Sofosbuvir
| Evidence Level: L5 | Predicted Indications: 8 |
Table of Contents
Sofosbuvir: From Chronic Hepatitis C to Hepatitis E Virus Infection
One-Sentence Summary
Sofosbuvir is a nucleotide-analog inhibitor of the hepatitis C virus (HCV) polymerase, originally used to treat chronic hepatitis C. The TxGNN model’s top-ranked prediction is hepatitis B virus infection, but the mechanistic and clinical review does not support it. The best-supported candidate is hepatitis E virus infection, with 1 completed Phase 2 pilot trial (n=10) and several in vitro and case-level publications. Its clinical results have been mixed.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection (no approved-indication text is available in the US licence records) |
| Predicted New Indication | Top TxGNN prediction: hepatitis B virus infection (rank 1). Best-supported candidate after evidence review: hepatitis E virus infection (rank 2) |
| TxGNN Prediction Score | Hepatitis B virus infection: 99.77%. Hepatitis E virus infection: 99.49% |
| Evidence Level | L2 for hepatitis E (one completed Phase 2 pilot, no Phase 3 data); L2 for hepatitis B (co-infection data only) |
| US Market Status | Cancelled only (all 7 licences cancelled) |
| Number of NDAs | 7 |
| Recommended Decision | Hold (hepatitis E may proceed as a research question) |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. Based on known pharmacology, sofosbuvir is a prodrug whose triphosphate metabolite inhibits the viral RNA-dependent RNA polymerase (NS5B in HCV).
Hepatitis B (top-ranked prediction): This link is weak. HBV replicates through a DNA polymerase/reverse transcriptase, which is a different mechanism from HCV NS5B. HBV changes seen in trials occur mainly in HCV/HBV co-infected patients and most likely reflect HCV clearance, not direct anti-HBV activity. HBV reactivation during direct-acting antiviral (DAA) therapy is a recognized safety concern. The high TxGNN score probably reflects network proximity among hepatitis viruses rather than true efficacy.
Hepatitis E (best-supported): HEV is a positive-strand RNA virus with its own RNA polymerase, so a nucleotide-analog mechanism is plausible. Cell-culture studies show sofosbuvir inhibits HEV replication, with an additive effect when combined with ribavirin, and a rabbit model showed inhibition at high doses. In patients, however, results were mixed: a pilot trial reduced viral RNA initially but did not produce a sustained virologic response, and resistance-associated variants emerged during treatment. Reports in ribavirin-refractory patients are inconsistent.
Other predictions (hepatitis A, Kyasanur forest disease, Omsk hemorrhagic fever, nonspecific animal viral hepatitis, HIV) rest on in vitro or enzyme-level data, or on no data at all. For HIV, sofosbuvir has no recognized activity, and the trials found only treat HCV in co-infected patients.
Clinical Trial Evidence
Trials below are for the two leading candidates.
Hepatitis E virus infection
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03282474 | Phase 2 | Completed | 10 | HepNet single-arm pilot of sofosbuvir in chronic hepatitis E. Directly relevant but small and uncontrolled |
Hepatitis B virus infection (co-infection and related studies)
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03312023 | Phase 2 | Completed | 21 | Ledipasvir/sofosbuvir for 12 weeks in HBV-infected subjects. Small, single-arm, and no clear evidence of direct anti-HBV efficacy |
| NCT02555943 | Phase 2/3 | Completed | 23 | DAAs in HCV/HBV co-infection, focused on HBV reactivation. Effect confounded by HCV clearance |
| NCT04997564 | Phase 4 | Unknown | 120 | Sofosbuvir/velpatasvir with prophylactic tenofovir alafenamide (TAF) in HCV/HBV co-infection. Addresses HBV reactivation prevention, not sofosbuvir efficacy |
| NCT03261349 | Phase 2 | Unknown | 21 | Ledipasvir/sofosbuvir in HCV-associated indolent B-cell lymphoma. Small pilot, limited interpretability |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36045503 | 2023 | Phase 2 open-label trial | J Med Virol | Ledipasvir/sofosbuvir in HBV mono-infection, testing for HBsAg and HBV DNA decline at week 12 |
| 37334496 | 2023 | Clinical analysis | Hepatology | In the sofosbuvir pilot in chronic HEV, viral RNA fell initially but no sustained response; resistance-associated variants emerged |
| 35814503 | 2022 | Review | J Clin Exp Hepatol | Review of in vitro and in vivo evidence for sofosbuvir in HEV |
| 35247472 | 2022 | Animal study | Antiviral Res | High-dose sofosbuvir, alone or with ribavirin, inhibited HEV replication in a rabbit model |
| 26408347 | 2016 | In vitro | Gastroenterology | Sofosbuvir inhibits HEV genotype 3 replication, with an additive effect with ribavirin |
| 36942308 | 2023 | Case report | IDCases | Ledipasvir/sofosbuvir plus ribavirin cleared ribavirin-refractory persistent HEV in a patient |
| 31404927 | 2019 | Case series | Open Forum Infect Dis | Sofosbuvir added to ribavirin in 3 transplant recipients did not eliminate HEV |
| 29653132 | 2018 | In vitro | Antiviral Res | Sofosbuvir inhibits hepatitis A virus replication in a cell-based reporter assay |
| 35268497 | 2022 | Cohort | J Clin Med | HBV-DNA and HBsAg kinetics in HCV co-infected patients on DAAs, reflecting virological interplay and reactivation risk |
| 36521285 | 2023 | Biochemical in vitro | Biochem Biophys Res Commun | Sofosbuvir and its triphosphate inhibit Kyasanur forest disease virus polymerase activity (enzyme level only) |
US Market Information
All seven US licences are cancelled. The licence records contain no approved-indication text.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA204671 | Sovaldi | Tablet, film coated | Not available |
| NDA212480 | Sovaldi | Pellet | Not available |
| NDA205834 | Ledipasvir and Sofosbuvir | Tablet, film coated | Not available |
| NDA214187 | Epclusa | Pellet | Not available |
| NDA208341 | Sofosbuvir and Velpatasvir | Tablet, film coated | Not available |
Two further licences are not listed here: NDA212477 (Harvoni, pellet) and NDA209195 (Vosevi, tablet, film coated).
Safety Considerations
- Drug Interactions (8 interactions recorded):
- Major: apalutamide, enzalutamide, lorlatinib
- Moderate: fostamatinib, warfarin, dicoumarol, encorafenib
- Minor: cyclosporine
- HBV reactivation: The literature documents HBV reactivation in patients with HBV co-infection or prior HBV exposure who receive sofosbuvir-based DAA therapy. HBV screening and monitoring are therefore important in any repurposing study.
- Resistance: Resistance-associated variants emerged during sofosbuvir treatment in chronic HEV patients.
For label warnings and contraindications, please refer to the package insert.
Conclusion and Next Steps
Decision: Hold (hepatitis E virus infection may continue as a research question)
Rationale:
- The top TxGNN prediction (hepatitis B) is not mechanistically supported, and observed HBV effects most likely reflect HCV clearance. Reactivation risk is a safety concern, not a benefit.
- Hepatitis E has a plausible RdRp mechanism and supportive in vitro and animal data, but the only clinical trial is a 10-patient pilot with no sustained virologic response and emerging resistance.
- Hepatitis A, Kyasanur forest disease, Omsk hemorrhagic fever and the nonspecific viral hepatitis category rest on in vitro, enzyme-level or no data. HIV evidence concerns HCV treatment in co-infected patients and is not repurposing evidence.
- All US licences are cancelled, which may complicate any US development path.
To proceed, the following is needed:
- FDA package insert warnings and contraindications (currently missing)
- Detailed mechanism-of-action data
- For hepatitis E: a larger controlled study, dose optimisation, and evaluation of combination use with ribavirin
- HBV screening and reactivation monitoring plan for any study population
- Review of the US regulatory pathway given the cancelled licences
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.