Advances in New Antivirals for Chronic Hepatitis B

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Advances in New Antivirals for Chronic Hepatitis B

Chronic hepatitis B virus (HBV) infection remains a significant global health burden, affecting approximately 5–6% of China’s population. Despite advancements in antiviral therapies, achieving functional cure (hepatitis B surface antigen [HBsAg] loss) or complete cure (elimination of covalently closed circular DNA [cccDNA]) remains challenging. Current treatments, including nucleos(t)ide analogs (NAs) and interferon-alfa (IFN-α), suppress viral replication but result in low HBsAg loss rates (1–13% with NAs, 3–11% with IFN-α). This review explores the limitations of existing therapies and highlights emerging antiviral strategies targeting HBV lifecycle steps and host immune modulation.

Current Antiviral Therapies

Nucleos(t)ide Analogs (NAs)

NAs inhibit HBV polymerase activity, suppressing viral DNA synthesis. First-line NAs—entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF)—demonstrate potent antiviral effects but limited HBsAg clearance:

  • Entecavir (ETV): In phase III trials, 90% of HBeAg-negative and 67% of HBeAg-positive patients achieved undetectable HBV DNA after 48 weeks. After 5 years, HBsAg loss occurred in only 5% of HBeAg-positive patients.
  • Tenofovir Disoproxil Fumarate (TDF): After 8 years, 99% of HBeAg-negative and 98% of HBeAg-positive patients had undetectable HBV DNA, but HBsAg loss rates were 1.1% and 13%, respectively.
  • Tenofovir Alafenamide (TAF): At 3 years, HBsAg loss rates were 0.4% (HBeAg-negative) and 1.4% (HBeAg-positive).

Interferon-Alfa (IFN-α)

IFN-α enhances immune-mediated viral clearance. Pegylated IFN-α (PEG IFN-α) therapy achieves HBsAg loss in 8–11% of patients after 3 years. However, adverse effects and modest efficacy limit its use.

Emerging Direct-Acting Antivirals

Entry Inhibitors

HBV entry into hepatocytes requires binding of the pre-S1 viral envelope protein to the sodium taurocholate cotransporting polypeptide (NTCP) receptor. Hepcludex (Bulevirtide), an NTCP inhibitor, blocks viral entry and reduces HBsAg in HBV/hepatitis D virus (HDV) co-infected patients:

  • In a phase IIb trial, 30 patients receiving Hepcludex + PEG IFN-α for 48 weeks showed >1 log 10 HBsAg decline in 9 patients.

Targeting Viral Transcripts

RNA Interference (siRNA) therapies degrade HBV mRNA, reducing viral antigens:

  • JNJ-3989: A phase IIb trial involving 40 patients reported ≥1 log 10 HBsAg reduction in 39 subjects. At follow-up, 22 patients maintained a 1.74 log10 HBsAg decline.
  • VIR-2218: In a phase II study, HBeAg-negative patients receiving 200 mg doses achieved 1.65 log 10 HBsAg reduction. However, HBsAg rebounded after 24 weeks in some cases.

Antisense Oligonucleotides (ASOs) bind HBV RNA to inhibit translation:

  • IONIS-HBVRx (GSK3228836): A phase II trial showed 1.56 log 10 HBsAg reduction in untreated patients after 4 weeks. Three patients experienced >3 log10 HBsAg decline but developed transient ALT flares.

Capsid Assembly Inhibitors

These drugs disrupt nucleocapsid formation, preventing pgRNA packaging and cccDNA replenishment:

  • GLS4: Combined with ritonavir (RTV) to prolong half-life, GLS4 + entecavir reduced HBV DNA by 5.02 log 10 and HBsAg by 0.43 log10 in untreated patients (phase IIb).
  • ABI-H0731 (Vebicorvir): In phase II trials, combining ABI-H0731 with NAs accelerated HBV DNA and RNA decline. However, 39/41 patients relapsed after stopping therapy in an extension study.

HBsAg Secretion Inhibitors

REP2139, a nucleic acid polymer, blocks subviral particle secretion:

  • In HBV/HDV co-infected patients, REP2139 + PEG IFN-α achieved 45% HBsAg clearance at 3.5-year follow-up.
  • A phase II trial in HBeAg-negative patients reported 70.6% achieving >1 log 10 HBsAg reduction, with 60% seroconversion.

Immunotherapeutic Strategies

Toll-Like Receptor (TLR) Agonists

TLR agonists stimulate innate immunity and cytokine production:

  • GS-9688 (Selgantolimod): A TLR8 agonist induced ≥0.5 log 10 HBsAg decline in 4/67 patients after 48 weeks (phase II).

Therapeutic Vaccines

Vaccines aim to restore HBV-specific T-cell responses:

  • HeberNasvac (ABX-203): Intranasal HBsAg/HBcAg vaccine led to undetectable HBV DNA in 5/6 patients over 5 years.
  • BRII-179: A phase Ib/IIa trial showed simultaneous B- and T-cell activation, supporting combination therapies.

Inhibitor of Apoptosis Proteins (IAP) Antagonists

APG-1387 degrades IAPs, enhancing T-cell-mediated viral clearance:

  • Preclinical studies demonstrated HBV clearance via TNFα-dependent CD4+/CD8+ T-cell activation. A phase II trial with entecavir is ongoing.

Immune Checkpoint Inhibitors

Blocking PD-1/PD-L1 reinvigorates exhausted T cells:

  • Nivolumab: In a phase I trial, 14% of patients achieved >0.5 log 10 HBsAg reduction, with one HBsAg loss case.

Monoclonal Antibodies

VIR-3434, an HBsAg-targeting monoclonal antibody, reduced HBsAg by >1 log 10 within 2 weeks in a phase Ib trial.

Challenges and Future Directions

While novel antivirals show promise, challenges remain:

  1. cccDNA Persistence: Current therapies cannot eradicate cccDNA, necessitating CRISPR-based gene editing approaches.
  2. Immune Restoration: Combining direct-acting antivirals with immunotherapies may reverse T-cell exhaustion and achieve durable responses.
  3. Safety Concerns: Immune-mediated flares (e.g., ALT elevations with IONIS-HBVRx) require careful monitoring.

Ongoing trials explore combination regimens, such as siRNA (VIR-2218) + monoclonal antibodies (VIR-3434) or capsid inhibitors (ABI-H0731) + siRNA (AB-729). These strategies aim to synergistically reduce viral load, suppress antigen production, and restore immune control.

Conclusion

The landscape of chronic hepatitis B therapy is evolving rapidly. Direct-acting antivirals targeting viral entry, transcription, and assembly, coupled with immunotherapies reactivating host immunity, offer hope for functional cure. While monotherapeutics show partial efficacy, combination regimens addressing multiple viral and host targets are essential to overcome HBV persistence. Clinical trials must prioritize safety, long-term outcomes, and biomarkers predicting treatment success.

doi.org/10.1097/CM9.0000000000001994

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