Nucleos(t)ide analogues such as entecavir and tenofovir suppress hepatitis B virus replication with remarkable potency, but they rarely eradicate the reservoir of covalently closed circular DNA that persists in hepatocytes. For HBeAg-negative patients without cirrhosis, treatment guidelines therefore allow, and in some settings encourage, a finite course of therapy followed by careful monitoring. The rationale is that stopping drugs can provoke an immune-mediated flare that, in a minority of patients, leads to durable viral control or even loss of hepatitis B surface antigen, the closest available surrogate of a functional cure. The challenge is that relapse is common, flares can be severe, and clinicians have lacked reliable tools to identify who will benefit and who will simply rebound.

Ethnicity has repeatedly been proposed as one such tool. Observational studies across Europe and Asia have suggested that patients of Asian descent relapse more frequently after treatment cessation than those of European background, and some guidelines have quietly incorporated this notion into patient selection. The problem, as the COIN-B investigators argue, is that ethnicity is a subjective and inconsistently applied construct, blending self-identification, place of birth, language and social factors into a category whose biological content is undefined. To test whether the apparent ethnic effect is real, the team designed a trial that would measure it prospectively and then dissect it with more rigorous instruments: genome-wide ancestry markers and viral genotype.

The trial enrolled long-term nucleos(t)ide analogue-treated patients who were HBeAg-negative at the start of their original treatment and who had no advanced fibrosis, a population considered safe enough to undergo supervised withdrawal of therapy. All participants stopped their antiviral drug under protocol and were followed intensively for 72 weeks, with serial measurements of HBV DNA, hepatitis B surface antigen, liver biochemistry and, where applicable, retreatment when predefined safety or virological thresholds were crossed. Of the 91 patients who discontinued treatment, 84 completed the full 72-week protocol, providing a substantial prospective dataset for the prespecified analyses.

The primary endpoint, off-treatment viral control at week 72, did not differ between the two prespecified ethnic groups. Among 41 patients classified as Caucasian, 41.5 percent maintained viral control, compared with 30.2 percent among 43 non-Caucasian patients, a difference that fell well short of statistical significance with a p value of 0.28. On its face, this negative result might seem to close the door on the ethnicity hypothesis. But the exploratory analyses that followed revealed a more interesting picture, one in which the blunt ethnic dichotomy had been masking genuine heterogeneity that finer-grained variables could detect.

When the researchers replaced self-reported ethnicity with genomic ancestry, inferred from genome-wide markers and quantified as the proportion of DNA attributable to reference populations, patterns emerged that the ethnic categories had obscured. Hepatitis B surface antigen loss, the secondary endpoint and the most desirable outcome short of eradication, occurred in 7.1 percent of participants overall, and every single case arose in a patient with predominantly European or North African and Middle Eastern ancestry. Conversely, a decline of at least one log in surface antigen levels, an accepted on-treatment marker of a favorable immune trajectory, was significantly less frequent among patients with Asian or Sub-Saharan African ancestry, with a p value of 0.01. These findings suggest that ancestry-related factors, whether immunogenetic, viral or both, do influence the probability of a functional cure after treatment withdrawal.

The viral side of the equation proved equally informative. Hepatitis B virus is classified into at least ten genotypes with distinct geographic distributions, and genotype has long been suspected to modulate disease course and treatment response. In the COIN-B analysis, lower hepatitis B surface antigen levels at the end of treatment independently predicted viral control, surface antigen loss and meaningful surface antigen decline, confirming that this biomarker remains the strongest single predictor available to clinicians. But even after adjusting for end-of-treatment surface antigen, patients infected with genotype C or genotype D achieved less viral control and required retreatment more often than those infected with genotype A. The result aligns with a growing body of evidence that viral genotype is not a passive phylogenetic label but a biologically active determinant of how the infection behaves once drug pressure is removed.

Methodologically, the trial illustrates why prospective design and molecular characterization matter in this field. Previous reports linking ethnicity to relapse were largely retrospective, drawn from heterogeneous cohorts treated with different drugs for different durations, and they relied on ethnic labels assigned inconsistently across centers. By registering the comparison in advance, standardizing the cessation protocol across Belgian centers, and applying genome-wide ancestry inference alongside viral sequencing, the COIN-B team was able to separate what the coarse label conflates. The trial is registered as NCT04779970 with ClinicalTrials.gov and as EudraCT 2021-001003-32 with the European clinical trials register, and it was funded in full by the Research Foundation Flanders under its Applied Biomedical Research program, with the funder having no role in the design, analysis or reporting.

The clinical implications are twofold. First, the study cautions against using ethnicity as a proxy for biological risk in treatment cessation decisions. A category that fails to reach statistical significance as a predictor, while its genomic and viral components do, is a poor foundation for patient selection, and its use risks embedding social classification into medical algorithms without justification. Second, the results argue for more granular characterization of patients considered for treatment withdrawal: quantified genomic ancestry, viral genotype and, above all, carefully measured end-of-treatment surface antigen levels. None of these variables alone is sufficient, but together they begin to explain why two patients with identical biochemical profiles can follow sharply divergent courses after the same drug is stopped.

For the field at large, COIN-B reframes a familiar question in more precise terms. The goal is no longer to ask whether a patient’s ethnicity predicts relapse, but to identify the specific host and viral factors that ancestry and genotype merely tag. Genotype-specific viral biology, human leukocyte antigen variation, and ancestry-linked immune gene polymorphisms are all plausible mediators, and disentangling them will require the kind of prospective, molecularly annotated cohorts this trial exemplifies. In the meantime, the study offers clinicians a sober and practical message: the decision to stop nucleos(t)ide analogue therapy should rest on measurable viral and serological variables rather than on broad demographic labels, and even the best current predictors leave most patients still infected, still monitored, and still waiting for a true functional cure.

Subject of Research: Determinants of off-treatment viral control after cessation of nucleos(t)ide analogue therapy in chronic hepatitis B

Article Title: Ethnicity, genomic ancestry, and HBV genotype in off-treatment outcomes following nucleos(t)ide analogue cessation: a prospective multicentre trial (COIN-B)

Article References: Furquim d’Almeida, A., Vanderlinden, A., Ralf, A., Bourgeois, S., Mulkay, J.-P., Sersté, T., Struyve, M., Deressa, B., Sprengers, D., de Vos, M., Callens, J., Shihao, B., François, S., Deltenre, P., Janssens, F., Negrin Dastis, S., Stärkel, P., Orlent, H., Van Roey, G., … Vanwolleghem, T. (2026). Ethnicity, genomic ancestry, and HBV genotype in off-treatment outcomes following nucleos(t)ide analogue cessation: a prospective multicentre trial (COIN-B). Nature Communications. https://doi.org/10.1038/s41467-026-78490-0

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78490-0

Keywords: hepatitis B, HBV genotype, genomic ancestry, nucleos(t)ide analogue cessation, HBsAg loss, functional cure, viral relapse, COIN-B trial, ethnicity, predictive biomarkers, HBeAg-negative, retreatment