Hepatitis D Coinfection: What Pharmacists Need to Know About Emerging Treatment Options

Hepatitis D, also known as hepatitis delta, is caused by the hepatitis D virus (HDV) and is a common coinfection with hepatitis B. HDV is a small RNA virus that depends on the hepatitis B virus (HBV) for entry into hepatocytes to further replicate.¹

Among individuals with chronic HBV infection, an estimated 13% of patients are coinfected with HDV. Worldwide, approximately 48 to 60 million infections are diagnosed globally. Patients with HDV are more likely to develop cirrhosis than patients with HBV alone, and on average, cirrhosis develops within 5 years of infection, and hepatocellular carcinoma develops within 10 years.²

Predictably, transmission is similar to HBV: HDV spreads parenterally, percutaneously, sexually, and perinatally.¹ Currently, the most effective option is prevention with the HBV vaccine; however, when a patient is already an HBV carrier, there are no effective options to prevent HDV infection.¹ When replicating, the HDV genome hides inside of HBV and enters the cell through the sodium taurocholate cotransporting polypeptide (NTCP) receptor, where it can then move to the hepatocyte nucleus.¹ There, the HDV RNA is replicated using host enzymes and translated to its antigens, prenylated L-HDAg and S-HDAg, and the antigens and RNA bind to each other to form a ribonucleoprotein, which is then secreted.¹

With no FDA-approved agents for HDV, only pegylated interferon ɑ (PEG-INFɑ) is available for off-label treatment, but there are several agents in the pipeline.³

Pegylated Interferon ɑ (Pegasys; pharma&)

Alpha interferons are proteins that are endogenously produced by nucleated cells that have antiviral, antiproliferative, and immune-regulating activity.⁴ These proteins alter cell surface antigen expression, increase phagocytic activity of macrophages, and augment cytotoxicity of lymphocytes for target cells.⁴ Clinical trials have found that PEG-INFɑ suppressed HDV RNA to undetectable levels, decreased liver inflammation and fibrosis, and improved event-free survival in approximately 30% of patients.¹

PEG-INFɑ is preferred over interferon ɑ due to the longer half-life and less frequent administration of once weekly as opposed to 3 times per week. The normal dosing of PEG-INFɑ is a subcutaneous dose of 180 mcg once weekly for 48 weeks into the stomach or thigh and does not require medical supervision during administration.³ Dose adjustment is necessary once creatinine clearance falls below 30 mL/min for hemodialysis or when alanine aminotransferase (ALT) is 5 to 10 times the upper limit of normal.⁴ Once ALT is above 10 times the upper limit of normal, PEG-INFɑ should be discontinued.⁴

PEG-INFɑ is a mild CYP1A2 inhibitor and should be avoided with myelosuppressive agents.⁴ It is contraindicated for use in patients with decompensated cirrhosis or autoimmune hepatitis, and it has many adverse drug reactions, such as fatigue, flu-like symptoms, depression, thrombocytopenia, risk of severe hepatitis flare, and exacerbation of underlying autoimmune illnesses.^2,4

Pegylated Interferon λ

Pegylated interferon λ acts on the interferon λ receptors, which are predominantly expressed in hepatocytes, thus resulting in fewer systemic adverse effects than PEG-INFɑ.³ This was also studied in COVID-19, HBV, and HCV. A phase 2 and 3 study in HDV showed significant reductions in HDV RNA levels, but the study was discontinued due to the development of hepatobiliary events and liver decompensation in some patients.³

Ezetimibe (Zetia; Merck)

Ezetimibe is currently approved for hyperlipidemia, but it is being studied for HDV because it was found to inhibit the NTCP receptor.⁵ Ezetimibe 10 mg daily for 12 weeks was studied in 44 patients with chronic HDV and was found to reduce viral load in 43% of the patients who completed therapy.⁵

Ezetimibe has minimal drug interactions and is generally well tolerated but has a risk of hepatotoxicity, myalgias, and rhabdomyolysis.⁶ There are no contraindications to active liver disease, and no dose adjustments are recommended by the manufacturer.⁶ Based on study results, ezetimibe can be considered as add-on therapy to interferon ɑ to further lower viral load but should not be used alone.

Bulevirtide (Hepcludex; Gilead)

Bulevirtide is the first specific anti-HDV treatment granted conditional marketing authorization by the European Medicines Agency in 2020, but its initial application to the FDA was rejected due to concerns regarding manufacture and delivery (not the safety and efficacy).^3,7 It is a myristoylated peptide and mimics a region of the pre-S1 HBsAg, which is recognized by the NTCP receptor to allow HBV and HDV entry.³ Therefore, the drug competitively inhibits the entry and decreases the number of HDV-infected hepatocytes.³

In studies, 2 mg or 10 mg subcutaneous daily injections of bulevirtide in combination with PEG-INFɑ for 48 weeks significantly decreased the viral load and improved physical and hepatitis-related quality of life compared to either bulevirtide or PEG-INFɑ monotherapy or placebo.³ Both doses were well tolerated and showed similar efficacy.³ Gilead has said they are working to improve the manufacturing and product delivery with the FDA and plan to resubmit for approval when that is achieved.⁷

Libevitug (HH-003; Huahui)

Libevitug is an anti-PreS1 human monoclonal antibody that works similarly to bulevirtide, blocking the binding of HBV and HDV to the NTCP receptor and preventing the entry of HBV and HDV.⁸ It has been granted breakthrough therapy designation from the FDA in 2024, which helps expedite the development and review of drugs that are intended to treat a serious or life-threatening disease or condition.⁸ A phase 2 study showed a favorable safety profile and significantly decreased HDV RNA levels and normalized ALT.³ The phase 2b study was recently completed with 3 arms, one receiving 20 mg/kg once every 2 weeks via intravenous infusion plus tenofovir alafenamide (TAF) for 48 weeks, and the other 2 arms receiving either libevitug 10 mg/kg or TAF monotherapy.³ Libevitug could be an alternative to bulevirtide with less frequent administrations, but one downside is that it is an intravenous infusion, making adherence more difficult.

Lonafarnib

Lonafarnib, a prenylation inhibitor, inhibits farnesyltransferase to prevent the prenylation of the HDV large antigen, which is essential for viral assembly and release.³ Oral lonafarnib 50 mg twice daily was studied in combination with ritonavir 100 mg and PEG-INFɑ with a primary composite end point of undetectable HDV RNA or decline from baseline or normalization of ALT at 48 weeks.³ It did not meet statistical significance, and there was limited sustained response after treatment discontinuation, highlighting a need for maintenance therapy.³ Although this is the only oral option, the efficacy of this drug was not shown.

Nucleic Acid Polymers

Nucleic acid polymers block HBV entry, subviral particle formation, and release of HBsAg.³ In HDV, they block the subviral particle-related assembly mechanism and thus the production.³

In patients with HBV/HDV coinfection, the investigational drug REP 2139-Mg (Replicor) 500 mg weekly intravenous injection for 15 weeks followed by a combination of REP 2139-Mg 250 mg and PEG-INFɑ 180 mcg weekly subcutaneous injection for 15 weeks, then PEG-INFɑ monotherapy for another 33 weeks was studied with a primary end point of the safety and tolerability of the treatment.³ It was found that most of the 12 patients enrolled experienced thrombocytopenia, increased liver function tests, or bilirubin; however, the viral load was undetectable, and ALT normalized even 1 year post-treatment.⁹ Although this could be efficacious, the tolerability of an extensive treatment period with PEG-INFɑ and REP 2139-Mg could limit how many patients could pursue this option.

Elebsiran (VIR-2218; Vir Biotechnology, Alnylam) and Tobevibart (VIR-3434; Vir Biotechnology)

Elebsiran is an RNA interference-based therapy that inhibits the production of HBV proteins, including HBsAg, by targeting its RNA.³ In its phase 2 study for HBV, 20% to 26% of patients reported treatment-emergent adverse reactions related to elebsiran, and 12 out of 26 participants (42%) had HBeAg seroclearance or anti-HBe seroconversion.¹⁰ Elebsiran is now being studied in HDV in combination with tobevibart.³

Tobevibart is a monoclonal antibody that binds to the antigenic loops of HBsAg and inhibits entry of HBV and HDV into naive hepatocytes and reduces circulating HBsAg.³ Thus far, tobevibart 300 mg with elebsiran 200 mg subcutaneous injection every 4 weeks for up to 96 weeks has shown preliminary efficacy, with 50% of patients achieving undetected HDV RNA and ALT normalization.³ The combination is planned to be compared head-to-head to bulevirtide, which would be the first study to compare the few treatment options for HDV.³

Conclusion

Hepatitis D is a rare infection with low prevalence but a common coinfection with hepatitis B. There are few options for treatment in the US, with the only commercially available ones being interferon ɑ and ezetimibe. However, new therapies such as bulevirtide and libevitug are on the horizon.

REFERENCES

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2. Miao Z, Zhang S, Ou X, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis. 2019;221(10):1677-1687. doi:10.1093/infdis/jiz633

3. Abbas Z, Abbas M. Hope on the horizon: emerging therapies for hepatitis D. World J Hepatol. 2025;17(6):107963. doi:10.4254/wjh.v17.i6.107963

4. Peginterferon alfa-2a (subcutaneous route). Mayo Clinic. Updated August 1, 2025. Accessed December 23, 2025. https://www.mayoclinic.org/drugs-supplements/peginterferon-alfa-2a-subcutaneous-route/description/drg-20067318

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7. Gilead receives complete response letter from US FDA for bulevirtide for the treatment of adults with hepatitis delta virus. News release. Gilead. October 27, 2022. Accessed December 23, 2025. https://www.gilead.com/company/company-statements/2022/gilead-receives-complete-response-letter-from-us-fda-for-bulevirtide-for-the-treatment-of-adults-with-hepatitis-delta-virus

8. FDA grants breakthrough therapy designation for Huahui Health’s libevitug (HH-003) for treatment of chronic hepatitis D virus infection. News release. BioSpace. November 18, 2024. Accessed December 23, 2025. https://www.biospace.com/press-releases/fda-grants-breakthrough-therapy-designation-to-huahui-healths-libevitug-hh-003-for-treatment-of-chronic-hepatitis-d-virus-infection

9. Bazinet M, Pântea V, Cebotarescu V, et al. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naïve patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2017;2(12):877-889. doi:10.1016/S2468(17)30288-1

10. Yuen MF, Lim YS, Yoon KT, et al. VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study. Lancet Gastroenterol Hepatol. 2024;9(12):1121-1132. doi:10.1016/S2468-1253(24)00237-1