BULEVIRTIDE improved the function of a small subset of hepatitis D virus (HDV)-specific immune cells, but most HDV-specific immune responses targeted viral regions altered by escape mutations, providing a possible explanation for why many patients require long-term treatment to reduce the risk of relapse.
Chronic hepatitis D is a severe liver disease caused by HDV, which depends on hepatitis B surface antigen to infect liver cells. The infection progresses to cirrhosis in around 75% of patients within 15 years, making effective long-term treatment an important clinical goal.
On average, around 70% of patients treated with bulevirtide achieve a virological response, defined as at least a two-log reduction in HDV RNA, according to previous evidence. Despite this, complete HDV RNA clearance remains uncommon after up to three years of therapy, and patients remain at high risk of relapse once treatment is stopped.
Researchers investigated whether lowering viral and antigen levels with bulevirtide could restore exhausted HDV-specific CD8+ T cells, which are thought to play an important role in controlling infection.
The study followed 28 patients with HDV-related cirrhosis receiving bulevirtide monotherapy for between 40 and 120 weeks. Participants underwent HLA class I typing, HDV sequencing and longitudinal immune profiling to assess changes in HDV-specific CD8+ T-cell responses during treatment.
At baseline, HDV-specific CD8+ T-cell responses were detected in 42% of patients and did not increase substantially during therapy. Most immune responses targeted viral regions containing sequence changes consistent with viral escape mutations, meaning many T cells could no longer effectively recognise their target viral epitopes.
Only one conserved viral epitope remained consistently targeted throughout treatment. T cells recognising this conserved target shifted from a predominantly terminally exhausted phenotype at baseline towards a more memory-like phenotype as HDV levels declined.
The researchers concluded that bulevirtide could improve exhausted HDV-specific CD8+ T cells directed against conserved viral targets. However, because most immune responses focused on viral epitopes altered by escape mutations, this did not translate into broad restoration of HDV-specific immunity.
The study was based on a small cohort of 28 patients, which the authors acknowledged as a limitation. Even so, the findings indicated that limited immune recovery may help explain why long-term bulevirtide treatment remained necessary to reduce the likelihood of HDV relapse after treatment discontinuation, even in patients who achieved undetectable HDV RNA.
Reference
Oberhardt V et al. Fate of hepatitis D virus-specific CD8+ T cells during bulevirtide monotherapy in patients with chronic hepatitis delta☆. JHEP Rep. 2026;DOI: 10.1016/j.jhepr.2026.101970.
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