Efavirenz

證據等級: L5

預測適應症: 6 個

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

One-Sentence Summary

Efavirenz is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used as part of combination antiretroviral therapy for HIV-1 infection in humans. The TxGNN model predicts it may also be effective for Simian Immunodeficiency Virus (SIV) Infection, with 1 registered clinical trial (withdrawn before enrolment) and 16 publications — predominantly preclinical macaque studies — currently supporting this direction.

Quick Overview

Item	Content
Original Indication	HIV-1 infection (combination antiretroviral therapy)
Predicted New Indication	Simian Immunodeficiency Virus Infection
TxGNN Prediction Score	99.80%
Evidence Level	L4
Denmark Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Efavirenz is a well-characterised NNRTI whose primary mechanism involves non-competitive, allosteric inhibition of HIV-1 reverse transcriptase (RT). It binds to a hydrophobic pocket approximately 10 Å from the RT active site, inducing conformational changes that suppress catalytic activity and block viral DNA synthesis. Currently, detailed mechanism of action data is not available in this Evidence Pack (Data Gap DG002). Based on established pharmacology, efavirenz selectively targets HIV-1 RT and has demonstrated potent antiviral activity as part of once-daily combination regimens such as Atripla (efavirenz/emtricitabine/tenofovir).

Simian Immunodeficiency Virus shares substantial genetic and structural homology with HIV-1, making it the canonical non-human primate model for HIV/AIDS research. However, a critical mechanistic caveat applies: wild-type SIV reverse transcriptase differs structurally from HIV-1 RT at the NNRTI binding pocket, rendering native SIV intrinsically resistant to efavirenz and all first- and second-generation NNRTIs. The entire body of efavirenz-related SIV literature in this pack concerns RT-SHIV, an engineered chimeric virus in which the SIV RT-coding region has been replaced by HIV-1 RT to create an NNRTI-susceptible primate model.

The TxGNN prediction almost certainly captures this mechanistic overlap between HIV-1 RT and the chimeric RT-SHIV construct rather than a genuinely new therapeutic opportunity. While the RT-SHIV macaque model has been invaluable for studying HAART pharmacology, viral reservoir dynamics, and NNRTI resistance evolution, this “indication” does not represent a distinct clinical need beyond efavirenz’s established HIV-1 indication in humans.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00863668	N/A	Withdrawn	0	Planned study of HIV/SIV RNA decay kinetics during ART including the integrase inhibitor raltegravir; withdrawn before any participants were enrolled — no efficacy or safety data available

Literature Evidence

PMID	Year	Type	Journal	Key Findings
15919889	2005	Preclinical (animal)	Journal of Virology	Efavirenz + lamivudine + tenofovir HAART suppressed RT-SHIV plasma viral RNA by >4 log₁₀ copies/mL in all 7 rhesus macaques, establishing the RT-SHIV model for HAART research
35856680	2022	Preclinical (imaging)	Antimicrobial Agents and Chemotherapy	Mass spectrometry imaging of 6 ARVs including efavirenz mapped drug penetration relative to viral RNA and fibrosis markers in spleens of RT-SHIV-infected nonhuman primates
24777106	2014	Preclinical (animal)	Antimicrobial Agents and Chemotherapy	Four- and five-drug enhanced HAART regimens incorporating efavirenz in RT-SHIV macaques; improved early viral decay kinetics compared to standard three-drug regimens
26559632	2015	Preclinical (animal)	Retrovirology	Well-mixed plasma and tissue viral populations in ART-treated RT-SHIV macaques suggest minimal ongoing viral replication in tissues during efavirenz-based combination therapy
20032180	2010	Preclinical (animal)	Journal of Virology	Comprehensive viral reservoir mapping in RT-SHIV macaques under HAART; resting CD4⁺ T cells and macrophages identified as persistence sites despite efavirenz-based suppression
21084490	2011	Preclinical (animal)	Journal of Virology	RT-SHIV genetic diversity persists in macaques despite ART; efavirenz monotherapy followed by combination ART used to characterise viral population dynamics
22933296	2012	Preclinical (animal)	Journal of Virology	Ultrasensitive allele-specific PCR detected rare pre-existing NNRTI-resistant variants in RT-SHIV macaques before efavirenz initiation, mirroring clinical HIV resistance patterns
20668516	2010	Preclinical (animal)	PLoS One	Viral decay kinetics modelled in HAART-treated RT-SHIV macaques; efavirenz-containing regimen used as standard for studying long-term HIV-1 persistence mechanisms
19889213	2009	Preclinical (animal)	Retrovirology	Short-course efavirenz monotherapy in RT-SHIV macaques followed by combination ART; wild-type and drug-resistant variant subpopulation dynamics characterised by single-genome sequencing
15328115	2004	Preclinical (animal)	Antimicrobial Agents and Chemotherapy	Founding evaluation of efavirenz antiviral activity in RT-SHIV-infected rhesus macaques; confirmed dose-dependent viral suppression, validating the chimeric model for NNRTI studies

Denmark Market Information

Efavirenz currently holds no marketing authorisations in Denmark and is recorded as not marketed by Laegemiddelstyrelsen (0 authorisations, 0 licensed products in this Evidence Pack).

Note for reviewers: This finding warrants verification. Efavirenz is approved through EMA centralised procedures under the brand name Stocrin (Merck Sharp & Dohme) and as a component of Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate; Bristol-Myers Squibb/Gilead). Both products hold valid centralised marketing authorisations that are legally binding across all EU/EEA member states including Denmark. The absence of records in this pack likely reflects a data gap in the Danish national registry query rather than a true absence of authorisation.

Safety Considerations

Please refer to the approved Summary of Product Characteristics (SmPC) for safety information.

Note: The Evidence Pack flags two blocking data gaps — absence of Laegemiddelstyrelsen-specific label warnings/contraindications (DG001, severity: Blocking) and absence of mechanism of action detail (DG002, severity: High). No drug-drug interaction data was retrieved. Before clinical use, the full SmPC for Stocrin and/or Atripla should be consulted for CNS adverse effects (dizziness, nightmares, psychiatric events), teratogenicity warnings (Category D), hepatotoxicity monitoring, and extensive CYP3A4/CYP2B6 interactions.

Conclusion and Next Steps

Decision: Hold

Rationale: The top TxGNN-predicted indication — simian immunodeficiency virus infection — is not a human therapeutic target in the conventional sense. The entirety of supporting evidence derives from the RT-SHIV chimeric macaque model, which was engineered specifically to carry HIV-1 RT (and therefore become susceptible to efavirenz); wild-type SIV is inherently NNRTI-resistant. This prediction reflects mechanistic overlap with efavirenz’s established HIV-1 indication rather than a novel repurposing opportunity, and no completed clinical trials exist. The Evidence Pack also contains two blocking data gaps (DG001, DG002) that preclude a standard safety assessment.

To proceed, the following is needed:

Confirm Denmark/EU registration status: Verify Stocrin and Atripla EMA centralised authorisation records against Laegemiddelstyrelsen’s registry to resolve the “not marketed” discrepancy
Retrieve full MOA data (DG002): Query DrugBank API for efavirenz pharmacology, including CYP3A4/CYP2B6 induction profile
Retrieve SmPC safety data (DG001): Download and parse Stocrin/Atripla label PDF from EMA or Laegemiddelstyrelsen for warnings, contraindications, and teratogenicity status
Re-evaluate genuinely novel human indications: The rank-5/6 prediction (neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter) represents a more unconventional repurposing hypothesis that warrants a dedicated evidence search with targeted PubMed and ClinicalTrials.gov queries
Consider the feline AIDS indication separately: PMID 38031646 (2023) describes direct biochemical testing of efavirenz against Feline Immunodeficiency Virus RT and may support a veterinary medicine repurposing track, which follows a different regulatory pathway (VMPA) than human medicines

Disclaimer: This report is intended for research reference purposes only and does not constitute medical advice. Drug repurposing candidates require clinical validation before any therapeutic application. All clinical decisions must comply with applicable Danish and EU regulatory requirements.

Disclaimer

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