Ledipasvir
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Ledipasvir: From Hepatitis C to Hepatitis B Virus Infection
One-Sentence Summary
Ledipasvir is an NS5A replication complex inhibitor, used as a fixed-dose combination with sofosbuvir (Harvoni) for the treatment of chronic Hepatitis C virus (HCV) infection. The TxGNN model predicts it may be effective for Hepatitis B Virus Infection with a prediction score of 99.91%, with 21 clinical trials and 20 publications currently supporting this direction. The evidence is anchored by a completed Phase 2 open-label study (NCT03312023) that directly evaluated LDV/SOF in HBV mono-infected subjects, providing direct proof-of-concept for this repurposing hypothesis.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic Hepatitis C (as component of ledipasvir/sofosbuvir fixed-dose combination; not separately registered in India) |
| Predicted New Indication | Hepatitis B Virus Infection |
| TxGNN Prediction Score | 99.91% |
| Evidence Level | L2 |
| India Market Status | ✗ Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in this Evidence Pack. Based on known information, Ledipasvir is a component of the fixed-dose combination Harvoni (ledipasvir + sofosbuvir), originally approved for chronic HCV treatment. Ledipasvir targets the HCV NS5A replication complex protein, disrupting viral RNA replication and assembly. Its partner drug, sofosbuvir, is an NS5B nucleotide polymerase inhibitor with a broader spectrum of antiviral activity that extends beyond HCV.
While HBV does not encode an NS5A homolog — making Ledipasvir’s direct anti-HBV effect mechanistically thin — the repurposing hypothesis is primarily driven by the combinatorial LDV/SOF regimen, where sofosbuvir’s nucleotide analog mechanism may exert activity against HBV’s reverse transcriptase–like polymerase. Retrospective observations from HCV/HBV co-infected patients treated with LDV/SOF revealed a modest but reproducible reduction in hepatitis B surface antigen (HBsAg) levels, even when HBV was not the primary treatment target. This serendipitous finding formed the scientific rationale for repurposing.
That observation directly motivated the design of NCT03312023, a Phase 2 open-label study exclusively enrolling HBV mono-infected subjects (i.e., no concurrent HCV). Published results (PMID 36045503, Journal of Medical Virology, 2023) confirmed measurable declines in both HBsAg and HBV DNA at Week 12, establishing a credible early-phase clinical signal. Multiple additional HCV/HBV co-infection trials provide secondary evidence, and an important safety consideration — HBV reactivation risk during HCV-directed DAA therapy — is well-documented across multiple published cohort studies, underscoring the biological interaction between LDV/SOF and HBV.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03312023 | Phase 2 | Completed | 21 | The only trial designed exclusively for HBV mono-infection (no concurrent HCV). Primary endpoint was HBsAg decline at Week 12. Published results (PMID 36045503) demonstrated measurable reductions in HBsAg and HBV DNA, providing the most direct proof-of-concept for this indication. |
| NCT02555943 | Phase 2/3 | Completed | 23 | Prospective study of DAA treatment in chronic HCV/HBV co-infected patients; evaluated incidence, morbidity, and predisposing factors for HBV replication reactivation during anti-HCV treatment. |
| NCT02613871 | Phase 3b | Completed | 111 | LDV/SOF 12 weeks in chronic HCV (genotype 1 or 2) patients co-infected with HBV in Taiwan. Highest phase-level trial in the co-infection context, providing robust efficacy and safety data. |
| NCT02219685 | Phase 2 | Completed | 40 | Double-blind, placebo-controlled RCT design evaluating LDV/SOF effect on cerebral metabolism and neurocognition alongside virologic endpoints; methodologically rigorous with potential for reliable secondary HBV-related data. |
| NCT03261349 | Phase 2 | Unknown | 21 | Pilot study of Harvoni (LDV/SOF) in HCV-associated indolent B-cell non-Hodgkin’s lymphoma; indirect relevance through HBV/lymphoma co-association. Requires status confirmation. |
| NCT02010255 | Phase 2 | Completed | 334 | LDV/SOF + ribavirin in advanced liver disease and post-transplant patients; provides large-scale safety and tolerability data across serious hepatitis-related liver disease. |
| NCT03823911 | Phase 4 | Completed | 87 | Cardiovascular outcomes after HCV eradication in mono-infected and HIV co-infected individuals; long-term post-treatment safety data relevant to hepatitis co-management. |
| NCT01826981 | Phase 2 | Completed | 359 | Multicenter sofosbuvir-containing regimen efficacy and safety study; provides foundational large-scale safety data for the SOF-based combination backbone. |
| NCT02597166 | Phase 3 | Completed | 14 | Antiviral therapy effect on clinical status, quality of life, and survival in decompensated cirrhosis due to HCV; exploratory long-term outcomes in a severe hepatic disease population. |
| NCT01457768 | N/A (Registry) | Completed | 570 | Long-term follow-up registry for patients who failed SVR in Gilead-sponsored HCV trials; provides real-world safety surveillance across diverse hepatitis patient populations. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36045503 | 2023 | Phase 2 Trial Result | Journal of Medical Virology | Directly evaluated LDV/SOF 12 weeks in HBV mono-infected subjects (n=21); demonstrated measurable HBsAg and HBV DNA declines at Week 12, providing direct clinical proof-of-concept for this repurposing indication. |
| 34864948 | 2022 | Cohort Study | Clinical Infectious Diseases | Long-term study (108 weeks post-treatment follow-up) of LDV/SOF in HCV/HBV co-infected patients in Taiwan; characterizes HBV reactivation patterns and long-term virology outcomes. |
| 29174546 | 2018 | Cohort Study | Gastroenterology | Prospective study of HBV co-infection risks and outcomes during LDV/SOF treatment; key data on HBV virologic response and reactivation predictors. |
| 29334502 | 2018 | Cohort Study | Journal of Clinical Gastroenterology | Examined HBV reactivation incidence and clinical outcomes in actively infected or previously exposed patients treated with DAAs including LDV/SOF. |
| 27367295 | 2016 | Cohort Study | Antiviral Therapy | Early pilot study evaluating LDV/SOF in HCV patients co-infected with HBV; provided foundational evidence for HBV virologic secondary endpoints suppression. |
| 27486112 | 2016 | Cohort Study | Clinical Infectious Diseases | Analysis from Taiwan/Korea trial (n=173); 60% had prior HBV exposure; demonstrated no evidence of HBV reactivation during LDV/SOF treatment, with important safety implications. |
| 33523503 | 2021 | Cohort Study | Journal of Viral Hepatitis | Prospective evaluation of HBV reactivation risk in cancer patients receiving DAAs for HCV co-infection; highlights special population safety considerations. |
| 28585404 | 2017 | Cohort Study | Hepatology Research | Japanese prospective cohort (n=790 HBV co-infected patients) analyzing frequency and risk factors for HBV reactivation in HCV patients on all-oral DAA regimens including SOF+LDV. |
| 29194858 | 2018 | Cohort Study | Journal of Viral Hepatitis | Reports low incidence of HBV reactivation and subsequent hepatitis during interferon-free DAA therapy; SOF+LDV administered to 438 patients, providing substantial real-world safety evidence. |
| 37254310 | 2024 | In Silico Study | Journal of Biomolecular Structure & Dynamics | Molecular docking and dynamics simulation targeting HBV X protein (HBx) with antiviral compounds; theoretical mechanistic support for small-molecule HBV targeting with DAA-class drugs. |
India Market Information
Ledipasvir is currently not marketed in India. No product authorizations, approved indications, or registered dosage forms are on record through the CDSCO. Any future development would require a full new drug application or new indication filing through Indian regulatory channels.
Safety Considerations
Drug Interactions: A total of 65 drug-drug interactions have been identified (source: DDInter). The following represent the key interactions from available data:
| Interacting Drug | Severity | Mechanism / Clinical Note |
|---|---|---|
| Aluminum hydroxide | Moderate | Antacids raise gastric pH, potentially reducing ledipasvir solubility and absorption |
| Calcium carbonate | Moderate | Similar antacid-mediated absorption reduction |
| Cimetidine | Moderate | H2 receptor antagonist; elevated gastric pH reduces LDV bioavailability |
| Dexlansoprazole | Moderate | Proton pump inhibitor; co-administration may substantially reduce LDV plasma exposure |
| Esomeprazole | Moderate | PPI-mediated pH elevation reduces LDV absorption |
| Famotidine | Moderate | H2 antagonist; timing-dependent interaction with LDV absorption window |
| Lansoprazole | Moderate | PPI interaction with gastric pH-dependent LDV solubility |
| Omeprazole | Moderate | PPI interaction; clinical significance may be dose-dependent |
| Pantoprazole | Moderate | PPI co-administration reduces LDV levels |
| Magnesium hydroxide / oxide / carbonate / Magaldrate | Moderate | Antacid class effects on LDV gastric absorption |
| Linagliptin | Moderate | P-glycoprotein substrate; potential for increased exposure via P-gp inhibition by LDV |
| Loperamide | Moderate | P-gp/BCRP transport substrate interaction |
| Naldemedine | Moderate | Transport protein-mediated interaction |
| Eliglustat | Moderate | CYP2D6/transporter-mediated pharmacokinetic interaction |
| Nizatidine | Moderate | H2 antagonist gastric pH interaction |
| Fidaxomicin | Minor | P-gp substrate; minor interaction with limited clinical significance |
| Naloxegol | Minor | Minor transport interaction with limited clinical significance |
Please refer to the package insert for complete warnings and contraindications, which were not available in the current Evidence Pack (Data Gap DG001).
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: A completed Phase 2 open-label study (NCT03312023, n=21) directly demonstrated measurable HBsAg and HBV DNA reduction with LDV/SOF in HBV mono-infected subjects, supported by multiple Phase 2/3 co-infection trials and a published 2023 journal article. While the evidence base is early-stage and the mechanistic contribution of ledipasvir versus sofosbuvir remains unresolved, the direct clinical signal is sufficient to justify structured further investigation rather than a hold decision.
To proceed, the following is needed:
- Mechanism deconvolution: Conduct in vitro studies to separately quantify ledipasvir’s and sofosbuvir’s individual contributions to HBsAg and HBV DNA reduction
- Larger Phase 2b trial: NCT03312023 enrolled only 21 subjects; a powered study with pre-specified primary endpoints (e.g., HBsAg ≥1 log decline or loss) is required to confirm the signal
- Comparative efficacy data: Head-to-head or add-on design vs. current standard-of-care HBV therapies (entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide)
- Safety data gap resolution (DG001): Download and parse TFDA/FDA package insert to obtain complete warnings, contraindications, and special population precautions
- India regulatory pathway assessment: Engage CDSCO for guidance on new indication filing requirements for a currently unregistered drug
- DDI review in HBV context: HBV patients may concurrently use other hepatitis treatments or antacids/PPIs (common in this population), which carry moderate interaction risk with ledipasvir
- Functional cure endpoint feasibility: Define whether HBsAg loss/seroconversion (functional cure) is a realistic endpoint given the modest signals observed in the pilot study
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.