Management of autoimmune hepatitis induced by hepatitis delta virus

Approximately 12-72 million people worldwide are co-infected with hepatitis B virus(HBV)and hepatitis delta virus(HDV).This concurrent infection can lead to several severe outcomes with hepatic disease,such as cirrhosis,fulminant hepatitis,and hepatocellular carcinoma,being the most common.Over the past few decades,a correlation between viral hepatitis and autoimmune diseases has been reported.Furthermore,autoantibodies have been detected in the serum of patients co-infected with HBV/HDV,and autoimmune features have been reported.However,to date,very few cases of clinically significant autoimmune hepatitis(AIH)have been reported in patients with HDV infection,mainly in those who have received treatment with pegylated interferon.Interestingly,there are some patients with HBV infection and AIH in whom HDV infection is unearthed after receiving treatment with immunosuppressants.Consequently,several questions remain unanswered with the challenge to distinguish whether it is autoimmune or“autoimmune-like”hepatitis being the most crucial.Second,it remains uncertain whether autoimmunity is induced by HBV or delta virus.Finally,we investigated whether the cause of AIH lies in the previous treatment of HDV with pegylated interferon.These pressing issues should be elucidated to clarify whether new antiviral treatments for HDV,such as Bulevirtide or immu-nosuppressive drugs,are more appropriate for the management of patients with HDV and AIH.

Hepatitis delta virus: From infection to new therapeutic strategies

The hepatitis delta virus(HDV)is a small RNA virus that encodes a single protein and which requires the hepatitis B virus(HBV)-encoded hepatitis B surface antigen(HBsAg)for its assembly and transmission.HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations,specifically intravenous drug users,practitioners of high-risk sexual behaviours,and patients with cirrhosis and hepatocellular carcinoma.The chronic form of HDV-related hepatitis is usually severe and rapidly progressive.Patterns of the viral infection itself,including the status of co-infection or super-infection,virus genotypes(both for HBV and HDV),and persistence of the virus’replication,influence the outcome of the accompanying and manifested liver disease.Unfortunately,disease severity is burdened by the lack of an effective cure for either virus type.For decades,the main treatment option has been interferon,administered as mono-therapy or in combination with nucleos(t)ide analogues.While its efficacy has been reported for different doses,durations and courses,only a minority of patients achieve a sustained response,which is the foundation of eventual improvement in related liver fibrosis.The need for an efficient therapeutic alternative remains.Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle;the most promising among these are myrcludex B,which inhibits virus entry into hepatocytes,lonafarnib,which inhibits farnesylation of the viral-encoded LHDAg large hepatitis D antigen,and REP-2139,which interferes with HBsAg release and assembly.

Structural and nucleic acid binding properties of hepatitis delta virus small antigen

AIM To further characterize the structure and nucleic acid binding properties of the 195 amino acid small delta antigen, S-HDAg, a study was made of a truncated form of S-HDAg, comprising amino acids 61-195(?60HDAg), thus lacking the domain considered necessary for dimerization and higher order multimerization.METHODS Circular dichroism, and nuclear magnetic resonance experiments were used to assess the structure of ?60HDAg. Nucleic acid binding properties were investigated by gel retardation assays. RESULTS Results showed that the truncated ?60HDAg protein is intrinsically disordered but compact, whereas the RNA binding domain, comprising residues 94-146, adopts a dynamic helical conformation. We also found that ?60HDAg fails to multimerize but still contains nucleic acid binding activity, indicating that multimerization is not essential for nucleic acid binding. Moreover, in agreement with what has been previously reported for full-length protein, no apparent specificity was found for the truncated protein regarding nucleic acid binding.CONCLUSION Taken together these results allowed concluding that ?60HDAg is intrinsically disordered but compact; ?60HDAg is not a multimer but is still capable of nucleic acid binding albeit without apparent specificity.

Performance of Hepatitis Delta Virus(HDV)RNA Testing for the Diagnosis of Active HDV Infection:Systematic Review and Meta-analysis

Background and Aims:Hepatitis delta virus(HDV)is a defective virus and causes severe liver disease.Several HDV RNA assays have been developed,however the diagnostic efficacy remains unclear.This systematic review and metaanalysis aims to evaluate the diagnostic accuracy of HDV RNA assays to aid in the diagnosis of active hepatitis D.Methods:The PubMed,Embase,and Cochrane Library databases were systematically searched from the beginning to June 31,2022.Information on the characteristics of the literature and data on sensitivity,specificity,and area under curve(AUC)of the receiver operating characteristic(ROC)were extracted.Stata 14.0 was used for meta-analysis of the combined sensitivity,specificity,positive likelihood ratio,and negative likelihood ratio.Results:A total of 10 studies were included in the meta-analysis.The summary sensitivity,specificity,positive likelihood ratio,negative likelihood ratio,and diagnostic odds ratio of HDV RNA assays for HDV diagnosis were 0.92(95%CI:0.87-0.95),0.90(95%CI:0.86-0.93),7.74(95%CI:5.31-11.29),0.10(95%CI:0.06-0.18)and 99.90(95%CI:47.08-211.99),respectively.The AUC of the pooled ROC curve was 0.95(95%CI:0.92-0.96).Conclusions:The results show that HDV RNA assays had high diagnostic performance.However,that is limited by the number and quality of studies.Standard protocols for the development of assays by manufacturers and larger studies on the use of the assays are needed.

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 and liver transplantation: Indications and outcomes

Hepatitis D virus(HDV)is a dependent virus that relies on hepatitis B virus for its replication and transmission.Chronic hepatitis D is a severe form of viral hepatitis that can result in end stage liver disease.Currently,pegylated interferon alpha is the only approved therapy for chronic HDV infection and is associated with significant side effects.Liver transplantation(LT)is the only treatment option for patients with end-stage liver disease,hepatocellular carcinoma,or fulminant hepatitis due to coinfection with HDV.As LT for HDV and hepatitis B virus coinfection is uncommon in the United States,most data on the long-term impact of LT on HDV are from international centers.In this review,we discuss the indications and results of LT with treatment options in HDV patients.

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis,cancer,and liver failure.Liver cancer is the third leading cause of cancer-associated mortality,of which hepatocellular carcinoma(HCC)represents 90%of all primary liver cancers.Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management.Chronic infection with hepatitis B virus(HBV),hepatitis delta virus(HDV),and hepatitis C virus(HCV)are the greatest etiological risk factors for HCC.Due to the significant role of chronic viral infection in HCC development,it is important to investigate direct(viral associated)and indirect(immune-associated)mechanisms involved in the pathogenesis of HCC.Common mechanisms used by HBV,HCV,and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response,immune and viral protein-mediated oxidative stress,and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection,and metabolic reprogramming leading to steatosis is driven by HCV infection.The current review aims to provide a brief overview of HBV,HCV and HDV molecular biology,and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC,and current as well as emerging treatments for HCC.

Folding Kinetics of HDV Ribozyme with C13A:G82U and A16U:U79A Mutations

Gene mutations influence the folding kinetics of hepatitis delta virus （HDV） ribozyme. In this work, we study the effect of the double mutation on the folding kinetics of HDV ribozyme. By using the master equation method combined with RNA folding free energy landscape, we predict the folding kinetics of C13A：G82U and A16U：U79A mutated HDV sequences. Their folding pathways are identified by recursively searching the states with high net flux-in（out） population starting from the native state. The results indicate that the folding kinetics of C 13A：G82U mutation sequence is bi-phasic, which is similar to the wild type （wtHDV） sequence. While the folding kinetics of A16U：U79A mutation sequence is mono-phasic, it quickly folds to the native state in 30 s. Thus, the folding kinetics of double mutated HDV ribozyme depends on the mutation sites.