Ledipasvir
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Ledipasvir: From Chronic Hepatitis C to Hepatitis B Virus Infection
One-Sentence Summary
Ledipasvir is an HCV NS5A inhibitor, used in combination with sofosbuvir (Harvoni) to treat chronic hepatitis C. The TxGNN model predicts it may be effective for hepatitis B virus infection, with 5 clinical trials and 20 publications matched to this prediction. Only one completed Phase 2 study tests the HBV indication directly, and the wider literature mainly describes HBV reactivation risk during HCV treatment.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection (from the knowledge graph; the New Zealand licence record has no indication text) |
| Predicted New Indication | Hepatitis B virus infection |
| TxGNN Prediction Score | 99.91% |
| Evidence Level | L2 |
| New Zealand Market Status | Cancelled only (no currently valid licence) |
| Number of Authorizations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Ledipasvir is known to inhibit the HCV NS5A protein, and it is used with the polymerase inhibitor sofosbuvir. Its efficacy in hepatitis C is well established.
Both HCV and HBV cause chronic viral liver infection, which likely explains the model's prediction. Mechanistically, however, the link is weak. NS5A has no known HBV homolog, so any anti-HBV effect is not explained by the original mechanism. A pilot study of HCV/HBV co-infected patients observed a modest drop in HBsAg during ledipasvir/sofosbuvir treatment. That observation led to a dedicated study in HBV mono-infection, but it remains hypothesis-generating.
The other predicted indications scored similarly (HEV, HAV, HIV, Omsk haemorrhagic fever, Kyasanur forest disease and others). They have little or no direct supporting evidence, and several (HIV, HAV) are HCV studies matched through the drug name only. HBV has the strongest data of the group.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03312023 | Phase 2 | Completed | 21 | Open-label ledipasvir/sofosbuvir for 12 weeks in HBV-infected subjects. Most direct test of the HBV indication; published (PMID 36045503) |
| NCT02555943 | Phase 2/3 | Completed | 23 | Direct-acting antivirals in HCV/HBV co-infection; focuses on HBV reactivation incidence and risk factors |
| NCT03261349 | Phase 2 | Unknown | 21 | Ledipasvir/sofosbuvir in HCV-associated indolent B-cell lymphoma; HBV relevance is indirect |
| NCT02836925 | Phase 2 | Completed | 40 | Interferon-free regimen in HCV-associated indolent B-cell lymphomas; indirect to HBV |
| NCT02768961 | Phase 4 | Completed | 64 | HCV screening and elimination programme in prisons; HBV is incidental |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36045503 | 2023 | Phase 2 trial | J Med Virol | Open-label pilot of ledipasvir/sofosbuvir for 12 weeks in HBV mono-infection; endpoints were HBsAg and HBV DNA decline at week 12 |
| 27367295 | 2016 | Pilot study | Antivir Ther | Ledipasvir/sofosbuvir for HCV in HBV-coinfected patients |
| 34864948 | 2022 | Cohort | Clin Infect Dis | HCV/HBV co-infection in Taiwan; HBV reactivation tracked for 108 weeks after treatment |
| 29334502 | 2018 | Cohort | J Clin Gastroenterol | Risk of HBV reactivation with ledipasvir-sofosbuvir in HCV patients |
| 33523503 | 2021 | Cohort | J Viral Hepat | HBV reactivation in cancer patients receiving DAAs for HCV |
| 28585404 | 2017 | Cohort | Hepatol Res | Frequency of and factors associated with HBV reactivation during DAA therapy in a Japanese cohort |
| 26967675 | 2016 | Review/Cohort | J Clin Virol | HBV reactivation as a challenge during DAA treatment of HCV |
| 28249574 | 2017 | Case report | BMC Infect Dis | Occult HBV reactivation in an HIV/HCV co-infected patient treated with sofosbuvir/ledipasvir |
| 34092970 | 2021 | Review | World J Gastroenterol | Management of paediatric viral hepatitis; HBV treatment is still far from curative |
| 37254310 | 2024 | In silico study | J Biomol Struct Dyn | Computational screening of antivirals against HBx protein |
New Zealand Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 2504111 | Harvoni | Tab 90 mg with sofosbuvir 400 mg | Not recorded (status: cancelled) |
Safety Considerations
- Drug Interactions: 65 interactions are recorded. The 20 listed in the compiled data are mostly Moderate, with two Minor (fidaxomicin, naloxegol). Main groups:
- Acid-reducing agents: proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole), H2 blockers (famotidine, cimetidine, nizatidine) and antacids (aluminium hydroxide, calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, magaldrate)
- Other: eliglustat, linagliptin, loperamide, naldemedine
- HBV reactivation: Several cohort studies and case reports describe HBV reactivation during DAA treatment of HCV in patients with HBV co-infection or prior exposure. This is a key concern for any use in HBV-positive patients.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: Only one small, completed open-label Phase 2 study (n=21) tests ledipasvir/sofosbuvir in HBV directly. There is no plausible HBV-specific target for an NS5A inhibitor, and the broader literature emphasises HBV reactivation rather than suppression. The only New Zealand licence is cancelled, and the package insert safety data are not available. These factors outweigh the high model score.
To proceed, the following is needed:
- Full results of the Phase 2 HBV study (PMID 36045503/NCT03312023): size and durability of HBsAg and HBV DNA reduction
- A larger controlled trial in HBV mono-infection, with comparison against standard nucleos(t)ide therapy
- Mechanistic data explaining any anti-HBV activity, including whether it comes from ledipasvir or from sofosbuvir
- Package insert warnings and contraindications (Medsafe), plus a current New Zealand supply and licensing pathway
- An HBV reactivation monitoring and risk-mitigation plan, including HBV screening before treatment
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.