Raltegravir
| Evidence Level: L4 | Predicted Indications: 3 |
Table of Contents
Raltegravir: Simian immunodeficiency virus infection
One-Sentence Summary
Raltegravir is an HIV-1 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, a non-human primate disease. Support comes from 0 registered clinical trials and 15 publications, all preclinical (mostly macaque and in vitro studies).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Simian immunodeficiency virus infection |
| TxGNN Prediction Score | 0.9978 |
| Evidence Level | L4 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, raltegravir is an HIV-1 integrase strand transfer inhibitor. Its efficacy in HIV infection is established, and mechanistically it may be applicable to SIV.
SIV integrase is structurally close to HIV-1 integrase. Macaque studies show raltegravir-containing regimens suppress SIVmac251, and resistance-profiling studies show similar integrase mutation patterns in SIV and HIV. Raltegravir has also been used as a component of antiretroviral regimens in SIV and SHIV macaque models.
SIV infection is a non-human primate disease and an animal model for HIV. The prediction therefore mainly confirms the drug’s existing antiviral activity. It does not create a new human therapeutic opportunity beyond the current HIV indication.
Other predictions in the list are weaker:
- AIDS related complex and congenital HIV are subsets of HIV disease already covered by the approved indication. The congenital HIV literature is mostly pregnancy safety surveillance rather than efficacy.
- Feline AIDS is a veterinary indication with no supporting evidence.
- The remaining predictions (for example neurodevelopmental disorder, benign neoplasms, Brenner tumour, fibrocystic breast disease) have no identified mechanistic link and look like TxGNN model (deep learning) artefacts.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 20233398 | 2010 | Preclinical (macaque) | Retrovirology | Regimen of two NRTIs plus raltegravir was effective in SIVmac251-infected macaques, supporting a simian AIDS treatment model |
| 22737073 | 2012 | Preclinical (macaque) | PLoS Pathog | Highly intensified ART induced long-term viral suppression and restricted the viral reservoir in simian AIDS |
| 29643246 | 2018 | Preclinical (macaque) | J Virol | Studied 2-LTR circle dynamics in SIV-infected macaques given an integrase inhibitor, with and without CD8+ cells |
| 29466356 | 2018 | Preclinical (macaque) | PLoS One | Resistance mutations emerged in two macaques on non-suppressive tenofovir/emtricitabine with raltegravir |
| 24622515 | 2014 | Preclinical (macaque) | Sci Transl Med | Topical integrase inhibitors protected macaques after vaginal SHIV exposure |
| 34903055 | 2021 | Preclinical (macaque) | mBio | Lentiviral infection persisted in brain despite effective ART |
| 26378179 | 2015 | Preclinical (in vitro) | J Virol | Integrase inhibitor resistance profiles in SIVmac239 were similar to HIV |
| 24920794 | 2014 | Preclinical (in vitro) | J Virol | HIV integrase resistance mutations introduced into SIV altered susceptibility to integrase inhibitors |
| 25583721 | 2015 | Preclinical (in vitro) | Antimicrob Agents Chemother | Simian-tropic HIV proposed as a model for integrase inhibitor resistance |
| 32166319 | 2020 | Preclinical (in vitro) | Clin Infect Dis | Dolutegravir and raltegravir showed proadipogenic and profibrotic effects and induced insulin resistance in human and simian adipose tissue |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 10286J | Isentress | Tablet 400 mg (as potassium) | Not stated in the available record |
Safety Considerations
- Knowledge-graph contraindication signals (from drug-disease links, not label text): myopathy, muscular disease, skeletal muscle disease, familial periodic paralysis, rhabdomyolysis and nodular fasciitis. These warrant attention to muscle-related adverse effects.
- Drug Interactions (36 recorded; the main ones are listed below):
- Major: zinc sulfate, zinc acetate, aluminium hydroxide, calcium carbonate. These polyvalent cation products may reduce raltegravir absorption.
- Moderate: magnesium oxide, magnesium sulfate, magnesium chloride, orlistat.
- Minor: H2 blockers and proton pump inhibitors (for example famotidine, ranitidine, omeprazole, pantoprazole), pioglitazone and dexamethasone.
- Pregnancy: Cohort and surveillance data on integrase inhibitor exposure in pregnancy exist, including UK/Ireland surveillance of raltegravir. They are relevant to safety assessment only.
Please also refer to the TGA-approved Product Information (PI) for full warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The predicted indication is a non-human primate disease. Evidence is entirely preclinical (L4), with no registered clinical trials. It adds no new human indication beyond the approved HIV use.
- Other predicted indications are either subsets of existing HIV disease, veterinary, or unsupported computational predictions.
To proceed, the following is needed:
- Mechanism of action data (the available data lacks MOA).
- Label warnings and contraindications from the TGA Product Information.
- Approved indication text for the ARTG entry.
- Reframing the question toward a human-relevant use (for example, a defined clinical question in a specific HIV population), since the SIV prediction does not translate into a human repurposing opportunity.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.