Updates on Recent Advancements in Hepatitis D Virus Treatment
Abstract
1. Introduction
2. Epidemiology
3. Pathogenesis
4. Prognostic Factors
4.1. Baseline Liver Injury
4.2. HDV Genotype
4.3. HBV Status
4.4. HDV RNA
5. Coinfection with HIV
6. Treatment Options
6.1. Pegylated Interferon-α
6.2. Bulevirtide
6.3. Combination Therapy of Bulevirtide and PegIFN-α
6.4. Lonafarnib
6.5. Pegylated Interferon-λ (PegIFN-λ)
6.6. Nucleic Acid-Based Therapies
6.7. Monoclonal Antibodies
6.8. Polyclonal Antibodies
7. Liver Transplantation
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Therapeutic Classes | Agent and Regimen(s) | Route | Key Antiviral Mechanism | Development/Regulatory Status | Typical Study Regimens † | Notes |
---|---|---|---|---|---|---|
Interferons | PegIFN-α-2a/-2b | SC | Broad immune activation | Approved for HBV/HCV → off-label HDV | 180 mcg qwk/1.5 mcg/kg qwk × 48 wk | SVR 23–57%; if no SVR → EVR < 5%; limited durability; contraindicated in decompensated cirrhosis; limited use due to side effects |
PegIFN-λ | SC | Type III IFN, hepatocyte-selective | Phase 2/3 (LIMT-2 Phase 3 trial terminated due to liver decompensation in participants) | 120–180 mcg qwk × 48 wk | CR ≤ 30%; trial halted due to liver decompensation secondary to hepatobiliary toxicity | |
Viral entry inhibition | Bulevirtide | SC | NTCP receptor inhibition | EMA-approved 2 mg qd | 2–10 mg qd; open-ended therapy | No dose-dependent differences in CR (~50% at week 48–144) or sustained HDV RNA negativity at post-treatment week 48; continued treatment needed for improved outcomes; delayed treatment linked to worse outcomes; better responses seen with lower baseline HDV RNA and HBsAg, on-treatment HBsAg loss or ≥1 log IU/mL decline, or ADA development; outcomes similar between patients with and without compensated cirrhosis. |
Bulevirtide + PegIFN-α | NTCP receptor inhibition + immune activation | Phase 2 (MYR203, MYR204, SEE-D) | 2–10 mg qd + PegIFN-α × 96 wk | Undetectable HDV RNA at post-treatment week 48 in ~25–45%; higher efficacy observed with combination therapy than pegIFN-α or bulevirtide monotherapy, but with increased pegIFN-α-related side effects | ||
Viral assembly inhibition | Lonafarnib + Ritonavir | PO | Inhibition L-HDAg prenylation → virion assembly | Phase 3 (D-LIVR) | 50 mg BID + Ritonavir × 48 wk | VR 14.6%, BR 24.7%, histologic improvement 33%; GI intolerance is dose-limiting; better bioavailability and tolerability with ritonavir (CYP3A4 inhibitor); compared to pegIFN-α monotherapy, better biochemical response but lower virologic and histologic outcomes |
Lonafarnib + Ritonavir + PegIFN-α | Inhibition L-HDAg prenylation + immune activation | 50 mg BID + Ritonavir + PegIFN-α × 48 wk | VR 32%, BR 34.4%, histologic improvement 53%; triple regimen shows superior efficacy across all outcomes compared to dual therapy, but with increased pegIFN-α-related side effects | |||
Nucleic-acid–directed therapies | Elebsiran (VIR-2218) + Tobevibart (VIR-3434) | SC | siRNA; silences HBV mRNA → ↓ HBsAg + mAb against HBsAg → HBsAg neutralisation | Phase 2 (SOLSTICE) → Phase 3 planned to commence in 2025 | 200 mg q4wk + Tobevibart × 24–60 wk | 100% VR at week 24; HDV RNA undetectable 41% at week 24, 64% at week 36, ≈80% at week 60 |
JNJ-3989 (JNJ-73763989) | SC | siRNA; designed to silence all HBV RNA transcription and accordingly translation of HBV viral proteins | Phase 2 (REEF-D) | 100 mg q4wk + NA × 144 wk (results announced until wk 48) | At week 48, VR 52%, BR 41%; increased risk of ALT flares in patients with baseline HBsAg levels > 10,000 IU/mL; higher baseline levels of HBsAg and HDV RNA were associated with worse outcomes | |
REP 2139-Ca/-Mg | IV/SC | NAP; binds host chaperones → blocking assembly and secretion of HBsAg | Phase 2 (REP 301, REP 301-LFT, RCAP ‡) | REP 2139-Ca: 500 mg IV qwk × 15 wk → 250 mg IV qwk + PegIFN-α × 15 wk → PegIFN-α × 33 wk (total 63 wk) REP 2139-Mg: 250 mg IV qwk ± PegIFN-α × 48 wk | REP 301: HDV RNA undetectable in 11/12 at end of therapy, 7/12 at 1 year post-treatment and 7/11 at 3.5 year post-treatment RCAP ‡: 76% VR and 61% HDV RNA undetectable at week 48; similar efficacy with/without pegIFN-α. | |
Antibody-based therapies—Monoclonal | Brelovitug (BJT-778) | SC | Anti-HBsAg IgG1 → HBsAg neutralisation | Phase 2 ongoing; FDA BTD, EMA PRIME/Orphan; Phase 2b/3 (AZURE-1) enrolling | 300–600 mg qwk × 48 wk | 100% VR with 60% undetectable HDV RNA at week 28 with 300 mg weekly dosing; better results with 600 mg weekly dosing at week 12 with no available data for week 28 |
Tobevibart (VIR-3434) ± Elebsiran (VIR-2218) | SC | Anti-HBsAg IgG1 → HBsAg neutralization + silencing of HBV mRNA | Phase 2 (SOLSTICE) | 300 mg q4wk + Elebsiran or 300 mg q2wk × 24–60 wk | Better results with combination therapy than monotherapy; see Elebsiran + Tobevibart | |
RG-6449 (RO7565020), 2H5-A14, E6F6, N6HB426-20, CIM212930 (early mAbs) | Anti-HBsAg (RG-6449); preS1-NTCP block (2H5-A14); Fc-mediated HBsAg clearance (E6F6); direct NTCP block (N6HB426-20, CIM212930) | Phase 1/pre-clinical | — | — | ||
Antibody-based therapies—Polyclonal | GIGA-2339 | IV | >1000 anti-HBsAg clones—broad neutralization | Phase 1 HBV; HDV pre-clinical | — | Potent in-vitro HDV neutralization |
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Bardak, A.E.; Ozturk, N.B.; Gurakar, M.; Sequeira, L.; Yildiz, E.; Ozmert, E.H.; Idilman, R.; Gurakar, A. Updates on Recent Advancements in Hepatitis D Virus Treatment. Viruses 2025, 17, 1100. https://doi.org/10.3390/v17081100
Bardak AE, Ozturk NB, Gurakar M, Sequeira L, Yildiz E, Ozmert EH, Idilman R, Gurakar A. Updates on Recent Advancements in Hepatitis D Virus Treatment. Viruses. 2025; 17(8):1100. https://doi.org/10.3390/v17081100
Chicago/Turabian StyleBardak, Ali Emre, Nazli Begum Ozturk, Merve Gurakar, Lynette Sequeira, Eda Yildiz, Enis Hikmet Ozmert, Ramazan Idilman, and Ahmet Gurakar. 2025. "Updates on Recent Advancements in Hepatitis D Virus Treatment" Viruses 17, no. 8: 1100. https://doi.org/10.3390/v17081100
APA StyleBardak, A. E., Ozturk, N. B., Gurakar, M., Sequeira, L., Yildiz, E., Ozmert, E. H., Idilman, R., & Gurakar, A. (2025). Updates on Recent Advancements in Hepatitis D Virus Treatment. Viruses, 17(8), 1100. https://doi.org/10.3390/v17081100