Hepatitis D

◆

Subtypes

2

HBV-HDV coinfection (simultaneous acquisition)

Simultaneous acquisition of hepatitis B and hepatitis D. The delta agent has to establish itself at the same time as its helper virus, and the outcome follows that of the acute HBV infection: more than 95% of coinfected patients clear both viruses within six months, so chronic hepatitis delta is an uncommon result. The acute illness can nonetheless be severe, and fulminant hepatitis is more common than in HBV monoinfection. This is NOT the route that produces the accelerated cirrhotic course modelled at the entry's progression node.

HDV superinfection of established chronic HBV

Acquisition of hepatitis D by someone already chronically infected with hepatitis B. Because HBsAg is already abundant, the delta agent has an established helper from the outset, and more than 80% of these patients develop chronic HDV infection. This is the route responsible for the accelerated course: among patients with chronic HDV superinfection, cirrhosis and liver failure occur in 70-80% within 5-10 years. Every chronic HBV carrier is at risk, which is why the accelerated progression this entry models should be attributed to superinfection rather than to HDV generically.

?

Discussions and Knowledge Gaps

1

Is HBsAg clearance achievable as the treatment goal in chronic hepatitis delta, and does sustained HDV RNA negativity translate into improved long-term liver outcomes?

KNOWLEDGE GAP hdv_hbsag_clearance_goal

Attached to

pathophysiology#L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly

Because HDV cannot assemble virions without HBsAg, clearing HBsAg would cure hepatitis delta outright, and the review literature identifies it as the ideal goal while conceding that the reasonably achievable goal is a sustained HDV virological response instead. The endpoints on which bulevirtide was approved are virological and biochemical - HDV RNA decline and ALT normalisation - not cirrhosis, decompensation, or hepatocellular carcinoma. Whether suppressing this node changes the trajectory of the downstream progression node is therefore not established, and curators should not curate the entry inhibitors as preventing cirrhosis or liver cancer.

Proposed experiments

Long-term hard-outcome follow-up of entry-inhibitor-treated patients

hdv_hard_outcome_followup

Extended follow-up of bulevirtide-treated cohorts reporting incident decompensation, hepatocellular carcinoma, and transplant-free survival against untreated or interferon-treated comparators would establish whether virological response on this pathway translates into changed liver outcomes.

⚙

Pathophysiology

5

Acquisition Route - Coinfection versus Superinfection

HDV is transmitted by the same routes as HBV, and because it cannot propagate without HBsAg it can be acquired in only two ways. In coinfection the two viruses are transmitted simultaneously, so the delta agent's persistence depends on whether the acute HBV infection resolves - and it usually does, with more than 95% of coinfected patients clearing both viruses within six months. In superinfection HDV is acquired by someone already chronically infected with HBV, so an abundant helper is present from the outset and more than 80% develop chronic HDV infection. The two routes therefore have opposite natural histories, and it is superinfection, not HDV as such, that feeds the accelerated cirrhotic course modelled downstream.

Downstream

HBsAg-Dependent Hepatocyte Entry via NTCP Either route delivers HDV virions, enveloped in HBV-supplied HBsAg, to the hepatocyte surface.

Show evidence (4 references)

PMID:26464754 SUPPORT Other

"it can be acquired either by co-infection (simultaneous transmission of the two viruses) or super-infection (acquisition of HDV by an already chronic carrier of HBV)"

Defines the two acquisition routes that this node distinguishes. Evidence source is OTHER because this is a review.

PMID:37338616 SUPPORT Other

"More than 95% of patients co-infected with HBV and HDV completely clear both viruses within six months"

Quantifies the coinfection outcome, establishing that this route usually does not chronify. Evidence source is OTHER because this is an expert panel guideline synthesising the literature.

PMID:37338616 SUPPORT Other

"In contrast to acute HBV/HDV co-infection that rapidly resolves, more than 80% of patients who acquire acute HDV superinfection will develop chronic HDV infection."

Quantifies the superinfection outcome and states the contrast with coinfection directly - the discriminating claim of this node. Evidence source is OTHER because this is an expert panel guideline.

+ 1 more reference

HBsAg-Dependent Hepatocyte Entry via NTCP

HDV virions are ribonucleoprotein cores wrapped in HBsAg supplied by a coinfecting hepatitis B virus. Because the envelope is HBV's, the receptor is HBV's too: HDV enters hepatocytes through the sodium taurocholate co-transporting polypeptide (NTCP), the hepatocyte bile acid uptake transporter that doubles as the HBV/HDV receptor. This shared entry step is the reason a single receptor blocker treats both viruses, and it is the conformance point to the entry-inhibitor drug mechanism.

hepatocyte CL:0000182

SLC10A1 hgnc:10905

liver UBERON:0002107

Downstream

Host-Polymerase-Mediated HDV Replication Once delivered into the hepatocyte the HDV ribonucleoprotein is replicated by host enzymes.

Show evidence (2 references)

PMID:32077603 SUPPORT Other

"HDV infects hepatocytes using the hepatitis B virus (HBV) receptor, the sodium taurocholate cotransporting polypeptide (NTCP)."

States the receptor and the borrowed-entry mechanism this node describes. Evidence source is OTHER because this is a review.

PMID:39494152 SUPPORT Other

"NTCP has been identified as the receptor that HBV and its satellite virus, hepatitis delta virus (HDV), use to enter hepatocytes."

Independently confirms NTCP as the shared entry receptor and frames HDV as a satellite of HBV. Evidence source is OTHER because this is a review.

Host-Polymerase-Mediated HDV Replication

The HDV genome is replicated by host RNA polymerases; the virus encodes no polymerase of its own. This has a direct therapeutic consequence that separates hepatitis D from hepatitis B and C: there is no viral replication enzyme to inhibit, so the nucleos(t)ide analogues that suppress HBV and the direct-acting antivirals that cure HCV are useless against HDV. Every drug developed for hepatitis D therefore targets an HBV-supplied step of the cycle instead.

hepatocyte CL:0000182

Downstream

L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly Replicated genomes are packaged with delta antigen into ribonucleoproteins that must then be enveloped in HBsAg to be exported.

Show evidence (1 reference)

PMID:32077603 SUPPORT Other

"its replication is mediated by the host RNA polymerases"

States that replication is host-enzyme-dependent, the fact underlying the absence of any HDV polymerase inhibitor. Evidence source is OTHER because this is a review.

L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly

HDV ribonucleoproteins consist of the RNA genome packaged with small and large delta antigen. Farnesylation of the large delta antigen is the rate-limiting step for anchoring the ribonucleoprotein to HBsAg, and so for assembling, secreting, and propagating virions. This is the second HBV-dependent bottleneck in the life cycle and the target of the prenylation inhibitor lonafarnib.

hepatocyte CL:0000182

Downstream

Accelerated Progression to Cirrhosis and Hepatocellular Carcinoma Sustained HDV propagation drives the aggressive necroinflammatory course that distinguishes hepatitis delta from HBV monoinfection.

Show evidence (2 references)

PMID:32077603 SUPPORT Other

"Farnesylation of the L-HDAg is the limiting step for anchoring this RNP to HBsAg, and thus for assembling, secreting and propagating virion particles."

Identifies the rate-limiting assembly step and its dependence on HBsAg, which is the rationale for prenylation inhibition. Evidence source is OTHER because this is a review.

PMID:32077603 SUPPORT Other

"The HBsAg-coated HDV virions contain a ribonucleoprotein (RNP) formed by the RNA genome packaged with small and large HDAg."

Describes the virion composition this node produces. Evidence source is OTHER because this is a review.

Accelerated Progression to Cirrhosis and Hepatocellular Carcinoma

Chronic hepatitis delta is the most severe form of chronic viral hepatitis, with high rates of progression to cirrhosis and its complications - end-stage liver disease and hepatocellular carcinoma. This accelerated course, on top of an HBV infection that would itself progress more slowly, is what makes HDV coinfection clinically decisive. The fibrotic and portal-hypertensive endpoints are those of the corresponding mechanism modules rather than HDV-specific processes. This node is reached predominantly by the SUPERINFECTION route: among patients with chronic HDV superinfection, cirrhosis and liver failure occur in 70-80% within 5-10 years. Simultaneous coinfection usually resolves and does not reach this node, so a conforming or citing entry should not attribute the accelerated course to HDV generically.

liver UBERON:0002107

Show evidence (4 references)

PMID:35942695 SUPPORT Other

"Chronic hepatitis delta (CHD) affects approximately 10-20 million people worldwide and represents the most severe form of chronic viral hepatitis, as it is characterized by high rates of progression to cirrhosis and its complications (end-stage liver disease, hepatocellular carcinoma)."

States the burden and the accelerated progression that define this consequence node. Evidence source is OTHER because this is a review.

PMID:32077603 SUPPORT Other

"There is an important risk of morbidity and mortality caused by end-stage liver disease and hepatocellular carcinoma with HDV"

Independently confirms the outcomes recorded at this node. Evidence source is OTHER because this is a review.

PMID:37338616 SUPPORT Other

"Of patients with chronic HDV superinfection, cirrhosis, and liver failure occur in 70%-80% within 5-10 years and in 15% within 1-2 years, respectively"

Quantifies the accelerated course and attributes it specifically to the superinfection route, which is why this node is scoped to that subtype. Evidence source is OTHER because this is an expert panel guideline.

+ 1 more reference

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

2

Cirrhosis Clinical HP:0001394

Show evidence (1 reference)

PMID:35942695 SUPPORT Other

"it is characterized by high rates of progression to cirrhosis and its complications (end-stage liver disease, hepatocellular carcinoma)"

Documents cirrhosis as a high-frequency outcome. Evidence source is OTHER because this is a review.

Hepatocellular Carcinoma Clinical HP:0001402

Show evidence (1 reference)

PMID:32077603 SUPPORT Other

"There is an important risk of morbidity and mortality caused by end-stage liver disease and hepatocellular carcinoma with HDV"

Documents hepatocellular carcinoma as an outcome of HDV infection. Evidence source is OTHER because this is a review.

💊

Medical Actions

4

Bulevirtide

Action: Antiviral Therapy NCIT:C16119

Agent: bulevirtide NCIT:C169819

A first-in-class HBV-HDV entry inhibitor: a lipopeptide derived from the HBV pre-S1 domain that blocks NTCP and so prevents virions from entering hepatocytes. It received conditional EMA approval in July 2020 for compensated chronic hepatitis delta at 2 mg/day subcutaneously. Monotherapy for 24 or 48 weeks produced virological response in 50-83% and ALT normalisation in 45-78%, with synergistic effects when combined with pegylated interferon, and the results held in patients with advanced cirrhosis and clinically significant portal hypertension. Its characteristic on-target effect follows directly from what NTCP normally does: blocking a bile acid transporter raises serum bile acids, though asymptomatically.

Mechanism Target:

INHIBITS HBsAg-Dependent Hepatocyte Entry via NTCP — Bulevirtide occupies NTCP and blocks receptor-mediated entry of HBsAg-enveloped HDV virions into hepatocytes, cutting the life cycle at its first step.

Show evidence (1 reference)

PMID:35942695 SUPPORT Human Clinical

"Administration of BLV monotherapy for 24 or 48 weeks resulted in 50%-83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%-78% ALT normalization."

Quantifies the virological and biochemical effect of blocking this node in treated patients. Evidence source is HUMAN_CLINICAL because these are Phase II and Phase III trial results.

Show evidence (2 references)

PMID:35942695 SUPPORT Human Clinical

"Recently, Bulevirtide (BLV), a first-in-class HBV-HDV entry inhibitor blocking Na+ -taurocholate co-transporting polypeptide (NTCP), has provided very promising efficacy data in Phase II and Phase III (interim analysis) trials as well as in preliminary real-life reports."

Establishes the drug class, its molecular target, and the evidence level. Evidence source is HUMAN_CLINICAL because it summarises trial and real-world patient data.

PMID:35942695 SUPPORT Human Clinical

"BLV treatment was optimally tolerated, resulting only in an asymptomatic increase of bile acids."

Marked PARTIAL because it records the on-target consequence of blocking a bile acid transporter - a mechanistically predictable effect rather than an unrelated adverse event. Evidence source is HUMAN_CLINICAL.

Pegylated Interferon Alpha

Action: Antiviral Therapy NCIT:C16119

Agent: recombinant interferon alfa NCIT:C225

For three decades the only treatment option for chronic hepatitis delta, given off-label for 48 weeks. Its limitations are what motivated the development of the entry and prenylation inhibitors: virological response was only 20-30%, side effects were substantial, and advanced liver disease - exactly the population most in need - is effectively a contraindication.

Mechanism Target:

INHIBITS Host-Polymerase-Mediated HDV Replication — Interferon-alpha acts through a host-directed antiviral state rather than on any virus-encoded enzyme, which is the only route available against a virus replicated by host RNA polymerases.

Show evidence (1 reference)

PMID:35942695 SUPPORT Human Clinical

"antiviral treatment, however, resulted in suboptimal (20-30%) virological response"

Marked PARTIAL because it quantifies how weakly interferon suppresses this node - a 20-30% virological response is the reason entry and assembly inhibitors were developed. Evidence source is HUMAN_CLINICAL because these are response rates in treated patients.

Show evidence (1 reference)

PMID:35942695 SUPPORT Other

"In the last 30 years, the only treatment option for CHD has been represented by the off-label administration of Interferon (or Pegylated Interferon)-alpha: antiviral treatment, however, resulted in suboptimal (20-30%) virological response and was burdened by several side effects, de facto..."

Marked PARTIAL because it establishes interferon as the historical standard while bounding its efficacy and excluding the advanced-disease population. Evidence source is OTHER because this is a review.

Lonafarnib

Action: Antiviral Therapy NCIT:C16119

Agent: lonafarnib CHEBI:47097

A prenylation (farnesyltransferase) inhibitor that blocks farnesylation of the large delta antigen, the rate-limiting step for anchoring the HDV ribonucleoprotein to HBsAg and hence for virion assembly and secretion. It attacks the assembly bottleneck rather than entry or replication.

Mechanism Target:

INHIBITS L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly — Inhibiting farnesyltransferase prevents prenylation of L-HDAg, so the ribonucleoprotein cannot be anchored to HBsAg and infectious virions cannot be assembled or secreted.

Show evidence (1 reference)

PMID:32077603 SUPPORT Other

"Farnesylation of the L-HDAg is the limiting step for anchoring this RNP to HBsAg, and thus for assembling, secreting and propagating virion particles."

States the step lonafarnib blocks and why blocking it stops virion propagation. Evidence source is OTHER because this is a review of the HDV life cycle and drug development.

Show evidence (1 reference)

PMID:32077603 SUPPORT Other

"we will present the new insights in the HDV life cycle that have led to the development of novel classes of drugs and discuss antiviral approaches in phase II and III of development: bulevirtide (entry inhibitor), lonafarnib, (prenylation inhibitor) and REP 2139 (HBsAg release inhibitor)"

Marked PARTIAL because at the time of this review lonafarnib was in phase II/III development rather than approved; conforming curation should not present it as established therapy. Evidence source is OTHER because this is a review.

Hepatitis B Vaccination

Action: Vaccination NCIT:C15346

Because HDV cannot infect a hepatocyte or assemble a virion without HBV-supplied HBsAg, preventing hepatitis B prevents hepatitis D outright. HBV vaccination is therefore fully protective against HDV in anyone not already infected with HBV, and is the mainstay of HDV prevention. Its one limitation defines the residual burden: it does nothing for the established chronic HBV carrier, who remains at lifelong risk of superinfection - the route that actually produces chronic hepatitis delta.

Mechanism Target:

INHIBITS Acquisition Route - Coinfection versus Superinfection — Preventing HBV infection removes the HBsAg on which HDV depends, foreclosing both acquisition routes in the previously uninfected and thereby preventing the entire downstream chain.

Show evidence (1 reference)

PMID:37338616 SUPPORT Other

"The mainstay of HDV prevention is HBV vaccination alongside harm reduction, including safe sexual practices."

States that HBV vaccination is the principal preventive intervention against HDV, which is what this mechanism link asserts. Evidence source is OTHER because this is an expert panel guideline.

Show evidence (1 reference)

PMID:26464754 SUPPORT Other

"As a consequence, every HBV carrier is potentially at risk for HDV superinfection."

Marked PARTIAL because it bounds the protection: vaccination cannot help the established HBV carrier, who remains at risk of the superinfection route. Evidence source is OTHER because this is a review.

🦠

Infectious Agent

1

Hepatitis delta virus (HDV)

A defective, satellite RNA virus with a circular single-stranded genome encoding a single protein, the hepatitis delta antigen, in a small (S-HDAg) and a large (L-HDAg) form. It carries no polymerase and no envelope protein of its own: replication is performed by host RNA polymerases and the virion envelope is HBsAg borrowed from a coinfecting hepatitis B virus.

Hepatitis delta virus NCBITaxon:12475

Show evidence (2 references)

PMID:32077603 SUPPORT Other

"Hepatitis delta virus (HDV) is a defective RNA virus requiring the presence of the hepatitis B virus surface antigen (HBsAg) to complete its life cycle."

States the defining property of the agent - obligate dependence on HBsAg - which is what makes hepatitis D a coinfection rather than an independent disease. Evidence source is OTHER because this is a review.

PMID:32077603 SUPPORT Other

"The HDV genome is a circular single-stranded RNA which encodes for a single hepatitis delta antigen (HDAg) that exists in two forms (S-HDAg and L-HDAg), and its replication is mediated by the host RNA polymerases."

Describes the genome, its single protein product in two forms, and the host-polymerase-dependent replication that removes any viral polymerase as a drug target. Evidence source is OTHER because this is a review.

{ }

Source YAML

click to show

name: Hepatitis D
creation_date: "2026-08-22T00:00:00Z"
category: Infectious Disease
description: >-
  Infection with hepatitis delta virus (HDV), a defective circular RNA virus
  that cannot complete its life cycle without the hepatitis B virus surface
  antigen (HBsAg) and therefore occurs only in people who are also infected with
  HBV. HDV borrows HBsAg to coat its ribonucleoprotein and uses the HBV
  receptor, the sodium taurocholate co-transporting polypeptide (NTCP), to enter
  hepatocytes; once inside, its genome is replicated by host RNA polymerases
  rather than by any virus-encoded enzyme, which is why no HDV polymerase
  inhibitor exists. Chronic hepatitis delta affects an estimated 10-20 million
  people and is the most severe form of chronic viral hepatitis, with high rates
  of progression to cirrhosis, end-stage liver disease, and hepatocellular
  carcinoma. Its therapeutic dependence on HBV is total: every approved or
  investigational agent targets an HBV-supplied step - viral entry through NTCP
  (bulevirtide), farnesylation of the large delta antigen needed to anchor the
  ribonucleoprotein to HBsAg (lonafarnib), or HBsAg release itself - rather than
  HDV replication.
disease_term:
  preferred_term: hepatitis D virus infection
  term:
    id: MONDO:0005789
    label: hepatitis D virus infection
parents:
- Liver Disease
- Viral Hepatitis
has_subtypes:
- name: Coinfection
  display_name: HBV-HDV coinfection (simultaneous acquisition)
  description: >-
    Simultaneous acquisition of hepatitis B and hepatitis D. The delta agent has
    to establish itself at the same time as its helper virus, and the outcome
    follows that of the acute HBV infection: more than 95% of coinfected
    patients clear both viruses within six months, so chronic hepatitis delta is
    an uncommon result. The acute illness can nonetheless be severe, and
    fulminant hepatitis is more common than in HBV monoinfection. This is NOT
    the route that produces the accelerated cirrhotic course modelled at the
    entry's progression node.
- name: Superinfection
  display_name: HDV superinfection of established chronic HBV
  description: >-
    Acquisition of hepatitis D by someone already chronically infected with
    hepatitis B. Because HBsAg is already abundant, the delta agent has an
    established helper from the outset, and more than 80% of these patients
    develop chronic HDV infection. This is the route responsible for the
    accelerated course: among patients with chronic HDV superinfection,
    cirrhosis and liver failure occur in 70-80% within 5-10 years. Every chronic
    HBV carrier is at risk, which is why the accelerated progression this entry
    models should be attributed to superinfection rather than to HDV generically.
infectious_agent:
- name: Hepatitis delta virus (HDV)
  description: >-
    A defective, satellite RNA virus with a circular single-stranded genome
    encoding a single protein, the hepatitis delta antigen, in a small (S-HDAg)
    and a large (L-HDAg) form. It carries no polymerase and no envelope protein
    of its own: replication is performed by host RNA polymerases and the virion
    envelope is HBsAg borrowed from a coinfecting hepatitis B virus.
  infectious_agent_term:
    preferred_term: Hepatitis delta virus
    term:
      id: NCBITaxon:12475
      label: Hepatitis delta virus
  evidence:
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hepatitis delta virus (HDV) is a defective RNA virus requiring the
      presence of the hepatitis B virus surface antigen (HBsAg) to complete its
      life cycle.
    explanation: >-
      States the defining property of the agent - obligate dependence on HBsAg -
      which is what makes hepatitis D a coinfection rather than an independent
      disease. Evidence source is OTHER because this is a review.
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The HDV genome is a circular single-stranded RNA which encodes for a
      single hepatitis delta antigen (HDAg) that exists in two forms (S-HDAg and
      L-HDAg), and its replication is mediated by the host RNA polymerases.
    explanation: >-
      Describes the genome, its single protein product in two forms, and the
      host-polymerase-dependent replication that removes any viral polymerase as
      a drug target. Evidence source is OTHER because this is a review.
pathophysiology:
- name: Acquisition Route - Coinfection versus Superinfection
  description: >-
    HDV is transmitted by the same routes as HBV, and because it cannot
    propagate without HBsAg it can be acquired in only two ways. In coinfection
    the two viruses are transmitted simultaneously, so the delta agent's
    persistence depends on whether the acute HBV infection resolves - and it
    usually does, with more than 95% of coinfected patients clearing both
    viruses within six months. In superinfection HDV is acquired by someone
    already chronically infected with HBV, so an abundant helper is present from
    the outset and more than 80% develop chronic HDV infection. The two routes
    therefore have opposite natural histories, and it is superinfection, not HDV
    as such, that feeds the accelerated cirrhotic course modelled downstream.
  role: trigger
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:26464754
    reference_title: "Hepatitis delta virus: Making the point from virus isolation up to 2014."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it can be acquired either by co-infection (simultaneous transmission of
      the two viruses) or super-infection (acquisition of HDV by an already
      chronic carrier of HBV)
    explanation: >-
      Defines the two acquisition routes that this node distinguishes. Evidence
      source is OTHER because this is a review.
  - reference: PMID:37338616
    reference_title: "Diagnosis and Management of Hepatitis Delta Virus Infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More than 95% of patients co-infected with HBV and HDV completely clear
      both viruses within six months
    explanation: >-
      Quantifies the coinfection outcome, establishing that this route usually
      does not chronify. Evidence source is OTHER because this is an expert
      panel guideline synthesising the literature.
  - reference: PMID:37338616
    reference_title: "Diagnosis and Management of Hepatitis Delta Virus Infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In contrast to acute HBV/HDV co-infection that rapidly resolves, more than
      80% of patients who acquire acute HDV superinfection will develop chronic
      HDV infection.
    explanation: >-
      Quantifies the superinfection outcome and states the contrast with
      coinfection directly - the discriminating claim of this node. Evidence
      source is OTHER because this is an expert panel guideline.
  - reference: PMID:26464754
    reference_title: "Hepatitis delta virus: Making the point from virus isolation up to 2014."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As a consequence, every HBV carrier is potentially at risk for HDV
      superinfection.
    explanation: >-
      Establishes the at-risk population for the superinfection route, which is
      what makes HBV vaccination the decisive preventive measure. Evidence
      source is OTHER because this is a review.
  downstream:
  - target: HBsAg-Dependent Hepatocyte Entry via NTCP
    causal_link_type: DIRECT
    description: >-
      Either route delivers HDV virions, enveloped in HBV-supplied HBsAg, to the
      hepatocyte surface.

- name: HBsAg-Dependent Hepatocyte Entry via NTCP
  description: >-
    HDV virions are ribonucleoprotein cores wrapped in HBsAg supplied by a
    coinfecting hepatitis B virus. Because the envelope is HBV's, the receptor
    is HBV's too: HDV enters hepatocytes through the sodium taurocholate
    co-transporting polypeptide (NTCP), the hepatocyte bile acid uptake
    transporter that doubles as the HBV/HDV receptor. This shared entry step is
    the reason a single receptor blocker treats both viruses, and it is the
    conformance point to the entry-inhibitor drug mechanism.
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "viral_entry_fusion_inhibition#Viral Attachment to the Host-Cell Receptor"
  genes:
  - preferred_term: SLC10A1
    term:
      id: hgnc:10905
      label: SLC10A1
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HDV infects hepatocytes using the hepatitis B virus (HBV) receptor, the
      sodium taurocholate cotransporting polypeptide (NTCP).
    explanation: >-
      States the receptor and the borrowed-entry mechanism this node describes.
      Evidence source is OTHER because this is a review.
  - reference: PMID:39494152
    reference_title: "The Culprit Behind HBV-Infected Hepatocytes: NTCP."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NTCP has been identified as the receptor that HBV and its satellite virus,
      hepatitis delta virus (HDV), use to enter hepatocytes.
    explanation: >-
      Independently confirms NTCP as the shared entry receptor and frames HDV as
      a satellite of HBV. Evidence source is OTHER because this is a review.
  downstream:
  - target: Host-Polymerase-Mediated HDV Replication
    causal_link_type: DIRECT
    description: >-
      Once delivered into the hepatocyte the HDV ribonucleoprotein is replicated
      by host enzymes.

- name: Host-Polymerase-Mediated HDV Replication
  description: >-
    The HDV genome is replicated by host RNA polymerases; the virus encodes no
    polymerase of its own. This has a direct therapeutic consequence that
    separates hepatitis D from hepatitis B and C: there is no viral replication
    enzyme to inhibit, so the nucleos(t)ide analogues that suppress HBV and the
    direct-acting antivirals that cure HCV are useless against HDV. Every drug
    developed for hepatitis D therefore targets an HBV-supplied step of the
    cycle instead.
  role: central_effector
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its replication is mediated by the host RNA polymerases
    explanation: >-
      States that replication is host-enzyme-dependent, the fact underlying the
      absence of any HDV polymerase inhibitor. Evidence source is OTHER because
      this is a review.
  downstream:
  - target: L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly
    causal_link_type: DIRECT
    description: >-
      Replicated genomes are packaged with delta antigen into ribonucleoproteins
      that must then be enveloped in HBsAg to be exported.

- name: L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly
  description: >-
    HDV ribonucleoproteins consist of the RNA genome packaged with small and
    large delta antigen. Farnesylation of the large delta antigen is the
    rate-limiting step for anchoring the ribonucleoprotein to HBsAg, and so for
    assembling, secreting, and propagating virions. This is the second
    HBV-dependent bottleneck in the life cycle and the target of the prenylation
    inhibitor lonafarnib.
  role: effector
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Farnesylation of the L-HDAg is the limiting step for anchoring this RNP to
      HBsAg, and thus for assembling, secreting and propagating virion
      particles.
    explanation: >-
      Identifies the rate-limiting assembly step and its dependence on HBsAg,
      which is the rationale for prenylation inhibition. Evidence source is
      OTHER because this is a review.
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The HBsAg-coated HDV virions contain a ribonucleoprotein (RNP) formed by
      the RNA genome packaged with small and large HDAg.
    explanation: >-
      Describes the virion composition this node produces. Evidence source is
      OTHER because this is a review.
  downstream:
  - target: Accelerated Progression to Cirrhosis and Hepatocellular Carcinoma
    causal_link_type: DIRECT
    description: >-
      Sustained HDV propagation drives the aggressive necroinflammatory course
      that distinguishes hepatitis delta from HBV monoinfection.

- name: Accelerated Progression to Cirrhosis and Hepatocellular Carcinoma
  description: >-
    Chronic hepatitis delta is the most severe form of chronic viral hepatitis,
    with high rates of progression to cirrhosis and its complications - end-stage
    liver disease and hepatocellular carcinoma. This accelerated course, on top
    of an HBV infection that would itself progress more slowly, is what makes
    HDV coinfection clinically decisive. The fibrotic and portal-hypertensive
    endpoints are those of the corresponding mechanism modules rather than
    HDV-specific processes. This node is reached predominantly by the
    SUPERINFECTION route: among patients with chronic HDV superinfection,
    cirrhosis and liver failure occur in 70-80% within 5-10 years. Simultaneous
    coinfection usually resolves and does not reach this node, so a conforming
    or citing entry should not attribute the accelerated course to HDV
    generically.
  role: consequence
  biological_scale: ORGANISM
  subtypes:
  - Superinfection
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:35942695
    reference_title: "Bulevirtide for patients with compensated chronic hepatitis delta: A review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic hepatitis delta (CHD) affects approximately 10-20 million people
      worldwide and represents the most severe form of chronic viral hepatitis,
      as it is characterized by high rates of progression to cirrhosis and its
      complications (end-stage liver disease, hepatocellular carcinoma).
    explanation: >-
      States the burden and the accelerated progression that define this
      consequence node. Evidence source is OTHER because this is a review.
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is an important risk of morbidity and mortality caused by end-stage
      liver disease and hepatocellular carcinoma with HDV
    explanation: >-
      Independently confirms the outcomes recorded at this node. Evidence source
      is OTHER because this is a review.
  - reference: PMID:37338616
    reference_title: "Diagnosis and Management of Hepatitis Delta Virus Infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Of patients with chronic HDV superinfection, cirrhosis, and liver failure
      occur in 70%-80% within 5-10 years and in 15% within 1-2 years,
      respectively
    explanation: >-
      Quantifies the accelerated course and attributes it specifically to the
      superinfection route, which is why this node is scoped to that subtype.
      Evidence source is OTHER because this is an expert panel guideline.
  - reference: PMID:37338616
    reference_title: "Diagnosis and Management of Hepatitis Delta Virus Infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HDV superinfection exacerbates and accelerates the progression of chronic
      HBV infection
    explanation: >-
      States the acceleration relative to HBV monoinfection that makes this node
      the clinically decisive feature of hepatitis delta. Evidence source is
      OTHER because this is an expert panel guideline.
phenotypes:
- category: Clinical
  name: Cirrhosis
  description: >-
    Chronic hepatitis delta progresses to cirrhosis at high rates, faster than
    HBV monoinfection.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:35942695
    reference_title: "Bulevirtide for patients with compensated chronic hepatitis delta: A review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it is characterized by high rates of progression to cirrhosis and its
      complications (end-stage liver disease, hepatocellular carcinoma)
    explanation: >-
      Documents cirrhosis as a high-frequency outcome. Evidence source is OTHER
      because this is a review.
- category: Clinical
  name: Hepatocellular Carcinoma
  description: >-
    Hepatocellular carcinoma is a recognised complication of chronic hepatitis
    delta, arising as a sequela of the accelerated cirrhotic course.
  phenotype_term:
    preferred_term: Hepatocellular carcinoma
    term:
      id: HP:0001402
      label: Hepatocellular carcinoma
  evidence:
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is an important risk of morbidity and mortality caused by end-stage
      liver disease and hepatocellular carcinoma with HDV
    explanation: >-
      Documents hepatocellular carcinoma as an outcome of HDV infection.
      Evidence source is OTHER because this is a review.
treatments:
- name: Bulevirtide
  description: >-
    A first-in-class HBV-HDV entry inhibitor: a lipopeptide derived from the HBV
    pre-S1 domain that blocks NTCP and so prevents virions from entering
    hepatocytes. It received conditional EMA approval in July 2020 for
    compensated chronic hepatitis delta at 2 mg/day subcutaneously. Monotherapy
    for 24 or 48 weeks produced virological response in 50-83% and ALT
    normalisation in 45-78%, with synergistic effects when combined with
    pegylated interferon, and the results held in patients with advanced
    cirrhosis and clinically significant portal hypertension. Its
    characteristic on-target effect follows directly from what NTCP normally
    does: blocking a bile acid transporter raises serum bile acids, though
    asymptomatically.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Antiviral Therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
    therapeutic_agent:
    - preferred_term: bulevirtide
      term:
        id: NCIT:C169819
        label: Bulevirtide
  target_mechanisms:
  - target: HBsAg-Dependent Hepatocyte Entry via NTCP
    treatment_effect: INHIBITS
    description: >-
      Bulevirtide occupies NTCP and blocks receptor-mediated entry of
      HBsAg-enveloped HDV virions into hepatocytes, cutting the life cycle at
      its first step.
    evidence:
    - reference: PMID:35942695
      reference_title: "Bulevirtide for patients with compensated chronic hepatitis delta: A review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Administration of BLV monotherapy for 24 or 48 weeks resulted in
        50%-83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%-78%
        ALT normalization.
      explanation: >-
        Quantifies the virological and biochemical effect of blocking this node
        in treated patients. Evidence source is HUMAN_CLINICAL because these are
        Phase II and Phase III trial results.
  evidence:
  - reference: PMID:35942695
    reference_title: "Bulevirtide for patients with compensated chronic hepatitis delta: A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, Bulevirtide (BLV), a first-in-class HBV-HDV entry inhibitor
      blocking Na+ -taurocholate co-transporting polypeptide (NTCP), has
      provided very promising efficacy data in Phase II and Phase III (interim
      analysis) trials as well as in preliminary real-life reports.
    explanation: >-
      Establishes the drug class, its molecular target, and the evidence level.
      Evidence source is HUMAN_CLINICAL because it summarises trial and
      real-world patient data.
  - reference: PMID:35942695
    reference_title: "Bulevirtide for patients with compensated chronic hepatitis delta: A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BLV treatment was optimally tolerated, resulting only in an asymptomatic
      increase of bile acids.
    explanation: >-
      Marked PARTIAL because it records the on-target consequence of blocking a
      bile acid transporter - a mechanistically predictable effect rather than an
      unrelated adverse event. Evidence source is HUMAN_CLINICAL.
- name: Pegylated Interferon Alpha
  description: >-
    For three decades the only treatment option for chronic hepatitis delta,
    given off-label for 48 weeks. Its limitations are what motivated the
    development of the entry and prenylation inhibitors: virological response
    was only 20-30%, side effects were substantial, and advanced liver disease -
    exactly the population most in need - is effectively a contraindication.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Antiviral Therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
    therapeutic_agent:
    - preferred_term: recombinant interferon alfa
      term:
        id: NCIT:C225
        label: Recombinant Interferon Alfa
  target_mechanisms:
  - target: Host-Polymerase-Mediated HDV Replication
    treatment_effect: INHIBITS
    description: >-
      Interferon-alpha acts through a host-directed antiviral state rather than
      on any virus-encoded enzyme, which is the only route available against a
      virus replicated by host RNA polymerases.
    evidence:
    - reference: PMID:35942695
      reference_title: "Bulevirtide for patients with compensated chronic hepatitis delta: A review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        antiviral treatment, however, resulted in suboptimal (20-30%)
        virological response
      explanation: >-
        Marked PARTIAL because it quantifies how weakly interferon suppresses
        this node - a 20-30% virological response is the reason entry and
        assembly inhibitors were developed. Evidence source is HUMAN_CLINICAL
        because these are response rates in treated patients.
  evidence:
  - reference: PMID:35942695
    reference_title: "Bulevirtide for patients with compensated chronic hepatitis delta: A review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the last 30 years, the only treatment option for CHD has been
      represented by the off-label administration of Interferon (or Pegylated
      Interferon)-alpha: antiviral treatment, however, resulted in suboptimal
      (20-30%) virological response and was burdened by several side effects, de
      facto contraindicating Interferon (IFN) administration in patients with
      more advanced liver disease.
    explanation: >-
      Marked PARTIAL because it establishes interferon as the historical
      standard while bounding its efficacy and excluding the advanced-disease
      population. Evidence source is OTHER because this is a review.
- name: Lonafarnib
  description: >-
    A prenylation (farnesyltransferase) inhibitor that blocks farnesylation of
    the large delta antigen, the rate-limiting step for anchoring the HDV
    ribonucleoprotein to HBsAg and hence for virion assembly and secretion. It
    attacks the assembly bottleneck rather than entry or replication.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antiviral Therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
    therapeutic_agent:
    - preferred_term: lonafarnib
      term:
        id: CHEBI:47097
        label: lonafarnib
  target_mechanisms:
  - target: L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly
    treatment_effect: INHIBITS
    description: >-
      Inhibiting farnesyltransferase prevents prenylation of L-HDAg, so the
      ribonucleoprotein cannot be anchored to HBsAg and infectious virions
      cannot be assembled or secreted.
    evidence:
    - reference: PMID:32077603
      reference_title: "Future treatments for hepatitis delta virus infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Farnesylation of the L-HDAg is the limiting step for anchoring this RNP
        to HBsAg, and thus for assembling, secreting and propagating virion
        particles.
      explanation: >-
        States the step lonafarnib blocks and why blocking it stops virion
        propagation. Evidence source is OTHER because this is a review of the
        HDV life cycle and drug development.
  evidence:
  - reference: PMID:32077603
    reference_title: "Future treatments for hepatitis delta virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      we will present the new insights in the HDV life cycle that have led to
      the development of novel classes of drugs and discuss antiviral approaches
      in phase II and III of development: bulevirtide (entry inhibitor),
      lonafarnib, (prenylation inhibitor) and REP 2139 (HBsAg release inhibitor)
    explanation: >-
      Marked PARTIAL because at the time of this review lonafarnib was in phase
      II/III development rather than approved; conforming curation should not
      present it as established therapy. Evidence source is OTHER because this
      is a review.
- name: Hepatitis B Vaccination
  description: >-
    Because HDV cannot infect a hepatocyte or assemble a virion without
    HBV-supplied HBsAg, preventing hepatitis B prevents hepatitis D outright.
    HBV vaccination is therefore fully protective against HDV in anyone not
    already infected with HBV, and is the mainstay of HDV prevention. Its one
    limitation defines the residual burden: it does nothing for the established
    chronic HBV carrier, who remains at lifelong risk of superinfection - the
    route that actually produces chronic hepatitis delta.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: Acquisition Route - Coinfection versus Superinfection
    treatment_effect: INHIBITS
    description: >-
      Preventing HBV infection removes the HBsAg on which HDV depends,
      foreclosing both acquisition routes in the previously uninfected and
      thereby preventing the entire downstream chain.
    evidence:
    - reference: PMID:37338616
      reference_title: "Diagnosis and Management of Hepatitis Delta Virus Infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The mainstay of HDV prevention is HBV vaccination alongside harm
        reduction, including safe sexual practices.
      explanation: >-
        States that HBV vaccination is the principal preventive intervention
        against HDV, which is what this mechanism link asserts. Evidence source
        is OTHER because this is an expert panel guideline.
  evidence:
  - reference: PMID:26464754
    reference_title: "Hepatitis delta virus: Making the point from virus isolation up to 2014."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As a consequence, every HBV carrier is potentially at risk for HDV
      superinfection.
    explanation: >-
      Marked PARTIAL because it bounds the protection: vaccination cannot help
      the established HBV carrier, who remains at risk of the superinfection
      route. Evidence source is OTHER because this is a review.

discussions:
- discussion_id: hdv_hbsag_clearance_goal
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is HBsAg clearance achievable as the treatment goal in chronic hepatitis
    delta, and does sustained HDV RNA negativity translate into improved
    long-term liver outcomes?
  attaches_to:
  - "pathophysiology#L-HDAg Farnesylation and HBsAg-Dependent Virion Assembly"
  rationale: >-
    Because HDV cannot assemble virions without HBsAg, clearing HBsAg would cure
    hepatitis delta outright, and the review literature identifies it as the
    ideal goal while conceding that the reasonably achievable goal is a sustained
    HDV virological response instead. The endpoints on which bulevirtide was
    approved are virological and biochemical - HDV RNA decline and ALT
    normalisation - not cirrhosis, decompensation, or hepatocellular carcinoma.
    Whether suppressing this node changes the trajectory of the downstream
    progression node is therefore not established, and curators should not
    curate the entry inhibitors as preventing cirrhosis or liver cancer.
  proposed_experiments:
  - experiment_id: hdv_hard_outcome_followup
    name: Long-term hard-outcome follow-up of entry-inhibitor-treated patients
    description: >-
      Extended follow-up of bulevirtide-treated cohorts reporting incident
      decompensation, hepatocellular carcinoma, and transplant-free survival
      against untreated or interferon-treated comparators would establish
      whether virological response on this pathway translates into changed
      liver outcomes.

Ask OpenScientist

OpenScientist Report

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Infectious Agent

Source YAML