Hepatitis C virus treatment advances for thalassaemia patients

Chronic infection with hepatitis C virus (HCV) is a major problem for thalassaemia patients, as blood transfusions before 1990 were associated with a high risk of HCV infection. Given the high prevalence of co-morbidities, thalassaemia patients are at an increased risk for dying from end-stage liver disease or hepatocellular carcinoma. HCV treatment in thalassaemia patients was challenging in the interferon-alfa (IFN) era not only due to its unfavourable safety and tolerability profile but due to necessary combined use of ribavirin (RBV) and the subsequent haemolysis and increased need for blood transfusions. The introduction of the current direct acting antivirals (DAAs), which can be used in IFNfree and RBV-free regimens, has dramatically improved the management of all HCV patients including those with thalassaemia. Currently, depending on HCV genotype and availability in each country, the main available DAAs combinations are the co-formulation of sofosbuvir with ledipasvir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor, one tablet of 400/90 mg once daily),, the co-formulation of paritaprevir boosted by ritonavir with ombitasvir (NS3/4 protease inhibitor/ritonavir/NS5A inhibitor, two tablets of 75/50/12.5 mg once daily) perhaps with addition of dasabuvir (non-nucleos(t)ide analogue NS5B polymerase inhibitor, one tablet of 250 mg twice daily), the co-formulation of grazoprevir with elbasvir (NS3/4 protease inhibitor/NS5A inhibitor, one tablet of 100/50 mg once daily) and the co-formulation of sofosbuvir with velpatasvir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor, one tablet of 400/100 mg once daily). In 2017, the co-formulation of glecaprevir with pibrentasvir (NS3/4 protease inhibitor/NS5A inhibitor, three tablets of 100/40 mg once daily) and the co-formulation of sofosbuvir with velpatasvir and voxilaprevir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor/ NS3/4 protease inhibitor, one tablet of 400/100/100 mg once daily) were also approved and started to be used in some countries. According to all international current guidelines, thalassaemia patients do not represent a special group for the current HCV treatment and can be treated with the same indications and regimens used for patients without haemoglobinopathies. However, in countries which still prioritize the use of DAAs according to the severity of liver disease, thalassaemia patients are often excluded from such prioritization and have access to DAAs therapy regardless of their fibrosis severity. Moreover, all guidelines recommend that thalassaemia patients should be preferentially treated not only with IFN-free but RBV-free DAAs regimens too. In a proper clinical trial, only a 12-week regimen of grazoprevir/ elbasvir has been evaluated and proven to be highly efficacious and well tolerated among patients with inherited blood disorders and HCV genotype 1 or 4 infection. In addition, different DAAs regimens have been reported to be safe and effective for the treatment of HCV thalassaemia patiens in clinical practice. Given the availability of the current effective and safe DAAs and the frequent follow-up of thalassaemia patients in a few specific units, such patients could be a targeted population for “HCV micro-elimination” on the road towards the global HCV elimination in each country

Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and can vary from benign steatosis to end-stage liver disease. The pathogenesis of non-alcoholic steatohepatitis (NASH) is currently thought to involve a multiple-hit process with the first hit being the accumulation of liver fat which is followed by the development of necroinflammation and fibrosis. There is mounting evidence that cytokines secreted from adipose tissue, namely, adipokines, are implicated in the pathogenesis and progression of NAFLD. In the current review, we explore the role of these adipokines, particularly leptin, adiponectin, resistin, tumor necrosis factor-a, and interleukin-6 in NASH, as elucidated in experimental models and clinical practice. We also comment on their potential use as noninvasive markers for differentiating simple fatty liver from NASH as well as on their potential future therapeutic role in patients with NASH

Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: A systematic review

Background & Aims: Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues. Methods: We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for ⩾24months. Results: Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32–108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466). Conclusions: Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC

The assessment of hepatocellular carcinoma risk in patients with chronic hepatitis B under antiviral therapy

Hepatocellular carcinoma (HCC) is a primary concern for patients with chronic hepatitis B (CHB). Antiviral therapy has been reasonably the focus of interest for HCC prevention, with most studies reporting on the role of the chronologically preceding agents, interferon-alfa and lamivudine. The impact of interferon-alfa on the incidence of HCC is clearer in Asian patients and those with compensated cirrhosis, as several meta-analyses have consistently shown HCC risk reduction, compared to untreated patients. Nucleos(t)ide analogues also seem to have a favorable impact on the HCC incidence when data from randomized or matched controlled studies are considered. Given that the high-genetic barrier agents, entecavir and tenofovir, are mainly used in CHB because of their favorable effects on the overall long-term outcome of such patients, the most clinically important challenge is the identification of patients who require close HCC surveillance despite on-therapy virological remission. Several risk scores have been developed for HCC prediction in CHB patients. Most of them, such as GAG-HCC, CU-HCC and REACH-B, have been developed and validated in Asian untreated and treated CHB patients, but they do not seem to offer good predictability in Caucasian CHB patients for whom a newer score, PAGE-B, has been recently developed

The Impact of Host Metabolic Factors on Treatment Outcome in Chronic Hepatitis C

Background. Recent data suggest that chronic hepatitis C has to be considered a metabolic disease further to a viral infection. The aim of this study was to elaborate on the complex interactions between hepatitis C virus, host metabolic factors, and treatment response. Methods. Demographic, virological, and histological data from 356 consecutive patients were analyzed retrospectively. Hepatic steatosis, obesity, and insulin resistance were examined in relation to their impact on treatment outcome. Comparison between genotype 1 and 3 patients was performed to identify differences in the determinants of hepatic steatosis. Results. Histological evidence of hepatic steatosis was found in 113 patients, distributed in 20.3%, 9.0%, and 2.5% for grades I, II, and III, respectively. Hepatic steatosis was associated with past alcohol abuse (P = 0.003) and histological evidence of advanced fibrosis (P < 0.001). Older age (OR 2.51, P = 0.002), genotype (OR 3.28, P < 0.001), cirrhosis (OR 4.23, P = 0.005), and hepatic steatosis (OR 2.48, P = 0.001) were independent predictors for nonresponse. Correlations of hepatic steatosis with alcohol, insulin resistance, and fibrosis stage were found similar for both genotypes 1 and 3. Conclusions. Host metabolic factors may predict treatment outcome, and this impact remains significant even in genotype 3, where steatosis has been believed to be exclusively virus related

Predictive performance of newer Asian hepatocellular carcinoma risk scores in treated Caucasians with chronic hepatitis B

Cirrosi; Tenofovir; PrediccióCirrosis; Tenofovir; PredicciónCirrhosis; Tenofovir; PredictionBackground & Aims Recently, several risk scores for prediction of hepatocellular carcinoma (HCC) were developed in cohorts of treated Asian patients with chronic hepatitis B (CHB), but they have not been assessed in non-Asian patients. We evaluated the predictability and comparative utility of our PAGE-B and recent Asian HCC risk scores in nucleos(t)ide analogue (NA)-treated adult Caucasian patients with CHB, with or without well-documented compensated cirrhosis but not previous diagnosis of HCC. Methods We included 1,951 patients treated with entecavir/tenofovir and followed up for a median of 7.6 years. The c-statistic was used to estimate the predictability of PAGE-B, HCC-Rescue, CAMD, mPAGE-B, and AASL score for HCC development within 5 or 10 years. The low- and high-risk group cut-offs were used for estimation of negative (NPV) and positive predictive values (PPV), respectively. Results HCC developed in 103/1,951 (5.3%) patients during the first 5 years and in another 39/1,428 (2.7%) patients between years 5 and 10. The 3-, 5-, and 10-year cumulative HCC rates were 3.3%, 5.9%, and 9.6%, respectively. All scores offered good 5- and 10-year HCC prediction (c-statistic: 0.78–0.82). NPVs were always >99% (99.3–100%), whereas PPV ranged between 13% and 24%. Conclusions In NA-treated Caucasian patients with CHB including compensated cirrhosis, HCC risk scores developed in NA-treated Asian patients offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. PAGE-B and mPAGE-B scores are simpler in clinical practice, as they do not require an accurate diagnosis of cirrhosis, but the addition of albumin in mPAGE-B score does not seem to offer an advantage in patients with well compensated liver disease. Lay summary Several risk scores for prediction of hepatocellular carcinoma (HCC) were recently developed in cohorts of treated Asian patients with chronic hepatitis B (CHB). In Caucasian patients with CHB treated with oral antivirals, newer Asian HCC risk scores offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. For clinical practice, PAGE-B and mPAGE-B scores are simpler, as they do not require an accurate diagnosis of cirrhosis

Risk of hepatocellular carcinoma in chronic hepatitis B: Assessment and modification with current antiviral therapy

SummaryIn the treatment of chronic hepatitis B (CHB), the ultimate goal is preventing hepatitis B virus (HBV)-associated liver disease, including hepatocellular carcinoma (HCC). Recently published studies show that in CHB patients treated with the currently recommended first-line nucleos(t)ide analogs (NAs) entecavir or tenofovir, annual HCC incidences range from 0.01% to 1.4% in non-cirrhotic patients, and from 0.9% to 5.4% in those with cirrhosis. In Asian studies including matched untreated controls, current NA therapy consistently resulted in a significantly lower HCC incidence in patients with cirrhosis, amounting to an overall HCC risk reduction of ∼30%; in non-cirrhotic patients, HCC risk reduction was overall ∼80%, but this was only observed in some studies. For patients of Caucasian origin, no appropriate comparative studies are available to date to evaluate the impact of NA treatment on HCC. Achievement of a virologic response under current NA therapy was associated with a lower HCC risk in Asian, but not Caucasian studies. Studies comparing entecavir or tenofovir with older NAs generally found no difference in HCC risk reduction between agents, except for one study which used no rescue therapy in patients developing lamivudine resistance. Overall, these data indicate that with the current, potent NAs, HCC risk can be reduced but not eliminated, probably due to risk factors that are not amenable to change by antiviral therapy, or events that may have taken place before treatment initiation. Validated pre- and on-therapy HCC risk calculators that inform the best practice for HCC surveillance and facilitate patient counseling would be of great practical value

Serum levels of advanced glycation end-products (AGEs) and the decoy soluble receptor for AGEs (sRAGE) can discriminate non-alcoholic fatty liver disease in age-, sex- and BMI-matched normo-glycemic adults

Background: Non-alcoholic fatty liver disease (NAFLD) is a serious health problem affecting ~25% of the global population. While NAFLD pathogenesis is still unclear, multiple NAFLD parameters, including reduced insulin sensitivity, impaired glucose metabolism and increased oxidative stress are hypothesised to foster the formation of advance glycation end-products (AGEs). Given the link of AGEs with end organ damage, there is scope to examine the role of the AGE/RAGE axis activation in liver injury and NAFLD. Methods: Age, sex and body mass index matched normo-glycemic NAFLD adults (n = 58) and healthy controls (n = 58) were enrolled in the study. AGEs were analysed by liquid chromatography-mass spectrometry (CML, CEL), fluorescence (pentosidine, AGE fluorescence), colorimetry (fructosamine) and ELISA (sRAGE). Their association with liver function, inflammation, fibrosis and stage of NAFLD was examined. Results: Early and advanced glycation end-products, except Nε-carboxymethyl-L-lysine (CML), were 10–30% higher, sRAGE levels 1.7-fold lower, and glycation/sRAGE ratios 4-fold higher in the NAFLD cases compared to controls. While AGEs presented weak to moderate correlations with indices of liver function and damage (AST/ALT, HOMA-IR, TNF-α and TGF-β1), including sRAGE to characterize the AGEs/sRAGE axis strengthened the associations observed. High glycation/sRAGE ratios were associated with 1.3 to 14-fold likelihood of lower AST/ALT ratios. The sum of AGEs/sRAGE ratios accurately distinguished between healthy controls and NAFLD patients (area under the curve of 0.85). Elevated AGEs/sRAGE (&gt;7.8 mmol/pmol) was associated with a 12-fold likelihood of the presence of NAFLD. Conclusion: These findings strengthen the involvement of AGEs-RAGE axis in liver injury and the pathogenesis of NAFLD

Elastography for Hepatic Fibrosis Severity in Chronic Hepatitis B or C

AIMS: To assess the value of transient elastography for predicting significant fibrosis or cirrhosis in chronic hepatitis B or C (CHB or CHC) patients. METHODS: 75 patients (CHB: 45, CHC: 32) were included. All underwent elastography and liver biopsy concurrently. Biopsies were evaluated using Ishak's classification. Fibrosis was mild, moderate or severe/cirrhosis when scores were 0-1 (n = 30), 2-3 (n = 20), 4-6 (n = 25), respectively. RESULTS: Median liver stiffness values were higher in patients with severe fibrosis or cirrhosis than in those with moderate or mild fibrosis (14.8 vs. 6.4 vs. 5.3 kPa, p < 0.001). The diagnostic accuracy of elastography for severe fibrosis and cirrhosis was excellent [area under the receiver operating characteristic (AUROC) curve 0.938 vs. 0.948], but it was not optimal for mild fibrosis (AUROC 0.78). Values of 7.5, 9.0 and 12 kPa had a sensitivity and specificity for severe fibrosis/cirrhosis of 96, 84 and 60%, and 76, 90 and 94%, respectively. The median stiffness value in cirrhotic patients (score 5-6) was 16.6 kPa (7.7-48). No differences in accuracy of elastography between CHB or CHC patients were found. Cutoff was 12.5 kPa for cirrhosis; 10/75 patients (13%) were misclassified. CONCLUSION: Transient elastography has an excellent diagnostic accuracy for severe fibrosis and cirrhosis in CHB and CHC, but the cutoffs need further evaluation

Securing sustainable funding for viral hepatitis elimination plans

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580\xC2\xA0000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct-acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries' health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro-elimination approach in specific populations is less complex and less costly than country-wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO