We searched PubMed, Embase, and the Cochrane Library, with no date or language restrictions. We used the search terms “hepatitis delta virus”, “hepatitis D virus”, and “Delta hepatitis”, in combination with the following terms: “replication”, “epidemiology”, “genotype”, “transmission”, “clinical presentation”, “pathogenesis”, “diagnosis”, and “treatment”. We largely selected publications in the past 5 years. We searched the reference lists of articles identified by this strategy, and selected
SeminarHepatitis delta virus
Introduction
Hepatitis delta virus (HDV) is a small, defective RNA virus that is related more to plant viroids than to other human pathogens. It can propagate only in an individual who has coexistent hepatitis B virus (HBV), either after simultaneous transmission of the two viruses, or via superinfection of an established HBV carrier.1 Clinical expression of HDV is wide, and although it sometimes follows a benign course, the disease is clinically important. Studies have consistently shown that most patients with HBV and HDV co-infection have more severe liver disease,2, 3 more rapid progression to cirrhosis,4, 5 and increased hepatic decompensation and death6, 7 than do those with HBV infection alone. Advances have improved our understanding of the transmission, replication, and pathogenesis of the virus; however, we do not yet fully understand the mechanisms by which it causes such severe liver disease. In this Seminar, we will review the biology, pathogenesis, epidemiology, natural history, clinical presentation, and management of this disease. We discuss how the most recent evidence might help in the design of novel therapeutic agents for HDV, the most severe of all the chronic viral hepatitides.
Section snippets
Historical perspective
Rizzetto and colleagues8 discovered HDV in the mid-1970s while investigating a group of patients with HBV who had severe hepatitis. They showed a novel antigen-antibody system, which they called delta-antigen and delta-antibody, and noted that this system occurred only in patients with HBV and was associated with severe liver disease. The disease was later associated with a particle consisting of an RNA genome of low molecular weight that was encapsidated by HBV envelope proteins.9 This
Viral structure
The HDV virion is a small, spherical particle of about 36 nm in diameter. It is composed of an outer coat containing the three HBV envelope proteins termed large, medium, and small hepatitis B surface antigen (HBsAg),10 and host lipids surrounding an inner nucleocapsid, consisting of a single-stranded, circular RNA of 1679 nucleotides and about 200 molecules of hepatitis D antigen (HDAg) per genome.11, 12 Because of the high GC content of the nucleotide sequence,12 the circular genome, which is
Virus life cycle
The HDV receptor on the human hepatocyte remains unidentified, but is thought to be the same as that of HBV because of the shared identity of their outer coat. HDV infectivity is dependent upon a receptor-binding domain in the N-terminal region of the pre-S1 moiety of large HBsAg.14, 15 For HDV infectivity, this domain requires modification by myristoylation.16 Fine mapping has identified aminoacid residues 9–15 as the receptor binding site.17 A second infectivity region in the antigenic loop
Viral heterogeneity
The sequence of the HDV RNA genome is highly variable, and there is divergence of up to 16% within the same genotype, compared with 20–40% between different genotypes. Even in one individual the virus is a pool of closely related quasispecies.40 This divergence is partly due to the scarcity of proofreading ability of RNA polymerases. The average mutation rate for the non-coding region of HDV is about 3·52×10−3 base substitutions per genome site per year, whereas for the HDV coding region, it is
Epidemiology
Of the 350 million chronic carriers of HBV worldwide, more than 15 million have serological evidence of exposure to HDV.47 Traditionally, the regions with high rates of HDV carriage where the virus is endemic are central Africa, the Horn of Africa, the Amazon Basin, eastern and Mediterranean Europe, the Middle East, and parts of Asia.48 Rates of HDV infection are generally highest in regions where HBV is endemic, but there are exceptions—eg, HDV co-infection is uncommon in Vietnam and Indonesia.
Modes of transmission
Like HBV, HDV is transmitted via the parenteral route through exposure to infected blood or body fluids, and tests in chimpanzees have shown that only a very small inoculum is sufficient to transmit infection.86 Thus, transmission rates remain high in intravenous drug users. There is evidence for sexual transmission,87 and people with high-risk sexual activity are at increased risk for infection.88 Intrafamilial spread occurs and seems to be common in regions of high prevalence, which is known
Clinical expression and natural history
With HBV and HDV co-infection, the fate of HDV is determined by the host response to HBV, which in more than 95% of adults results in viral clearance. Acute co-infection can be more severe than acute mono-infection with HBV, thereby resulting in acute liver failure; however, disease expression is wide-ranging. By contrast, HDV superinfection of an individual with chronic HBV results in chronic HDV infection in most people. In the remainder, replication of HDV stops, and the natural history of
Pathogenesis
The mechanisms that determine whether an individual clears HDV spontaneously or becomes chronically infected, and the processes that cause severe hepatitis and rapid progression of fibrosis, remain unclear. HDAg is not directly cytotoxic in human hepatocytes or in transgenic mice.113, 114 Viral load of HDV was not associated with severity of liver injury in a cohort of patients in a clinical trial.106 However, evidence from observational cohort studies suggests that in the acute phase of HDV
Diagnosis
The development of anti-HDV antibodies is universal in individuals with HDV; therefore, every patient who is HBsAg positive should be tested for anti-HDV IgG antibodies, which persist even after the patient has cleared HDV infection. Although active HDV infection was diagnosed historically by the presence of anti-HDV IgM antibodies, it is now confirmed by the detection of serum HDV RNA with sensitive real-time PCR assay.127 Covert HDV infection has not been reported; therefore, testing of HDV
Treatment
The ideal endpoint of any treatment for HDV is not only clearance of HDV, but also of the helper virus HBV. Hence, a major challenge of defining the optimum therapy is the added complexity of targeting two persistent viral infections. A meta-analysis of five studies of treatment with recombinant interferon concluded that such treatment was beneficial for HDV in terms of serum aminotransferase reduction, but the response was poorly sustained after discontinuation of treatment, and was not
Search strategy and selection criteria
References (156)
Hepatitis D: thirty years after
J Hepatol
(2009)- et al.
Fulminant B viral hepatitis: role of delta agent
Gastroenterology
(1984) - et al.
Rapidly progressive HBsAg-positive hepatitis in Italy. The role of hepatitis delta virus infection
J Hepatol
(1987) - et al.
A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma
Gastroenterology
(2009) - et al.
Myristoylation signal transfer from the large to the middle or the small HBV envelope protein leads to a loss of HDV particles infectivity
Virology
(2007) - et al.
The hepatitis delta virus RNA genome interacts with the human RNA polymerases I and III
Virology
(2009) - et al.
Immunohistochemical differentiation of hepatitis D virus genotypes
Hepatology
(2000) - et al.
Genotyping of hepatitis D virus by restriction-fragment length polymorphism and relation to outcome of hepatitis D
Lancet
(1995) - et al.
Hepatitis delta virus as a global health problem
Vaccine
(1990) - et al.
Geographic distribution and genetic variability of hepatitis delta virus genotype I
Virology
(1997)
Decrease in HDV endemicity in Italy
J Hepatol
Chronic hepatitis D: a vanishing Disease? An Italian multicenter study
Hepatology
Evidence of transmission of hepatitis D virus to spouses from sequence analysis of the viral genome
Hepatology
Delta hepatitis in inapparent carriers of hepatitis B surface antigen. A disease simulating acute hepatitis B progressive to chronicity
Gastroenterology
Long-term delta superinfection in hepatitis B surface antigen carriers and its relationship to the course of chronic hepatitis
Gastroenterology
Prevalence of delta-antibody among chronic hepatitis B virus infected patients in the Los Angeles area: its correlation with liver biopsy diagnosis
Gastroenterology
Long-term clinical and virological outcome after liver transplantation for cirrhosis caused by chronic delta hepatitis
Hepatology
HBsAg level at time of liver transplantation determines HBsAg decrease and anti-HBs increase and affects HBV DNA decrease during early immunoglobulin administration
J Hepatol
Liver transplantation and HBsAg-positive postnecrotic cirrhosis: adequate immunoprophylaxis and delta virus co-infection as the significant determinants of long-term prognosis
J Hepatol
Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients
Gastroenterology
Delta virus infection and severe hepatitis. An epidemic in the Yucpa Indians of Venezuela
Ann Intern Med
Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B
J Infect Dis
Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep)
Gut
Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers
Gut
Delta Agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees
Proc Natl Acad Sci USA
The role of the HBV envelope proteins in the HDV replication cycle
Curr Top Microbiol Immunol
Parameters of human hepatitis delta virus genome replication: the quantity, quality, and intracellular distribution of viral proteins and RNA
J Virol
Structure, sequence and expression of the hepatitis delta (delta) viral genome
Nature
The hepatitis delta (delta) virus possesses a circular RNA
Nature
Mapping of the hepatitis B virus pre-S1 domain involved in receptor recognition
J Virol
Characterization of a hepatitis B and hepatitis delta virus receptor binding site
Hepatology
Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction
J Virol
Entry of hepatitis delta virus requires the conserved cysteine residues of the hepatitis B virus envelope protein antigenic loop and is blocked by inhibitors of thiol-disulfide exchange
J Virol
A function essential to viral entry underlies the hepatitis B virus “a” determinant
J Virol
Characterization of nuclear targeting signal of hepatitis delta antigen: nuclear transport as a protein complex
J Virol
RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus
J Virol
RNA-templated replication of hepatitis delta virus: genomic and antigenomic RNAs associate with different nuclear bodies
J Virol
An ultraviolet-sensitive RNA structural element in a viroid-like domain of the hepatitis delta virus
Science
Human hepatitis delta virus RNA subfragments contain an autocleavage activity
Proc Natl Acad Sci USA
Origin of hepatitis delta virus
Future Microbiol
A genomewide search for ribozymes reveals an HDV-like sequence in the human CPEB3 gene
Science
A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24 delta and p27 delta
J Virol
Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated knockdown of ADAR1 but not ADAR2 expression
J Virol
Structure and replication of hepatitis delta virus RNA
Curr Top Microbiol Immunol
Stimulation of RNA polymerase II elongation by hepatitis delta antigen
Science
Mutational analysis of delta antigen: effect on assembly and replication of hepatitis delta virus
J Virol
Identification of a prenylation site in delta virus large antigen
Science
ERK1/2-mediated phosphorylation of small hepatitis delta antigen at serine 177 enhances hepatitis delta virus antigenomic RNA replication
J Virol
Phosphorylation of serine 177 of the small hepatitis delta antigen regulates viral antigenomic RNA replication by interacting with the processive RNA polymerase II
J Virol
Modification of small hepatitis delta virus antigen by SUMO protein
J Virol
Cited by (426)
Adjusted estimate of the prevalence of hepatitis delta virus in 25 countries and territories
2024, Journal of HepatologyPrevalence of hepatitis D virus infection in Central Italy has remained stable across the last 2 decades with dominance of subgenotypes 1 and characterized by elevated viral replication
2024, International Journal of Infectious DiseasesWhat Is the Real Epidemiology of Hepatitis D Virus and Why so Many Mixed Messages?
2023, Clinics in Liver Disease