Hepatitis D virus

Hepatitis D virus (HDV) is the smallest virus known to infect humans, and one of the strangest. It is a satellite: it cannot build its own coat, so it borrows the surface protein of hepatitis B virus (HBV) and can only infect people who already carry hepatitis B. That dependence makes it rarer than the other hepatitis viruses, infecting somewhere between 12 million and 72 million people worldwide, roughly 5 per cent of hepatitis B carriers, in sharply defined geographic pockets. Where it does take hold it is the most dangerous of the viral hepatitides: chronic hepatitis D progresses to cirrhosis faster than any other, carries a high risk of liver cancer, and for decades had only one modest treatment. Two developments have renewed attention on it. The arrival of bulevirtide, the first drug designed specifically for hepatitis D, has given clinicians a targeted therapy for the first time; and wider recognition that the infection is heavily under-diagnosed has prompted a shift towards testing every hepatitis B patient for it. No vaccine targets hepatitis D directly, but because the virus cannot survive without hepatitis B, the hepatitis B vaccine prevents it.

Discovery and historical significance

Hepatitis D was discovered in 1977 by Mario Rizzetto and colleagues in Turin. Studying liver biopsies from hepatitis B patients with unusually aggressive disease, they found a new antigen in the cell nuclei, which they named the delta antigen. At first it was thought to be a previously unrecognised hepatitis B protein. Transmission experiments in chimpanzees then showed that the delta agent was a separate, transmissible virus that needed hepatitis B to propagate. The genome was cloned and sequenced in the mid-1980s, revealing a tiny circular RNA quite unlike any other animal virus and resembling the viroids that infect plants. Rizzetto’s work established hepatitis D as a distinct cause of severe liver disease and explained why some hepatitis B carriers deteriorated so rapidly.

Classification, structure, and genome

Classification

Under current taxonomy hepatitis D virus sits in the genus Deltavirus, family Kolmioviridae, having been moved out of the former family Deltaviridae as related delta-like agents were discovered in fish, birds, amphibians and invertebrates. Eight genotypes (1 to 8) are recognised and are now assigned to separate species within the genus, the globally dominant human prototype, genotype 1, being the species Deltavirus italiense. The genotypes differ in geography and in severity: genotype 1 is found worldwide, genotype 3 in the Amazon basin causes particularly severe disease, and genotypes 5 to 8 are largely African.

Virion structure

The infectious particle is about 36 nanometres across and enveloped. The crucial point is that the envelope is not the virus’s own: it is made of hepatitis B surface antigen (HBsAg) supplied by hepatitis B virus. Inside the envelope is a ribonucleoprotein, the circular RNA genome coated by around 200 copies of the delta antigen. Hepatitis D therefore makes only one protein of its own and depends on its helper virus for the structure that lets it leave one cell and enter the next.

Genome organisation

The genome is approximately 1.7 kilobases of circular, negative-sense, single-stranded RNA, the smallest of any human virus. Extensive internal base-pairing folds it into an unbranched, rod-like structure. It contains a ribozyme, a stretch of RNA that cuts itself, which is used to process the products of replication. A single reading frame encodes the delta antigen in two forms: the small hepatitis delta antigen (s-HDAg), which supports replication, and the large hepatitis delta antigen (l-HDAg), which is needed for assembly. The large form is produced only after a host enzyme edits the RNA (see the replication cycle). The virus encodes no polymerase, so it relies entirely on host enzymes to copy itself.

Replication cycle

Hepatitis D enters the hepatocyte through the same doorway as hepatitis B. The preS1 region of the HBsAg envelope binds the sodium taurocholate co-transporting polypeptide (NTCP, a bile-acid transporter on the liver-cell surface), and the particle is taken inside. The ribonucleoprotein then travels to the nucleus, where replication takes place.

Because hepatitis D has no polymerase, it hijacks the host’s own RNA polymerases (chiefly RNA polymerase II, the enzyme that normally transcribes cellular genes) and copies its circular genome by a rolling-circle mechanism, the same strategy plant viroids use. The long multimeric copies produced this way are cut into unit lengths by the ribozyme and re-joined into circles. During replication a host enzyme, adenosine deaminase acting on RNA 1 (ADAR1), edits a single site in the genome. This edit changes the stop codon of the delta antigen gene so that translation reads further, producing the longer large delta antigen alongside the small one. The large form is then tagged with a lipid (farnesylation), which lets it bind HBsAg and drive packaging. New genomes are wrapped in the HBsAg envelope provided by hepatitis B and released. Nucleos(t)ide analogue drugs that suppress the hepatitis B polymerase do not touch this cycle, because hepatitis D is copied by host enzymes, not by an HBV enzyme.

Pathogenesis

Hepatitis D is not directly toxic to the hepatocyte. The liver damage comes from the immune response to infected cells, and that response is particularly intense: co-infected livers show the most severe necroinflammation of any chronic viral hepatitis, which is why disease progresses so quickly. The delta antigen interferes with the interferon response, helping the virus persist. A characteristic feature of the interaction with the helper virus is that hepatitis D usually suppresses hepatitis B replication, so a patient with active, damaging delta hepatitis may have a low or undetectable hepatitis B viral load. This can be misleading, because the hepatitis B markers make the patient look quiescent while the liver disease advances.

Epidemiology

Because hepatitis D needs hepatitis B, its distribution is bounded by hepatitis B prevalence but is far more uneven. Worldwide estimates range from about 12 million to 72 million infections, around 5 per cent of hepatitis B carriers, but the burden clusters into high-prevalence foci rather than spreading evenly. Long-recognised hotspots include Mongolia (where up to around 40 per cent of hepatitis B carriers are co-infected), the Amazon basin, parts of Central and West Africa, the Mediterranean basin, Eastern Europe, and the Middle East including Pakistan. The eight genotypes map onto these regions.

The picture is not static. Universal infant hepatitis B vaccination has shrunk the pool of susceptible carriers and reduced hepatitis D prevalence in countries such as Italy, while migration has carried the virus into new foci in Northern and Western Europe. Transmission is mainly percutaneous, through injecting drug use and unsafe medical or cosmetic procedures, with sexual and household spread also recognised.

Natural history

How hepatitis D behaves depends almost entirely on whether hepatitis B is acquired at the same time or already present.

Co-infection means catching both viruses together. The illness looks like an acute hepatitis B, and because the delta virus depends on the simultaneously-acquired hepatitis B establishing itself, both are usually cleared: roughly 95 per cent of immunocompetent adults recover, and chronic hepatitis D follows in only a small minority.

Superinfection means catching hepatitis D when already a hepatitis B carrier. Here the virus lands on a fully supported background and becomes chronic in more than 90 per cent of cases. Chronic hepatitis D is the most rapidly progressive chronic viral hepatitis: a large share of patients, in the order of 30 to 70 per cent, already have cirrhosis at diagnosis, and more than half may die of liver disease within ten years. That said, more recent follow-up shows the course is variable, and over half of patients may run a relatively indolent course, so the classic figures describe the severe end of a spectrum rather than every case. The long-term risks are cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC, primary liver cancer).

Clinical presentations and complications

The clinical picture follows the natural history.

Acute co-infection presents as an acute hepatitis with jaundice, malaise and raised transaminases, sometimes biphasic, and usually resolving.

Acute superinfection typically presents as an unexplained severe hepatitis or a sudden flare in someone known to be a stable hepatitis B carrier. Any such flare should raise the possibility of hepatitis D.

Chronic hepatitis D is the dominant long-term problem after superinfection: progressive fibrosis, early cirrhosis, portal hypertension and its complications, and an increased risk of hepatocellular carcinoma compared with hepatitis B alone.

Fulminant hepatitis, with acute liver failure, is more common when hepatitis D is involved than with hepatitis B alone, and can complicate both co-infection and superinfection.

Diagnosis

The first message about diagnosis is that hepatitis D is heavily under-diagnosed: only an estimated 20 to 50 per cent of cases are identified, partly because testing has often been restricted to recognised risk groups who are missed when their risk is unknown. Current practice is therefore to screen every hepatitis B surface antigen positive person at least once, most efficiently by reflex testing (running the delta test automatically on any hepatitis B positive sample).

The cascade is straightforward:

• Anti-HDV antibody (total, with IgM where available) is the screening test. A positive result shows exposure but cannot by itself separate past from current infection, because antibody persists after clearance.
• HDV RNA by reverse transcription polymerase chain reaction confirms active, replicating infection and gives a baseline viral load. Results are standardised against a World Health Organization international unit (IU) so they can be compared between laboratories. HDV RNA is the reference marker of active infection.
• Genotyping adds prognostic information where available.

Active infection then prompts staging of the liver: transaminases, synthetic function (albumin and the international normalised ratio, or INR), platelet count, non-invasive fibrosis assessment, and, in cirrhosis, six-monthly hepatocellular carcinoma surveillance. Hepatitis B markers are measured in parallel, remembering that hepatitis D often suppresses them.

Management

Hepatitis D has been hard to treat because it offers no viral enzyme of its own to target. The realistic long-term goal is loss of hepatitis B surface antigen, which removes the envelope the delta virus needs, but this is rarely achieved, so treatment aims to suppress HDV RNA, normalise liver enzymes, and slow progression.

Pegylated interferon alpha was for many years the only option. It suppresses HDV RNA in a minority and, importantly, reduces liver-related events (decompensation, liver cancer, transplant or death) from around 8.5 per cent per year to around 3.3 per cent per year. It is poorly tolerated and cannot be used in decompensated cirrhosis, but it remains useful in compensated disease.

Bulevirtide is a first-in-class entry inhibitor. It is a small lipopeptide copied from the preS1 part of the hepatitis B envelope, and it binds and blocks the NTCP receptor, stopping the virus from infecting new liver cells. Given as a daily subcutaneous injection, it received European approval (conditional in 2020, full in 2023) and is not yet approved in the United States. In trials roughly half of patients reach a combined virological and biochemical response by 96 weeks, far more than with no treatment, and the main expected effect is a rise in blood bile-acid levels from NTCP blockade.

Lonafarnib, a farnesyl-transferase inhibitor, blocks the lipid tagging the large delta antigen needs for assembly and is in late-stage trials, usually combined with a booster and interferon.

Nucleos(t)ide analogues for hepatitis B do not act on hepatitis D directly but are used where the hepatitis B infection itself warrants treatment. Liver transplantation is effective for end-stage disease, with hepatitis B prophylaxis used to protect the graft.

Prevention and public health

Vaccination

There is no vaccine against hepatitis D itself, and this leaves a specific gap. Because the virus cannot establish itself without hepatitis B, the hepatitis B vaccine prevents hepatitis D by preventing the infection it depends on, and universal infant hepatitis B vaccination is the single most effective public-health measure against delta hepatitis. The limitation is that the vaccine does nothing for people who already carry hepatitis B: they remain susceptible to superinfection, and there is no immunoglobulin or vaccine that protects them. This group, the existing hepatitis B carriers, is where the residual disease burden sits.

Harm reduction

Because percutaneous transmission, especially through injecting drug use, drives much of the remaining spread, harm-reduction services, needle and syringe programmes, opioid agonist therapy, and safe medical injection practices reduce new infections among the most exposed populations.

South African context

Hepatitis D is uncommon in South Africa despite the country’s high hepatitis B burden. Reported prevalence among hepatitis B carriers has been low, in the region of 0 to under 1 per cent, so it is not a major contributor to the national liver-disease burden, but it still warrants detection in the right patients.

• Testing: the 2019 National Department of Health Viral Hepatitis Guideline frames hepatitis D as a co-infection to consider in hepatitis B surface antigen positive patients, identified by anti-HDV testing with HDV RNA confirmation, with management at tertiary level.
• Prevention: the country’s main defence is its hepatitis B programme. Infant hepatitis B vaccination through the Expanded Programme on Immunisation, and the targeted measures to prevent mother-to-child hepatitis B transmission, indirectly protect against hepatitis D. No hepatitis D specific vaccine or immunoglobulin is available.
• Notification: viral hepatitis is a notifiable medical condition in South Africa, so confirmed cases are reported through the national surveillance system.

References and recommended reading

• Negro F, Lok AS. Hepatitis D: A Review. JAMA 2023;330(24):2376-2387. The current authoritative clinical review, covering taxonomy, the modern natural-history picture, screening, and the new treatments.
• Rizzetto M, Smedile A, Ciancio A. Hepatitis D. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 58. Washington: ASM Press; 2016. Foundational account of the virus, its discovery, and its biology.
• Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 2012;1:e00049. The identification of NTCP, the shared entry receptor that bulevirtide now targets.
• National Department of Health, South Africa. National Guidelines for the Management of Viral Hepatitis. December 2019. The South African programmatic source for testing and referral.