Dolutegravir

證據等級: L5

預測適應症: 3 個

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

One-Sentence Summary

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI), originally approved for the treatment of HIV-1 infection. The TxGNN model predicts it may be effective for Simian Immunodeficiency Virus (SIV) Infection, with 1 clinical trial and 15 publications currently supporting this direction. Given that SIV is the direct progenitor of HIV and shares high integrase homology, this prediction has a strong mechanistic basis supported primarily by preclinical animal model studies.

Quick Overview

Item	Content
Original Indication	HIV-1 infection (antiretroviral therapy)
Predicted New Indication	Simian Immunodeficiency Virus Infection
TxGNN Prediction Score	99.85%
Evidence Level	L3 (Preclinical animal model studies)
Malaysia Market Status	✓ Marketed
Number of Registrations	7
Recommended Decision	Hold

Why is This Prediction Reasonable?

Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) that blocks HIV-1 integrase from inserting viral DNA into the host cell genome. Currently, detailed mechanism of action data was not available in the evidence pack; however, dolutegravir is well-established as a cornerstone of first-line HIV-1 combination antiretroviral therapy (cART) due to its high genetic barrier to resistance, once-daily dosing, and favourable tolerability profile.

Simian immunodeficiency virus (SIV) and HIV-1 both belong to the Lentivirus genus, and their integrase enzymes share high structural and functional homology. This is precisely why SIV-infected non-human primate (NHP) models serve as the standard preclinical platform for evaluating antiretroviral drugs destined for human HIV treatment. Dolutegravir’s mechanism of inhibiting integrase-mediated strand transfer is directly applicable to SIV integrase, as confirmed by multiple in vitro and in vivo studies demonstrating effective viral suppression in SIV-infected macaques.

While this prediction is mechanistically sound, it is important to note that SIV infection is a veterinary/research condition rather than a human clinical indication. The practical value of this prediction lies in validating dolutegravir’s utility in NHP research models rather than identifying a new human therapeutic application. Nevertheless, the strong evidence base from preclinical studies confirms the biological plausibility of the TxGNN model’s prediction.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03577782	Phase 1/2	Unknown	12	Vedolizumab combined with ART (including dolutegravir as background) to achieve virological remission in HIV-infected subjects. Dolutegravir served as part of the ART backbone rather than the primary investigational agent.

Note: Only 1 clinical trial was identified with direct relevance to SIV/HIV integrase inhibitor research. The trial evaluated vedolizumab rather than dolutegravir as the primary intervention.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
30381490	2019	Preclinical (animal)	J Virol	Dolutegravir monotherapy in SIV-infected macaques selected for multiple resistance mutation patterns with variable virological outcomes
26378179	2015	Preclinical (in vitro)	J Virol	Characterized INSTI drug resistance profiles in SIVmac239, showing similar resistance phenotypes between SIV and HIV
24920794	2014	Preclinical (in vitro)	J Virol	HIV-1 integrase resistance mutations inserted into SIVmac239 showed similar susceptibility patterns to INSTIs including dolutegravir
36365101	2022	Preclinical (animal)	Pharmaceutics	Pharmacologically validated long-term ART (including dolutegravir) in SIVmac251-infected NHP model
26150024	2016	Preclinical (animal)	AIDS Res Hum Retroviruses	Evaluated novel cART regimens containing dolutegravir in SIVmac239-infected rhesus macaques
34903055	2021	Preclinical (animal)	mBio	Demonstrated lentiviral persistence in brain despite effective ART in both human and SIV-infected NHP models
32506843	2021	Structural biology	FEBS J	HIV/SIV intasome structures reveal how dolutegravir binds integrase and explain the high barrier to resistance
28923862	2017	Preclinical (in vitro)	Antimicrob Agents Chemother	Compared antiviral activity of bictegravir and cabotegravir against INSTI-resistant SIVmac239 and HIV-1
25583721	2015	Preclinical (in vitro)	Antimicrob Agents Chemother	Used simian-tropic HIV as a model to study INSTI drug resistance, confirming cross-species applicability
30161247	2018	Preclinical (animal)	PLoS Pathog	p38 MAPK inhibition combined with ART (including dolutegravir) reduced SIV-induced immune activation in macaques

Malaysia Market Information

Authorization Number	Product Name	Dosage Form	Approved Indication
—	—	—	—

Registration details (authorization numbers, product names, dosage forms, and approved indication text) were not available in the evidence pack. There are 7 registered products containing dolutegravir on the Malaysian market.

Safety Considerations

Please refer to the package insert for safety information. Key warnings, contraindications, and drug interaction data were not available in the current evidence pack.

Additional Predicted Indications

Rank 2: Feline Acquired Immunodeficiency Syndrome

Item	Content
TxGNN Prediction Score	99.85%
Evidence Level	L4 (Preclinical veterinary study)
Clinical Trials	5 (all HIV-1 human trials, none directly studying FIV)
Literature	1 publication (dolutegravir-based cART in FIV-infected cats)
Recommendation	Hold

Rationale: Feline immunodeficiency virus (FIV) belongs to the same Lentivirus genus as HIV, but FIV integrase has lower homology to HIV integrase compared to SIV. One published study (PMID 37112803, 2023) evaluated dolutegravir-based cART in FIV-infected domestic cats, but efficacy against FIV remains insufficiently validated. All 5 matched clinical trials were actually HIV-1 human studies mismatched due to keyword overlap on “immunodeficiency.”

Rank 3: Neurodevelopmental Disorder with Ataxic Gait, Absent Speech, and Decreased Cortical White Matter

Item	Content
TxGNN Prediction Score	99.80%
Evidence Level	L5 (Model prediction only)
Clinical Trials	0
Literature	0
Recommendation	Hold

Rationale: There is no known mechanistic link between dolutegravir’s INSTI mechanism and this rare genetic neurodevelopmental disorder. This prediction lacks any supporting evidence. Of particular concern, dolutegravir has been associated with potential neural tube defect risks in pregnancy, raising the possibility that this drug could be harmful rather than beneficial in the context of neurodevelopmental conditions. This prediction should not be pursued.

Conclusion and Next Steps

Decision: Hold

Rationale: The primary prediction (SIV infection) is mechanistically sound — dolutegravir demonstrably suppresses SIV in preclinical NHP models, which is well-supported by 15 publications. However, SIV infection is not a human clinical indication but rather a research model for HIV drug development. The remaining predictions (feline AIDS and a rare neurodevelopmental disorder) lack sufficient evidence or mechanistic justification for clinical pursuit.

To proceed, the following is needed:

Clarify the clinical utility goal: if the objective is to validate dolutegravir for veterinary use in SIV/FIV, dedicated veterinary pharmacology studies are needed
Obtain detailed mechanism of action (MOA) data from DrugBank to complete the evidence pack
Retrieve Malaysia NPRA registration details (authorization numbers, product names, approved indications)
Download and parse package insert PDFs for safety information (key warnings, contraindications, drug interactions)
Consider whether TxGNN predictions for this drug should be re-evaluated with focus on human diseases with unmet therapeutic need rather than animal lentivirus infections
Disclaimer

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