Darunavir

證據等級: L5

預測適應症: 4 個

Darunavir: From HIV-1 Infection to Simian Immunodeficiency Virus Infection

One-Sentence Summary

Darunavir is a second-generation HIV-1 protease inhibitor approved for treating HIV-1 infection in adults and pediatric patients. The TxGNN model predicts it may be effective for Simian Immunodeficiency Virus (SIV) Infection, with 0 clinical trials and 4 non-human primate studies currently supporting this direction.

Quick Overview

Item	Content
Original Indication	HIV-1 infection
Predicted New Indication	Simian Immunodeficiency Virus Infection
TxGNN Prediction Score	99.97%
Evidence Level	L4
Saudi Arabia Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Darunavir is a second-generation HIV-1 protease inhibitor that binds tightly to the active site of the HIV-1 protease enzyme, preventing cleavage of viral polyprotein precursors and blocking the production of mature, infectious virions. Its exceptionally high genetic barrier to resistance — compared with first-generation agents such as lopinavir — and broad activity against wild-type and multi-drug-resistant HIV-1 strains have made it a backbone of modern combination antiretroviral therapy (cART).

The mechanistic case for activity against SIV rests on structural homology: SIV and HIV-1 are both primate lentiviruses, and their protease enzymes share approximately 85–90% amino acid sequence identity. Consistent with this, all four supporting publications used Darunavir as a component of intensified cART regimens in SIVmac239- or SIVmac251-infected rhesus macaques, demonstrating clinically relevant viral suppression and enabling study of latent reservoir dynamics — the same scientific problems driving HIV cure research in humans.

However, the residual 10–15% amino acid divergence between SIV and HIV-1 proteases means that binding affinity cannot be assumed equivalent without dedicated enzyme assays. More importantly, SIV infection is a non-human primate pathogen with no direct human clinical counterpart: this TxGNN prediction reflects Darunavir's validated utility in preclinical animal models rather than a conventional repurposing opportunity targeting a new human disease.

Clinical Trial Evidence

Currently no related clinical trials registered for Darunavir in simian immunodeficiency virus infection.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
26150024	2016	NHP Experiment	AIDS Res Hum Retroviruses	Evaluated two novel coformulated cART regimens including darunavir in SIVmac239-infected rhesus macaques; both regimens achieved sustained, clinically relevant viral suppression suitable for reservoir studies
22737073	2012	NHP Experiment	PLoS Pathogens	Highly intensified multi-drug ART (including darunavir) suppressed SIVmac251 viremia across a broad viral load range (10³–10⁷ copies/mL) and significantly restricted the measurable viral reservoir in rhesus macaques
25033210	2014	NHP Experiment	PLoS One	cART (including darunavir) combined with the HDAC inhibitor SAHA in SIV-infected Chinese-origin rhesus macaques; examined reservoir persistence and the "shock-and-kill" latency reversal concept
21505294	2011	NHP Experiment	AIDS (London)	Auranofin co-administered with cART (including darunavir) in an SIV monkey model; demonstrated restriction of lentiviral reservoir cells and containment of viral load following ART suspension

Note: All four studies are Tier 3 non-human primate experiments. No randomized controlled trials or observational human studies were identified for this indication.

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: The entire evidence base for this prediction consists of non-human primate animal model studies (L4), and SIV infection is by definition a primate pathogen with no direct human clinical target — the prediction captures Darunavir's established role as a cART component in preclinical HIV research, rather than identifying a novel clinical repurposing opportunity. The remaining three TxGNN predictions further support a conservative posture: feline AIDS (L5) is mechanistically unsupported given FIV protease divergence; the neurodevelopmental disorder (L5) has no biological rationale linking HIV protease inhibition to neurodevelopment; and familial combined hyperlipidemia (L5) is a pharmacological reversal signal — Darunavir/ritonavir is a known inducer of hypertriglyceridemia and elevated LDL-C, making this a documented adverse effect rather than a therapeutic target.

⚠️ Data Pipeline Note: The clinical trial NCT02770508 retrieved for the "feline AIDS" indication is a Phase 4 human HIV-1 study with no feline disease relevance (Grade C mapping error). This reflects a false-positive retrieval in the evidence pipeline and should be corrected upstream.

To proceed, the following is needed:

Formal in vitro enzyme-binding assays confirming Darunavir activity against SIV protease specifically (to resolve the 10–15% sequence divergence uncertainty)
Clarification of the intended clinical context: if the goal is optimizing NHP model fidelity for HIV cure research, this evidence supports continued use; if pursuing a de novo human clinical indication, redirect effort to higher-evidence human disease associations
Full MOA and safety profile data (currently unavailable in this dataset) to enable S1 safety screening
Package insert review to complete contraindication and warning assessment (DG001 gap, currently blocking S1 entry)
Disclaimer

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