Bulevirtide Approved as First US Treatment for Chronic Hepatitis Delta Virus

The FDA approved bulevirtide-gmod (Hepcludex; Gilead Sciences) injection on May 22, 2026, marking a historic regulatory milestone: the first approved treatment for chronic hepatitis delta virus (HDV) infection in the United States.¹ The approval covers adults without cirrhosis or with compensated cirrhosis and was granted to Gilead Sciences under the FDA's Accelerated Approval pathway, with Priority Review, Breakthrough Therapy Designation, and Orphan-Drug Designation all previously conferred on the agent.

The decision closes a longstanding therapeutic void in a disease that, despite its severity, has carried no approved pharmacologic options in the US until now.

"Today's approval fills a critical gap in care for patients with chronic HDV infection, who until now have had no FDA-approved therapies available," said Wendy Carter, DO, Acting Director of the Office of Infectious Diseases in FDA's Center for Drug Evaluation and Research, in a statement.¹

Trial Design and Efficacy

Approval was supported by MYR301, a multicenter, randomized, open-label, parallel-arm phase 3 trial evaluating bulevirtide-gmod 8.5 mg administered subcutaneously once daily.¹ Participants were assigned either to immediate treatment for 144 weeks or to a 48-week observational (delayed-treatment) period followed by 96 weeks of active therapy.

The primary endpoint was a combined virologic and biochemical response at week 48, defined as undetectable HDV RNA (below the lower limit of quantification of 50 IU/mL with target not detected) or a reduction of 2 log₁₀ IU/mL or greater from baseline, plus alanine aminotransferase (ALT) normalization. The immediate-treatment group achieved this combined response in 48% of participants, compared with 2% in the delayed-treatment group—a clinically meaningful separation in a disease with few historical benchmarks for pharmacologic response.

Virologic deepening was observed with extended therapy. Undetectable HDV RNA rates were 20% at week 48, rising to 36% at week 96 and 50% at week 144 in the immediate-treatment arm. No participants in the delayed-treatment group achieved undetectable HDV RNA at week 48.

Safety Profile

The FDA labeling for bulevirtide-gmod carries a boxed warning: discontinuation of therapy may result in severe acute exacerbations of both HDV and hepatitis B virus (HBV) infection, given the obligate coinfection biology of HDV. Clinicians initiating therapy should counsel patients accordingly and ensure post-treatment monitoring protocols are in place.

Reported adverse effects include hypersensitivity reactions (including anaphylaxis), injection site reactions, headache, abdominal pain, fatigue, and pruritus. The overall safety findings appear consistent with the agent's mechanism and administration route, though longer-term surveillance data will be essential given the chronic treatment course.

Disease Burden and Clinical Context

HDV infection is a defective RNA virus that requires HBV surface antigen for viral assembly and transmission; it cannot establish infection in individuals without concurrent or prior HBV infection.² Among individuals with chronic HBV, HDV superinfection or coinfection substantially accelerates hepatic disease progression—increasing the risk of liver fibrosis, hepatocellular carcinoma, decompensated cirrhosis, and liver-related mortality compared with HBV monoinfection.² Risk factors for acquisition include injection drug use, unprotected sexual contact, and occupational blood exposure. HBV vaccination confers protection against both viruses.

Prior to this approval, off-label use of pegylated interferon-alfa represented the only available therapeutic strategy, with limited efficacy and significant tolerability concerns—leaving most patients without a viable long-term treatment option.³

Bulevirtide is a synthetic lipopeptide derived from the preS1 domain of the HBV large surface protein. It blocks entry of both HBV and HDV into hepatocytes by competitively inhibiting the sodium taurocholate cotransporting polypeptide (NTCP) receptor, thereby preventing de novo infection of hepatocytes.⁴ The agent received earlier conditional marketing authorization from the European Medicines Agency in 2020, providing initial real-world experience in European clinical practice.

Limitations and Next Steps

As an accelerated approval, continued approval is contingent on verification of clinical benefit in confirmatory trials. The open-label design of MYR301 introduces potential for assessment bias, and the absence of a placebo-controlled arm limits interpretation of ALT normalization data. Long-term durability of virologic suppression after treatment discontinuation remains an unanswered question, as does the optimal treatment duration in patients achieving sustained undetectable HDV RNA. Post-marketing studies will be critical to defining these parameters.

References

1. US Food and Drug Administration. FDA approves first treatment for chronic hepatitis delta virus (HDV) infection. Published May 22, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-chronic-hepatitis-delta-virus-hdv-infection
2. Sureau C, Negro F. The hepatitis delta virus: replication and pathogenesis. J Hepatol. 2016;64(1 suppl):S102-S116.
3. Wedemeyer H, Yurdaydin C, Hardtke S, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis. 2019;19(3):275-286.
4. Nkongolo S, Ni Y, Lempp FA, et al. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol. 2014;60(4):723-731.