treatment. Rates of change in eGFR, aspartate aminotransferase/platelet ratio, alanine aminotransferase and controlled attenuation parameter were defined from baseline (baseline to 12 weeks after treatment). Binary logistic regression analysis was used to compare the risk factors and factors influencing high and low uric acid level. Results: 161 cases with chronic hepatitis C who received DAA treatment were included, of which 19.3% patients were hyperuricemic. eGFR < 60 ml/(min·1.73 m(2)) and body mass index were independent risk factors for hyperuricemia in patients with chronic hepatitis C (eGFR: OR = 0.123, P = 0.002; body mass index: OR = 1.220, P = 0.002). SUA levels was changed significantly before treatment, at the end of treatment and at 12 weeks after treatment (327.96 vs. 320.76 vs. 314.92, F = 3.272, P = 0.042). At 12 weeks after treatment, SUA, liver stiffness, alanine aminotransferase and control attenuation parameters were all significantly lower than baseline (P < 0.05). The rate of increase in eGFR from baseline and the rate of decrease in controlled attenuation parameter during treatment were the factors influencing SUA reduction (eGFR: OR = 5124, P = 0.000; controlled attenuation index: OR = 0.010, P = 0.039). Conclusion: In chronic hepatitis C, reduced eGFR and body mass index are the risk factors for the development of hyperuricemia and a significant reduction in serum uric acid levels after DAA treatment can eradicate the virus.

Diabetes influences liver stiffness in chronic hepatitis C patients with and without virological cure: A longitudinal study

OBJECTIVES: The aim was to prospectively assess the variation in liver stiffness (LS) and the associated factors for LS progression in a cohort of naïve, non-responder (NR), and sustained virological response (SVR) chronic hepatitis C (CHC) patients. METHODS: This was a longitudinal study on CHC patients prospectively followed with serial elastography (Fibroscan®). The LS progression rate was determined, and the associated factors for progression were assessed using multiple linear regression analysis. RESULTS: A total of 406 patients were followed up for 44 (35-53) months [naïve (29%), NR (24%), and SVR (47%)]. At the end of the follow-up period, the SVR group had a significant decrease in LS [11.8 (9.2) vs. 8.8 (8.4) kPa (p<0.001)], the NR group had a significant increase in LS [6.6 (5.2) vs. 7.1 (4.5) kPa (p=0.069)], and the naïve group had no change in LS [6.3 (3.0) vs. 6.0 (3.8) kPa (p=0.22)]. The related factors for LS progression were lack of SVR (p=0.002) and diabetes (p=0.05). In the non-diabetic SVR group, a negative rate of progression (-0.047 kPa/month) was observed, whereas in the diabetic SVR group, a positive rate of progression (+0.037 kPa/month) was observed. The highest rate of progression was observed in NR with diabetes at the rate of +0.044 kPa/month. CONCLUSION: LS in diabetes patients progresses despite SVR, suggesting the need for a close follow-up of this group post-treatment considering the risk of progression of liver disease even after SVR.

Relationship between genotyping and liver related indexes of patients with chronic hepatitis C in Aksu, Xinjiang / 公共卫生与预防医学

Objective Though HCV genotyping , liver ultrasound and liver function indicators were used to assess the relationship between HCV genotyping, viral RNA copy number and liver damage related indicators in patients with chronic hepatitis C. Methods A total of 105 Uyghur hepatitis C patients in Aksu, Xinjiang were recruited in our hospital. All patients were carried out a test of HCV RNA copy number. HCV genotyping was performed by fluorescence quantitative PCR method. Fully automatic biochemical analyzer was used for alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DIBL) and total bilirubin (TIBL) by commercial kits. Color doppler ultrasound system was used for liver ultrasound. Results The genotyping results of 105 Uyghur hepatitis C patients showed that type 1b, 2a, 3a, 3b and 6a were 46, 41, 8, 8 and 2, respectively. Type 1b was the main type of HCV virus. The proportion of RNA copy number, AST and ALT levels, and liver cirrhosis were higher in patients with type 1b. Statistical analysis showed that there was a significant correlation between different HCV virus types and HCV RNA copy number (P = 0.032). In terms of AST and ALT levels, there were significant differences between type 1b, type 2a and other genotypes (type 3b and type 3a and type 6a) (P < 0.01). In addition, patients with normal liver, enlarged liver spots, fatty liver and cirrhosis have significant differences among type 1b, type 2a and other genotypes (P < 0.01). Conclusion There are regional differences in HCV genotyping among Uygur people in Aksu, Xinjiang. HCV RNA copy number and degree of liver damage are correlated with different HCV genotypes, which is of great significance to guide the clinical diagnosis and treatment of HCV in local populations.

Meta-analysis of Efficacy and Sa fety of 5 Direct Antiviral Agents in the Treatment of Chronic Hepatitis C Infection / 中国药房

OBJECTIVE：To com pare the efficacy and safety of 5 direct antiviral agents in the treatment of chronic hepatitis C infection as glecaprevir （GLE）/pibrentasvir（PIB），ledipasvir（LDV）/sofosbuvir（SOF），SOF/velpatasvir（VEL），elbasvir（EBR）/ grazoprevir（GZR）compound preparation and danoprevir （DNV）+ peginterferon combined with ribavirin （P/R）. METHODS ： Retrieved from PubMed ，Embase，Cochrane Library ，Web of Science ，CNKI，VIP，Wanfang database and other databases ，RCTs about 5 direct antiviral agents in the treatment of chronic hepatitis C infection were collected during the inception to Jun. 2020. After literature screening and data extraction ，the quality of included literatures were evaluated with bias risk evaluation tool recommended by Cochrane system evaluator manual 5.1.0. Meta-analysis was performed by using Stata 15.0 software. RESULTS ： A total of 48 RCTs with 12 227 patients in trial group were included. Results of Meta-analysis showed that the descending order of sustained virological response （SVR）rate was GLE/PIB ＞LDV/SOF＞SOF/VEL＞EBR/GZR＞DNV+P/R；weighted SVR rates of GLE/PIB，LDV/SOF，SOF/VEL and EBR/GZ were more than 95％. The incidence of any severe adverse event and adverse event in ascending order was EBR/GZR ＜GLE/PIB＜SOF/VEL＜LDV/SOF＜DNV+P/R. The incidence of nausea/vomiting in ascending order was GLE/PIB ＜LDV/SOF＜EBR/GZR＜SOF/VEL＜DNV+P/R. The incidence of rash in ascending order was LDV/SOF ＜ GLE/PIB＜SOF/VEL＜EBR/GZR＜DNV + P/R. The incidence of insomnia from low to high was GLE/PIB ＜EBR/GZR＜SOF/ VEL＜LDV/SOF＜DNV+P/R. CONCLUSIONS ：GLE/PIB，LDV/SOF，SOF/VEL and EBR/GZR have higher and similar effective rates in the treatment of chronic hepatitis C ，especially the weighted SVR rate of GLE/PIB is the best ，and the safety of EBR/GZR and GLE/PIB is relatively better.

Cost-utility Analysis of the Pan-genotypic Direct-acting Antivirals in the Treatment of Chronic Hepatitis C Infection / 中国药房

OBJECTIVE：To evaluate the cost-utility of the pan-genotypic direct-acting antivirals （DAAs）in the treatment of patients with chronic hepatitis C infection ，and to provide pharmacoeconomic evidence for relevant health care decisions. METHODS：A Markov model was established from a societal perspective with newly diagnosed chronic hepatitis C patients in China as the target population ，and analyzed quality-adjusted life years （QALYs）and incremental cost-utility ratios （ICERs）of patients with chronic hepatitis C with sofosbuvir/velpatasvir ，glecaprevir/pibrentasvir，sofosbuvir+coblopasvir. Sensitivity analysis was used to verity the robustness of the results. RESULTS ：Glecaprevir/pibrentasvir increased QALYs by 0.002 1 and costs by 25 021 RMB，compared to sofosbuvir/velpatasvir ；its ICERs was 12 129 031 yuan/QALY（willingness to pay threshold was 70 892 yuan/QALY），which had no cost-utility ；glecaprevir/pibrentasvir need to cut down the price by 64.65％ to have cost-utility. Sofosbuvir+coblopasvir increased QALYs by 0.002 0 and saved costs by 515 yuan，so it was the optimal regimen which was cost-saving. Sensitivity analysis showed that SVR rates and drug prices were the most influential factors. The probability of having cost-utility for sofosbuvir+coblopasvir was higher than glecaprevir/pibrentasvir. CONCLUSIONS ：Glecaprevir/pibrentasvir need to reduce the price to achieve better affordability. Sofosbuvir+coblopasvir shows economical advantage.

Relationship of serum vitamin D with hepatic fibrosis in patients with chronic hepatitis C

Background: Serum vitamin D concentration is proposed to have an important role on outcome in patients with chronic hepatitis C virus (HCV) infection. A few studies have shown an inverse association of vitamin D level with stage of fibrosis. The aim of the present study was to verify whether serum vitamin D level is an independent predictor of significant hepatic fibrosis.Methods: Seventy-two treatment naive chronic HCV subjects and 40 healthy age and sex matched controls were included in the study. A serum vitamin D level was assessed in both HCV subjects and controls, and liver biopsy was performed in all HCV subjects to assess for stage of fibrosis.Results: Serum vitamin D levels were significantly lower HCV patients in comparison to age and sex matched controls (18.04±6.92 versus 21.53±8.2, p<0.01). Most common genotype in HCV patients was genotype 3 (62.5%) and blood transfusion was the most common mode of transmission (28%) followed by intravenous drug user (IVDU) (17%). The HCV patients with vitamin D level <20 ng/ml had higher metavir score as compared to vitamin D≥20 ng/ml (1.67±0.66 versus 2.5±0.67, p<0.001). Both univariate and multivariate analysis performed using logistic regression revealed that vitamin D<20 ng/dl is a significant negative predictor of liver fibrosis (p<0.05).Conclusions: Chronic HCV patients had significantly lower vitamin D levels as compared to healthy controls. Serum vitamin D was a negative predictor of stage of fibrosis in patients with chronic hepatitis C.

Tratamento da hepatite C em pacientes com doença renal crônica e pós-tranplante renal: eficácia e segurança dos esquemas de antivirais de ação direta contendo sofosbuvir / Hepatitis c treatment of renal transplant and chronic kidney disease patients: efficacy and safety of direct-acting antiviral regimens containing sofosbuvir

ABSTRACT BACKGROUND: Direct-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min. OBJECTIVE: To evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients. METHODS: All patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively. CONCLUSION: The direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.

RESUMO CONTEXTO: Os antivirais de ação direta revolucionaram o tratamento da hepatite C, inclusive para os pacientes com doença renal crônica (DRC), porém ainda há divergências no emprego do sofosbuvir (SOF) quando taxa de filtração glomerular (TFG) <30 mL/min. OBJETIVO: Avaliar a eficácia e segurança desses esquemas no tratamento da hepatite C em pacientes com DRC e pós-transplante renal, além de avaliar o impacto do SOF sobre a função renal dos não-dialíticos. MÉTODOS: Todos os pacientes com hepatite C e DRC ou transplante renal que realizaram tratamento com antivirais de ação direta em centro referenciado do Brasil no período de janeiro/2016 a agosto/2017 foram incluídos. A eficácia foi avaliada por meio da carga viral (HCV-RNA), considerando-se cura uma resposta virológica sustentada (RVS) com resultado indetectável após 12 e/ou 24 semanas do término do tratamento (RVS12 e RVS24). A segurança foi determinada pelos eventos adversos e a ribavirina, quando associada, foi introduzida de forma escalonada em todos os pacientes com TFG <60 mL/min. Para determinação do impacto do SOF sobre a função renal, foram observadas as dosagens de creatinina basal, durante e após término do tratamento com seu incremento avaliado por meio da classificação de AKIN (acute kidney injury network). RESULTADOS: Foram incluídos 241 pacientes, sendo 52,7% do sexo feminino, com média de idade de 60,72±10,47 anos. A associação de SOF+daclatasvir predominou em 75,6% dos casos e anemia esteve presente em 28% dos pacientes que utilizaram ribavirina (P=0,040). As taxas de RVS12 e RVS24 foram de 99,3% e 97,1%. O tratamento foi bem tolerado, com eventos adversos pouco relevantes, sendo os mais prevalentes: astenia (57,7%), prurido (41,1%), cefaleia (40,7%) e irritabilidade (40,2%). Entre os pacientes em tratamento conservador e transplantados renais, os valores de creatinina sofreram oscilações AKIN I em 12,5% dos casos, durante o tratamento, persistindo em apenas 8,5% da amostra após o término, dos quais 2,0% apresentavam TFG <30 mL/min inicialmente, com queda para 1,1% após uso do SOF. Apenas 0,5% e 1,6% evoluíram com elevação AKIN II e AKIN III. CONCLUSÃO: Os antivirais de ação direta foram seguros e eficazes em pacientes com DRC tratados com esquemas contendo SOF, apresentando altas taxas de RVS, boa tolerabilidade e poucos eventos adversos graves. A associação com ribavirina aumentou o risco de anemia, portanto sua introdução de forma escalonada parece ser útil nos pacientes com TFG <60 mL/min. Em pacientes com TFG <30 mL/min o SOF não apresentou impacto renal significativo, com creatinina sérica retornando a valores próximos ao basal após o tratamento.

Clinical outcomes of patients with chronic hepatitis C after generic direct-acting antiviral treatments in Vietnam: A retrospective analysis

Objective: To evaluate the outcomes of generic direct-acting antiviral treatments for chronic hepatitis C in Vietnam. Methods: The medical records of 522 patients (median 45 years; Female, 25.3%) with chronic hepatitis C treated at a tertiary hospital in northern Vietnam in 2016 were retrospectively reviewed. Results: Female patients were significantly older than male patients (median 52, IQR 41-59 vs. 43 years, IQR: 39-55; P<0.001). Among 522 patients, 49.4% were infected with hepatitis C virus (HCV) genotype 6, followed by 1a (19.0%), 1b (13.0%), and 3 (5.9%). Coinfection with hepatitis B virus or human immunodeficiency virus was noted in 5.8% and 3.1% of patients, respectively. Patients were treated with ledipasvir/sofosbuvir with or without ribavirin (70.9%), sofosbuvir/pegylated-interferon + ribavirin (13.2%), daclatasvir/ sofosbuvir with or without ribavirin (12.5%), or sofosbuvir/ribavirin (3.4%), and 96.4% (n=503) completed the direct-acting antiviral treatment. No patient discontinued treatment due to adverse event(s). A sustained virologic response 12 weeks after the end of the treatment (SVR12) was evaluated in 62.6% of patients. Overall sustained virologic response 12 weeks after the end of the treatment was 98.7% regardless of HCV genotypes or direct-acting antiviral regimens. The severity of liver stiffness was significantly decreased from 10.2 to 6.3 kilopascals measured by transient elastography by the treatment (P<0.001). Among patients who completed the directacting antiviral treatment, 17.7% returned for further follow-ups after SVR12. Conclusions: In Vietnam, the current generic direct-acting antiviral treatment for chronic hepatitis C was effective regardless of HCV genotypes and direct-acting antiviral regimens with the attenuation of liver stiffness. It is feasible to implement direct-acting antiviral treatment to cure chronic hepatitis C patients at any liver fibrosis stages in Vietnam.

Enfermedades hepáticas y su relación con hiperglicemia / The relationship between liver diseases and hyperglycemia

La Diabetes Mellitus tipo 2 (DM2) y las enfermedades crónicas del hígado(ECH), definida para esta revisión como cualquier alteración funcional o estructural de este órgano, desde inflamación hasta fibrosis, son patologías que frecuentemente se asocian, y su coexistencia se relaciona con peor pronóstico y mayores complicaciones de ambas entidades. El objetivo de este artículo es describir la relación entre hiperglicemia y enfermedades del hígado, sus procesos fisiopatológicos comunes y tratamiento, distinguiendo las patologías más relevantes, entre ellas la Diabetes Hepatogénica (DH), la enfermedad hepática por Virus Hepatitis C (VHC) y la Enfermedad Hepática Grasa No Alcohólica (EHGNA). La DH es aquella diagnosticada en pacientes con cirrosis asociada a insuficiencia hepática, sin antecedentes previos de alteración de la glicemia. En la actualidad el diagnóstico se realiza en etapas tardías de la enfermedad. El VHC tiene un efecto diabetogénico conocido. Algunas terapias antivirales usadas para VHC evidencian mejoría de las alteraciones metabólicas al lograr respuestas virológicas sostenidas. En DM2, la EHGNA es frecuente, con mayor incidencia de fibrosis, hepatocarcinoma (HCC) y riesgo cardiovascular (RCV). Es necesario realizar una pesquisa e intervención precoz de EHGNA a los pacientes con DM2. En el manejo de éstos, la baja de peso ha demostrado ser efectiva en el control glicémico y en la mejoría histológica. Dentro de las terapias antidiabéticas, además del uso de metformina, debería considerarse aquellas que han demostrado a la fecha beneficios en EHGNA, como son tiazolidinedionas (pioglitazona) y/o análogos de GLP-1 (liraglutide) y optimizar el control de otros factores de RCV.

Type 2 Diabetes Mellitus (DM2) and chronic liver diseases (CLD) defined in this revision as any functional or structural alteration in the organ, covering from inflammation to fibrosis, are pathologies that are frequently associated, and when found together are related to worse prognosis and higher complications in both conditions. The objective of this article is to describe the relationship between hyperglycemia and liver diseases, their common physio-pathological processes and treatments, identifying the most important pathologies, including Hepatogenic Diabetes (HD), Hepatitis C Virus (HCV) liver disease and Non-Alcoholic Fatty Liver Disease (NAFLD). Hepatogenic diabetes (HD) is diagnosed in patients with liver failure associated to cirrhosis with no previous record of impaired glycemia. Currently, diagnosis is made during the late stages of the disease. Hepatitis C virus (HCV) has a known diabetogenic effect. Some antiviral therapies used for HCV show improvement in metabolic alterations by achieving sustained virological responses. Non-alcoholic fatty liver disease (NAFLD) in DM2 patients is common, presenting higher risk for fibrosis, hepatocellular carcinoma (HCC) and increased cardiovascular risk (CVR). Early screening and interventions for NAFLD in DM patients are necessary. Weight loss has been shown to be effective in glycemic control and histological improvement. Anti-diabetic therapies, in addition to the use of metformin, should consider therapies that have shown benefits for managing NAFLD, such as thiazolidinedione (pioglitazones) and/or aGLP-1 (Liraglutide), and optimally controlling other cardiovascular risk (CVR) factors.

Efficacy and safety of glecaprevir and pibrentasvir combination therapy in old-aged patients with chronic hepatitis C virus infection / Journal of Rural Medicine

Objective: Combination therapy with glecaprevir and pibrentasvir (G/P) has been shown to provide a sustained virologic response (SVR) rate of >97% in patients with chronic hepatitis C virus (HCV) infection in the first published real-world Japanese data. However, a recently published study showed that the treatment was often discontinued in patients ≥75 years old, resulting in low SVR in intention-to-treat (ITT) analysis. Thus, our aim was to evaluate real-world data for G/P therapy in patients ≥75 years of age, the population density of which is high in “rural” regions.Patients and Methods: We conducted a multicenter study to assess the efficacy and safety of G/P therapy for chronic HCV infection, in the North Kanto area in Japan.Results: Of the 308 patients enrolled, 294 (95.5%) completed the treatment according to the protocol. In ITT and per-protocol analyses, the overall SVR12 rate was 97.1% and 99.7%, respectively. The old-aged patients group consisted of 59 participants, 56 of whom (94.9%) completed the scheduled protocol. Although old-aged patients tended to have non-SVR factors such as liver cirrhosis, history of HCC, and prior DAA therapies, the SVR12 rates in old-aged patients were 98.3% and 100% in the ITT and PP analyses, respectively. Of 308 patients enrolled, adverse events were observed in 74 patients (24.0%), with grade ≥3 events in 8 patients (2.6%). There was no significant difference in any grade and grade ≥3 adverse events between the old-aged group and the rest of the study participants. Only one patient discontinued the treatment because of adverse events.Conclusion: G/P therapy is effective and safe for old-aged patients.

Clinical outcomes of patients with chronic hepatitis C after generic direct-acting antiviral treatments in Vietnam: A retrospective analysis

Objective: To evaluate the outcomes of generic direct-acting antiviral treatments for chronic hepatitis C in Vietnam. Methods: The medical records of 522 patients (median 45 years; Female, 25.3%) with chronic hepatitis C treated at a tertiary hospital in northern Vietnam in 2016 were retrospectively reviewed. Results: Female patients were significantly older than male patients (median 52, IQR 41-59 vs. 43 years, IQR: 39-55; P<0.001). Among 522 patients, 49.4% were infected with hepatitis C virus (HCV) genotype 6, followed by 1a (19.0%), 1b (13.0%), and 3 (5.9%). Coinfection with hepatitis B virus or human immunodeficiency virus was noted in 5.8% and 3.1% of patients, respectively. Patients were treated with ledipasvir/sofosbuvir with or without ribavirin (70.9%), sofosbuvir/pegylated-interferon + ribavirin (13.2%), daclatasvir/ sofosbuvir with or without ribavirin (12.5%), or sofosbuvir/ribavirin (3.4%), and 96.4% (n=503) completed the direct-acting antiviral treatment. No patient discontinued treatment due to adverse event(s). A sustained virologic response 12 weeks after the end of the treatment (SVR12) was evaluated in 62.6% of patients. Overall sustained virologic response 12 weeks after the end of the treatment was 98.7% regardless of HCV genotypes or direct-acting antiviral regimens. The severity of liver stiffness was significantly decreased from 10.2 to 6.3 kilopascals measured by transient elastography by the treatment (P<0.001). Among patients who completed the directacting antiviral treatment, 17.7% returned for further follow-ups after SVR12. Conclusions: In Vietnam, the current generic direct-acting antiviral treatment for chronic hepatitis C was effective regardless of HCV genotypes and direct-acting antiviral regimens with the attenuation of liver stiffness. It is feasible to implement direct-acting antiviral treatment to cure chronic hepatitis C patients at any liver fibrosis stages in Vietnam.

Cost-effectiveness Analysis of Glecaprevir/Pibrentasvir versus Elbasvir/Grazoprevir in Chronic Hepatitis C Genotype 1b Treatment-naive Patients without Cirrhosis / 中国药房

OBJECTIVE：To evalua te the economics of glecaprevir/pibrentasvir （G/P）versus elbasvir/grazoprevir （EBR/GZR） in chronic hepatitis C genotype 1b（GT1b）treatment-naive patients without cirrhosis ，and to provide evidence support for medical and health decision-making. METHODS ：Under assuming the bid price of G/P and EBR/GZR therapy schemes before medical insurance negotiation was adopted （scenario 1）and assuming that the price of EBR/GZR was reduced by 85％ and the price of G/P was reduced by 80％（scenario 2），Markov model was developed to simulate the lifetime cost and health outcomes progress of 10 000 untreated chronic hepatitis C GT 1b treatment-naive patients without cirrhosis and calculate incremental cost-effectiveness ratio（ICER）. Single factor sensitivity analysis and probability sensitivity analysis were conducted to verify the results. The highest price（price reduction ratio ）of G/P scheme was analyzed with cost-effectiveness advantage ，when other parametes kept stable under scenario 2. RESULTS ：Under 2 kinds of scenarios ，compared with EBR/GZR scheme ，G/P scheme had higher cost （scenario 1：68 800 yuan vs. 62 338 yuan；scenario 2：13 760 yuan vs. 11 490 yuan）and healty utility （scenario 1：14.97 QALY vs. 14.90 QALY；scenario 2：14.97 QALY vs. 14.90 QALY），and ICER value of G/P was lower than willingness-to-pay threshold （scenario 1：92 314 yuan/QALY；scenario 2：32 428 yuan/QALY）. The change of most parameters in single factor sensitivity analysis didn ’t influence the results of base-case analysis ，and the findings from the base-case analysis were confirmed by probability sensitivity analyses. The price of G/P scheme needed to be reduced by at least 62％ to realize cost-effective advantage. CONCLUSIONS ： Under the set price scenario ，G/P scheme has cost-effectiveness advantages than EBR/GZR scheme in chronic hepatitis C GT 1b treatment-naive patients without cirrhosis.

Taxa de resposta viral sustentada em pacientes de hepatite C crônica tratados com antivirais de ação direta / Sustained virologic response rate in chronic hepatitis c patients through direct-acting antivirals therapy

ABSTRACT BACKGROUND: In recent years the management of hepatitis C virus infection and the possibility of its eradication have been researched due to the importance that they represent in the health of the world population. Obtaining data that help to cope with this pathology improves the quality of life of those affected by it. The present study evaluated the effectiveness of direct-acting antiviral therapies provided by the Brazilian Ministry of Health in accordance to the Clinical Protocol and Therapeutic Guidelines of 2015. OBJECTIVE: To evaluate the epidemiological profile of patients with chronic hepatitis C and the rate of sustained virologic response using direct-acting antivirals of all individuals that attended the referral service for the treatment of chronic hepatitis C at the Hospital of the Federal University of Rio Grande. METHODS: This was an observational, retrospective/prospective study with all patients with chronic hepatitis C who had their treatments available from December 2015 to August 2017 according to the criteria of the Clinical Protocol and Therapeutic Guidelines of 2015. In the first phase, the clinical and demographic variables of all individuals enrolled in a treatment for hepatitis C were selected and collected from the Reference Service database. In the second phase, treatment data were collected. The outcome variable, sustained virologic response, was defined as an undetectable viral load on the blood test three months after the end of treatment. The descriptive and bivariate analyzes were performed with Pearson's chi-square and Fisher's Exact test, adopting a P value ≤0.05 in the SPSS 20 software. RESULTS: Of the 252 participants in the study, 228 (90.5%) had a sustained virologic response, 55.2% were male with an average age of 58.6 years (SD±9.1). Genotype 1 was the most prevalent, observed in 54.4% of the participants, and 87.4% of the patients had moderate/advanced hepatic fibrosis. After the statistical analysis, it was observed that the individuals with genotype 3 and moderate/advanced hepatic fibrosis had lower sustained virologic response rate (P=0.05 and P=0.04, respectively). CONCLUSION: It was observed that the use of direct-acting antivirals, in comparison to previous therapeutic regimens, increases the sustained virologic response, reaching all patients with mild fibrosis. This study provides information that helps in the hepatitis C treatment by showing that prescribing early treatment for patients without hepatic fibrosis and/or genotype 3 virus could increase therapeutic effectiveness.

RESUMO CONTEXTO: O manejo e a possibilidade de erradicação da infecção pelo vírus da hepatite C têm sido muito pesquisados nos últimos anos pela importância que representam na saúde pública para a população mundial. A obtenção de dados que auxiliem o enfrentamento dessa patologia resulta na melhor qualidade de vida dos seus portadores. O presente estudo avaliou a efetividade da terapêutica com os antivirais de ação direta, fornecida pelo Ministério da Saúde, através do Protocolo Clínico e Diretrizes Terapêuticas de 2015. OBJETIVO: Avaliar o perfil epidemiológico dos portadores de hepatite C crônica e a taxa de resposta viral sustentada com o uso dos antivirais de ação direta em todos os indivíduos atendidos no Centro de Referência no tratamento da hepatite C crônica do Hospital Universitário da Universidade Federal do Rio Grande. MÉTODOS: Estudo observacional retrospectivo/prospectivo com todos os portadores de hepatite C crônica que tiveram seus tratamentos disponibilizados no período de dezembro de 2015 a agosto de 2017 segundo os critérios do Protocolo Clínico e Diretrizes Terapêuticas de 2015. Na primeira fase foram selecionadas e coletadas as variáveis demográficas e clínicas, no banco de dados do centro de referência de todos os indivíduos cadastrados para tratamento para hepatite C e na segunda fase foram coletados dados referentes ao tratamento. A variável desfecho, resposta viral sustentada, foi definida pela carga viral indetectável no exame sanguíneo três meses após o término do tratamento. Foram realizadas as análises descritivas e bivariadas com cálculo do qui quadrado de Pearson e Exato de Fisher, adotando um valor P≤0,05, no programa SPSS 20. RESULTADOS: Dos 252 participantes do estudo 228 (90,5%) obtiveram resposta viral sustentada, sendo 55,2% do sexo masculino com média de idade de 58,6 anos (DP±9,1). O genótipo 1 foi o mais prevalente, presente em 54,4% dos participantes, 87,4% dos estudados apresentavam grau de fibrose hepática moderada/avançada. Após a análise estatística observou-se que os indivíduos com genótipo 3 e fibrose hepática moderada/avançada, tiveram menor taxa de resposta viral sustentada (P=0,05 e P=0,04 respectivamente). CONCLUSÃO: Observou-se que com o uso dos antivirais de ação direta as taxas de resposta viral sustentada foram altas, em relação aos esquemas terapêuticos anteriores, podendo chegar à totalidade nos pacientes com fibrose leve. Este estudo mostra que a realização do tratamento precoce, ou seja, de forma antecipada em pacientes sem fibrose hepática e genótipo 3 pode aumentar a taxa de sucesso.

Fisiopatología de la hepatitis C y diabetes mellitus. Hacia la cura de dos epidemias en el siglo XXI / Pathophysiology of Hepatitis C and Diabetes Mellitus: Towards the cure of two epidemics in the 21 st century

Resumen La infección crónica por virus de la hepatitis C (VHC) y la diabetes mellitus (DM) son dos problemas de salud pública que impactan los sistemas de salud, con una alta carga económica global. La infección por VHC produce manifestaciones hepáticas tales como hepatitis, cirrosis y carcinoma hepatocelular; asimismo, se ha involucrado en la patogénesis de manifestaciones extrahepáticas, entre las cuales se ha asociado con alteraciones metabólicas como la DM. Estudios longitudinales y transversales han reportado mayor incidencia y prevalencia de DM en pacientes con infección crónica por VHC. La DM acelera la progresión histológica y clínica en pacientes con infección crónica por VHC y las complicaciones cardiovasculares. Recientemente se ha avanzado en el tratamiento y la introducción de nuevos medicamentos como los antivirales de acción directa, que mejoran el control glucémico en estos pacientes.

Abstract Chronic hepatitis C virus (HCV) and diabetes mellitus (DM) are two public health problems that impact health care systems with overall high costs. HCV infections cause liver manifestations such as hepatitis, cirrhosis and hepatocellular carcinoma. They have also been involved in the pathogenesis of extrahepatic manifestations among which are metabolic disorders such as DM. Longitudinal and cross-sectional studies have reported a higher incidence and prevalence of DM in patients with chronic HCV infections. DM accelerates histological and clinical progression of chronic HCV infections and leads to cardiovascular complications. Recently, progress has been made in treatment with the introduction of new medications such as direct-acting antiviral drugs that improve glycemic control in these patients.