How retrospective studies are revealing the alarming prevalence of this aggressive liver pathogen
Imagine a defective satellite that can't function independently, a viral parasite that hijacks another virus to wreak havoc on the human liver. This is the hepatitis delta virus (HDV), one of the most fascinating and severe human pathogens that exists in a biological gray area—somewhere between a conventional virus and a primitive viroid. When it partners with hepatitis B, this unlikely duo creates the most aggressive form of viral hepatitis known to medicine, accelerating the progression to cirrhosis and liver cancer at an alarming rate 2 5 .
Despite its severity, HDV has largely flown under the radar of public awareness and even medical attention. Recent retrospective studies analyzing historical patient data have revealed a troubling reality: not only are testing rates dangerously low, but the infection is more common than previously thought 1 3 .
This article explores what scientists are learning about HDV seroprevalence through retrospective analyses and why this forgotten virus deserves our immediate attention.
HDV is scientifically fascinating because it breaks all the conventional rules of virology. It's the smallest known animal virus with a circular, single-stranded RNA genome that structurally resembles plant viroids 2 . But unlike those simple pathogens, HDV encodes one critical protein—the hepatitis delta antigen (HDAg)—which comes in two isoforms that perform different functions in the viral life cycle 2 .
HDV enters liver cells by hijacking hepatitis B surface proteins
Once inside, it commandeers human host polymerases to copy its RNA genome 2
It uses HBV's surface antigen (HBsAg) as packaging material to form new viral particles
These new HDV particles leave the cell, ready to infect more liver cells 2
When someone acquires both HBV and HDV at the same time
When HDV invades someone who already has chronic hepatitis B 2
The superinfection scenario is particularly dangerous, as it leads to chronic HDV in approximately 80% of cases and dramatically accelerates liver disease progression 7 .
Understanding HDV prevalence has been challenging due to inconsistent testing practices worldwide. Recent meta-analyses estimate that between 4.5% to 15% of people living with hepatitis B also have HDV infection, translating to approximately 12 to 72 million people globally 2 5 . This staggering range highlights how much uncertainty still exists about the true scale of the pandemic.
| Region/Country | Estimated HDV Seroprevalence | Notes |
|---|---|---|
| Mongolia | 8.03% | Highest national prevalence globally 5 |
| Republic of Moldova | 1.40% | Representative of Eastern European hotspots 5 |
| Turkey (Southeastern region) | 14.1%-27.1% | Marked regional variation within country 7 |
| Pakistan | 2.43% | High burden due to population size 5 |
| Nigeria | 5.04% | Representative of West African pattern 5 |
| Spain | 5.15% | With reflex testing implementation 6 |
| United States | 4.7%-15.7% | Varies significantly by study and region 1 3 |
What makes this geographical distribution particularly interesting is how it has evolved. While universal HBV vaccination programs initially reduced HDV incidence in many developed regions, migration patterns have reshaped the epidemiology, making HDV a renewed concern even in historically low-endemic countries 2 .
Retrospective studies—those that analyze past medical records—have consistently revealed an alarming truth: we're dramatically underdiagnosing HDV. The numbers are startling:
Only 6.1% of chronic hepatitis B patients received HDV testing in a major U.S. study 1
Merely 2.6% of individuals with HBV were tested for HDV antibodies in Florida 3
Only about 8.2% of HBsAg-positive patients undergo HDV testing in Europe 5
This testing gap has serious consequences. When researchers actually look for HDV in hepatitis B patients, they find it at surprisingly high rates. The same U.S. safety-net study found that among those tested, 15.7% were positive for HDV antibodies—and this jumped to 22.9% among patients who met formal testing criteria 1 . In Diyarbakır, Turkey, a retrospective analysis found 14.1% of chronic hepatitis B patients had HDV antibodies, with more than half of these (55.8%) already diagnosed with cirrhosis 7 .
The reasons for this diagnostic failure are multifaceted. They include limited provider awareness, historical lack of effective treatments, and inconsistent screening recommendations between major liver societies 5 . While European guidelines recommend universal HDV screening for all hepatitis B patients, American guidelines suggest a more targeted, risk-based approach 5 .
Between April and October 2022, researchers in Valencia, Spain, conducted a groundbreaking study that demonstrated a powerful solution to the HDV testing gap. They implemented a reflex testing protocol—an automated system where any positive hepatitis B surface antigen test would automatically trigger an HDV antibody test in the same laboratory workflow 6 .
15,541 individuals were tested for hepatitis B surface antigen across multiple healthcare settings
Any positive HBsAg result automatically triggered testing for HDV IgG/IgM antibodies
All antibody-positive samples underwent HDV RNA PCR testing to identify active infections
Researchers collected data on age, sex, and country of origin to identify risk patterns 6
The reflex testing protocol achieved what targeted testing had failed to do for decades—near-comprehensive HDV screening. The results were revealing:
| Metric | Result | Significance |
|---|---|---|
| HBsAg-positive rate | 2.3% (351/15,541) | Identified HBV-infected population |
| HDV testing coverage | 99.4% (349/351) | Near-universal screening achieved |
| HDV antibody positivity | 5.15% (18/349) | Seroprevalence rate with complete testing |
| Active HDV infection rate | 38.8% (7/18) | Proportion with current viremic infection |
| Migrant population among positives | 77.8% (14/18) | Highlighted key risk population |
The reflex testing approach was particularly effective at capturing migrant populations, who accounted for the majority of HDV cases but might otherwise have been missed in routine care. This single intervention increased HDV diagnostic coverage from approximately 24% to 99.4% 6 .
Studying HDV requires specialized tools and reagents, each serving a distinct purpose in unraveling the virus's mysteries. Here are the key components of the HDV researcher's toolkit:
| Research Tool | Primary Function | Application in HDV Research |
|---|---|---|
| Anti-HDV ELISA | Detection of HDV antibodies | Seroprevalence studies and diagnosis 7 |
| HDV RNA RT-PCR Kits | Quantification of viral load | Confirming active infection and treatment monitoring 6 |
| HDV Antigen Immunoassays | Detection of viral proteins | Basic research and pathogenesis studies 9 |
| Recombinant HBsAg | Provision of essential envelope protein | In vitro studies of HDV entry and replication 2 |
| Polymerase Inhibitors | Blocking host replication machinery | Investigating HDV replication mechanism 2 |
| Cell Culture Systems | Supporting HDV replication in lab | Drug screening and basic virology research 4 |
These tools have been instrumental in advancing our understanding of HDV biology and developing better diagnostics. The continued refinement of these reagents—particularly the development of standardized commercial HDV RNA assays—is critical for improving both clinical management and research comparability 5 .
One significant challenge in HDV management has been inconsistent screening recommendations across major liver societies:
| Organization | Recommendation Type | Key Populations Identified |
|---|---|---|
| European Association for the Study of the Liver (EASL) | Universal screening | All patients with chronic HBV infection 5 |
| Asian Pacific Association for the Study of the Liver (APASL) | Universal screening | All patients with chronic HBV infection 5 |
| American Association for the Study of Liver Diseases (AASLD) | Risk-based screening | Persons from endemic regions, people who inject drugs, men who have sex with men, HCV co-infected 5 |
This lack of consensus has contributed to the testing gaps identified in retrospective studies. However, the striking findings from these studies are beginning to shift the conversation toward more comprehensive screening approaches.
Retrospective seroprevalence studies have revealed two parallel stories about hepatitis delta virus. First, they've exposed a substantial diagnostic gap—systematic undertesting that has hidden the true scale of HDV infection for decades. Second, they've demonstrated that when we actually look for HDV, we find it at concerning rates, with significant implications for patient outcomes.
The solution lies in adopting more systematic approaches to HDV testing, such as the reflex testing model proven successful in Valencia. Combined with greater clinician awareness and standardized testing protocols, such approaches could dramatically improve diagnosis rates.
Perhaps most importantly, the HDV story underscores a fundamental truth in medicine: what we don't look for, we don't find. As one research team noted, "Among an ethnically diverse, multi-center safety-net cohort of patients with CHB, low rates of HDV testing were observed, even among those with high-risk HDV risk factors" 1 . Closing this diagnostic gap is the essential first step toward addressing the significant disease burden of this severe form of viral hepatitis.
While hepatitis B vaccination remains our most powerful weapon against HDV , for those already living with chronic hepatitis B, improved screening and emerging treatments offer new hope in managing this aggressive coinfection. The retrospective evaluations of HDV seroprevalence have given us both a warning and a roadmap—now we must follow it.