Etravirine

證據等級: L5

預測適應症: 10 個

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

One-Sentence Summary

Etravirine (Intelence) is a second-generation diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), approved internationally for the treatment of HIV-1 infection in treatment-experienced adults and children from 2 years of age. The TxGNN model’s highest-ranked prediction is Feline Acquired Immunodeficiency Syndrome (FIV infection), with no clinical trials and no publications directly supporting this specific veterinary direction. Across the full prediction landscape, the most clinically novel repurposing signal is Etravirine’s potential role in Friedreich’s Ataxia, supported by a completed Phase 2 trial (NCT04273165, n=30) — a finding that warrants independent review separate from the top-ranked prediction.

⚠️ Report Scope Note: The top TxGNN-ranked indication is a veterinary disease regulated by the APVMA (not TGA). The Quick Overview and primary evidence sections follow the required template format (predicted_indications[0]) while sections below provide additional clinical context for the more actionable human-disease signals identified in this evidence pack.

Quick Overview

Item	Content
Original Indication	HIV-1 infection (treatment-experienced adults and children ≥2 years)
Predicted New Indication	Feline Acquired Immunodeficiency Syndrome
TxGNN Prediction Score	99.98%
Evidence Level	L5
Australia Market Status	Not marketed
Number of ARTG Entries	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this evidence pack. Based on known pharmacology, Etravirine is a diarylpyrimidine (DAPY) NNRTI that binds directly and flexibly to the reverse transcriptase (RT) enzyme of HIV-1. Its characteristic “butterfly” binding conformation allows it to accommodate conformational changes caused by resistance mutations, giving it activity against many HIV-1 strains resistant to first-generation NNRTIs such as efavirenz and nevirapine.

The TxGNN model assigns a high score (0.9998) to Feline Acquired Immunodeficiency Syndrome because HIV and FIV are ontologically adjacent in the biomedical knowledge graph: both are lentiviruses causing progressive CD4+ T-cell depletion, immune dysfunction, and ultimately fatal immunodeficiency. This structural proximity in the disease ontology network — not pharmacological cross-reactivity — drives the prediction.

However, the biological rationale is not supported by the available evidence. FIV reverse transcriptase has well-characterised structural differences in the NNRTI binding pocket (key residue substitutions compared to HIV-1 RT), and published data indicate that most human NNRTI compounds, including etravirine, have negligible inhibitory activity against FIV RT. Furthermore, feline AIDS is a veterinary indication with a distinct regulatory pathway in Australia (APVMA jurisdiction, not TGA). The high TxGNN score should be interpreted as a knowledge graph artefact of disease ontology proximity, not as pharmacological evidence.

Noteworthy repurposing signal for clinical consideration: The most clinically novel finding in this evidence pack is Etravirine’s potential use in Friedreich’s Ataxia (FA), where a completed Phase 2 trial (NCT04273165) demonstrated that etravirine increases frataxin protein both in vitro (FA patient-derived cells) and in vivo (YG8 frataxin-deficient mouse model). The proposed mechanistic hypothesis involves NNRTI-mediated inhibition of human endogenous retrovirus (HERV) transcription, which may reduce neuroinflammation, and a possible frataxin-independent pathway influencing mitochondrial function. This signal was misclassified in the evidence pack under the “Congenital HIV” indication and should be independently reviewed.

Clinical Trial Evidence

No clinical trials are registered for Etravirine in feline acquired immunodeficiency syndrome.

Currently no related clinical trials registered for this specific indication.

Selected trials of broader clinical relevance from the full evidence pack (for reference):

Trial Number	Phase	Status	Enrolment	Key Findings
NCT04273165	Phase 2	Completed	30	⭐ Friedreich’s Ataxia — drug repositioning trial; etravirine increased frataxin protein in FA patient cells and YG8 mouse model; assessed safety and efficacy in FA patients (Note: misclassified in evidence pack under congenital HIV)
NCT00855335	Phase 3	Completed	77	Pharmacokinetics of etravirine (and darunavir/ritonavir, cobicistat, rilpivirine) in HIV-1 infected pregnant women — supports use in prevention of vertical transmission
NCT01076179	N/A (Observational)	Completed	502	PROTEKT study: tolerability of lopinavir/ritonavir (Kaletra) combined with new agents including NNRTIs; etravirine as potential combination partner in AIDS-related complex
NCT04630002	Phase 1	Completed	54	Drug-drug interaction study: effects of darunavir/ritonavir and/or etravirine on PK of GSK3640254, and vice versa — important for combination regimens
NCT00042289	Phase 4	Completed	1,578	IMPAACT P1026s: PK of ARV drugs (including etravirine) in pregnant women and infants — supports safety data for prevention of congenital HIV
NCT07412977	N/A (Observational)	Not yet recruiting	5,160	VIROPREG: French prospective cohort on viral infections (HIV, HBV, HCV, arboviruses) during pregnancy and impact on maternal/child health; highly relevant to congenital HIV prevention
NCT01199731	Phase 2	Terminated	30	Dose-ranging study of GSK2248761 vs. etravirine 200 mg BID (control arm) + DRV/r + raltegravir in NNRTI-resistant HIV-1 patients — etravirine used as active comparator
NCT02422797	Phase 3	Completed	518	Non-inferiority study: switching virologically suppressed HIV-1 adults to dolutegravir + rilpivirine — includes participants on prior NNRTI-based regimens relevant to congenital HIV

Literature Evidence

No literature is directly available for feline acquired immunodeficiency syndrome.

Currently no related literature available for this specific indication.

Selected publications of broader clinical relevance from the full evidence pack (for reference):

PMID	Year	Type	Journal	Key Findings
20587860	2010	Case Series	Antiviral Therapy	Use of etravirine with darunavir ± raltegravir in highly treatment-experienced pregnant women with HIV — safety data supporting prevention of congenital HIV transmission
27067022	2016	Lab / Resistance Characterisation	AIDS Research and Human Retroviruses	Novel RT mutations L228I and Y232H (in HIV-1 CRF08_BC) confer NNRTI resistance including low-level resistance relevant to etravirine; confirms drug-target interaction in HIV
26529558	2015	In vitro / Preclinical	Molecular Pharmaceutics	Nanoparticle-based ARV combination delivery (including etravirine) for synergistic inhibition of cell-free and cell-cell HIV transmission; not directly related to SIV but demonstrates etravirine’s role in combination platforms
19290032	2009	Retrospective Cohort	AIDS Reviews	Risk factors for gastrointestinal adverse events in HIV-treated and untreated patients; provides contextual safety data on ARV class GI tolerability

Australia Market Information

Etravirine is not registered on the Australian Register of Therapeutic Goods (ARTG). There are currently no TGA-approved products containing etravirine available in Australia.

No ARTG entries exist. Etravirine is approved in multiple major regulatory jurisdictions (US FDA: Intelence®, 2008; EMA: Intelence®, 2008) and has been used internationally for treatment-experienced HIV-1 infection for nearly two decades. Australian prescribers requiring access may need to consider the TGA Special Access Scheme (SAS) or Authorised Prescriber pathways.

Safety Considerations

Please refer to the TGA-approved Product Information (PI) — or the FDA/EMA product labelling in the absence of a TGA-approved PI — for complete safety information.

Based on international regulatory labelling, Australian healthcare professionals should be aware of the following key points:

Skin reactions: Severe skin reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme have been reported. Patients should be monitored closely for skin rashes, especially in the first weeks of treatment.
Hypersensitivity: Severe hypersensitivity reactions (including DRESS — Drug Reaction with Eosinophilia and Systemic Symptoms) have been associated with etravirine; discontinuation is required if suspected.
Drug interactions: Etravirine is both a substrate and inducer/inhibitor of multiple CYP450 enzymes (CYP3A4, CYP2C9, CYP2C19) and P-glycoprotein; clinically significant interactions with other ARVs (e.g. unboosted protease inhibitors, tipranavir/ritonavir, full-dose ritonavir), rifampicin, carbamazepine, phenytoin, and St John’s Wort. Formal DDI data was not returned in this evidence pack — refer to current product labelling.
Pregnancy: Limited human data (including PMID 20587860 case series); use only if clearly indicated and benefit outweighs risk; pharmacokinetic changes during pregnancy may reduce etravirine exposure.
Paediatric use: Approved from 2 years of age internationally; weight-based dosing required.

Conclusion and Next Steps

Decision: Hold

Rationale: The top TxGNN-ranked prediction (feline acquired immunodeficiency syndrome) is a veterinary indication outside TGA jurisdiction, and the high model score (0.9998) reflects disease ontology graph proximity between HIV and FIV rather than pharmacological cross-reactivity — published evidence demonstrates that etravirine lacks meaningful activity against FIV reverse transcriptase due to binding pocket residue differences.

To proceed, the following is needed:

Redirect clinical evaluation to Friedreich’s Ataxia: NCT04273165 (Phase 2, completed, n=30) represents the most actionable human-disease repurposing signal in this evidence pack. Full trial results should be retrieved and reviewed independently.
Retrieve mechanism of action data: MOA information from DrugBank (DB06414) is required to complete the pharmacological profile and enable mechanistic link analysis for all predicted indications.
Obtain safety data: TGA PI equivalent (FDA Intelence® PI or EMA SmPC) should be retrieved and parsed to complete the S1 safety evaluation — this is currently a blocking data gap (DG001).
Assess FIV signal (if veterinary scope is intended): In vitro data demonstrating etravirine activity against FIV RT would be a prerequisite before any veterinary repurposing consideration; existing evidence suggests this is unlikely.
ARTG pathway planning: If etravirine is to be pursued for any indication in Australia, the TGA SAS Category B or Authorised Prescriber pathway, or a full ARTG submission, would be required given current non-marketed status.
Reclassify evidence pack: The NCT04273165 trial (Friedreich’s Ataxia) should be removed from the “Congenital HIV” indication and tracked as a standalone repurposing candidate at L2 evidence level.

This report is generated for research purposes only and does not constitute medical or therapeutic advice. All repurposing candidates require clinical validation before any therapeutic application. Data cutoff: 5 April 2026.

Disclaimer

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