Commentary: Progress and Challenges in the Global Elimination of Viral Hepatitis D

Over the past five years, global understanding of HDV epidemiology has advanced substantially. Enhanced population-based screening strategies and more sensitive diagnostic platforms have refined prevalence estimates and revealed a broader geographic distribution than previously recognized. Regional analyses demonstrate marked heterogeneity in HDV prevalence among HBsAg-positive populations (4), with rates ranging from 10%–15% in Central and West Africa, 5%–10% in Eastern Europe, and 3–8% in the Middle East, while most high-income settings in North America and East Asia report prevalence below 1% (5). Notably, targeted surveys have identified exceptionally high seroprevalence rates of 20%–40% among Indigenous communities in the Amazon Basin (6). These epidemiological insights have prompted an increasing number of countries to integrate routine anti-HDV screening into HBV management protocols and strengthen surveillance systems for high-risk populations.

Diagnostic and therapeutic capacities have similarly expanded. Standardized HDV RNA quantitative PCR assays, improved anti-HDV antibody testing platforms, and automated molecular diagnostic systems have enhanced case detection and enabled programmatic screening initiatives (7-8). For more than four decades, pegylated interferon-α (Peg-IFNα) remained the only available therapy for HDV, despite limited efficacy and poor tolerability (9). The regulatory approval of bulevirtide, an NTCP entry inhibitor, represented a milestone as the first targeted antiviral therapy for HDV, demonstrating substantial reductions in HDV RNA levels and improvements in biochemical markers (10). Several complementary investigational agents — including lonafarnib (11), REP 2139-Mg (12), VIR-2218 (13), and the monoclonal antibody libetavimab (HH-003) (14) — have now advanced to mid- and late-stage clinical development (Table 1). Increasing policy attention from the WHO and international hepatology societies has further strengthened the integration of routine HDV testing into national viral hepatitis elimination programs (3).

HDV control is hindered primarily by substantial diagnostic gaps. The vast majority of HBsAg-positive individuals worldwide have never been tested for HDV (15). Limited clinician awareness, restricted access to HDV RNA and antibody testing, and lack of reimbursement contribute to this diagnostic gap (16), leading many patients to be identified only at advanced liver disease stages.

Although bulevirtide represents a therapeutic milestone, its high cost and restrictive reimbursement policies limit availability to only a few countries. Other emerging agents are also expected to be expensive, leaving patients in low- and middle-income regions with few effective treatment options (17). Peg-IFNα further adds limitations due to modest efficacy and poor suitability for decompensated cirrhosis.

Effective HDV control is fundamentally linked to HBV prevention strategies. Given that HDV transmission requires concurrent HBV infection, robust HBV immunization programs represent a cornerstone of HDV prevention. However, substantial gaps persist: adult vaccination coverage remains below 20%–30% in many regions (18), and prevention of mother-to-child transmission fails in 5%–10% of births in some low- and middle-income countries (19). With nearly 300 million individuals living with chronic HBV infection globally, sustained immunoprevention and comprehensive long-term management are critical to reducing HDV incidence. Figure 1 illustrates the substantial gap between HBV-infected populations and HDV patients who ultimately access effective treatment.

Figure 1. 

Global estimated prevalence of HDV infection and the diagnostic and therapeutic gaps.

Note: This figure depicts the cascade from HBV infection to HDV diagnosis and treatment, highlighting critical gaps at each stage. Data sources include WHO Global Hepatitis Reports (2022–2024), multi-country HDV screening surveys, and regional epidemiological analyses. Estimated proportions represent: 1) the global HBsAg-positive population; 2) the proportion screened for anti-HDV antibodies; 3) the proportion diagnosed with HDV RNA viremia; and 4) the proportion receiving HDV-targeted therapy. Values illustrate the substantial magnitude of missed diagnoses and limited treatment access rather than country-specific estimates.

Abbreviation: HBV=hepatitis B virus; HDV=hepatitis D virus; WHO=World Health Organization; HBsAg=hepatitis B surface antigen.

Disease heterogeneity further complicates the evaluation of HDV treatment efficacy. While HBsAg clearance represents the ideal therapeutic endpoint, it remains difficult to achieve in clinical practice. Consequently, most trials rely on surrogate markers such as HDV RNA reduction and ALT normalization. However, these markers lack full validation, introducing uncertainty when assessing long-term clinical benefit (20).

HDV disproportionately affects several high-risk groups, particularly people who inject drugs (PWID) and migrants from high-endemic regions. Among PWID, HDV seroprevalence can reach 10%–30%, substantially exceeding rates observed in the general HBsAg-positive population. Similarly, migrants from high-burden areas demonstrate elevated anti-HDV positivity compared with local residents. Despite this heightened risk, screening coverage in these populations frequently remains below 20%. Tailored, community-engaged approaches will be essential to strengthen prevention, expand testing, and improve linkage-to-care.

Achieving HDV elimination requires coordinated efforts to address critical gaps in prevention, diagnosis, and treatment access.

Expand universal screening by implementing one-time anti-HDV testing for all HBsAg-positive individuals and improving access to affordable diagnostics. Improve access to emerging therapies by establishing pricing mechanisms and targeted access programs in high-burden settings. Strengthen HBV prevention by maintaining high infant immunization coverage and expanding adult catch-up vaccination programs. Enhance linkage-to-care by increasing provider awareness and integrating HDV services into existing HBV management programs.

Integrate anti-HDV testing into national HBV screening programs, with particular emphasis on newly diagnosed HBsAg-positive individuals. Strengthen laboratory and surveillance capacity through expanded HDV RNA testing and incorporation of HDV indicators into national reporting systems. Improve management of high-burden and mobile populations through targeted outreach programs and standardized referral pathways.