Sofosbuvir
| Evidence Level: L3 | Predicted Indications: 8 |
Table of Contents
Sofosbuvir: From Chronic Hepatitis C to Hepatitis B Virus Infection
One-Sentence Summary
Sofosbuvir is an HCV NS5B polymerase inhibitor, originally used to treat chronic hepatitis C virus infection (in New Zealand, as part of the ledipasvir/sofosbuvir combination, Harvoni). The TxGNN model predicts it may be effective for hepatitis B virus infection, but the data compiled for this report show 10 related clinical trials and 20 publications that mostly concern HCV/HBV co-infection, not anti-HBV efficacy. The mechanistic basis is weak, and the data point to HBV reactivation risk during HCV therapy rather than an antiviral benefit against HBV.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection (the New Zealand licence record contains no approved-indication text; this comes from the knowledge graph) |
| Predicted New Indication | Hepatitis B virus infection |
| TxGNN Prediction Score | 99.77% |
| Evidence Level | L3 |
| New Zealand Market Status | ✗ Cancelled only (no currently valid authorization) |
| Number of Authorizations | 1 (cancelled) |
| 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 information, sofosbuvir is a nucleotide analogue inhibitor of the HCV NS5B RNA-dependent RNA polymerase, and its efficacy in hepatitis C is well established.
Mechanistically, however, the prediction is not well supported. HBV is a DNA virus that replicates through a reverse transcriptase, and sofosbuvir does not target that enzyme. The high TxGNN score most likely reflects the shared hepatitis/antiviral context in the knowledge graph rather than a true antiviral mechanism.
The clinical data come mainly from HCV/HBV co-infected patients, where HCV clearance is the intended effect. The main HBV-related findings are HBV reactivation risk and changes in HBV DNA and HBsAg kinetics during DAA therapy. A small Phase 2 pilot of ledipasvir/sofosbuvir in HBV (NCT03312023, n=21) was designed to test whether the HBsAg reductions seen in co-infection could be reproduced, but a small single-arm design cannot establish an anti-HBV effect.
For context, among the other predicted indications hepatitis E virus infection has the most credible mechanism, because HEV is an RNA virus with an RNA polymerase. Even there, clinical results are mixed and efficacy is not established.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03312023 | Phase 2 | Completed | 21 | Open-label ledipasvir/sofosbuvir for 12 weeks in HBV infection; directly relevant population but a small single-arm design |
| NCT02555943 | Phase 2/3 | Completed | 23 | DAAs in HCV/HBV co-infection; studies HBV reactivation during anti-HCV treatment |
| NCT04997564 | Phase 4 | Unknown | 120 | SOF/VEL with prophylactic TAF in HCV/HBV co-infection; TAF is the HBV-active agent and addresses reactivation |
| NCT03186313 | Phase 3 | Completed | 72 | Sofosbuvir/daclatasvir (± ribavirin) in genotype 4 HCV; HBV evidence is indirect |
| NCT02483156 | Phase 2/3 | Completed | 80 | Sofosbuvir plus ribavirin in genotype 4 HCV; HBV relevance only through co-infected patients |
| NCT03261349 | Phase 2 | Unknown | 21 | Ledipasvir/sofosbuvir in HCV-associated indolent B-cell lymphoma; small pilot |
| NCT02363517 | Phase 3 | Unknown | 420 | Ledipasvir/sofosbuvir for HCV in people who inject drugs; HBV is not an endpoint |
| NCT03549312 | Phase 4 | Unknown | 25 | HIV/HCV switch study; the HBV-active component is TAF |
| NCT03579576 | N/A | Completed | 803 | Simplified HCV treatment model in Myanmar; HBV is incidental |
| NCT02768961 | Phase 4 | Completed | 64 | HCV screening and treatment in prisons; not relevant to HBV efficacy |
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, testing the HBsAg reduction seen in co-infected patients |
| 42558970 | 2026 | Clinical study | J Clin Transl Hepatol | Safety and efficacy of SOF/VEL with TAF pre-treatment in HBV/HCV co-infection, focused on HBV reactivation |
| 35268497 | 2022 | Cohort | J Clin Med | Different HBV-DNA and HBsAg kinetics in HCV co-infected patients during DAA therapy |
| 33523503 | 2021 | Prospective observational | J Viral Hepat | HBV reactivation in cancer patients receiving DAAs for HCV |
| 26967675 | 2016 | Review | J Clin Virol | HBV reactivation during DAA treatment of HCV as a further clinical challenge |
| 27621502 | 2015 | Adverse-event report | Hosp Pharm | HBV reactivation during simeprevir plus sofosbuvir treatment of HCV |
| 31542053 | 2019 | Case report | J Med Case Rep | HBV reactivation with a surface antigen immune-escape mutant during sofosbuvir/velpatasvir therapy |
| 25027705 | 2014 | Review | Minerva Gastroenterol Dietol | Antivirals for hepatitis B and C and their effects on kidney function |
Safety Considerations
- Drug Interactions (8 interactions identified in the DDI database):
- Major: apalutamide, enzalutamide, lorlatinib
- Moderate: fostamatinib, warfarin, dicoumarol, encorafenib
- Minor: cyclosporine
- HBV reactivation: Published reports and cohort data show that treating HCV with sofosbuvir-based regimens can reactivate HBV in co-infected patients. HBV screening before therapy, monitoring, and prophylaxis (for example TAF) are clinically important.
For other safety information, please refer to the package insert.
Conclusion and Next Steps
Decision: Hold
Rationale: Sofosbuvir has no plausible mechanism against HBV, and the available evidence (L3) consists of co-infection studies in which HCV clearance is the goal and HBV reactivation is the main concern. The high TxGNN score is not backed by evidence of anti-HBV efficacy. Sofosbuvir is also not currently marketed in New Zealand under this licence (cancelled).
To proceed, the following is needed:
- Mechanism of action data and package insert warnings and contraindications (not yet available in the data compiled for this report)
- A controlled study of anti-HBV efficacy in HBV mono-infection, with HBsAg and HBV DNA endpoints
- Clarification of the status of the cancelled New Zealand authorization
- If the programme is to be pursued at all, consider redirecting to hepatitis E virus infection, where a plausible RNA polymerase mechanism and in vitro and early clinical data exist (the pilot Phase 2 trial, NCT03282474, n=10, did not achieve sustained virologic response)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.