Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy

Patients with chronic hepatitis B are at increased risk of hepatocellular carcinoma(HCC),while the inhibition of viral replication can represent a reasonable target for HCC prevention.Interferon-αtherapy results in decreased HCC risk,which is more evident in patients with high baseline HCC risk.The majority of chronic hepatitis B patients are treated with a nucleos(t)ide analogue(NA)for several reasons including the nonsustained response after interferon-α.The effect of the first licensed and low genetic barrier NA,lamivudine,on HCC incidence,has been repeatedly evaluated.Lamivudine,compared to no treatment,reduces the HCC incidence,which may increase again in cases with lamivudine resistance.Emerging data with the currently first-line NAs,entecavir and tenofovir,suggest that they also reduce the HCC incidence.The treatment benefit in reduction of the HCC incidence is always greater in patients with high baseline HCC risk,particularly cirrhotics,and without virological remission under entecavir/tenofovir.However,the HCC risk is not eliminated even in the vast majority of patients who remain in virological remission under entecavir/tenofovir.Therefore,patients at increased baseline HCC risk should continue to undergo HCC surveillance even if they have achieved complete long-term inhibition of viral replication and improvements in liver histology.

Interferon-free regimens for the treatment of hepatitis C virus in liver transplant candidates or recipients

The goal of therapy in chronic hepatitis C virus(HCV) infection is sustained virological response(SVR) which reflects HCV eradication. Treatment against HCV has dramatically improved with the recent availability of direct-acting antivirals(DAAs) including sofosbuvir, simeprevir, daclatasvir, ledipasvir/sofosbuvir, paritaprevir/ombitasvir and dasabuvir. Carefully selected combinations of these DAAs offer the potential for highly effective all-oral safe regimens even for patients with decompensated cirrhosis or liver transplant(LT) recipients. Like all current protease inhibitors, simeprevir and paritaprevir should not be used in patients with Child C cirrhosis, while sofosbuvir and ledipasvir/sofosbuvir should not be given in patients with severe renal impairment and glomerular filtration rate less than 30 m L/min. Drug-drug interactions may still occur with the current DAAs particularly in postLT patients, in whom simeprevir should not be coadministered with cyclosporine and dose adjustments of calcineurin inhibitors are required in case of regimens including the ritonavir boosted paritaprevir. Phase Ⅱ clinical trials and real life cohort studies have shown that sofosbuvir based combinations are safe and can achieve improvements of clinical status, high SVR rates and even prevention of post-LT HCV recurrence in patients with decompensated cirrhosis or LT-candidates. In the post-LT setting, sofosbuvir based regimens and the combination of paritaprevir/ombitasvir and dasabuvir have been reported to be safe and achieve high SVR rates, similar to those in non-transplantpatients, being effective even in cases with cholestatic fibrosing hepatitis. Ongoing clinical trials and rapidly emerging real life data will further clarify the safety and efficacy of the new regimens in these settings.

Serum zonulin levels in patients with liver cirrhosis:Prognostic implications

BACKGROUND Increased gut permeability and bacterial translocation play an important role in liver cirrhosis.Zonulin is a recently recognized protein involved in the disintegration of the intestinal barrier.AIM To investigate possible differences in serum zonulin levels among patients with different cirrhosis stages and their potential prognostic implications.METHODS Consecutive cirrhotic patients who attended our liver clinic were included in the study.Serum zonulin levels,clinical,radiological and biochemical data were collected at baseline.Patients who accepted participation in a regular surveillance program were followed-up for at least 12 mo.RESULTS We enrolled 116 cirrhotics[mean Child-Turcotte-Pugh(CTP)score:6.2±1.6;model for end-stage liver disease score:11±3.9].The causes of cirrhosis were viral hepatitis(39%),alcohol(30%),non-alcoholic fatty liver disease(17%),and other(14%).At baseline,53% had decompensated cirrhosis,48% had ascites,and 32% had history of hepatic encephalopathy.Mean zonulin levels were significantly higher in patients with CTP-B class than CTP-A class(4.2±2.4 ng/dL vs 3.5±0.9 ng/dL,P=0.038),with than without ascites(P=0.006),and with than without history of encephalopathy(P=0.011).Baseline serum zonulin levels were independently associated with the probability of decompensation at 1 year(P=0.039),with an area under the receiving operating characteristic of 0.723 for predicting hepatic decompensation.Higher CTP score(P=0.021)and portal vein diameter(P=0.022)were independent predictors of mortality.CONCLUSION Serum zonulin levels are higher in patients with more advanced chronic liver disease and have significant prognostic value in identifying patients who will develop decompensation.

Economic evaluation of the hepatitis C elimination strategy in Greece in the era of affordable direct-acting antivirals

BACKGROUND Hepatitis C virus(HCV) is a leading cause of worldwide liver-related morbidity and mortality. The World Health Organization released an integrated strategy targeting HCV-elimination by 2030. This study aims to estimate the required interventions to achieve elimination using updated information for direct-acting antiviral(DAA) treatment coverage, to compute the total costs(including indirect/societal costs) of the strategy and to identify whether the elimination strategy is cost-effective/cost-saving in Greece.AIM To estimate the required interventions and subsequent costs to achieve HCV elimination in Greece.METHODS A previously validated mathematical model was adapted to the Greek HCVinfected population to compare the outcomes of DAA treatment without the additional implementation of awareness or screening campaigns versus an HCV elimination strategy, which includes a sufficient number of treated patients. We estimated the total costs(direct and indirect costs), the disability-adjusted life years and the incremental cost-effectiveness ratio using two different price scenarios.RESULTS Without the implementation of awareness or screening campaigns,approximately 20000 patients would be diagnosed and treated with DAAs by2030. This strategy would result in a 19.6% increase in HCV-related mortality in2030 compared to 2015. To achieve the elimination goal, 90000 patients need to be treated by 2030. Under the elimination scenario, viremic cases would decrease by78.8% in 2030 compared to 2015. The cumulative direct costs to eliminate the disease would range from 2.1-2.3 billion euros(€) by 2030, while the indirect costs would be €1.1 billion. The total elimination cost in Greece would range from €3.2-3.4 billion by 2030. The cost per averted disability-adjusted life year is estimated between €10100 and €13380, indicating that the elimination strategy is very costeffective. Furthermore, HCV elimination strategy would save €560-895 million by2035.CONCLUSION Without large screening programs, elimination of HCV cannot be achieved. The HCV elimination strategy is feasible and cost-saving despite the uncertainty of the future cost of DAAs in Greece.

Oxidative imbalance increases the risk for colonic polyp and colorectal cancer development

BACKGROUND The role of oxidative stress in the pathogenesis of colorectal carcinoma(CRC)has garnered considerable interest recently.Specific oxidative factors have been implicated in the pathogenesis of adenomatous polyps and ultimately adenocarcinoma.AIM To evaluate the effect of oxidative imbalance as quantified by specific serological markers in the development of sporadic colon adenocarcinoma.METHODS A total of 170 patients that underwent endoscopy of the lower gastrointestinal tract in a tertiary center within 3 years were included in the study.They were allocated in three groups;those with sporadic colon adenocarcinoma(n=56,32.9%),those with colonic polyps(n=33,19.4%)and healthy controls(n=81,47.7%).All patients were evaluated for oxidant activity and antioxidant capacity with serum measurements of specific markers such as vitamins A,25(OH)D3,E,C,B12,folic acid,glutathione,selenium(Se),zinc(Zn),free iron(Fe^(2+)),and malondialdehyde and results were compared between groups.RESULTS Serum levels of vitamins C,E,D,Se,Zn,vitamin B12 and total antioxidant capacity were significantly lower in the combined neoplasia/polyp group than in the control group(P=0.002,P=0.009,P<0.001,P<0.001,P<0.001,P=0.020 and P<0.001,correspondingly).Increased levels of vitamin E(P=0.004),vitamin D(P<0.001),Se(P<0.001)and Zn(P<0.001)seem to bestow a protective effect on the development of CRC.For vitamin D(P<0.001)and Zn(P=0.036),this effect seems to extend to the development of colon polyps as well.On the other hand,elevated serum levels of malondialdehyde are associated with a higher risk of CRC(OR=2.09 compared to controls,P=0.004).Regarding colonic polyp development,increased concentrations of vitaminΑand Fe^(2+) are associated with a higher risk,whereas lower levels of malondialdehyde with a lower risk.CONCLUSION Increased oxidative stress may play an important role in the pathogenesis and progression of CRC.Antioxidants’presence may exert a protective effect in the very early stages of colon carcinogenesis.

Managing Hepatitis C Patients in Greece: A Budget Impact Analysis of Simeprevir plus Pegylated Interferon/Ribavirin Regimen at Early Stages of the Disease

Objectives: To identify local resource use such as pharmaceutical treatment, medical follow-up, and patient hospitalization and estimate the budget impact of simeprevir (SMV) plus pegylated interferon (P)/ribavirin (R) as a treatment option in the early stages of the disease in Greece. Methods: A budget impact tool was developed with a two-year time horizon, which estimated the impact on the Social Insurance Funds (SIFs) of introducing SMV + PR in the management of the early disease stages. Total direct and indirect costs were estimated for each of the following health states: non-cirrhotic chronic Hepatitis C (and within that by fibrosis stage), compensated cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma. Data gaps on treatment algorithms, resource use and productivity losses were covered via an expert panel of eight leading hepatologists. Epidemiology data were taken from the published literature. Unit costs were obtained from the Ministry of Health and SIFs. The perspective was that of the SIF and the cost base year was 2015. Results: The total (direct and indirect) cost per patient per year (excluding cost of antiviral treatment) was estimated at €647, €703, €5,753, €16,313 and €37,237 for non-cirrhotic CHC, compensated cirrhosis, decompensated cirrhosis, HCC and liver transplantation, respectively. The budget impact analysis showed that adding SMV to PR in the early stages of the disease would lead to an increase in the cost of antiviral treatment by €2.03 million. Conclusions: Costs of managing CHC increase dramatically with disease severity. SMV + PR for naive patients at early disease stages has a significant but manageable budget impact, and could prevent high costs in advanced stages.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease

Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 2020,the more inclusive term metabolic dysfunction-associated fatty liver disease(MAFLD)was proposed to replace the term non-alcoholic fatty liver disease(NAFLD).The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD.However,to date,there is no appropriate guidance on CKD in individuals with MAFLD.Furthermore,there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.Methods and Results:Using a Delphi-based approach,a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.Conclusions:This Delphi-based consensus statement provided guidance on the epidemiology,mechanisms,management and treatment of MAFLD and CKD,as well as the relationship between the severity of MAFLD and risk of CKD,which establish a framework for the early prevention and management of these two common and interconnected diseases.

Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis:an international registry study

Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may be useful in diagnosing NASH,but results across studies have been inconsistent.We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.Methods:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease(NAFLD),and in all patients,circulating CK-18 M30 levels were measured.Individuals with a NAFLD activity score(NAS)≥5 with a score of≥1 for each of steatosis,ballooning,and lobular inflammation were diagnosed as having definite NASH;individuals with a NAS≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver(NAFL).Results:A total of 2571 participants were screened,and 1008(153 with NAFL and 855 with NASH)were finally enrolled.Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL(mean difference 177 U/L;standardized mean difference[SMD]:0.87[0.69–1.04]).There was an interaction between CK-18 M30 levels and serum alanine aminotransferase,body mass index(BMI),and hypertension(P<0.001,P=0.026 and P=0.049,respectively).CK-18 M30 levels were positively associated with histological NAS in most centers.The area under the receiver operating characteristics(AUROC)for NASH was 0.750(95%confidence intervals:0.714–0.787),and CK-18 M30 at Youden’s index maximum was 275.7 U/L.Both sensitivity(55%[52%–59%])and positive predictive value(59%)were not ideal.Conclusion:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.

The upward trend in the immunotherapy utilization for hepatobiliary cancers

Hepatobiliary cancers(HBCs)include those of the liver[mainly hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma]and biliary tract(extrahepatic cholangiocarcinoma and gallbladder cancer).Based on the 2020 global cancer statistics,liver cancer ranks seventh in incidence and third in mortality among all malignant tumors,while gallbladder cancer ranks 25th in incidence and 21st in mortality(1).Due to the lack of typical symptoms and signs at the early stages,HBCs are often diagnosed at intermediate or advanced stages,and thus the opportunity of curative surgical interventions is missed(2).Therefore,most patients with HBC can only be treated with noncurative treatments,including immunotherapy.Several immunotherapeutic approaches have been attempted for HBCs,including oncolytic viruses,tumor vaccines,adoptive immunotherapy,and immune checkpoint inhibitors(ICIs;Figure 1).