Is there a need for universal double reflex testing of HBsAg-positive individuals for hepatitis D infection?

Hepatitis D virus(HDV)can infect HBsAg-positive individuals,causing rapid fibrosis progression,early decompensation,increased hepatocellular carcinoma risk,and higher mortality than hepatitis B virus(HBV)mono-infection.Most countries lack high-quality HDV prevalence data,and the collection techniques employed often bias published data.In recent meta-analyses,HDV prevalence in HBsAg-positive patients reaches 5%-15%and is even significantly higher in endemic areas.Since HBV vaccination programs were implemented,HDV prevalence has decreased among younger populations.However,owing to immigrant influx,it has increased in some Western countries.The current practice of HDV screening in HBsAg-positive individuals is stepwise,based on physician’s discretion,and limited to at-risk populations and may require numerous visits.Double reflex testing,which includes anti-HDV testing in all HBsAg-positive individuals and then HDV RNA testing for anti-HDV-positive ones,is uncommon.Reflex testing can identify more HDV infection cases and link identified patients to further care and follow-up.Moreover,laboratory-based double reflex screening is less biased than physician-led testing.Therefore,health-care providers should learn about reflex testing,and federal and provincial hepatitis control programs should implement laboratory-based double reflex testing to obtain reliable HDV prevalence estimates.The test’s cost-effectiveness depends on the number of HBV-positive patients screened to identify one HDV-positive patient.Such testing may be viable in areas with low HBsAg but high HDV prevalence.However,its economic impact on areas with low HDV prevalence needs further study.

Hepatitis B virus/hepatitis D virus epidemiology: Changes over time and possible future influence of the SARS-CoV-2 pandemic

Hepatitis D virus(HDV)is a defective liver-tropic virus that needs the helper function of hepatitis B virus(HBV)to infect humans and replicate.HDV is transmitted sexually or by a parenteral route,in co-infection with HBV or by super-infection in HBV chronic carriers.HDV infection causes acute hepatitis that may progress to a fulminant form(7%-14%by super-infection and 2%-3%by HBV/HDV co-infection)or to chronic hepatitis(90%by HDV super-infection and 2%-5%by HBV/HDV co-infection),frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma(HCC).Peg-interferon alfa the only recommended therapy,clears HDV in only 10%-20%of cases and,consequently,new treatment strategies are being explored.HDV endemicity progressively decreased over the 50 years from the identification of the virus,due to improved population lifestyles and economic levels,to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs.Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic,unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments,lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.

Hepatitis D virus dual-infection among Chinese hepatitis B patient related to hepatitis B surface antigen,hepatitis B virus DNA and age

The screening practices for hepatitis D virus(HDV)are diverse and nonstandardized worldwide,and the exact prevalence of HDV is uncertain.AIM To estimate HDV prevalence and investigate viral marker quantity trends in patients with hepatitis D.METHODS We collected 5594 serum samples from patients with hepatitis B in Jilin Province,China(3293 males and 2301 females,age range of 2 to 89 years).We then conducted tests for hepatitis B surface antigen(HBsAg),hepatitis B Virus(HBV)DNA,anti-hepatitis D antigen(HDAg),and HDV RNA.RESULTS We found that the prevalence of anti-HDAg and HDV RNA among hepatitis B patient were 3.6%(3.2-4.2%)and 1.2%(0.9-1.5%),respectively,87.69%of hepatitis D patients were 51-70 years old.HDV infection screening positive rate of patients with HBV DNA levels below 2000 IU/mL(2.0%)was higher than those above 2000 IU/mL(0.2%).Among anti-HDAg positive patients,the HDV RNA positive rate was positively correlated with the HBsAg level and anti-HDAg level.There was a weak correlation between HBsAg and anti-HDAg levels among hepatitis D patients.CONCLUSION Our study highlights the importance of considering multiple factors when assessing the severity of HDV infection,comprehensive evaluation of patients’clinical and laboratory parameters is necessary for proper diagnosis and treatment.

Co-treatment with pegylated interferon alfa-2a and entecavir for hepatitis D: a randomized trial

AIM: To investigate the efficacy of pegylated interferon alfa(PEG-IFNα) therapy with and without entecavir in patients with chronic hepatitis D. METHODS: Forty hepatitis D virus(HDV) RNA positive patients were randomized to receive either PEG-IFNα-2a 180 μg weekly in combination with entecavir 0.5 mg daily(n = 21) or PEG-IFNα alone(n =19). Patients who failed to show 2 log reduction in HDV RNA level at 24 wk of treatment, or had detectable HDV RNA at 48 wk of therapy were considered as treatment failure. Treatment was continued for 72 wk in the rest of the patients. All the patients were followed for 24 wk post treatment. Intention to treat analysis was performed.RESULTS: The mean age of the patients was 26.7 ± 6.8 years, 31 were male. Two log reduction in HDV RNA levels at 24 wk of therapy was achieved in 9(43%) patients receiving combination therapy and 12(63%) patients receiving PEG-IFNα alone(P = 0.199). Decline in hepatitis B surface antigen(HBs Ag) levels was insignificant. At the end of treatment, HDV RNA was negative in 8 patients(38%) receiving combination therapy and 10 patients(53%) receiving PEG-IFNα-2a alone. Virological response persisted in 7(33%) and 8(42%) patients, respectively at the end of the 24 wk follow-up period. One responder patient in the combination arm lost HBs Ag and became hepatitis B surface antibody positive. Six out of 14 baseline hepatitis B e antigen reactive patients seroconverted and four of these seroconverted patients had persistent HDV RNA clearance.CONCLUSION: Administration of PEG-IFNα-2a with or without entecavir, resulted in persistent HDV RNA clearance in 37% of patients. The addition of entecavir did not improve the overall response.

"Defective" mutations of hepatitis D viruses in chronic hepatitis D patients

AIM: To verify whether 'defective' mutations existed in hepatitis D virus (HDV).METHODS: Hepatitis delta antigen (HDAg)-codingsequences were amplified using Pfu DNA polymerases with proof-reading activities from sera of five patients with chronic hepatitis D. Multiple colonies were sequenced for each patient. Pfu analyzed a total of 270 HDV clones.Three representative defective HDV clones were constructed in expression plasmids and transfected into a human hepatoma cell line. Cellular proteins were extracted and analyzed by Western blot.RESULTS: Four of five cases (80%) showed defective HDV genomes in their sera. The percentage of defective genomes was 3.7% (10/270). The majority (90%) of the defective mutations were insertions or deletions that resulted in frameshift and abnormal stop translation of the HDAg. The predicted mutated HDAg ranged from 45amino acids to ＞214 amino acids in length. Various domains of HDAg associated with viral replication or packaging were affected in different HDV isolates. Western blot analysis showed defected HDAg in predicted positions.CONCLUSION: 'Defective' viruses do exist in chronic HDV infected patients, but represented as minor strains. The clinical significance of the 'defected' HDV needs further study to evaluate.

Serum cholinesterase: A predictive biomarker of hepatic reserves in chronic hepatitis D

To determine the predictive performance of cholinesterase compared to existing prognostic models in evaluating liver function in patients with chronic hepatitis D. METHODSIn an observational, cross-sectional and retrospective study, consecutive patients with hepatitis D cirrhosis were evaluated. Demographic, clinical and laboratory parameters were recorded. Serum cholinesterase levels were correlated with existing scoring models for chronic liver disease and Liver function tests. Receiver operating characteristic (ROC) curves were constructed to find an optimal cholinesterase level predicting ascites, Child Turcotte Pugh (CTP) score ≥ 10, model for end stage liver disease (MELD) score ≥ 15, baseline-event-anticipation (BEA) score for hepatitis D ≥ 5 and the aspartate transaminase to Platelet Ratio Index (APRI) ≥ 1.5. RESULTSThis study investigated 233 patients with chronic liver disease due to hepatitis D; 192 were male, median age 42 (16-69 years). Fifty patients had ascites and 15 had encephalopathy. One hundred and sixty-seven (71.7%) were in Child class A, 52 (22.3%) in Child class B and 14 (5.0%) in class C. A MELD score of 15 or more was seen in 24 patients. Cholinesterase levels correlated well with the INR, albumin, CTP score, MELD, MELD sodium, BEA and APRI scores (P < 0.001 each). Area under the ROC curve for ascites, CTP ≥ 10, MELD ≥ 15, BEA ≥ 5, APRI ≥ 1.5 was 0.836, 0.966, 0.913, 0.871 and 0.825 respectively (P < 0.001 each). Cut off values of cholinesterase (IU/L) for predicting ascites, CTP ≥ 10, MELD ≥ 15, BEA ≥ 5 and APRI ≥ 1.5 were < 3812, < 2853, < 2829, < 4719 and < 3954 with a sensitivity of 80%, 100%, 91.67%, 82.50%, 58.0% and specificity of 81.97%, 84.79%, 87.56%, 77.06% and 55.64% respectively. CONCLUSIONSerum cholinesterase demonstrates promising correlations with serum albumin, INR and CTP, MELD, BEA and APRI scores and is predictive of liver reserves in hepatitis D cirrhosis.

Hepatitis D and hepatocellular carcinoma

Hepatitis D virus(HDV) is a defective circular shape single stranded HDV RNA virus with two types of viral proteins,small and large hepatitis D antigens,surrounded by hepatitis B surface antigen.Superinfection with HDV in chronic hepatitis B is associated with a more threatening form of liver disease leading to rapid progression to cirrhosis.In spite of some controversy in the epidemiological studies,HDV infection does increase the risk of hepatocellular carcinoma(HCC) compared to hepatitis B virus(HBV) monoinfection.Hepatic decompensation,rather than development of HCC,is the first usual clinical endpoint during the course of HDV infection.Oxidative stress as a result of severe necroinflammation may progress to HCC.The large hepatitis D antigen is a regulator of various cellular functions and an activator of signal transducer and activator of transcription(STAT)3 and the nuclear factor kappa B pathway.Another proposed epigenetic mechanism by which HCC may form is the aberrant silencing of tumor suppressor genes by DNA Methyltransferases.HDV antigens have also been associated with increased histone H3 acetylation of the clusterin promoter.This enhances the expression of clusterin in infected cells,increasing cell survival potential.Any contribution of HBV DNA integration with chromosomes of infected hepatocytes is not clear at this stage.The targeted inhibition of STAT3 and cyclophilin,and augmentation of peroxisome proliferatoractivated receptor γ have a potential therapeutic role in HCC.

Hepatitis D: Scenario in the Asia-Pacifi c region

Hepatitis D virus (HDV) infection is present worldwide and affects all age groups. Around 18 million people are estimated to be infected with HDV. An important trend in HDV infection is global decline. HDV prevalence has decreased significantly in Europe since the 1970s and 1980s when it was f irst reported. The Asia-Pacif ic region now seems to be where HDV is a major health concern. There is a lack of available data from most of the countries from this region; hence, the true status of HDV cannot be determined. In South Asia, most of the countries have conditions that are favorable for the spread of hepatitis B and other related infections. Countries like Pakistan and Iran have shown an increase in HDV prevalence over a period of time. Other countries and region like China, Turkey, Australia, Japan, India and Taiwan, some of which had very high HDV prevalence in the past, have shown a decline in the incidence, but high prevalence persists in some. Intravenous drug abusers, homosexual men and women, prostitutes, and people on hemodialysis are the groups with very high HDV prevalence.

Hepatitis D virus infection, replication and cross-talk with the hepatitis B virus

Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a single open reading frame(ORF)and requires HBV supplying surface antigens(HBsAgs)to assemble a new HDV virion.During HDV replication,two isoforms of a delta antigen,a small delta antigen(SDAg)and a large delta antigen(LDAg),are produced from the same ORF of the HDV genome.The SDAg is required for HDV replication,whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA.Various clinical outcomes of HBV/HDV dual infection have been reported,but the molecular interaction between HBV and HDV is poorly understood,especially regarding howHBV and HDV compete with HBsAgs for assembling virions.In this paper,we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export.Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications(PTMs),including acetylation,phosphorylation,and isoprenylation,we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling,LDAg PTMs,and nuclear export mechanisms in this review.

Innate immune recognition and modulation in hepatitis D virus infection

Hepatitis D virus(HDV)is a global health threat with more than 15 million humans affected.Current treatment options are largely unsatisfactory leaving chronically infected humans at high risk to develop liver cirrhosis and hepatocellular carcinoma.HDV is the only human satellite virus known.It encodes only two proteins,and requires Hepatitis B virus(HBV)envelope protein expression for productive virion release and spread of the infection.How HDV could evolve and why HBV was selected as a helper virus remains unknown.Since the discovery of Na+-taurocholate co-transporting polypeptide as the essential uptake receptor for HBV and HDV,we are beginning to understand the interactions of HDV and the immune system.While HBV is mostly regarded a stealth virus,that escapes innate immune recognition,HBV-HDV coinfection is characterized by a strong innate immune response.Cytoplasmic RNA sensor melanoma differentiation antigen 5 has been reported to recognize HDV RNA replication and activate innate immunity.Innate immunity,however,seems not to impair HDV replication while it inhibits HBV.In this review,we describe what is known up-to-date about the interplay between HBV as a helper and HDV’s immune evasion strategy and identify where additional research is required.

Treatment of chronic hepatitis delta virus with peg-interferon and factors that predict sustained viral response

AIM： To observe the efficacy of peg-interferon in the treatment of hepatitis delta virus （HDV） and to identify the factors that would be predictive of the sustained viral response （SVR）. METHODS： This prospective study was conducted in Medical Unit IV of the Liaquat University of Medi- cal and Health Sciences Hospital Jamshoro from June 2008 to September 2011. This study cohort included all patients of either sex who presented during this time with hepatitis B surface antigen positivity, hepa- titis B virus DNA 〉 20 000 IU/ml, serum glutamic py- ruvic transaminase （SGPT） 〉 2（upper limit of normal）, HDV-RNA positivity with fibrosis stage ≥ 2. Informed consent was obtained from each of these individuals. Patients were diagnosed with hepatitis D on the ba- sis of detectable viral antibodies and the presence of HDV-RNA in their serum. A liver biopsy was performed in all cases and fibrosis staging was performed in ac- cordance with the METAVIR scoring system. All eligible patients were administered peg-interferon at a weekly dosage of 1.5 μg/kg body weight for 48 wk. HDV-RNA was assayed at the end of this treatment period and again at 24 wk later. A biochemical response was de- termined by a normalization of SGPT at the end of the treatment or during follow up. The end of treatment response was defined by a HDV-RNA negative status. A sustained virological response was defined by unde- tectable serum HDV-RNA at six months after the end of treatment. RESULTS： Among the 277 patients enrolled in our present study, 238 completed a course of peg-interfer- on therapy of which 180 （75.6%） were male and 58 （24.4%） female. Biochemical responses were achieved in 122/238 （51.3%） patients. End of treatment re- sponses were achieved in 71/238 （29.8%） cases. A SVR was achieved in 70 of these patients （29.4%）. A strong association was found between the SVR and the end of treatment responses （P = 0.001）, biochemical responses （P = 0.001） and the degree of fibrosis （P = 0.002）. CONCLUSION： Peg-interferon therapy can induce re- mission in nearly one third of patients harboring HDV.

Prevalence and Predictors of Viral Hepatitis D Co-Infection in Chronic HbsAg Carriers

The characteristics of viral hepatitis B and D co-infection are poorly documented in Chad. The aim of our study was to determine the prevalence of HBV/HDV co-infection and the characteristics of this co-infection. Materials and Methods: This was a retrospective study including all patients with chronic HBsAg carriers referred in our department from January 2014 to December 2018. Non-inclusion criteria were: absence of anti-HDV testing, presence of anti-viral hepatitis C or Human Immunodeficiency Virus antibodies or excessive alcohol consumption. The variables studied were age, sex, blood transaminase level, HBV DNA level, HDV RNA level, and liver fibrosis and activity score (Actitest Fibrotest). The prevalence of HDV and the characteristics of HDV/HBV co-infection were determined. Results: During the study period, 403 patients were seen in these two hospitals for chronic HBsAg carriage. Of these, 378 (75%) had performed the anti HDV assay. Anti-HDV antibodies were positive in 53 patients (14%). In multivariate analysis, HBV/HDV co-infected patients were less frequently HBeAg positive (5.4% vs. 28.1%;p = 0.0001), older (35 years vs. 32 years;p = 0.001), and more frequently had significant necrotic-inflammatory activity (3.9% vs. 3.2%;p = 0.031) compared with mono infected patients. Neither gender (76.9% male vs. 77.4% male;p = ns), nor viral load (median 530 IU/ml vs. 195 IU/ml;p = ns), nor significant liver fibrosis (35.1% vs. 47.1%;p = ns), nor transaminases (median 26 vs. 32 IU/ml) were different with mono infected patients. Conclusion: VHD is common in Chad. It is associated with increased hepatic necrotic-inflammatory activity.

Hepatitis D in Patients Infected with Hepatitis B Virus in Cotonou:Characteristics and Risk Factors

Introduction: Hepatitis D virus (HDV) is a satellite virus of hepatitis B virus (HBV). The purpose of this work was to describe the epidemiological, clinical and biological characteristics of HBV/HDV co-infection and the factors associated with this co-infection in Cotonou. Methods: This was a cross-sectional, descriptive study with prospective data collection. It took place from June to October 2016 at CNHU/HKM and the Atinkanmey Polyclinic in Cotonou. Subjects over 15 years of age with HBsAg and untreated for hepatitis were included consecutively. Sociodemographic, clinical and biological characteristics were collected for each patient using only a standardized questionnaire. Then, a blood sample was taken for the determination of anti-HDV antibodies as well as the viral load of HBV. Results: A total of 156 subjects were included, predominantly male (sex-ratio = 2), and of median age 36 years. The majority were monogamous married (50%) or single (41.7%), and were from south of Benin (84.6%). Most subjects were asymptomatic (49.4%). The prevalence of total HDV antibodies was 3.9% (6/156). In subjects with total HDV antibodies, the prevalence of HDV IgM was 33.3%. Origin in northern Benin appears to be a risk factor for HDV infection (p = 0.042). Similarly, married subjects were statistically more infected with HDV than unmarried subjects (p = 0.002). Conclusion: The prevalence of HDV infection varies according to the origin of the patients and their marital status.

Prospective study of hepatitis B and D epidemiology and risk factors in Romania:A 10-year update

BACKGROUND The global burden of hepatitis D virus(HDV)infection represents a major medical challenge and a public health crisis worldwide.However,there is a lack of accurate data on the epidemiology and risk factors for HDV.Hepatitis B virus(HBV)and HDV coinfection causes the most severe form of viral hepatitis,leading to a higher cumulative incidence of liver-related events compared with HBV monoinfection,including the need for liver transplantation and death.AIM To investigate the epidemiology,natural history,risk factors and clinical management of HBV and HDV coinfection in Romanian patients.METHODS This prospective study was conducted between January and July 2022 in six tertiary gastroenterology and hepatology referral centres in Romania.All consecutive adults admitted for any gastroenterology diagnosis who were HBV-positive were enrolled.Patients with acute hepatitis or incomplete data were excluded.Of the 25390 individuals who presented with any type of gastroenterology diagnosis during the study period,963 met the inclusion criteria.Testing for anti-HDV antibodies and HDV RNA was performed for all participants.Demographic and risk factor data were collected by investigators using medical charts and patient questionnaires.All data were stored in an anonymized online database during the study.RESULTS The prevalence of HBV was 3.8%;among these patients,the prevalence of HBV/HDV coinfection was 33.1%.The median age of the study population was 54.0 years,and it consisted of 55.1%men.A higher prevalence of HBV/HDV coinfection was observed in patients 50–69 years old.Patients with HBV/HDV coinfection were significantly older than those with HBV monoinfection(P=0.03).Multivariate multiple regression analysis identified female gender(P=0.0006),imprisonment(P<0.0001),older age at diagnosis(P=0.01)and sexual contact with persons with known viral hepatitis(P=0.0003)as significant risk factors for HDV.CONCLUSION This study shows that HDV infection among those with HBV remains endemic in Romania and updates our understanding of HDV epidemiology and associated risk factors.It emphasizes the need for systematic screening for HDV infection and collaborative initiatives for controlling and preventing HBV and HDV infection.

Viral hepatitis update: Progress and perspectives

Viral hepatitis,secondary to infection with hepatitis A,B,C,D,and E viruses,are a major public health problem and an important cause of morbidity and mortality.Despite the huge medical advances achieved in recent years,there are still points of conflict concerning the pathogenesis,immune response,development of new and more effective vaccines,therapies,and treatment.This review focuses on the most important research topics that deal with issues that are currently being solved,those that remain to be solved,and future research directions.For hepatitis A virus we will address epidemiology,molecular surveillance,new susceptible populations as well as environmental and food detections.In the case of hepatitis B virus,we will discuss host factors related to disease,diagnosis,therapy,and vaccine improvement.On hepatitis C virus,we will focus on pathogenesis,immune response,direct action antivirals treatment in the context of solid organ transplantation,issues related to hepatocellular carcinoma development,direct action antivirals resistance due to selection of resistanceassociated variants,and vaccination.Regarding hepatitis D virus,we describe diagnostic methodology,pathogenesis,and therapy.Finally,for hepatitis E virus,we will address epidemiology(including new emerging species),diagnosis,clinical aspects,treatment,the development of a vaccine,and environmental surveillance.

Viral hepatitis:Past,present,and future

Each hepatitis virus—Hepatitis A,B,C,D,E,and G—poses a distinct scenario to the patient and clinician alike.Since the discovery of each virus,extensive knowledge regarding epidemiology,virologic properties,and the natural clinical and immunologic history of acute and chronic infections has been generated.Basic discoveries about host immunologic responses to acute and chronic viral infections,combined with virologic data,has led to vaccines to prevent Hepatitis A,B,and E and highly efficacious antivirals for Hepatitis B and C.These therapeutic breakthroughs are transforming the fields of hepatology,transplant medicine in general,and public and global health.Most notably,there is even an ambitious global effort to eliminate chronic viral hepatitis within the next decade.While attainable,there are many barriers to this goal that are being actively investigated in basic and clinical labs on the local,national,and international scales.Herein,we discuss pertinent clinical information and recent organizational guidelines for each of the individual hepatitis viruses while also synthesizing this information with the latest research to focus on exciting future directions for each virus.

Viral hepatitis:Milestones,unresolved issues,and future goals

In this review the current overall knowledge on hepatitis A,B,C,D,and E will be discussed.These diseases are all characterized by liver inflammation but have significant differences in distribution,transmission routes,and outcomes.Hepatitis B virus and hepatitis C virus are transmitted by exposure to infected blood,and in addition to acute infection,they can cause chronic hepatitis,which in turn can evolve into cirrhosis.It is estimated that more than 300 million people suffer from chronic hepatitis B or C worldwide.Hepatitis D virus,which is also transmitted by blood,only affects hepatitis B virus infected people,and this dual infection results in worse liver-related outcomes.Hepatitis A and E spread via the fecal-oral route,which corresponds mainly to the ingestion of food or water contaminated with infected stools.However,in developed countries hepatitis E is predominantly a zoonosis.Although hepatitis A virus and hepatitis E virus are usually responsible for a self-limiting hepatitis,a serious,rarely fatal illness is also possible,and in immunosuppressed patients,such as organ transplant recipients,hepatitis E virus infection can become chronic.The description of goals achieved,unresolved issues,and the latest research on this topic may make it possible to speculate on future scenarios in the world of viral hepatitis.

Viral hepatitis and hepatocellular carcinoma:From molecular pathways to the role of clinical surveillance and antiviral treatment

Hepatocellular carcinoma(HCC)is a global health challenge.Due to the high prevalence in low-income countries,hepatitis B virus(HBV)and hepatitis C virus infections remain the main risk factors for HCC occurrence,despite the increasing frequencies of non-viral etiologies.In addition,hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection.The molecular processes underlying HCC development are complex and various,either independent from liver disease etiology or etiology-related.The reciprocal interlinkage among non-viral and viral risk factors,the damaged cellular microenvironment,the dysregulation of the immune system and the alteration of gutliver-axis are known to participate in liver cancer induction and progression.Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis.The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance,both through clinical-biochemical scores and periodic ultrasound assessment.This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.

Viral hepatitis in 2021:The challenges remaining and how we should tackle them

Viral hepatitis results in 1.4 million deaths annually.The World Health Organization(WHO)set an ambitious target to eliminate viral hepatitis by 2030,but significant challenges remain.These include inequalities in access to healthcare,reaching at risk populations and providing access to screening and effective treatment.Stigma around viral hepatitis persists and must be addressed.The WHO goal of global elimination by 2030 is a worthy aim,but remains ambitious and the coronavirus 2019 pandemic undoubtedly has set back progress.This review article will focus on hepatitis A to E,highlighting problems that have been resolved in the field over the past decade,those that remain to be resolved and suggest directions for future problem solving and research.

Impact of comorbidities on the severity of chronic hepatitis B at presentation

AIM:To evaluate the clinical relevance of each cofactor on clinical presentation of chronic hepatitis B.METHODS:Out of 1366 hepatitis B surface antigen(HBsAg) positive subjects consecutively observed in 79 Italian hospitals,53(4.3%) showed as the only cofactor hepatitis D virus(HDV) infection [hepatitis B virus(HBV)/HDV group],130(9.5%) hepatitis C virus(HCV)(group HBV/HCV),6(0.4%) human immunodeficiencyvirus(HIV)(group HBV/HIV),138(10.2%) alcohol abuse(group HBV/alcohol);109(8.0%) subjects had at least two cofactors and 924 were in the cofactor-free(CF) group.RESULTS:Compared with patients in group CF those in group HBV/alcohol were older and more frequently had cirrhosis(P < 0.001),those in group HBV/HDV were younger(P < 0.001),more frequently resided in the south of the country and had cirrhosis(P <0.001),those in group HBV/HCV were older(P < 0.001) and more frequently had cirrhosis(P < 0.001).These cofactors were all independent predictors of liver cirrhosis in HBsAg positive patients.Multivariate analysis showed that an older age [odds ratio(OR) 1.06,95% CI:1.05-1.08],alcohol abuse with more than 8 drinks daily(OR 2.89,95% CI:1.81-4.62) and anti-HDV positivity(OR 3.48,95% CI:2.16-5.58) are all independently associated with liver cirrhosis.This association was found also for anti-HCV positivity in univariate analysis,but it was no longer associated(OR 1.23,95% CI:0.84-1.80) at multivariate analysis.CONCLUSION:Older age,HDV infection and alcohol abuse are the major determinants of severe liver disease in chronic HBV infection,while HCV replication plays a lesser role in the severity of hepatic damage.