Tenofovir Disoproxil

證據等級: L5

預測適應症: 4 個

Tenofovir Disoproxil: From HIV Infection to Simian Immunodeficiency Virus Infection

One-Sentence Summary

Tenofovir disoproxil is a nucleotide reverse transcriptase inhibitor whose established use — referenced within this evidence pack's own literature (the iPrEx study, PMID 20874040) — is HIV pre-exposure prophylaxis and treatment. The TxGNN model's top-ranked prediction is Simian Immunodeficiency Virus (SIV) Infection, a disease of non-human primates rather than a human indication, supported by 2 clinical trials and 20 publications, most of which are macaque/animal-model studies. Given the non-human nature of the top prediction and multiple blocking data gaps, this candidate is not currently actionable for human repurposing.

Quick Overview

Item	Content
Original Indication	Not available — no license/indication text on file for Finland; the drug's already-approved human use (HIV infection/PrEP) is inferred only from context within the supplied literature, not from `taiwan_regulatory`
Predicted New Indication	Simian Immunodeficiency Virus Infection (non-human primate disease — not a human indication)
TxGNN Prediction Score	99.95%
Evidence Level	L3
Finland Market Status	Not marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available (original_moa: [Data Gap]). Based on the context available in this evidence pack, tenofovir disoproxil is the oral prodrug of tenofovir (PMPA), a nucleotide analog reverse transcriptase inhibitor. Its supplied repurposing rationale notes that the only human RCT-grade literature in this pack (PMID 20874040, the iPrEx pre-exposure prophylaxis study) actually evaluates tenofovir's already-approved use in human HIV prevention — not a novel indication.

Mechanistically, tenofovir's antiretroviral activity against HIV reverse transcriptase is directly analogous to its activity against SIV reverse transcriptase in macaques, since SIV and HIV are closely related lentiviruses. This explains the very high TxGNN score. However, SIV infection is a disease of non-human primates used as a laboratory model for HIV research — it is not a human diagnosis, so this prediction does not represent a genuine new human indication; it reflects the model correctly clustering tenofovir with lentivirus-related disease labels in its knowledge graph, several of which happen to be animal disease ontology terms.

The pack's next three ranked candidates reinforce this pattern rather than offsetting it: rank 2 ("feline acquired immunodeficiency syndrome") is a veterinary disease in cats; rank 3 (a rare neurodevelopmental disorder) has zero supporting evidence and no plausible mechanistic link to an antiviral NRTI; and rank 4 ("obsolete familial combined hyperlipidemia") is flagged in its own disease label as an obsolete ontology term with only indirect, non-mechanistic literature support. All four received a "Hold" recommendation in the source scoring.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00863668	NA	Withdrawn	0	Studied HIV/SIV viral decay kinetics with raltegravir (an integrase inhibitor, not tenofovir); trial was withdrawn with zero enrollment. Low relevance (Grade C) — different drug, no actual SIV patients.
NCT03577782	Phase 1/2	Unknown	12	Evaluated vedolizumab combined with antiretroviral therapy for HIV virologic remission in treatment-naïve human subjects; tenofovir was not the primary intervention, and the study population was human HIV, not SIV. Low relevance (Grade C).

Note: both trials were flagged as low relevance (Grade C) by the source evidence pack — neither directly tests tenofovir disoproxil against SIV infection.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
20874040	2010	RCT (human)	Pharmacotherapy	Reviews systemic HIV pre-exposure prophylaxis (PrEP) in humans — this is tenofovir's established use, not a novel SIV indication; disease-label mismatch noted in source rationale.
14557287	2003	Review	Clinical Microbiology Reviews	Reviews clinical potential of acyclic nucleoside phosphonates (cidofovir, adefovir, tenofovir) against DNA viruses and retroviruses, including SIV models.
27465645	2016	Animal study (macaque)	J Infect Dis	Oral tenofovir alafenamide + emtricitabine protected macaques from rectal SHIV infection (PrEP model).
36477356	2022	Animal study (macaque)	JCI Insight	Hypo-osmolar rectal tenofovir douche formulation prevented SHIV acquisition in macaques.
16810108	2006	Animal study (infant macaque)	J Acquir Immune Defic Syndr	Oral tenofovir DF and topical tenofovir GS-7340 protected infant macaques against repeated oral SIV challenge (pediatric transmission model).
16960777	2006	Animal study (macaque)	J Infect Dis	Tenofovir DF chemoprophylaxis gave partial protection against SHIV infection under multiple viral challenges.
22072766	2012	Animal study (macaque)	J Virol	Vaginal tenofovir gel provided durable protection against SHIV infection in macaques, correlated with tissue drug levels.
26743846	2016	Animal study (macaque)	J Infect Dis	Emtricitabine/tenofovir DF prevented vaginal SHIV infection in macaques co-infected with Chlamydia and Trichomonas.
38134382	2024	Animal study (macaque)	J Infect Dis	Tenofovir alafenamide/elvitegravir vaginal inserts gave extended post-exposure protection against SHIV in macaques.
23633402	2013	Animal study (macaque)	J Infect Dis	Emtricitabine/tenofovir DF prevented transmission of a tenofovir-resistant (K65R) SHIV strain in macaques.
18216122	2008	Natural history (African green monkey)	J Virol	Characterized SIVagm viral dynamics under tenofovir/emtricitabine treatment in a natural-host, non-progressor monkey species.

10 additional PMIDs in the source pack (e.g., 41959211, 14963139, 20497048) remain unclassified ("pending" study type) and were not prioritized here.

Finland Market Information

Not applicable — TENOFOVIR DISOPROXIL currently has 0 marketing authorizations on file for Finland (market_status: 未上市). No product/dosage form/indication data is available.

Safety Considerations

Please refer to the package insert for safety information. (All safety fields in the evidence pack — key warnings, contraindications, and DDI query — are data gaps; TFDA/Fimea package insert warnings are flagged as a Blocking-severity gap (DG001) that must be resolved before any S1 safety assessment.)

Conclusion and Next Steps

Decision: Hold

Rationale:

The top-ranked predicted indication (SIV infection) is a non-human primate disease model, not a human indication that can be pursued through a repurposing pathway; ranks 2–4 are similarly non-actionable (veterinary disease, obsolete ontology term, or zero evidence). All four candidates carry a source-assigned "Hold" recommendation.
Two Blocking/High-severity data gaps remain open: TFDA/Fimea package insert warnings and contraindications (Blocking — blocks S1 safety review), and confirmed mechanism of action (High).

To proceed, the following is needed:

Resolve DG001 (TFDA/Fimea package insert warnings/contraindications) before any safety-stage review can begin
Resolve DG002 (confirmed MOA via DrugBank) to properly assess mechanistic relevance
Re-run TxGNN disease matching with a human-only disease ontology filter to exclude animal-model and obsolete disease labels from candidate ranking
If a genuine human indication is desired, source additional predicted candidates beyond the current top 4, since none of them are currently viable
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.