Elsevier

The Lancet

Volume 378, Issue 9785, 2–8 July 2011, Pages 73-85
The Lancet

Seminar
Hepatitis delta virus

https://doi.org/10.1016/S0140-6736(10)61931-9Get rights and content

Summary

Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.

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

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

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