Dolutegravir

證據等級: L5

預測適應症: 3 個

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

One-Sentence Summary

Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) established for human HIV-1 treatment, acting by blocking viral DNA integration into the host genome. The TxGNN model predicts it may be effective for Feline Acquired Immunodeficiency Syndrome (Feline AIDS) caused by Feline Immunodeficiency Virus (FIV), with 5 clinical trials (all indirect human HIV-1 studies, computationally cross-classified) and 1 direct veterinary publication currently supporting this direction.

Quick Overview

Item	Content
Original Indication	HIV-1 Infection (antiretroviral therapy; inferred from clinical trial context — no Philippines regulatory record available)
Predicted New Indication	Feline Acquired Immunodeficiency Syndrome
TxGNN Prediction Score	99.85%
Evidence Level	L4
Philippines Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available from the DrugBank data pipeline (recorded as a High-severity data gap). However, based on information present within the Evidence Pack, Dolutegravir belongs to the integrase strand transfer inhibitor (INSTI) class of antiretrovirals. DTG inhibits HIV-1 replication by chelating divalent metal ions (Mg²⁺/Mn²⁺) at the active site of the viral integrase enzyme through a diketoacid (DKA) pharmacophore, thereby blocking the strand transfer step of viral DNA integration into the host chromosome. This two-metal-ion chelation mechanism confers a notably high genetic barrier to resistance compared to first-generation INSTIs such as raltegravir and elvitegravir.

Feline Immunodeficiency Virus (FIV), the causative agent of Feline AIDS, belongs to the same Lentivirus genus as HIV-1. The FIV integrase shares approximately 40% amino acid sequence similarity with HIV-1 integrase, with the catalytic core domain — including the conserved DDE motif that coordinates the active-site metal ions — being structurally homologous. This conservation is the primary rationale behind the TxGNN model’s prediction: DTG’s DKA pharmacophore may engage the FIV integrase active site in a mechanistically analogous manner to its action on HIV-1 integrase.

The prediction gains direct experimental support from a 2023 veterinary pharmacology study (PMID 37112803) which administered DTG-containing combination antiretroviral therapy (cART: DTG 2.5 mg/kg + tenofovir 20 mg/kg + emtricitabine 40 mg/kg) to FIV-infected domestic cats, evaluating both pharmacokinetics and immunophenotypic outcomes. This represents the only directly relevant clinical evidence. Significant knowledge gaps remain, particularly regarding feline-specific pharmacokinetics (protein binding rates, plasma half-life, and CYP metabolism profiles differ substantially between cats and humans), which must be resolved before clinical application.

Clinical Trial Evidence

⚠️ Data Quality Notice: All 5 trials below are human HIV-1 studies. They were computationally cross-classified under the “feline acquired immunodeficiency syndrome” indication based on mechanistic overlap (shared lentiviral integrase pharmacology), and serve as indirect mechanistic evidence only. They do not count toward direct feline clinical trial evidence. No dedicated feline AIDS clinical trials are currently registered on ClinicalTrials.gov.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01263015	Phase 3	Completed	844	SINGLE trial: DTG 50 mg + ABC/3TC once daily vs. EFV/TDF/FTC (Atripla) in ART-naïve HIV-1 adults over 96 weeks; established DTG non-inferiority and supports integrase inhibition efficacy as a drug class
NCT01227824	Phase 3	Completed	828	SPRING-2 trial: DTG 50 mg once daily vs. raltegravir 400 mg twice daily in ART-naïve HIV-1 adults; DTG demonstrated non-inferior antiviral activity with a favourable resistance profile across lentiviral integrase inhibitor class
NCT01231516	Phase 3	Completed	724	DTG 50 mg once daily vs. raltegravir in ART-experienced, integrase-naïve HIV-1 adults; confirmed DTG efficacy in the treatment-experienced setting
NCT00951015	Phase 2	Completed	208	Phase IIb dose-selection study establishing DTG 50 mg QD as the optimal human dose; provides indirect PK context for future cross-species allometric dose extrapolation
NCT01499199	Phase 3	Completed	13	CNS/plasma PK study: DTG 50 mg + ABC/3TC in HIV-1 ART-naïve subjects; CSF/plasma Kp,uu ≈ 0.32, indicating moderate CNS penetration — indirectly relevant to FIV-associated neurological pathology assessment

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37112803	2023	Veterinary Clinical / Observational	Viruses	Only direct feline evidence: cART regimen (DTG 2.5 mg/kg + tenofovir 20 mg/kg + emtricitabine 40 mg/kg) administered to FIV-infected specific-pathogen-free domestic cats; evaluated pharmacokinetics and CD4/CD8 immunophenotypic changes — critical baseline data for any future feline efficacy trial

Philippines Market Information

Dolutegravir currently holds no drug registrations with the Philippine FDA and is classified as not marketed in the Philippines. There are no active authorisation numbers, licensed products, or approved indications on record. Any clinical or veterinary application in the Philippines would require a new drug registration or compassionate use application.

Safety Considerations

Please refer to the package insert for safety information.

Note: Two blocking data gaps were identified in this Evidence Pack. TFDA package insert warnings and contraindications (DG001, Blocking severity) and DrugBank mechanism of action data (DG002, High severity) were not retrieved. One specific safety signal identified in the mechanistic literature is DTG’s known interference with folate (one-carbon) metabolism, associated with elevated neural tube defect risk in periconceptional exposure (Botswana pregnancy cohort data). This is of particular relevance to the rank 3 neurodevelopmental indication assessment (see below).

Additional Predicted Indications

Rank 2 — Simian Immunodeficiency Virus (SIV) Infection

Item	Content
TxGNN Score	99.85%
Evidence Level	L3
Recommended Decision	Proceed with Guardrails

The SIV prediction rests on a mechanistically stronger foundation than the feline AIDS prediction. SIV integrase shares >60% amino acid sequence similarity with HIV-1 integrase in the catalytic core domain, and cryo-EM/X-ray structural studies of HIV/SIV intasome complexes (PMID 32506843) have directly confirmed DTG’s binding mode is conserved across these viruses. This indication has dual application value: (1) as a translational HIV research model in non-human primates (NHPs), and (2) for conservation veterinary medicine in captive great apes infected with SIVcpz.

Supporting literature (up to 10 key publications):

PMID	Year	Type	Journal	Key Findings
30381490	2019	Animal Study (NHP/PK-PD)	Journal of Virology	DTG monotherapy in SIV-infected macaques: rapid viral suppression confirmed, but resistance mutations selected under monotherapy pressure; supports use within combination regimens
26150024	2016	Animal Study (NHP/cART)	AIDS Research and Human Retroviruses	DTG-containing cART regimens effectively suppress SIVmac239 replication in rhesus macaques to clinically relevant levels; validates NHP model for HIV cure research
36365101	2022	Animal Study (NHP/Longitudinal PK)	Pharmaceutics	Long-term PK validation of DTG + TDF + FTC in SIVmac251-infected NHPs; critical pharmacological data confirming drug exposures achievable in the NHP model
32506843	2021	Structural Biology / Mechanistic Review	The FEBS Journal	Intasome crystal and cryo-EM structures confirm DTG binding to SIV integrase; mechanistically explains the high genetic barrier to resistance for second-generation INSTIs
26378179	2015	In Vitro Resistance Phenotyping	Journal of Virology	SIVmac239 susceptible to DTG; INSTI resistance mutation profiles in SIV mirror HIV-1 patterns, validating SIV as a drug resistance model
28576126	2017	Case Report (Conservation Veterinary)	Retrovirology	Successful ART treatment of SIVcpz-induced immunodeficiency in a captive western chimpanzee; proof-of-concept for great ape conservation medicine application
34903055	2021	Animal Study (NHP/CNS Reservoir)	mBio	Lentiviral CNS reservoirs persist despite ART across HIV/SIV models; relevant for evaluating DTG CNS penetration adequacy in SIV-infected NHPs
32166319	2020	In Vitro Safety / Metabolic	Clinical Infectious Diseases	DTG and raltegravir exhibit proadipogenic and profibrotic effects and induce insulin resistance in human/simian adipose tissue; metabolic safety signal requiring monitoring in long-term NHP use
40093003	2025	Animal Study (NHP/CNS Imaging)	Frontiers in Immunology	DTG-containing cART modulates CNS white matter tract deficits in SIV-infected rhesus macaques; provides neuroimaging data relevant to CNS reservoir assessment
28923862	2017	In Vitro / Comparative Pharmacology	Antimicrobial Agents and Chemotherapy	Bictegravir and cabotegravir activity against INSTI-resistant SIVmac239; comparative context establishing DTG’s position within the INSTI resistance landscape for SIV

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

Item	Content
TxGNN Score	99.80%
Evidence Level	L5
Recommended Decision	Hold

This prediction is assessed as a likely computational false positive. No clinical trials or supporting literature were identified (0/0). The described phenotype — progressive ataxic gait, absent speech, and cortical white matter loss — is characteristic of genetic leukodystrophies (e.g., POLR3-related disorders, mitochondrial leukoencephalopathy) or inborn errors of metabolism, conditions requiring targeted gene- or enzyme-based therapies with no plausible mechanistic link to integrase inhibition.

Furthermore, DTG carries a known safety signal in this disease context: documented interference with folate/one-carbon metabolism raises neural tube defect risk and potential neurodevelopmental toxicity. This constitutes a contraindication concern rather than a therapeutic rationale for a CNS developmental disorder. The high TxGNN score (0.9980) in the absence of any experimental support is treated as a model artefact requiring hypothesis-generation studies before further evaluation.

Conclusion and Next Steps

Primary Indication — Feline Acquired Immunodeficiency Syndrome

Decision: Hold

Rationale: The mechanistic basis is plausible (~40% FIV/HIV integrase homology) and is supported by a single 2023 veterinary study, but the overall evidence base (L4) is insufficient for a repurposing decision — no controlled feline efficacy trial exists, and feline-specific PK/safety data is critically absent.

To proceed, the following is needed:

Feline-specific multi-dose PK study to validate the 2.5 mg/kg/day dose from PMID 37112803 and establish appropriate therapeutic drug monitoring thresholds
Randomised controlled efficacy trial in FIV-positive cats with virological and immunological endpoints
Long-term feline safety data (hepatotoxicity panel, haematology, neurological monitoring)
Assessment of veterinary pharmaceutical registration pathway under the Philippine FDA

Secondary Indication — Simian Immunodeficiency Virus Infection

Decision: Proceed with Guardrails

Rationale: Multiple NHP animal studies and structural biology evidence (L3) support DTG-containing cART efficacy against SIV, with the mechanistic basis substantially stronger than for the feline indication. The primary application context is translational HIV research and conservation medicine for captive great apes.