Ledipasvir

證據等級: L5

預測適應症: 10 個

Ledipasvir: From Hepatitis C Virus Infection to Hepatitis B Virus Infection

One-Sentence Summary

Ledipasvir is the NS5A inhibitor component of the fixed-dose combination Ledipasvir/Sofosbuvir (Harvoni), originally developed and extensively studied for chronic Hepatitis C virus (HCV) infection. The TxGNN model predicts it may also be effective for Hepatitis B Virus Infection, with 20 clinical trials and 20 publications currently retrieved — but on closer review, the vast majority of this evidence describes HCV treatment in HCV/HBV-coinfected patients or HBV reactivation risk during HCV therapy, not direct antiviral efficacy against HBV itself. Only one small, uncontrolled Phase 2 pilot study directly tested Ledipasvir/Sofosbuvir as HBV monoinfection therapy. Nine other TxGNN-predicted indications for this drug (rank 2–10) carry weaker evidence (L4–L5) and are not addressed further here.

Quick Overview

Item	Content
Original Indication	Chronic Hepatitis C Virus (HCV) infection (as part of Ledipasvir/Sofosbuvir fixed-dose combination; not formally licensed in Germany per available data)
Predicted New Indication	Hepatitis B Virus Infection
TxGNN Prediction Score	99.91%
Evidence Level	L3
Germany Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in the drug record. Based on the evidence pack's mechanistic notes, Ledipasvir is an NS5A protein inhibitor used within the Ledipasvir/Sofosbuvir combination, and its efficacy in chronic HCV infection is well established through numerous Phase 2–3 trials. However, Ledipasvir has no known direct inhibitory activity against HBV polymerase or cccDNA — its target protein (HCV NS5A) has no structural or functional counterpart in HBV.

The relationship between the original and predicted indications is therefore largely a matter of shared patient populations rather than shared drug mechanism: HCV and HBV frequently co-infect the same individuals (shared transmission routes), so almost all retrieved trials and publications involve HCV/HBV-coinfected cohorts being treated with Ledipasvir/Sofosbuvir for their HCV, with HBV monitored only as a safety endpoint. Several of these publications (e.g., PMID 29334502, PMID 34864948, PMID 27486112) specifically study HBV reactivation risk during DAA-based HCV therapy — a safety signal, not a therapeutic effect.

The one exception is a Phase 2 open-label pilot study (NCT03312023 / PMID 36045503) that directly administered Ledipasvir/Sofosbuvir to HBV-infected (not HCV-coinfected) subjects and observed a modest reduction in HBsAg. This is the only piece of evidence offering a plausible efficacy signal, but it is a small, single-arm, uncontrolled study, and given that Ledipasvir/Sofosbuvir has separately been explored for Hepatitis D virus (HDV) — which depends on the HBV envelope but replicates via an HBV-independent RNA mechanism more plausibly affected by NS5A-class inhibitors — this trial's true target disease (HBV vs. HDV) should be verified before drawing conclusions.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03312023	Phase 2	Completed	21	Only trial directly testing LDV/SOF as therapy in HBV-infected (not HCV-coinfected) subjects; assessed HBsAg/HBV DNA decline as primary/secondary endpoints
NCT02613871	Phase 3	Completed	111	LDV/SOF FDC in Taiwanese subjects with chronic genotype 1/2 HCV and HBV coinfection; primary endpoint remains HCV antiviral efficacy
NCT02555943	Phase 2/3	Completed	23	Prospective study of HBV reactivation incidence/morbidity during DAA treatment of HCV/HBV coinfection — a safety, not efficacy, endpoint
NCT02768961	Phase 4	Completed	64	Prison-population screening/treatment program covering HCV, HBV and HIV; HBV prevalence characterized but treatment targeted at HCV
NCT02597166	Phase 3	Completed	14	Antiviral therapy effects on decompensated cirrhosis in HCV genotype 1 population; may include HBV-exposed patients but HCV-focused (Grade B relevance)
NCT01384383	Phase 2	Terminated	248	Response-guided GS-5885/GS-9451+peg-IFN regimen in genotype 1 HCV; population includes HCV/HBV coinfection, primary endpoint is HCV SVR (Grade C relevance)
NCT02219685	Phase 2	Completed	40	LDV/SOF drug-interaction/neurocognition study in chronic HCV; not HBV-related (Grade C relevance)

Note: The remaining 13 trials retrieved for this candidate (e.g., NCT03823911, NCT02605304, NCT02421211) are HCV-only treatment or retreatment studies with no direct HBV therapeutic endpoint and have been excluded as low relevance.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
36045503	2023	RCT (Phase 2)	Journal of Medical Virology	Only study directly testing LDV/SOF in HBV-monoinfected subjects; modest reduction in HBsAg/HBV DNA reported at Week 12 — key primary evidence for this indication
34864948	2022	Cohort	Clinical Infectious Diseases	Taiwan HCV/HBV coinfection cohort treated with LDV/SOF; 108-week follow-up on HBV reactivation, not HBV cure
29334502	2018	Cohort	Journal of Clinical Gastroenterology	Examined HBV reactivation risk in HCV patients (previously/actively HBV-infected) treated with LDV/SOF for HCV
27486112	2016	Cohort	Clinical Infectious Diseases	Taiwan/Korea LDV/SOF trial cohort (103/173 HBV pre-exposed); no evidence of HBV reactivation observed
33523503	2021	Cohort/Observational	Journal of Viral Hepatitis	HBV reactivation risk in cancer patients receiving DAAs for HCV
27367295	2016	Pilot study	Antiviral Therapy	LDV/SOF for HCV suppression in HBV-coinfected patients; not an HBV efficacy endpoint
29174546	2018	Prospective study	Gastroenterology	Prospective assessment of HCV treatment efficacy and HBV reactivation risk/outcome in coinfected patients
37254310	2024	In silico	Journal of Biomolecular Structure & Dynamics	Molecular docking study of antiviral compounds against HBx protein — mechanistic/computational only, does not include ledipasvir directly tested against HBV target

Germany Market Information

Ledipasvir is currently not marketed in Germany (market status: "未上市" / Not marketed), and no marketing authorizations were found in the available regulatory dataset. No product listings, dosage forms, or approved indication texts are on file for this jurisdiction.

Safety Considerations

Please refer to the package insert for safety information.

(Note: while no structured safety/warning/contraindication data was available in this evidence pack, the clinical evidence above surfaced an important safety-relevant signal: multiple studies describe HBV reactivation occurring in HBV/HCV-coinfected patients during Ledipasvir/Sofosbuvir treatment of HCV. This is a known class effect of DAA therapy and should be explicitly addressed once formal safety documentation is obtained — see Next Steps.)

Conclusion and Next Steps

Decision: Hold

Rationale: The mechanistic basis for using Ledipasvir against HBV is weak — Ledipasvir's target (HCV NS5A) has no known role in HBV replication, and the great majority of retrieved evidence reflects HBV reactivation risk during HCV treatment rather than antiviral efficacy against HBV. Only one small, uncontrolled Phase 2 pilot study directly supports an HBV efficacy signal, and its true target disease (HBV vs. HDV) requires verification. Combined with the drug's absence from the German market, current evidence does not support progression beyond a research question at this time.

To proceed, the following is needed:

Confirm whether NCT03312023 / PMID 36045503 truly evaluated HBV monoinfection or HDV (given Ledipasvir/Sofosbuvir's established mechanistic plausibility for HDV) — this may redirect the repurposing hypothesis entirely
Obtain TFDA/EMA package insert data (Data Gap DG001) to enable a formal S1 safety screen, particularly regarding HBV reactivation risk
Obtain confirmed mechanism-of-action documentation from DrugBank (Data Gap DG002) to formally assess mechanistic plausibility
If HBV monoinfection remains the target, a larger controlled trial with virologic cure endpoints (not just HBsAg decline) is needed before advancing past L3
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.