Sofosbuvir
| Evidence Level: L3 | Predicted Indications: 8 |
Table of Contents
Sofosbuvir: Hepatitis B virus infection
One-Sentence Summary
Sofosbuvir is a nucleotide analogue antiviral that is currently marketed in Canada. The TxGNN model predicts it may be effective for hepatitis B virus infection. Direct support is thin: one small, single-arm Phase 2 trial of ledipasvir/sofosbuvir in people with hepatitis B (NCT03312023, published as PMID 36045503). Most other studies are in hepatitis C patients and report on hepatitis B reactivation during treatment.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Hepatitis B virus infection |
| TxGNN Prediction Score | 0.9977 |
| Evidence Level | L3 |
| Canada Market Status | Marketed (marketed DINs: 4 of 4) |
| Number of DINs | 4 (marketed: 4) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Sofosbuvir is known as a prodrug of a nucleotide analogue that inhibits a viral RNA-dependent RNA polymerase.
The link to hepatitis B is indirect. Hepatitis B virus is a DNA virus that replicates through reverse transcription, so sofosbuvir has no direct target in it. The rationale rests on clinical observations. In patients with both hepatitis B and C, ledipasvir/sofosbuvir was associated with a modest drop in hepatitis B surface antigen (HBsAg). This led investigators to test the combination in people with hepatitis B alone (PMID 36045503). That study was small, open-label and single-arm, and the effect cannot be attributed to sofosbuvir alone, because ledipasvir was given together with it.
The remaining literature shows that antiviral treatment for hepatitis C can trigger hepatitis B reactivation in co-infected patients. That is a safety issue, not evidence of anti-hepatitis B benefit.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03312023 | Phase 2 | Completed | 21 | Open-label ledipasvir/sofosbuvir for 12 weeks in people with hepatitis B. Primary endpoint was HBsAg decline; secondary was HBV DNA decline. |
| NCT02555943 | Phase 2/3 | Completed | 23 | Prospective study of hepatitis B reactivation during direct-acting antiviral treatment in HCV/HBV co-infected patients |
| NCT04997564 | Phase 4 | Unknown | 120 | Sofosbuvir/velpatasvir for 12 weeks with prophylactic tenofovir alafenamide in HCV/HBV co-infection. Focus is preventing HBV reactivation. |
| NCT03186313 | Phase 3 | Completed | 72 | Randomized open-label comparison of sofosbuvir-based regimens. The population includes HBV co-infection, but the endpoint is HCV. |
| NCT02483156 | Phase 2/3 | Completed | 80 | Randomized open-label sofosbuvir plus ribavirin study. HBV relevance depends on co-infection and cannot be confirmed. |
| NCT03549312 | Phase 4 | Unknown | 25 | Regimen switch followed by sofosbuvir/velpatasvir. Any anti-HBV activity comes from tenofovir alafenamide, not sofosbuvir. |
| NCT02768961 | Phase 4 | Completed | 64 | Prison screening and treatment program that also screened for HBV. Not an HBV efficacy study. |
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-infected subjects. It tested whether HBsAg and HBV DNA fall from baseline, building on a modest HBsAg reduction seen in co-infected patients. |
| 35268497 | 2022 | Cohort | J Clin Med | HBV-DNA and HBsAg kinetics in HCV co-infected patients on direct-acting antivirals, with or without sofosbuvir. Reactivations were possible. |
| 42558970 | 2026 | Multicenter study | J Clin Transl Hepatol | Safety and efficacy of sofosbuvir/velpatasvir with tenofovir alafenamide pre-treatment on HBV reactivation in HBV/HCV co-infection. |
| 33523503 | 2021 | Prospective observational | J Viral Hepat | HBV reactivation in cancer patients with HBV/HCV co-infection receiving direct-acting antivirals. |
| 26967675 | 2016 | Review | J Clin Virol | HBV reactivation as a further challenge when treating HCV with direct-acting antivirals. |
| 31542053 | 2019 | Case report | J Med Case Rep | HBV reactivation with a surface-antigen immune-escape mutant during sofosbuvir/velpatasvir treatment. |
| 27621502 | 2015 | Adverse-event report | Hosp Pharm | Hepatitis B reactivation during simeprevir plus sofosbuvir therapy. |
| 25027705 | 2014 | Review | Minerva Gastroenterol Dietol | Antiviral medications for hepatitis B and C and their effects on kidney function. |
Canada Market Information
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 02418355 | SOVALDI | Not available | Not available |
| 02432226 | HARVONI | Not available | Not available |
| 02456370 | EPCLUSA | Not available | Not available |
| 02467542 | VOSEVI | Not available | Not available |
All four authorizations are currently valid.
Safety Considerations
- Hepatitis B reactivation: Several publications describe hepatitis B reactivation in co-infected patients during sofosbuvir-based therapy, including a case with an immune-escape mutant. Screening and monitoring or prophylaxis are therefore important.
- Drug Interactions (8 recorded interactions):
- Major: apalutamide, enzalutamide, lorlatinib
- Moderate: fostamatinib, warfarin, dicoumarol, encorafenib
- Minor: cyclosporine
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The only direct evidence in hepatitis B is a small, single-arm Phase 2 study of a ledipasvir/sofosbuvir combination, so any effect cannot be attributed to sofosbuvir. There is no direct mechanistic target in the hepatitis B virus, and the broader literature mainly documents reactivation risk. The high prediction score is a model signal, not clinical proof.
To proceed, the following is needed:
- Full results of the Phase 2 study (PMID 36045503) and a sofosbuvir-alone comparison with a control arm
- Mechanism of action data, to explain any effect on HBsAg
- A safety plan for hepatitis B reactivation, including screening and monitoring
- Review of the package insert warnings and contraindications, which are not in the data compiled for this report
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.