Sofosbuvir
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Sofosbuvir: From Hepatitis C Virus Infection to Hepatitis B Virus Infection
One-Sentence Summary
Sofosbuvir is an oral nucleotide polymerase inhibitor, originally used to treat chronic hepatitis C virus infection. The TxGNN model predicts it may be effective for hepatitis B virus infection, but the 11 clinical trials and 20 publications retrieved for this prediction are mostly about hepatitis C, and the evidence for hepatitis B efficacy is indirect and weak.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection (the Singapore licence records contain no indication text; this is taken from the drug's knowledge-graph indications) |
| Predicted New Indication | Hepatitis B virus infection |
| TxGNN Prediction Score | 99.77% |
| Evidence Level | L2 (as assigned in the compiled data; see the caveat below) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 3 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available for this report. From known information, sofosbuvir is a nucleotide analogue that inhibits the HCV NS5B RNA-dependent RNA polymerase. Its efficacy in hepatitis C is well established, and it is marketed in Singapore alone and in fixed-dose combinations (with velpatasvir, ledipasvir, or velpatasvir plus voxilaprevir).
The mechanistic link to hepatitis B is weak. HBV replicates through a reverse-transcriptase (DNA polymerase) mechanism, so direct anti-HBV activity is mechanistically unclear. The high TxGNN score most likely reflects the shared class of hepatotropic viruses and the drug's HCV indication, rather than a true antiviral rationale.
Most clinical data come from patients co-infected with HCV and HBV. In these patients, HBV-DNA and HBsAg levels change during therapy as a secondary effect of clearing HCV. HBV reactivation during direct-acting antiviral treatment is also a recognised safety concern. One small phase 2 study of ledipasvir/sofosbuvir in HBV-infected patients (PMID 36045503) reported on HBsAg and HBV DNA changes. However, it was single-arm and small, and it used a combination product.
Caveat on the evidence level: The L2 label is based on the presence of a phase 2/3 study. That study (NCT02555943) is a small co-infection study of reactivation monitoring, not a trial of anti-HBV efficacy. In practice, the evidence for this specific indication is weaker than L2 suggests.
Clinical Trial Evidence
The table lists the 10 trials judged most relevant to hepatitis B.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03312023 | Phase 2 | Completed | 21 | Ledipasvir/sofosbuvir for 12 weeks in HBV infection. Closest to direct HBV evidence, but single-arm and small. |
| NCT02555943 | Phase 2/3 | Completed | 23 | Direct-acting antivirals in HCV/HBV co-infection. Studies HBV reactivation during anti-HCV treatment, not HBV efficacy. |
| NCT04997564 | Phase 4 | Unknown | 120 | Sofosbuvir/velpatasvir with prophylactic tenofovir alafenamide (TAF) in HCV/HBV co-infection. Any anti-HBV effect is attributable to TAF. |
| NCT02483156 | Phase 2/3 | Completed | 80 | Sofosbuvir plus ribavirin in genotype 4 HCV. HBV relevance only through co-infection. |
| NCT03186313 | Phase 3 | Completed | 72 | Single-dose sofosbuvir/daclatasvir combination in genotype 4 HCV. HCV is the primary target. |
| NCT03261349 | Phase 2 | Unknown | 21 | Ledipasvir/sofosbuvir in HCV-associated B-cell lymphoma. HCV-focused. |
| NCT03549312 | Phase 4 | Unknown | 25 | HIV-HCV co-infection switch study. Indirect relevance. |
| NCT02768961 | Phase 4 | Completed | 64 | HCV screening and treatment in prisons. Not relevant to HBV efficacy. |
| NCT02363517 | Phase 3 | Unknown | 420 | HCV treatment in people who inject drugs. Not relevant to HBV efficacy. |
| NCT03579576 | N/A | Completed | 803 | Simplified HCV treatment model in Myanmar. HCV programme only. |
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 infection. Primary endpoint was HBsAg decline, secondary endpoint was HBV DNA decline. |
| 35268497 | 2022 | Cohort | J Clin Med | Different kinetics of HBV-DNA and HBsAg in HCV co-infected patients during direct-acting antiviral therapy. |
| 42558970 | 2026 | Multicentre study | J Clin Transl Hepatol | Safety and efficacy of sofosbuvir/velpatasvir with TAF pre-treatment on HBV reactivation in HBV/HCV co-infection. |
| 42145438 | 2026 | Comparative effectiveness study | Bioinformation | Compares tenofovir or entecavir for HBV with sofosbuvir-based or glecaprevir/pibrentasvir regimens for HCV. |
| 33523503 | 2021 | Prospective observational study | J Viral Hepat | HBV reactivation in cancer patients receiving direct-acting antivirals for HCV. |
| 26967675 | 2016 | Review | J Clin Virol | HBV reactivation as a challenge during direct-acting antiviral treatment of HCV. |
| 31542053 | 2019 | Case report | J Med Case Rep | HBV reactivation with an immune-escape mutant during sofosbuvir/velpatasvir treatment. |
| 27621502 | 2015 | Case report | Hosp Pharm | HBV reactivation during simeprevir plus sofosbuvir treatment. |
| 25027705 | 2014 | Review | Minerva Gastroenterol Dietol | Antiviral medications for hepatitis B and C and their effects on kidney function. |
| 34092970 | 2021 | Review | World J Gastroenterol | Management of paediatric viral hepatitis. Notes HBV treatment is far from curative. |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN15351P | EPCLUSA TABLET 400MG/100MG | Film-coated tablet | Indication text not provided in the registration record |
| SIN14920P | HARVONI TABLET 90MG/400MG | Film-coated tablet | Indication text not provided in the registration record |
| SIN15705P | VOSEVI FILM-COATED TABLETS 400MG/100MG/100MG | Film-coated tablet | Indication text not provided in the registration record |
All three licences are valid, and all are oral products.
Safety Considerations
- Drug Interactions (8 interactions recorded; major ones are the most important):
- Major: apalutamide, enzalutamide, lorlatinib
- Moderate: fostamatinib, warfarin, dicoumarol, encorafenib
- Minor: cyclosporine
- HBV reactivation: The literature repeatedly reports HBV reactivation in HBV/HCV co-infected patients receiving sofosbuvir-based regimens. This is directly relevant to any use in HBV, and monitoring and prophylaxis need to be considered.
For warnings and contraindications, please refer to the package insert.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction score is very high, but it is not backed by a plausible direct mechanism, since HBV uses a reverse transcriptase rather than the polymerase sofosbuvir targets. The available clinical data are mostly HCV studies, or HCV/HBV co-infection studies where HBV changes are secondary and reactivation is a safety risk. The one HBV-specific study is small, single-arm, and used a combination product.
To proceed, the following is needed:
- Mechanistic or in vitro data on direct anti-HBV activity of sofosbuvir
- Controlled studies in HBV mono-infected patients that separate the effect of sofosbuvir from that of ledipasvir or other agents
- Mechanism of action data and package insert warnings and contraindications from the HSA
- An HBV reactivation monitoring and prophylaxis plan
Other predicted indications (for reference): Hepatitis E virus infection (rank 2) has the most direct evidence. A completed phase 2 pilot (NCT03282474, n=10) and in vitro work support activity, but the pilot showed only a transient viral load decline without sustained clearance. This may be a more promising research direction than hepatitis B. The remaining predictions (hepatitis A, Kyasanur forest disease, Omsk hemorrhagic fever, HIV, and animal or other retroviral conditions) have only in vitro evidence or no evidence, and the retroviral ones have no plausible mechanism.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.