Why a Landmark Hepatitis D Drug May Not Be Enough on Its Own

Hepatitis D (HDV) pushes patients toward cirrhosis faster than any other chronic viral hepatitis, and until this spring, clinicians in the US had no FDA-approved drug to interrupt that course.¹ A new review lays out the immune biology behind that trajectory and argues that outrunning the virus will likely take more than 1 drug at a time.

A Disease That Outpaced Its Own Treatment Options

HDV is a defective RNA virus that can only infect people already living with hepatitis B virus (HBV), and the resulting coinfection causes the most severe form of chronic viral hepatitis known. Anti-HDV antibodies are present in an estimated 4.5% of hepatitis B surface antigen (HBsAg)-positive patients across 95 countries, in 2.2% of similar patients in the US, and in roughly 12 million people worldwide. Most individuals with chronic hepatitis D (CHD) develop cirrhosis within 5 to 10 years of infection, and mortality is more than double that seen in HBV monoinfection.

Until recently, clinicians had only 1 approved option and 1 off-label option to offer: the entry inhibitor bulevirtide, cleared by the European Medicines Agency and several other regulators, and pegylated interferon alfa, used off-label since the 1980s. That changed on May 22, 2026, when the FDA granted bulevirtide (Hepcludex; Gilead Sciences) accelerated approval as the first treatment for chronic HDV infection in the US, based on phase 3 data showing a combined response of undetectable HDV RNA, or at least a 2-log decline, plus normalized alanine aminotransferase (ALT) in 48% of treated patients vs 2% of those on delayed treatment at week 48.² The approval rests on that surrogate end point; whether it also reduces cirrhosis or liver failure has not yet been established.

Tracing HDV From Cell Entry to T-Cell Exhaustion

The current review draws on preclinical and clinical literature to trace HDV's life cycle, from its reliance on the HBV envelope and the sodium taurocholate co-transporting polypeptide receptor for cell entry, through the innate interferon response it triggers, to the adaptive immune failures that let infection become chronic.¹ It describes how virus-specific CD8-positive T cells in CHD are outnumbered by T cells targeting other, more common viruses, and how roughly 60% of HDV-specific CD8-positive T cells settle into a partially functional, memory-like state rather than clearing the virus; only about 40% still recognize circulating viral strains at all.

That immune standoff, the review argued, is a major reason viral suppression alone has struggled to produce lasting remission. It organizes current and emerging drug classes, including entry inhibitors, neutralizing antibodies, small interfering RNAs, antisense oligonucleotides, interferons, checkpoint inhibitors, T-cell therapies, and vaccines, around whether each one restores immune function or lowers viral load.

Combination Regimens Outperform Single-Agent Suppression

Combining approaches already outperforms monotherapy in the data the review cites. Bulevirtide plus pegylated interferon alfa produced undetectable HDV RNA in 46% of patients on the higher bulevirtide dose and 26% on the lower dose 48 weeks after stopping treatment, compared with 12% of patients on bulevirtide alone. In extended follow-up of the pivotal bulevirtide trial, 36% of patients who cleared HDV RNA by the end of treatment remained undetectable through week 96 after stopping therapy.

A newer combination goes further. Pairing the monoclonal antibody tobevibart with the small interfering RNA elebsiran brought 66% of patients with CHD to undetectable HDV RNA and 56% to normalized ALT after 48 weeks of treatment, vs 48% and 61%, respectively, with tobevibart alone; it also reduced HBsAg to below 10 IU/mL in 91% of patients, compared with 21% on monotherapy.

That regimen's response climbed further with longer follow-up, reaching 88% undetectable HDV RNA at week 96 in a company update the review cites.

“The overarching goal should be to stop disease progression,” the authors wrote. “By doing so, we will buy patients more time until we accomplish viral elimination.”

Immunological Gaps Could Slow Personalized Hepatitis D Care

The investigators cautioned that much of what is known about restoring antiviral immunity comes from HBV research and cannot be assumed to translate directly to HDV. Also, clinical trials of newer HDV therapies have rarely included the detailed immunological studies needed to identify which patients are most likely to respond. Without that data, matching patients to specific combinations, or knowing when treatment can safely be stopped, will remain difficult.

For payers and health systems now covering the first approved HDV therapy, the review's message is that bulevirtide is unlikely to be a stand-alone solution for most people with HBV/HDV coinfection. Its authors called for immunological profiling to be built into ongoing and future trials, particularly in regions carrying the heaviest HDV burden, so that clinicians can identify which combinations and which patients stand to benefit most as additional agents move through the pipeline.

References

1. Albarghash R, Jacobsen C, Kefalakes H. Exploiting the immunopathogenesis of hepatitis D virus infection to develop superior treatment options. Antiviral Res. 2026;250:106416. doi:10.1016/j.antiviral.2026.106416
2. Steinzor P. Where the field of viral hepatitis stands and where it’s heading. AJMC^®. May 29, 2026. Accessed July 28, 2026. https://www.ajmc.com/view/where-the-field-of-viral-hepatitis-stands-and-where-it-s-heading