Bulevirtide for hepatitis D infection

Background:
Hepatitis delta virus (HDV) infection, also known as hepatitis D, is the most severe form of chronic viral hepatitis. Chronic HDV infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatitis D infection occurs only in people living with hepatitis B, as HDV requires the hepatitis B virus for replication and transmission. Hepatitis D is bloodborne and transmitted through exposure to infected body fluids (e.g. blood, saliva, semen, vaginal fluid) via needle punctures, broken skin or mucous membranes.¹

Previously, there was no approved treatment for hepatitis D in Australia. Peginterferon alfa has been used off label but is associated with serious adverse effects and frequent relapse,^1-3 highlighting the need for more effective and safer therapies. Bulevirtide is approved in Australia for adults with chronic hepatitis D infection and compensated liver disease.

Mechanism of action:
Bulevirtide binds to and inactivates the sodium taurocholate cotransporting polypeptide (NTCP), blocking the entry of hepatitis B and D viruses (and bile acids) into hepatocytes.⁴ This prevents viral replication, thereby reducing inflammation and associated liver damage.

Clinical trials:
The efficacy and safety of bulevirtide were assessed in an open-label phase 3 study.⁵ Adults with chronic hepatitis D infection were randomised to receive immediate treatment with subcutaneous bulevirtide at 2 mg (n=49) or 10 mg (n=50) once daily for 144 weeks, or no treatment for 48 weeks followed by bulevirtide 10 mg once daily for 96 weeks (n=51). All patients had HDV genotype 1 (the most common HDV genotype globally), and 63% of patients were on concomitant nucleoside or nucleotide analogue therapy (e.g. tenofovir) for chronic hepatitis B infection. Almost half had Child–Pugh class A cirrhosis (compensated liver disease).

The primary endpoint was combined response at week 48, defined as (1) an undetectable HDV RNA or a decrease in HDV RNA by at least 2 log₁₀ units/mL from baseline (virological response) and (2) normalisation of alanine aminotransferase (ALT) concentration (biochemical response).

At week 48, combined response was achieved in 45% of patients who received immediate treatment with bulevirtide 2 mg daily compared with 2% of those who had not started treatment. Virological response occurred in 71% versus 4%, and ALT normalisation occurred in 51% versus 12%, respectively.⁵ Results were similar between the 2 mg and 10 mg immediate-treatment groups at week 48, and the 10 mg dose has not been approved in Australia.

After the 144-week treatment period, there was a further 96 weeks of follow-up without further bulevirtide therapy. Combined response rates declined from 57% in those who had received immediate treatment with bulevirtide and 56% in those who received delayed treatment to 24% in both groups. Of the total 64 patients with undetectable HDV RNA at the end of treatment and available follow-up data, 23 (36%) sustained undetectable HDV RNA through to the end of follow up, while 41 (64%) had viral relapse.⁶

Adverse effects:
Adverse effects that were more common in the group that received bulevirtide 2 mg compared with those who did not receive bulevirtide in the first 48 weeks of the phase 3 trial included headache, pruritus, fatigue, eosinophilia, injection-site reactions, arthralgia and asthenia.⁵ All adverse effects were mild to moderate and did not lead to drug discontinuation. Hypersensitivity reactions, including anaphylaxis, have been reported during post-approval use.⁷ Due to its mechanism of action, bulevirtide may cause asymptomatic elevation of serum bile salts.

Dosage and administration:
The recommended dosage of bulevirtide is 2 mg once daily, administered by subcutaneous injection into the upper thigh or lower abdomen. The injection site should be rotated.⁷

Unreconstituted vials must be stored in the refrigerator. For detailed instructions on how to prepare and administer a dose, refer to the approved Product Information.⁷

Precautions:
No dosage adjustment is required in patients with mild hepatic or renal impairment.⁷

It is not recommended to co-administer bulevirtide with other drugs that inhibit, or are substrates of, NTCP (e.g. sulfasalazine, ketoconazole, irbesartan, ciclosporin).⁴

Use in pregnancy and breastfeeding:
Data on bulevirtide use in pregnancy are limited; animal studies have not shown increased fetal toxicity. The drug is classified as Therapeutic Goods Administration pregnancy category B1. Bulevirtide should only be used during pregnancy if the potential benefits outweigh the potential harms to the fetus. It is not known whether bulevirtide is secreted in human breastmilk.⁷

Practice points:
All patients with hepatitis B should be tested for hepatitis D,^3,8 and those with confirmed co-infection should be managed by a specialist with expertise in viral hepatitis. Nucleoside or nucleotide analogue therapy should be started or continued, if indicated, for hepatitis B.

Place in therapy:
Bulevirtide is the first treatment approved in Australia for adults with chronic hepatitis D infection. Clinical trial data demonstrate that bulevirtide provides virological and biochemical improvements that remained evident after 144 weeks.⁶ While some patients maintained undetectable HDV load for 96 weeks after stopping bulevirtide treatment, a majority experienced viral relapse,⁶ highlighting uncertainty around optimal treatment duration and the need for ongoing viral load monitoring if treatment is stopped. The approved Product Information states that treatment should continue for as long as it is associated with clinical benefit.⁷

Evidence remains limited in specific populations. Bulevirtide has not been studied in people with Child–Pugh class B or C cirrhosis (decompensated liver disease), a creatinine clearance below 60 mL/minute, or in those younger than 18 years.⁷ Patients in the pivotal trial all had HDV genotype 1 and were predominantly of White ethnicity. Further studies are needed to understand the long-term clinical benefit of bulevirtide and its safety and efficacy in other populations.

Emerging data suggest a potential benefit from combination treatment with bulevirtide and peginterferon alfa.⁹ The use of peginterferon alfa to treat hepatitis D is off label in Australia.

This new drug comment was finalised on 20 April 2026. It was prepared by Sherilyn Wong, Clinical Editor, Australian Prescriber, and reviewed by Amy Legg, Pharmacist and Assistant Director of Pharmacy, Caboolture Hospital, Queensland.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

This article is peer reviewed.

 

References

1. World Health Organization. Hepatitis D. World Health Organization; 2025. [cited 2026 Apr 14]
2. ASHM Health. Complex situations Co-infection and Immunosuppression. ASHM Health; 2020. [cited 2026 Mar 24]
3. Hepatitis B Consensus Statement Working Group. Australian consensus recommendations for the management of hepatitis B infection. Melbourne: Gastroenterological Society of Australia; 2022. [cited 2026 Mar 25]
4. Billi M, Soloperto S, Bonora S, D'Avolio A, De Nicolo A. Clinical Pharmacology of Bulevirtide: Focus on Known and Potential Drug-Drug Interactions. Pharmaceutics 2025;17.
5. Wedemeyer H, Aleman S, Brunetto MR, Blank A, Andreone P, Bogomolov P, et al. A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D. N Engl J Med 2023;389:22-32.
6. Wedemeyer H, Aleman S, Blank A, Andreone P, Bogomolov P, Chulanov V, et al. P158 Final results of MYR301: a randomised phase 3 study evaluating the efficacy and safety of up to 144 weeks of bulevirtide monotherapy for chronic hepatitis delta and 96 weeks of posttreatment follow-up [abstract]. Gut 2025;74:A117-A.
7. Therapeutic Goods Administration. Australian Product Information – HEPCLUDEX (bulevirtide) injection. Department of Health, Disability and Ageing; [cited 2026 Mar 24]
8. ASHM Health. Adult Antiretroviral Guidelines. Hepatitis B Virus/HIV Coinfection. ASHM Health; 2025. [cited 2026 Mar 24]
9. Ouranos K, Mylona EK, Dellis C, Bakaloudi DR, Shehadeh F, Noureddin M, et al. Comparative Efficacy of Treatment Regimens for Chronic Hepatitis D Virus Infection: A Systematic Review and Network Meta-Analysis. Liver Int 2025;45:e70232.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by subject matter experts. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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