Questions

Hepatitis D virus — Questions

Study questions about Hepatitis D virus — exam-style, clinical-scenario and FAQ.

Mock Exam mode

Sit this set one question at a time. Multiple-choice questions mark themselves; written questions reveal a tickable mark scheme so you can score your own answer. You get a combined score at the end.

8 questions: 3 MCQ, 5 written.

High-priority (past-paper) questions only

A complete answer separates the geographic epidemiology of the infection from the structural description of the genome, and links both to the dependence of hepatitis D virus (HDV) on hepatitis B virus (HBV).

Endemicity. HDV infects only people who are already hepatitis B surface antigen (HBsAg) positive, so its distribution is bounded by HBV prevalence but is far more geographically uneven. Roughly 5% of HBsAg carriers worldwide carry HDV, giving global estimates spanning about 12 million (the commonly cited figure) to 72 million (the higher modelled estimate), but prevalence clusters sharply into high-endemicity foci. Long-recognised hotspots include the Mediterranean basin, Eastern Europe, the Middle East (notably Pakistan and Iran), Mongolia, the Amazon basin of South America, and parts of Central and West Africa. In several of these settings 20 to 60% of HBsAg carriers are co-infected.

The pattern is dynamic. Universal infant HBV vaccination has reduced HDV prevalence in countries such as Italy by removing the susceptible HBsAg-positive pool, while migration has introduced new foci into low-prevalence regions of Northern and Western Europe. Eight genotypes (1 to 8) show geographic structure: genotype 1 is global, genotype 3 in the Amazon is associated with particularly severe disease, and genotypes 5 to 8 are largely African.

The genome. HDV has the smallest genome of any virus infecting humans: approximately 1.7 kilobases of circular, negative-sense, single-stranded RNA. Extensive internal base-pairing folds it into an unbranched rod-like structure. It contains a ribozyme, a self-cleaving RNA sequence that resolves the multimeric products of rolling-circle replication. The genome encodes a single protein, the delta antigen, produced in a small and a large form; host adenosine-deaminase RNA editing generates the large form. The virus carries no polymerase of its own and is replicated in the nucleus by host RNA polymerase II, and it borrows the HBsAg envelope of HBV to assemble infectious particles.

The vignette describes hepatitis D superinfection: hepatitis D virus (HDV) acquired by someone with established chronic hepatitis B virus (HBV), signalled by long-standing hepatitis B surface antigen (HBsAg) positivity with HDV RNA appearing for the first time. Superinfection lands on a fully supported HBV background, so the delta virus chronifies in about 70 to 90% of cases (option C), the most rapidly progressive form of chronic viral hepatitis, with accelerated fibrosis and a raised risk of cirrhosis and hepatocellular carcinoma.

This is separated from co-infection, where HBV and HDV are acquired together: that behaves like an acute hepatitis B, self-limited in about 95% of immunocompetent adults, with chronic hepatitis D in under 5% (options A and B describe co-infection, not the scenario asked). Option D understates the outcome, and option E overstates it, since the dominant long-term problem of superinfection is chronicity, not near-universal fatal liver failure. New or worsening hepatitis in a known HBsAg carrier should prompt testing for HDV.

Guidance has shifted from risk-based to universal screening: every hepatitis B surface antigen (HBsAg) positive person should be tested at least once for hepatitis D virus (HDV), most efficiently by reflex anti-HDV testing of any HBsAg-positive sample (option A). Risk-based strategies (option B) miss a large share of infections, because risk factors are often unknown or unreported.

Option C is false: delta infection can be present with near-normal enzymes, and HDV typically suppresses hepatitis B virus (HBV) DNA, so a low HBV DNA does not exclude it. Option D confuses the requirement: HDV needs the HBsAg envelope, not hepatitis B e antigen, so patients negative for that antigen are fully susceptible. Option E would leave most cases undiagnosed; identifying HDV changes prognosis and management, and a positive anti-HDV result should be followed by an HDV RNA test to confirm active infection.

The hepatitis D virus (HDV) genome is the smallest of any human virus: about 1.7 kilobases of circular, negative-sense, single-stranded RNA folded into an unbranched rod-like shape (option E). It contains a ribozyme that self-cleaves the multimeric products of replication, and because HDV encodes no polymerase, replication proceeds in the nucleus by host RNA polymerase II through a rolling-circle mechanism. The single protein product, the delta antigen, exists in a small (replication) and a large (assembly) form.

Option A describes hepatitis B virus (partially double-stranded circular DNA, reverse transcriptase); option B a picornavirus-like positive-sense RNA strategy (as in hepatitis A or hepatitis E); option C a segmented cytoplasmic negative-sense RNA virus such as influenza; and option D a large double-stranded DNA virus encoding its own capsid, whereas HDV borrows its envelope (HBsAg) from hepatitis B and has no capsid of its own.

A complete answer gives an ordered cascade from screening serology to confirmatory viral load, and notes who to test and how to assess disease stage.

Who to test. Current guidance favours screening every hepatitis B surface antigen (HBsAg) positive person for hepatitis D virus (HDV) at least once, rather than restricting testing to recognised risk groups, since risk-based screening misses a substantial fraction of cases. Many laboratories achieve this by reflex testing: an anti-HDV assay is run automatically on any HBsAg-positive sample.

The serological and molecular cascade.

Screen with total anti-HDV antibody. A positive result indicates exposure but does not by itself distinguish past from current infection, because antibody persists after clearance.
Confirm active infection with HDV RNA. A quantitative reverse transcription polymerase chain reaction (RT-PCR) on serum confirms ongoing replication and provides a baseline viral load for monitoring. Standardisation against the World Health Organization international unit allows comparison across assays. HDV RNA is the reference marker of active infection.
Genotype where available, since genotype influences prognosis (genotype 1 is global; genotype 3 in the Amazon is more severe).

Staging the liver disease. Active hepatitis D requires assessment of the underlying liver: alanine aminotransferase, a full liver profile and synthetic function (albumin, international normalised ratio), platelet count, and non-invasive fibrosis assessment by transient elastography or the APRI or FIB-4 scores. Because chronic hepatitis D progresses rapidly, established cirrhosis must be sought, and cirrhotic patients enter six-monthly hepatocellular carcinoma surveillance with ultrasound and alpha-fetoprotein. HBV markers (hepatitis B e antigen, HBV DNA) are quantified in parallel, since HDV typically suppresses HBV replication.

A complete answer contrasts the tempo of disease and the principal complications of chronic hepatitis D against hepatitis B alone, and gives the reason for the difference.

Tempo of progression. Chronic hepatitis D is the most rapidly progressive form of chronic viral hepatitis. Cirrhosis develops in a large proportion of patients within 5 to 10 years of chronic infection, considerably faster than in hepatitis B virus (HBV) monoinfection, where progression to cirrhosis typically unfolds over decades. Once cirrhosis is established, hepatitis D carries a higher annual risk of hepatic decompensation and an increased risk of hepatocellular carcinoma compared with HBV alone.

Why hepatitis D is more severe. The acceleration reflects the added burden of a second replicating virus driving immune-mediated injury on top of the HBV background, producing more intense necroinflammation. The route of acquisition shapes outcome: superinfection of an established HBV carrier chronifies in the great majority and is the usual path to progressive disease, whereas simultaneous co-infection mostly resolves like an acute hepatitis B and only occasionally becomes chronic.

The HBV interaction. Hepatitis D characteristically suppresses HBV replication, so HBV DNA is often low or undetectable even as liver disease advances. This can mislead, because a patient who looks like an inactive HBV carrier on HBV markers may in fact have aggressive ongoing delta hepatitis. Outcomes improve only with sustained suppression of HDV RNA or, ideally, loss of hepatitis B surface antigen, which removes the envelope the delta virus requires.

A complete answer states precisely which step of the life cycle hepatitis D virus (HDV) cannot perform alone, and distinguishes what it borrows from hepatitis B virus (HBV) from what it provides itself.

Why HDV is defective. HDV is a satellite virus: it can replicate its genome inside a hepatocyte without help, but it cannot make its own envelope and therefore cannot assemble or transmit infectious particles without a helper. That helper is HBV. Infection with HDV occurs only in people who are also hepatitis B surface antigen (HBsAg) positive.

What HDV provides itself. HDV supplies its own genome (a small circular negative-sense RNA), its ribozyme for processing replication products, and its single protein, the delta antigen. The small delta antigen supports genome replication; the large delta antigen, generated by host RNA editing and modified by farnesylation, drives packaging. Replication itself uses host RNA polymerase II, not an HBV enzyme, which is why nucleos(t)ide analogues that suppress HBV polymerase have no direct effect on HDV.

What it borrows from HBV. The single essential contribution from HBV is the surface (envelope) protein, HBsAg. HDV wraps its ribonucleoprotein in the HBsAg envelope to form an infectious virion, and uses the same preS1-mediated binding to the sodium taurocholate co-transporting polypeptide (NTCP) receptor that HBV uses to enter hepatocytes. This dependence has two consequences: HDV can only be acquired alongside or after HBV, and any therapy or vaccine that removes HBsAg (or prevents HBV infection) also defeats HDV.

A complete answer states why hepatitis D is hard to treat, describes the established and newer agents with their mechanisms, and defines a realistic endpoint.

The therapeutic problem. Chronic hepatitis D is the most rapidly progressive viral hepatitis, yet the delta virus encodes no enzyme of its own to target: it is replicated by host RNA polymerase II. Nucleos(t)ide analogues that suppress hepatitis B virus (HBV) polymerase therefore do nothing directly to hepatitis D virus (HDV). The durable goal of therapy is loss of hepatitis B surface antigen (HBsAg), which removes the envelope HDV depends on, but this is rarely achieved.

Established therapy. Pegylated interferon-alpha was for decades the only option. A 48-week course achieves an undetectable HDV RNA in roughly a quarter of patients, but relapse is common, the drug is poorly tolerated, and it is contraindicated in decompensated cirrhosis. It remains an option in compensated disease.

Newer and emerging therapy.

Bulevirtide is a first-in-class entry inhibitor: a myristoylated lipopeptide derived from the HBV preS1 sequence that binds and blocks the sodium taurocholate co-transporting polypeptide (NTCP), the shared HBV and HDV hepatocyte receptor, preventing infection of new cells. Given as a daily subcutaneous injection, it is licensed in Europe for chronic hepatitis D, reducing HDV RNA and normalising transaminases in a substantial proportion of patients (bile-acid elevation is an expected on-treatment effect of NTCP blockade).
Lonafarnib, a farnesyl-transferase inhibitor, blocks the prenylation step the large delta antigen needs for assembly, and is under trial evaluation, including in combination with interferon.

Realistic goals. Outside the rare achievement of HBsAg loss, therapy aims to suppress HDV RNA, normalise transaminases, and slow fibrosis progression. Access is a major constraint: bulevirtide is licensed mainly in Europe and is not yet widely available in high-burden African and Asian settings.

High priorityExam-styleDiscuss how the endemicity of hepatitis D varies between different settings, and describe the hepatitis D virus genome. [7]
Model answer
A complete answer separates the geographic epidemiology of the infection from the structural description of the genome, and links both to the dependence of hepatitis D virus (HDV) on hepatitis B virus (HBV).

Endemicity. HDV infects only people who are already hepatitis B surface antigen (HBsAg) positive, so its distribution is bounded by HBV prevalence but is far more geographically uneven. Roughly 5% of HBsAg carriers worldwide carry HDV, giving global estimates spanning about 12 million (the commonly cited figure) to 72 million (the higher modelled estimate), but prevalence clusters sharply into high-endemicity foci. Long-recognised hotspots include the Mediterranean basin, Eastern Europe, the Middle East (notably Pakistan and Iran), Mongolia, the Amazon basin of South America, and parts of Central and West Africa. In several of these settings 20 to 60% of HBsAg carriers are co-infected.

The pattern is dynamic. Universal infant HBV vaccination has reduced HDV prevalence in countries such as Italy by removing the susceptible HBsAg-positive pool, while migration has introduced new foci into low-prevalence regions of Northern and Western Europe. Eight genotypes (1 to 8) show geographic structure: genotype 1 is global, genotype 3 in the Amazon is associated with particularly severe disease, and genotypes 5 to 8 are largely African.

The genome. HDV has the smallest genome of any virus infecting humans: approximately 1.7 kilobases of circular, negative-sense, single-stranded RNA. Extensive internal base-pairing folds it into an unbranched rod-like structure. It contains a ribozyme, a self-cleaving RNA sequence that resolves the multimeric products of rolling-circle replication. The genome encodes a single protein, the delta antigen, produced in a small and a large form; host adenosine-deaminase RNA editing generates the large form. The virus carries no polymerase of its own and is replicated in the nucleus by host RNA polymerase II, and it borrows the HBsAg envelope of HBV to assemble infectious particles.
MCQ
A 30-year-old man with chronic hepatitis B (hepatitis B surface antigen positive for eight years) develops an acute severe hepatitis, and hepatitis D virus RNA is now detectable for the first time. Compared with a person who acquires hepatitis B and hepatitis D simultaneously, which outcome is most characteristic of this situation?
- A. Clearance of both viruses in over 95% of cases, with durable immunity and no raised cirrhosis risk
- B. A self-limited illness resolving in about 95% of cases, with chronic hepatitis D in under 5%
- C. Chronic hepatitis D in about 70 to 90%, with accelerated fibrosis and raised cirrhosis risk
- D. Inactive surface-antigen carriage with loss of HDV RNA and normal enzymes within about 3 months
- E. Fulminant hepatic failure in the great majority, with mortality over 80% without emergency transplantation
Show answer
Correct answer: C
The vignette describes hepatitis D superinfection: hepatitis D virus (HDV) acquired by someone with established chronic hepatitis B virus (HBV), signalled by long-standing hepatitis B surface antigen (HBsAg) positivity with HDV RNA appearing for the first time. Superinfection lands on a fully supported HBV background, so the delta virus chronifies in about 70 to 90% of cases (option C), the most rapidly progressive form of chronic viral hepatitis, with accelerated fibrosis and a raised risk of cirrhosis and hepatocellular carcinoma.

This is separated from co-infection, where HBV and HDV are acquired together: that behaves like an acute hepatitis B, self-limited in about 95% of immunocompetent adults, with chronic hepatitis D in under 5% (options A and B describe co-infection, not the scenario asked). Option D understates the outcome, and option E overstates it, since the dominant long-term problem of superinfection is chronicity, not near-universal fatal liver failure. New or worsening hepatitis in a known HBsAg carrier should prompt testing for HDV.
MCQ
According to current recommendations, which hepatitis B surface antigen positive patients should be tested for hepatitis D virus co-infection?
- A. All HBsAg-positive people, screened at least once with an anti-HDV antibody test
- B. Only people who inject drugs or come from high-endemicity regions or report parenteral risk
- C. Only those with raised liver enzymes and hepatitis B virus DNA over 2,000 IU/mL
- D. Only hepatitis B e antigen positive patients
- E. No routine screening; test only after nucleos(t)ide analogue failure
Show answer
Correct answer: A
Guidance has shifted from risk-based to universal screening: every hepatitis B surface antigen (HBsAg) positive person should be tested at least once for hepatitis D virus (HDV), most efficiently by reflex anti-HDV testing of any HBsAg-positive sample (option A). Risk-based strategies (option B) miss a large share of infections, because risk factors are often unknown or unreported.

Option C is false: delta infection can be present with near-normal enzymes, and HDV typically suppresses hepatitis B virus (HBV) DNA, so a low HBV DNA does not exclude it. Option D confuses the requirement: HDV needs the HBsAg envelope, not hepatitis B e antigen, so patients negative for that antigen are fully susceptible. Option E would leave most cases undiagnosed; identifying HDV changes prognosis and management, and a positive anti-HDV result should be followed by an HDV RNA test to confirm active infection.
MCQ
Which statement best describes the hepatitis D virus genome and the way it is replicated?
- A. A small circular partially double-stranded DNA replicated via an RNA pregenome by a virus-encoded reverse transcriptase in the nucleus
- B. A linear positive-sense single-stranded RNA translated as one polyprotein cleaved by a viral protease in the cytoplasm
- C. A segmented negative-sense single-stranded RNA replicated in the cytoplasm by a virion-carried RNA-dependent RNA polymerase
- D. A linear double-stranded DNA replicated in the nucleus by host DNA polymerase, encoding its own capsid and glycoproteins
- E. A small circular negative-sense single-stranded RNA with a self-cleaving ribozyme, replicated by host RNA polymerase II
Show answer
Correct answer: E
The hepatitis D virus (HDV) genome is the smallest of any human virus: about 1.7 kilobases of circular, negative-sense, single-stranded RNA folded into an unbranched rod-like shape (option E). It contains a ribozyme that self-cleaves the multimeric products of replication, and because HDV encodes no polymerase, replication proceeds in the nucleus by host RNA polymerase II through a rolling-circle mechanism. The single protein product, the delta antigen, exists in a small (replication) and a large (assembly) form.

Option A describes hepatitis B virus (partially double-stranded circular DNA, reverse transcriptase); option B a picornavirus-like positive-sense RNA strategy (as in hepatitis A or hepatitis E); option C a segmented cytoplasmic negative-sense RNA virus such as influenza; and option D a large double-stranded DNA virus encoding its own capsid, whereas HDV borrows its envelope (HBsAg) from hepatitis B and has no capsid of its own.
Exam-styleA patient is chronically hepatitis B surface antigen positive. Outline how you would test for and stage hepatitis D virus infection. [6]
Model answer
A complete answer gives an ordered cascade from screening serology to confirmatory viral load, and notes who to test and how to assess disease stage.

Who to test. Current guidance favours screening every hepatitis B surface antigen (HBsAg) positive person for hepatitis D virus (HDV) at least once, rather than restricting testing to recognised risk groups, since risk-based screening misses a substantial fraction of cases. Many laboratories achieve this by reflex testing: an anti-HDV assay is run automatically on any HBsAg-positive sample.

The serological and molecular cascade.
1. Screen with total anti-HDV antibody. A positive result indicates exposure but does not by itself distinguish past from current infection, because antibody persists after clearance.
2. Confirm active infection with HDV RNA. A quantitative reverse transcription polymerase chain reaction (RT-PCR) on serum confirms ongoing replication and provides a baseline viral load for monitoring. Standardisation against the World Health Organization international unit allows comparison across assays. HDV RNA is the reference marker of active infection.
3. Genotype where available, since genotype influences prognosis (genotype 1 is global; genotype 3 in the Amazon is more severe).
Staging the liver disease. Active hepatitis D requires assessment of the underlying liver: alanine aminotransferase, a full liver profile and synthetic function (albumin, international normalised ratio), platelet count, and non-invasive fibrosis assessment by transient elastography or the APRI or FIB-4 scores. Because chronic hepatitis D progresses rapidly, established cirrhosis must be sought, and cirrhotic patients enter six-monthly hepatocellular carcinoma surveillance with ultrasound and alpha-fetoprotein. HBV markers (hepatitis B e antigen, HBV DNA) are quantified in parallel, since HDV typically suppresses HBV replication.
Exam-styleDescribe the natural history of chronic hepatitis D and explain how it differs from hepatitis B monoinfection. [6]
Model answer
A complete answer contrasts the tempo of disease and the principal complications of chronic hepatitis D against hepatitis B alone, and gives the reason for the difference.

Tempo of progression. Chronic hepatitis D is the most rapidly progressive form of chronic viral hepatitis. Cirrhosis develops in a large proportion of patients within 5 to 10 years of chronic infection, considerably faster than in hepatitis B virus (HBV) monoinfection, where progression to cirrhosis typically unfolds over decades. Once cirrhosis is established, hepatitis D carries a higher annual risk of hepatic decompensation and an increased risk of hepatocellular carcinoma compared with HBV alone.

Why hepatitis D is more severe. The acceleration reflects the added burden of a second replicating virus driving immune-mediated injury on top of the HBV background, producing more intense necroinflammation. The route of acquisition shapes outcome: superinfection of an established HBV carrier chronifies in the great majority and is the usual path to progressive disease, whereas simultaneous co-infection mostly resolves like an acute hepatitis B and only occasionally becomes chronic.

The HBV interaction. Hepatitis D characteristically suppresses HBV replication, so HBV DNA is often low or undetectable even as liver disease advances. This can mislead, because a patient who looks like an inactive HBV carrier on HBV markers may in fact have aggressive ongoing delta hepatitis. Outcomes improve only with sustained suppression of HDV RNA or, ideally, loss of hepatitis B surface antigen, which removes the envelope the delta virus requires.
Exam-styleExplain why hepatitis D virus is described as a defective or satellite virus, and what it requires from hepatitis B virus to complete its life cycle. [5]
Model answer
A complete answer states precisely which step of the life cycle hepatitis D virus (HDV) cannot perform alone, and distinguishes what it borrows from hepatitis B virus (HBV) from what it provides itself.

Why HDV is defective. HDV is a satellite virus: it can replicate its genome inside a hepatocyte without help, but it cannot make its own envelope and therefore cannot assemble or transmit infectious particles without a helper. That helper is HBV. Infection with HDV occurs only in people who are also hepatitis B surface antigen (HBsAg) positive.

What HDV provides itself. HDV supplies its own genome (a small circular negative-sense RNA), its ribozyme for processing replication products, and its single protein, the delta antigen. The small delta antigen supports genome replication; the large delta antigen, generated by host RNA editing and modified by farnesylation, drives packaging. Replication itself uses host RNA polymerase II, not an HBV enzyme, which is why nucleos(t)ide analogues that suppress HBV polymerase have no direct effect on HDV.

What it borrows from HBV. The single essential contribution from HBV is the surface (envelope) protein, HBsAg. HDV wraps its ribonucleoprotein in the HBsAg envelope to form an infectious virion, and uses the same preS1-mediated binding to the sodium taurocholate co-transporting polypeptide (NTCP) receptor that HBV uses to enter hepatocytes. This dependence has two consequences: HDV can only be acquired alongside or after HBV, and any therapy or vaccine that removes HBsAg (or prevents HBV infection) also defeats HDV.
Exam-styleOutline the current and emerging treatment options for chronic hepatitis D, including their mechanisms and the realistic goals of therapy. [8]
Model answer
A complete answer states why hepatitis D is hard to treat, describes the established and newer agents with their mechanisms, and defines a realistic endpoint.

The therapeutic problem. Chronic hepatitis D is the most rapidly progressive viral hepatitis, yet the delta virus encodes no enzyme of its own to target: it is replicated by host RNA polymerase II. Nucleos(t)ide analogues that suppress hepatitis B virus (HBV) polymerase therefore do nothing directly to hepatitis D virus (HDV). The durable goal of therapy is loss of hepatitis B surface antigen (HBsAg), which removes the envelope HDV depends on, but this is rarely achieved.

Established therapy. Pegylated interferon-alpha was for decades the only option. A 48-week course achieves an undetectable HDV RNA in roughly a quarter of patients, but relapse is common, the drug is poorly tolerated, and it is contraindicated in decompensated cirrhosis. It remains an option in compensated disease.

Newer and emerging therapy.
- Bulevirtide is a first-in-class entry inhibitor: a myristoylated lipopeptide derived from the HBV preS1 sequence that binds and blocks the sodium taurocholate co-transporting polypeptide (NTCP), the shared HBV and HDV hepatocyte receptor, preventing infection of new cells. Given as a daily subcutaneous injection, it is licensed in Europe for chronic hepatitis D, reducing HDV RNA and normalising transaminases in a substantial proportion of patients (bile-acid elevation is an expected on-treatment effect of NTCP blockade).
- Lonafarnib, a farnesyl-transferase inhibitor, blocks the prenylation step the large delta antigen needs for assembly, and is under trial evaluation, including in combination with interferon.
Realistic goals. Outside the rare achievement of HBsAg loss, therapy aims to suppress HDV RNA, normalise transaminases, and slow fibrosis progression. Access is a major constraint: bulevirtide is licensed mainly in Europe and is not yet widely available in high-burden African and Asian settings.