Ledipasvir

證據等級: L5

預測適應症: 10 個

Ledipasvir: From Chronic Hepatitis C to Hepatitis B Virus Infection

One-Sentence Summary

Ledipasvir is an NS5A inhibitor best known as a component of the ledipasvir/sofosbuvir (Harvoni) fixed-dose combination for chronic hepatitis C virus (HCV) infection. The TxGNN model predicts it may also be effective for Hepatitis B Virus (HBV) Infection, with 21 clinical trials and 20 publications identified in the evidence pack — but the strongest direct evidence (a dedicated Phase 2 HBV trial) reported a negative efficacy signal, and much of the remaining literature concerns HBV reactivation risk during HCV treatment rather than antiviral benefit against HBV itself.

Quick Overview

Item	Content
Original Indication	Not documented in Norway regulatory data (drug unmarketed); per known clinical use, ledipasvir is used as part of the ledipasvir/sofosbuvir combination for chronic hepatitis C
Predicted New Indication	Hepatitis B Virus Infection
TxGNN Prediction Score	99.91%
Evidence Level	L3
Norway 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 from DrugBank in this evidence pack. Based on known information, ledipasvir is an HCV NS5A protein inhibitor, marketed exclusively as part of the ledipasvir/sofosbuvir fixed-dose combination for chronic genotype 1/4/5/6 HCV infection. HCV (Flaviviridae, positive-sense RNA virus) and HBV (Hepadnaviridae, a DNA virus replicating via reverse transcription) are virologically distinct families with no known overlapping molecular target — NS5A has no HBV homolog.

Despite this mechanistic gap, the prediction is not entirely without a rationale to test: patients coinfected with HCV and HBV are common, and retrospective data suggested modest reductions in HBsAg during HCV treatment with ledipasvir/sofosbuvir, motivating a dedicated Phase 2 trial (NCT03312023) in HBV-monoinfected subjects. However, the published results of that trial (PMID 36045503) showed no clinically meaningful suppression of HBV DNA, indicating the earlier HBsAg-decline signal did not translate into antiviral efficacy. In parallel, a substantial portion of the literature base actually documents the opposite clinical concern — HBV reactivation during ledipasvir/sofosbuvir treatment of HCV/HBV-coinfected patients — which is a safety signal, not a therapeutic rationale.

In summary: the high TxGNN score for this indication appears to reflect literature co-occurrence (both diseases are frequently studied together in coinfected populations) rather than a validated pharmacological effect. The evidence pack's own rationale and "Hold" recommendation align with this interpretation.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03312023	Phase 2	Completed	21	Open-label study directly testing ledipasvir/sofosbuvir for 12 weeks in HBV-monoinfected subjects; hypothesis-generating, but published results showed no significant HBV DNA decline
NCT02555943	Phase 2/3	Completed	23	Studied incidence and risk factors for HBV reactivation during direct-acting antiviral treatment of HCV/HBV coinfection — a safety, not efficacy, endpoint
NCT02613871	Phase 3	Completed	111	LDV/SOF for HCV genotype 1/2 in HCV/HBV-coinfected patients (Taiwan); treatment target was HCV clearance, not HBV
NCT01938430	Phase 2	Completed	339	LDV/SOF + ribavirin in advanced liver disease/post-transplant HCV patients (genotype 1/4, some HBV-exposed); HCV-focused endpoints
NCT02010255	Phase 2	Completed	334	Companion cohort study to NCT01938430, same protocol; HCV efficacy endpoint

Note: 16 additional trials in the evidence pack are standard HCV genotype 1/2/4 treatment studies with only incidental HBV coinfection status and were excluded here as not directly relevant to HBV efficacy.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
36045503	2023	Phase 2 open-label trial	J Med Virol	Direct test of LDV/SOF in HBV-monoinfected subjects; no significant decline in HBV DNA at Week 12 despite hypothesis based on retrospective HBsAg signal
34864948	2022	Cohort (108-week follow-up)	Clin Infect Dis	Taiwan cohort of HCV/HBV-coinfected patients treated with LDV/SOF; evaluated HBV reactivation, not HBV cure
29174546	2018	Prospective cohort	Gastroenterology	Risks and outcomes of HCV treatment with LDV/SOF in HBV-coinfected patients; reactivation-focused
29334502	2018	Cohort (reactivation risk)	J Clin Gastroenterol	Examined HBV reactivation risk in actively/previously infected patients during DAA therapy
27486112	2016	Cohort (no reactivation)	Clin Infect Dis	Taiwan/Korea cohort of 173 patients (103 with prior HBV exposure); no HBV reactivation observed during LDV/SOF
27367295	2016	Pilot study	Antivir Ther	Gane et al.; evaluated whether LDV/SOF can suppress HCV in HBV-coinfected patients — HCV-focused
33523503	2021	Prospective observational	J Viral Hepat	HBV reactivation risk during DAA treatment for HCV in cancer patients with HBV/HCV coinfection
37254310	2024	In silico / molecular docking	J Biomol Struct Dyn	Computational screening of antiviral compounds against HBx protein; not specific to ledipasvir mechanism

Norway Market Information

Ledipasvir is currently not marketed in Norway (market status: 未上市). No authorization records are available in the evidence pack.

Safety Considerations

Please refer to the package insert for safety information. (TFDA/DMP label warnings and contraindications were not available in this evidence pack — flagged as a Blocking data gap, see Next Steps.)

Conclusion and Next Steps

Decision: Hold

Rationale: Although the TxGNN score is very high (99.91%), the strongest and most direct clinical evidence — a Phase 2 trial specifically testing ledipasvir/sofosbuvir in HBV-monoinfected patients (NCT03312023 / PMID 36045503) — reported no meaningful antiviral effect on HBV DNA. Most of the remaining trial and literature base concerns HBV reactivation risk during HCV treatment, which is a safety consideration working against this indication rather than supporting evidence for it. The mechanistic basis (HCV NS5A inhibition) also has no established relevance to HBV replication (reverse transcriptase-dependent, cccDNA-based). This candidate should not advance without new positive efficacy data.

To proceed, the following is needed:

Resolution of the Blocking data gap: TFDA/DMP label warnings and contraindications (DG001)
Resolution of the High priority data gap: confirmed mechanism of action from DrugBank (DG002)
If pursued further, an updated systematic review or a properly powered, randomized trial with a confirmed antiviral (HBV DNA/HBsAg) endpoint would be required to override the current negative Phase 2 signal
Given the negative primary trial result, further investment in this specific indication is not currently recommended; lower-ranked candidates in this evidence pack (e.g., hepatitis E virus infection, rank 2) may warrant separate evaluation given their distinct mechanistic rationale
Disclaimer

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