Darunavir

證據等級: L5

預測適應症: 4 個

Darunavir: From HIV-1 Infection to Feline Acquired Immunodeficiency Syndrome

One-Sentence Summary

Darunavir is a second-generation HIV-1 protease inhibitor used as part of combination antiretroviral therapy (cART) for the treatment of HIV/AIDS in adults and paediatric patients. The TxGNN model predicts it may be effective for Feline Acquired Immunodeficiency Syndrome (FIV infection), with 1 indirectly related clinical trial and no direct feline publications currently supporting this direction. This prediction is primarily driven by structural homology between the HIV-1 and Feline Immunodeficiency Virus (FIV) proteases, rather than direct veterinary clinical evidence.

Quick Overview

Item	Content
Original Indication	HIV-1 infection (combination antiretroviral therapy)
Predicted New Indication	Feline Acquired Immunodeficiency Syndrome (FIV Infection)
TxGNN Prediction Score	99.97%
Evidence Level	L4
Canada Market Status	Not marketed (no DINs on file)
Number of DINs	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this evidence pack. Based on established clinical knowledge, Darunavir is a second-generation HIV-1 aspartyl protease inhibitor. It binds to the active site of the HIV-1 protease, blocking cleavage of viral polyprotein precursors (Gag and Gag-Pol) and preventing the maturation of new infectious viral particles. It is always co-administered with a pharmacokinetic booster (ritonavir or cobicistat) to maintain therapeutic plasma levels.

The Feline Immunodeficiency Virus (FIV) and HIV-1 both belong to the genus Lentivirus within the family Retroviridae. Their aspartyl proteases share structural homology, particularly around the catalytic Asp-Thr-Gly triad. In vitro experiments have demonstrated that several HIV-1 protease inhibitors retain measurable inhibitory activity against FIV protease, providing a legitimate mechanistic rationale for cross-species application.

However, a critical caveat applies: TxGNN’s high prediction score for this indication is primarily the result of disease ontology similarity mapping (HIV/AIDS ↔ FIV) rather than direct experimental evidence in feline subjects. The single identified clinical trial (NCT02770508) is a human HIV-1 study with only indirect relevance. Real-world pharmacokinetic data in cats — including bioavailability, metabolism by feline cytochrome P450, and tolerability — is absent from this evidence pack. This prediction therefore represents a biologically plausible hypothesis requiring dedicated veterinary investigation before any application.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02770508	Phase 4	Completed	145	Compared Darunavir/ritonavir + lamivudine (dual therapy) versus standard Darunavir/ritonavir + tenofovir/emtricitabine or tenofovir/lamivudine triple ART in ART-naïve HIV-1 patients. This is a human HIV-1 trial. Its relevance to feline FIV is indirect only (Grade C — cross-species ontological mapping); it does not constitute direct evidence for FIV treatment.

Literature Evidence

Currently no direct literature on Darunavir for feline acquired immunodeficiency syndrome is available.

Context note: Although no feline-specific publications were identified, 4 animal studies were retrieved under the closely related Rank 2 prediction (Simian Immunodeficiency Virus infection; see Additional Predictions below). These NHP/SIV studies demonstrate that Darunavir-containing cART regimens effectively suppress lentiviral replication in non-human primates, lending indirect biological plausibility to broader lentiviral applications.

Canada Market Information

No Health Canada Drug Identification Numbers (DINs) are currently on file for Darunavir in the regulatory dataset used for this analysis.

Important caveat: Darunavir (brand name Prezista®, Janssen) is a globally approved antiretroviral agent with regulatory approvals in the US (FDA), EU (EMA), and numerous other jurisdictions. If the 0-DIN result reflects a data gap in the queried database rather than actual Health Canada non-approval, manual verification via the Health Canada Drug Product Database is strongly recommended before drawing conclusions about Canadian market status.

Safety Considerations

Please refer to the package insert for safety information.

Data Gap DG001 (Blocking): Package insert warnings and contraindications have not been retrieved for this evaluation. This is classified as a blocking gap — formal safety review cannot be completed until the full monograph is obtained. Known drug class effects for HIV protease inhibitors include hepatotoxicity risk (particularly in patients with underlying hepatitis B/C), skin rash (including Stevens-Johnson syndrome), lipid metabolic effects, and complex drug-drug interactions via CYP3A4 inhibition.

Additional Predicted Indications (Summary)

The following lower-ranked predictions are noted for completeness:

Rank	Disease	TxGNN Score	Evidence Level	Recommendation	Notes
2	Simian Immunodeficiency Virus Infection	99.97%	L3	Research Question	4 NHP/SIV animal studies (2011–2016) support Darunavir-containing cART for viral suppression in macaque models — the strongest mechanistic evidence in this pack
3	Neurodevelopmental Disorder with Ataxic Gait, Absent Speech, and Decreased Cortical White Matter	99.97%	L5	Hold	No mechanistic link; model-only prediction
4	Obsolete Familial Combined Hyperlipidemia	99.19%	L5	Hold	Contraindicated direction — HIV protease inhibitors are known to cause dyslipidaemia; this prediction should be discarded

Conclusion and Next Steps

Decision: Hold

Rationale: The top TxGNN prediction for Darunavir points to a veterinary indication (feline FIV infection) rather than a new human therapeutic application. While structural homology between HIV-1 and FIV proteases provides biological plausibility, there are no direct feline clinical trials, no feline-specific publications, and the single identified clinical trial is a human HIV-1 study with only indirect relevance (Grade C). Separately, Rank 4 (familial combined hyperlipidemia) represents a potentially harmful direction given HIV protease inhibitors’ known dyslipidaemic effects, and should be explicitly deprioritised.

To proceed, the following is needed:

Clarify the repurposing scope: Determine whether the target is veterinary (cats with FIV) or human repurposing. If human, the Rank 2 prediction (SIV infection as a research model bridge) offers more tractable evidence to build on.
Resolve Data Gap DG001 (Blocking): Retrieve Health Canada / TFDA package insert warnings, contraindications, and drug interaction profile before any safety evaluation can proceed.
Resolve Data Gap DG002 (High): Obtain full MOA data from DrugBank API (DB01264) to support mechanistic rationale scoring.
Conduct dedicated veterinary literature search: Search PubMed and CAB Abstracts for in vitro FIV protease inhibition studies and in vivo feline pharmacokinetic studies using HIV protease inhibitors.
Verify Canada regulatory status: Manually confirm Darunavir’s current DIN status via the Health Canada Drug Product Database; the 0-DIN result is likely a database query gap rather than true non-approval.
Review Rank 2 (SIV) evidence: If the objective is to establish proof-of-concept for lentiviral protease cross-reactivity, the SIV/NHP literature (4 studies, L3 evidence) provides a more substantial starting point than the feline data.
Disclaimer

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