Dolutegravir
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Dolutegravir: From HIV Infection to Simian Immunodeficiency Virus Infection
One-Sentence Summary
Dolutegravir is an HIV integrase strand transfer inhibitor, originally used to treat HIV infection and AIDS. The TxGNN model predicts it may be effective for simian immunodeficiency virus (SIV) infection, with no registered clinical trials and 14 publications (mostly animal and in vitro studies) currently supporting this direction. This is essentially a preclinical or veterinary model of the already-approved HIV indication, not a new human indication.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | HIV infection / AIDS (taken from the knowledge-graph indication data; the Singapore licence records contain no indication text) |
| Predicted New Indication | Simian immunodeficiency virus infection |
| TxGNN Prediction Score | 99.85% |
| Evidence Level | L3 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 4 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the data compiled for this report. Based on known information, dolutegravir is an integrase strand transfer inhibitor (INSTI) used as part of HIV combination therapy. Its efficacy in HIV infection is established, and mechanistically it may be applicable to SIV infection.
SIV is a lentivirus closely related to HIV and carries a homologous integrase enzyme. Studies in macaques and cell culture show that dolutegravir inhibits SIV integrase and has antiviral activity. They also show that SIV develops resistance mutations similar to those seen in HIV, including during dolutegravir monotherapy in macaques.
SIV infection of macaques is mainly used as a research model for HIV. The prediction is therefore biologically sensible, but it restates the approved HIV indication in an animal setting. It does not point to a new treatment for human disease.
Other predictions in the list are weaker or not relevant to human repurposing:
- Feline AIDS (FIV): a single veterinary combination-therapy study.
- AIDS-related complex and congenital HIV: population or terminology extensions of the existing HIV indication.
- Hepatitis C, hepatitis A, hepatitis E: no antiviral mechanism. The evidence concerns drug interactions with HIV co-infection or is unrelated.
- Familial combined hyperlipidaemia and a rare neurodevelopmental disorder: no mechanistic link and no evidence. These are likely network artifacts.
Clinical Trial Evidence
Currently no related clinical trials registered for the predicted indication (SIV infection).
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 30381490 | 2019 | Animal study | J Virol | Dolutegravir monotherapy in SIV-infected macaques selected several resistance-mutation patterns, with variable virological outcomes |
| 28923862 | 2017 | In vitro/animal | Antimicrob Agents Chemother | Bictegravir and cabotegravir activity against integrase-inhibitor-resistant SIVmac239 and HIV-1 |
| 25583721 | 2015 | Preclinical model | Antimicrob Agents Chemother | Simian-tropic HIV proposed as a model for studying integrase inhibitor resistance |
| 24920794 | 2014 | In vitro | J Virol | HIV integrase resistance mutations introduced into SIVmac239 changed susceptibility to integrase inhibitors including dolutegravir |
| 26378179 | 2015 | In vitro | J Virol | Tissue-culture selection with INSTIs in SIVmac239 yielded resistance profiles comparable to HIV |
| 36365101 | 2022 | Animal PK study | Pharmaceutics | Pharmacological validation of long-term tenofovir, emtricitabine and dolutegravir treatment in SIV-infected non-human primates |
| 26150024 | 2016 | Animal study | AIDS Res Hum Retroviruses | Comparison of coformulated injectable ART regimens in SIV-infected rhesus macaques |
| 34903055 | 2021 | Animal study | mBio | Lentiviruses persist in the brain despite effective ART |
| 41959211 | 2026 | Animal study (preprint) | bioRxiv | SIV and ART alter brain lipid distribution in rhesus macaques |
| 32506843 | 2021 | Review | FEBS J | HIV/SIV intasome structures explain integrase inhibitor binding and viral escape |
No randomised controlled trials in humans exist for this predicted indication.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16504P | TIVICAY Dispersible Tablet 5 mg | Tablet, for suspension | Not stated in the available data |
| SIN14579P | TIVICAY Tablet 50 mg | Tablet, film coated | Not stated in the available data |
| SIN15989P | DOVATO Film-Coated Tablet 50 mg/300 mg | Tablet, film coated | Not stated in the available data |
| SIN15100P | TRIUMEQ Film-Coated Tablet 50 mg/600 mg/300 mg | Tablet, film coated | Not stated in the available data |
All four licences are valid, and all products are oral formulations.
Safety Considerations
- Drug Interactions: 62 interactions are recorded. The main ones are:
- Major (polyvalent cation products): aluminium hydroxide, magaldrate, kaolin, attapulgite, calcium salts (acetate, carbonate, citrate, gluconate, lactate, phosphate, glubionate), magnesium salts (carbonate, chloride, citrate) and iron. These products can reduce dolutegravir absorption, so dosing needs to be separated in time.
- Minor: aprepitant, cimetidine, clarithromycin, clotrimazole, dexamethasone.
- Pregnancy signal (from the literature on congenital HIV): early surveillance in Botswana raised a possible neural tube defect signal with dolutegravir exposure at conception. Later meta-analyses and pharmacovigilance analyses did not definitively confirm it. This remains relevant for women of child-bearing potential.
- Metabolic effects: studies report weight gain and adipose tissue changes with integrase inhibitors, including dolutegravir.
For other warnings and contraindications, please refer to the package insert.
Conclusion and Next Steps
Decision: Hold
Rationale: The SIV prediction is mechanistically plausible and well supported by animal and in vitro work. However, it is an animal model of the already-approved HIV indication, with no clinical trials, and it offers no new therapeutic opportunity for human patients. The other top-ranked predictions are either population extensions of the HIV indication or lack mechanism and evidence.
To proceed, the following is needed:
- A defined human use case, since SIV and FIV are not human diseases
- Detailed mechanism of action data
- Package insert warnings and contraindications from the HSA, and approved indication text for the Singapore licences
- If congenital or perinatal HIV is pursued, a pregnancy safety review covering the neural tube defect signal and dosing in children
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.