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, marketed in the fixed-dose combination with sofosbuvir (Harvoni) for chronic hepatitis C virus infection. The TxGNN model predicts it may be effective for Hepatitis B virus infection, but the supporting evidence is thin: 5 related clinical trials (only 1 directly in HBV) and 20 publications. Most of these concern HCV treatment in HCV/HBV co-infected patients and HBV reactivation risk, not direct HBV treatment.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection (approved indication text not available in the local registration record; taken from the knowledge graph) |
| Predicted New Indication | Hepatitis B virus infection |
| TxGNN Prediction Score | 99.91% |
| Evidence Level | L2 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, ledipasvir is an inhibitor of the HCV NS5A protein and is used together with sofosbuvir, an NS5B polymerase inhibitor, for chronic hepatitis C.
The mechanistic case for HBV is weak. HBV has no NS5A homologue, so direct anti-HBV activity is not expected. The high TxGNN score probably reflects shared viral hepatitis network features (the two viruses infect the same organ and often co-occur) rather than a true antiviral mechanism.
There is one signal worth noting. In retrospective data from HBV/HCV co-infected patients treated with ledipasvir/sofosbuvir, a modest reduction in hepatitis B surface antigen (HBsAg) was observed. This led to a small Phase 2 pilot in HBV mono-infected subjects (NCT03312023, published as PMID 36045503). It is hypothesis-generating only.
The other predicted indications (hepatitis E, hepatitis A, flavivirus diseases, HIV, and animal viral diseases) have even less support: either no trials at all, or HCV-focused studies that were matched by keyword or network overlap. They are not evaluated further here.
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. The only trial directly addressing HBV. It is small and single-arm. |
| NCT02555943 | Phase 2/3 | Completed | 23 | DAA treatment in chronic HCV/HBV co-infection, focused on HBV reactivation incidence and risk factors |
| NCT02836925 | Phase 2 | Completed | 40 | Interferon-free ledipasvir/sofosbuvir or sofosbuvir/velpatasvir in HCV-associated indolent B-cell lymphoma. Only indirectly relevant to HBV. |
| NCT03261349 | Phase 2 | Unknown | 21 | Harvoni in HCV-associated indolent B-cell non-Hodgkin lymphoma. Status unclear. |
| NCT02768961 | Phase 4 | Completed | 64 | HCV/HBV/HIV screening and HCV elimination programme in prisons. Only incidentally related to HBV. |
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. Endpoints were HBsAg and HBV DNA decline at Week 12. |
| 29174546 | 2018 | Prospective study | Gastroenterology | Ledipasvir/sofosbuvir for HCV in HBV co-infected patients, assessing risks and outcomes including HBV reactivation |
| 34864948 | 2022 | Cohort | Clin Infect Dis | HCV/HBV co-infected patients in Taiwan, followed for 108 weeks after treatment, assessing HBV reactivation |
| 27367295 | 2016 | Pilot study | Antivir Ther | Ledipasvir/sofosbuvir suppresses HCV in HBV co-infected patients |
| 29334502 | 2018 | Cohort | J Clin Gastroenterol | Risk of HBV reactivation during ledipasvir/sofosbuvir treatment |
| 33523503 | 2021 | Cohort | J Viral Hepat | 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 in Japan |
| 26967675 | 2016 | Review/cohort | J Clin Virol | HBV reactivation as a challenge during DAA treatment of HCV |
| 28249574 | 2017 | Case report and review | 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, noting HBV treatment remains far from curative |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14920P | HARVONI TABLET 90MG/400MG | Film-coated tablet | Not stated in the registration record |
Safety Considerations
- Drug Interactions: 65 interactions were identified. Those listed here are mostly moderate, with a few minor.
- Antacids (aluminium hydroxide, calcium carbonate, magaldrate, magnesium carbonate, magnesium hydroxide, magnesium oxide): moderate
- Acid-suppressing drugs, which can reduce ledipasvir absorption: H2 blockers (cimetidine, famotidine, nizatidine) and proton pump inhibitors (omeprazole, esomeprazole, dexlansoprazole, lansoprazole, pantoprazole), all moderate
- Others: eliglustat, linagliptin, loperamide and naldemedine (moderate); fidaxomicin and naloxegol (minor)
- HBV reactivation: Published cohorts and case reports show that HBV can reactivate during direct-acting antiviral therapy in HCV/HBV co-infected patients. This is a key safety consideration for the proposed indication and the target population.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: Ledipasvir has no expected direct anti-HBV mechanism. The only directly relevant study is a small single-arm Phase 2 pilot (n=21) in which the outcome was a modest HBsAg change. The co-infection trials mainly show that HCV is cured and that HBV reactivation is a safety concern. The high TxGNN score is better explained by network proximity than by antiviral biology. The evidence level of L2 reflects the existence of a completed Phase 2 study, not proof of efficacy.
To proceed, the following is needed:
- Full results of NCT03312023, including HBsAg and HBV DNA change and durability, ideally confirmed in a larger controlled study
- Preclinical or in vitro data showing whether ledipasvir, as opposed to sofosbuvir, has any anti-HBV activity
- Mechanism of action data
- Package insert warnings and contraindications, since these are currently missing from the data compiled for this report
- An HBV reactivation monitoring plan for any co-infected population
- Clarification of the approved indication text in the Singapore registration record
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.