Ledipasvir
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
- Ledipasvir
- Pharmacist Assessment Report
- Ledipasvir: From Hepatitis C Virus Infection to Hepatitis B Virus Infection
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- Canada Market Information
- Safety Considerations
- Conclusion and Next Steps
- Disclaimer
Ledipasvir: From Hepatitis C Virus Infection to Hepatitis B Virus Infection
One-Sentence Summary
Ledipasvir is an HCV NS5A inhibitor, marketed in Canada as part of the Harvoni combination (with sofosbuvir) and originally used to treat chronic hepatitis C. The TxGNN model predicts it may be effective for hepatitis B virus infection, but the mechanistic rationale is weak. Support consists of 1 directly relevant Phase 2 trial (n=21, no control arm) and several co-infection studies that mainly address safety (HBV reactivation) rather than HBV efficacy.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection |
| Predicted New Indication | Hepatitis B virus infection |
| TxGNN Prediction Score | 0.9991 |
| Evidence Level | L2 |
| Canada Market Status | Marketed (marketed DINs: 1 of 1) |
| Number of DINs | 1 (marketed: 1) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the data compiled for this report. Based on known information, ledipasvir is an NS5A inhibitor used together with sofosbuvir, and its efficacy in hepatitis C is established.
HBV has no known counterpart to HCV NS5A, so an anti-HBV effect is not explained by ledipasvir’s original mechanism. The most plausible source of signal is observational: in patients co-infected with HCV and HBV, treatment with ledipasvir/sofosbuvir was associated with a modest reduction in HBV surface antigen (HBsAg). That observation prompted a Phase 2 pilot in HBV mono-infected patients (NCT03312023, published 2023). The data compiled for this report do not show a robust HBV antiviral effect from that study.
The high TxGNN score is therefore best read as a hypothesis-generating signal, not as a mechanistically supported finding. The main clinical concern in HBV-exposed patients is the documented risk of HBV reactivation after HCV clearance with direct-acting antivirals.
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; directly targets the indication; no control arm, small sample |
| NCT02555943 | Phase 2/3 | Completed | 23 | Direct-acting antivirals in chronic HCV/HBV co-infection; examines HBV reactivation during anti-HCV treatment (indirect evidence) |
| NCT02836925 | Phase 2 | Completed | 40 | Interferon-free ledipasvir/sofosbuvir or sofosbuvir/velpatasvir in HCV-associated indolent B-cell lymphoma; HBV relevance uncertain |
| NCT03261349 | Phase 2 | Unknown | 21 | Harvoni in HCV-associated indolent B-cell non-Hodgkin lymphoma; target population unclear for HBV |
| NCT02768961 | Phase 4 | Completed | 64 | HCV screening and elimination programme in prisons; not related to HBV treatment |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36045503 | 2023 | Phase 2 open-label trial | J Med Virol | Ledipasvir/sofosbuvir for 12 weeks in HBV mono-infection; primary endpoint was HBsAg decline, secondary was HBV DNA decline at Week 12 |
| 29174546 | 2018 | Prospective study | Gastroenterology | Ledipasvir/sofosbuvir in HCV patients co-infected with HBV; risks and outcomes including HBV reactivation |
| 34864948 | 2022 | Cohort | Clin Infect Dis | HCV/HBV co-infected patients in Taiwan; HBV reactivation followed for 108 weeks after treatment |
| 27367295 | 2016 | Pilot study | Antivir Ther | Ledipasvir/sofosbuvir suppressing HCV in patients co-infected with HBV |
| 29334502 | 2018 | Cohort | J Clin Gastroenterol | Risk of HBV reactivation during or after ledipasvir/sofosbuvir treatment |
| 33523503 | 2021 | Cohort | J Viral Hepat | Prospective study of HBV reactivation in cancer patients receiving DAAs for HCV |
| 28585404 | 2017 | Prospective cohort | Hepatol Res | Frequency of and factors associated with HBV reactivation during all-oral DAA therapy |
| 26967675 | 2016 | Review | J Clin Virol | HBV reactivation as a further challenge in DAA treatment of HCV |
| 28249574 | 2017 | Case report | BMC Infect Dis | Occult HBV reactivation in an HIV/HCV co-infected patient treated with ledipasvir/sofosbuvir |
Canada Market Information
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 02432226 | HARVONI | Not specified | Not specified |
Safety Considerations
- Drug Interactions: 65 interactions were identified in total. Those listed here are mostly Moderate, with a few Minor.
- Acid-reducing agents (reduce ledipasvir absorption): aluminum hydroxide, calcium carbonate, magaldrate, magnesium carbonate, magnesium hydroxide, magnesium oxide; H2 blockers cimetidine, famotidine, nizatidine; proton pump inhibitors omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole (all Moderate)
- Other Moderate interactions: eliglustat, linagliptin, loperamide, naldemedine
- Minor interactions: fidaxomicin, naloxegol
- HBV reactivation: Multiple cohort studies and case reports describe HBV reactivation in HBV-exposed patients after HCV clearance with direct-acting antivirals. This is the central safety issue for any use in HBV-infected populations.
For other warnings and contraindications, please refer to the package insert.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The only directly relevant evidence is a small, uncontrolled Phase 2 pilot (n=21) in HBV mono-infection. No robust antiviral effect is shown in the data compiled, and there is no mechanistic basis for NS5A inhibition acting on HBV. Co-infection data mainly document HBV reactivation risk, not benefit.
- Other predicted indications (hepatitis E, hepatitis A, HIV, Omsk hemorrhagic fever, Kyasanur forest disease and animal-model indications) have weaker or no supporting evidence, and none offers a stronger repurposing case than HBV.
To proceed, the following is needed:
- Full results of the HBsAg and HBV DNA endpoints from NCT03312023 (PMID 36045503), to judge the size and durability of any effect
- Mechanistic data (MOA) and an explanation of how an NS5A inhibitor could affect HBV, or evidence that any effect comes from sofosbuvir
- A controlled study, ideally randomized, in HBV mono-infection
- A monitoring plan for HBV reactivation
- The Health Canada package insert, to confirm warnings, contraindications and approved indication text
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.