Lamivudine
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Lamivudine: From HIV-1 Infection to Chronic Hepatitis B Virus Infection
One-Sentence Summary
Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) originally used to treat HIV-1 infection as part of combination antiretroviral therapy. Among the disease associations generated by the TxGNN model, Chronic Hepatitis B Virus Infection is the only prediction backed by substantial, human-relevant clinical evidence, with 50 clinical trials and 20 publications identified. The model’s other top-ranked, higher-scoring predictions (simian/feline immunodeficiency virus infection, a rare paediatric neurodevelopmental disorder, an obsolete lipid-disorder term, and hepatitis C) were reviewed and screened out as not clinically actionable for human patients — see the note below.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | HIV-1 infection (combination antiretroviral therapy) — based on known pharmacology; no Australian ARTG licence data is available for this drug in the evidence pack |
| Predicted New Indication | Chronic Hepatitis B Virus Infection |
| TxGNN Prediction Score | 97.84% (rank 19,904 of all drug–disease pairs scored) |
| Evidence Level | L1 |
| Australia Market Status | Not Marketed |
| Number of ARTG Entries | 0 |
| Recommended Decision | Proceed with Guardrails |
Note on other TxGNN predictions: The model’s five highest-scoring associations for lamivudine (>99.6%) were: simian immunodeficiency virus infection, feline acquired immunodeficiency syndrome, a rare paediatric neurodevelopmental disorder, and an “obsolete” familial hyperlipidaemia term, plus hepatitis C virus infection. All five were assessed in the evidence pack itself as not usable human repurposing candidates — two are veterinary/animal-model infections, one is a medically obsolete disease label likely reflecting a drug-adverse-effect confound rather than a treatment relationship, one has zero supporting evidence and no plausible mechanism, and HCV does not replicate via reverse transcription so lamivudine’s mechanism does not apply. This report therefore focuses on the next-ranked candidate, hepatitis B virus infection, which is the only one with a coherent mechanism and real supporting evidence.
Why is This Prediction Reasonable?
Lamivudine is a synthetic (-)-enantiomer cytidine nucleoside analogue. After intracellular phosphorylation to lamivudine triphosphate, it competitively inhibits viral DNA polymerase/reverse transcriptase enzymes and causes DNA chain termination once incorporated into the growing viral DNA strand. This mechanism underlies its established action against HIV-1 reverse transcriptase.
Hepatitis B virus (family Hepadnaviridae) is unusual among DNA viruses in that its replication cycle includes an obligate reverse-transcription step, carried out by the HBV polymerase, which itself has reverse transcriptase activity closely related to that of HIV. Because lamivudine’s active triphosphate does not discriminate strongly between these two structurally similar reverse transcriptases, the same mechanism responsible for its anti-HIV effect is directly applicable to HBV.
This is, in effect, a positive-control finding rather than a purely novel discovery: lamivudine already received approval overseas (as Epivir-HBV, 1998) specifically for chronic hepatitis B, and the clinical trial and publication record below reflects an already mature body of evidence rather than early-stage repurposing. In the Australian context, however, the product is recorded as not currently marketed with 0 ARTG entries, so this evidence needs to be considered as if introducing lamivudine as a “new” option locally.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00001457 | Phase 2 | Completed | 60 | Titled “Lamivudine for Chronic Hepatitis B” — foundational trial establishing lamivudine’s antiviral effect in chronic HBV |
| NCT00131742 | Phase 3 | Completed | N/A | Telbivudine vs lamivudine in Chinese adults with compensated chronic hepatitis B; lamivudine used as active comparator |
| NCT00410202 | Phase 3 | Completed | 629 | DEFINE study: entecavir+adefovir vs entecavir vs adefovir+lamivudine in lamivudine-resistant chronic HBV |
| NCT01726439 | Observational | Completed | 3,434 | EVOLVE study: large real-world 5-year comparison of entecavir vs lamivudine-based therapies in NUC-naïve CHB patients |
| NCT00076336 | Phase 3 | Completed | 232 | Randomised double-blind trial of telbivudine vs lamivudine in decompensated chronic hepatitis B with cirrhosis |
| NCT01580202 | Phase 3 | Completed | 180 | Entecavir vs lamivudine as prophylaxis against HBV reactivation during cytotoxic chemotherapy for solid tumours |
| NCT00124241 | Phase 2 | Completed | N/A | Extension study of telbivudine, lamivudine, or telbivudine+lamivudine combination in chronic hepatitis B |
| NCT03236584 | Phase 3 | Unknown | 76 | Switching to tenofovir monotherapy vs continuing lamivudine+adefovir in patients with complete viral suppression |
| NCT00380614 | Phase 4 | Completed | N/A | Randomised controlled trial of lamivudine specifically in acute hepatitis B |
| NCT00354653 | Phase 4 | Completed | 100 | Open-label study of lamivudine in HBeAg-negative (pre-core mutant) chronic hepatitis B, Iran |
No ANZCTR-registered trials were identified in the evidence reviewed.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31272463 | 2019 | Meta-analysis | Virology Journal | Meta-analysis of lamivudine therapy for chronic hepatitis B in children |
| 16984494 | 2006 | Systematic Review | Aliment Pharmacol Ther | Systematic review of lamivudine prophylaxis for chemotherapy-induced HBV reactivation |
| 35499182 | 2022 | Review | Antiviral Therapy | Reviews adefovir’s development in response to lamivudine resistance in chronic HBV |
| 12526729 | 2003 | Review | Medical Journal of Australia | Australian-context review of managing chronic HBV in remote Aboriginal and Torres Strait Islander communities |
| 19207972 | 2009 | Cohort/Review | Liver International | Natural history of chronic HBV infection and long-term outcomes under nucleoside analogue treatment |
| 12269843 | 2002 | Review | Paediatric Drugs | Lamivudine dosing, efficacy and tolerability in children/adolescents with chronic HBV |
| 22077578 | 2011 | Cohort/Economic | PharmacoEconomics | Cost-effectiveness of prophylactic lamivudine for preventing vertical (mother-to-child) HBV transmission |
| 12702032 | 2003 | Cohort | Journal of Internal Medicine | Lamivudine therapy outcomes before and after liver transplantation for chronic HBV |
| 16980024 | 2006 | Case series | Transplantation Proceedings | Successful treatment of HBV infection with lamivudine after heart transplantation (Taiwan) |
| 11231955 | 2001 | Review | Gastroenterology | Molecular basis of lamivudine resistance (YMDD/M184V mutation) in HBV reverse transcriptase |
Australia Market Information
Lamivudine currently has no ARTG entries in the evidence pack reviewed, and market status is recorded as Not Marketed in Australia. No product listing, dosage form, or approved indication text is available to summarise in table form.
Safety Considerations
No specific key warnings, contraindications, or drug interaction (DDI) data were available in the evidence reviewed for this candidate (the underlying data gaps are flagged in the evidence pack as Blocking — TGA warnings/contraindications not yet retrieved — and High severity — mechanism of action not yet confirmed via DrugBank). Please refer to the TGA-approved Product Information (PI) for safety information once available, or the equivalent PI from an established overseas regulator (e.g. FDA, EMA) in the interim.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale:
- The evidence level for chronic hepatitis B virus infection is L1, supported by multiple completed Phase 2–4 trials directly testing lamivudine (including a trial titled explicitly “Lamivudine for Chronic Hepatitis B”) and a large real-world cohort (n=3,434).
- Guardrails are needed because (a) lamivudine is not currently registered in Australia (0 ARTG entries), and (b) lamivudine monotherapy for HBV is associated with well-documented long-term resistance (YMDD/M184V mutation), meaning current international guidelines generally favour higher-barrier agents (entecavir, tenofovir) as first-line therapy.
To proceed, the following is needed:
- TFDA/TGA-equivalent Product Information: approved warnings, contraindications, and drug interaction data (currently a Blocking data gap)
- Confirmed mechanism-of-action documentation via DrugBank or equivalent source (currently a High-severity data gap)
- Clarification of pathway and rationale for ARTG registration if this indication is to be pursued locally
- A comparative resistance/efficacy assessment against current first-line CHB agents (entecavir, tenofovir) to contextualise where lamivudine would fit in an Australian treatment pathway
- Confirmation of the original approved indication(s) for lamivudine, since this was not captured in the regulatory data reviewed
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.