Raltegravir
| Evidence Level: L4 | Predicted Indications: 3 |
Table of Contents
Raltegravir: From HIV Infection to Simian Immunodeficiency Virus Infection
One-Sentence Summary
Raltegravir is an HIV-1 integrase inhibitor, originally used to treat HIV infection and AIDS. The TxGNN model predicts it may be effective for simian immunodeficiency virus infection, but this is an animal-model pathogen rather than a human disease. Currently there are 0 clinical trials and 15 publications (mostly preclinical) supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | HIV infectious disease; AIDS |
| Predicted New Indication | Simian immunodeficiency virus infection |
| TxGNN Prediction Score | 99.78% |
| Evidence Level | L4 |
| US Market Status | Cancelled only (all listed licenses are cancelled) |
| Number of NDAs | 3 |
| 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 pharmacology, raltegravir is an integrase strand transfer inhibitor (INSTI). It blocks the step in which viral DNA is integrated into the host genome.
SIV is a close lentiviral relative of HIV-1, and its integrase is highly conserved. This makes it plausible that raltegravir acts on SIV in the same way. Studies in rhesus macaques and in cell culture (SIVmac251 and SIVmac239) show that raltegravir is active against SIV and that resistance mutations resemble those seen in HIV.
An important caveat is that SIV is a pathogen of non-human primates and a research model, not a human disease. The prediction therefore supports using raltegravir in preclinical HIV research models. It does not point to a new human indication.
The other predictions are weaker:
- Feline acquired immunodeficiency syndrome (score 99.78%): a veterinary condition with no trials or literature. The score probably reflects shared lentiviral classification.
- Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter (score 99.77%): no credible mechanistic link, and likely a knowledge-graph artifact.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
All publications below are preclinical (animal or in vitro). The compiled data contains 15 publications in total, and the 10 most relevant are listed.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 20233398 | 2010 | Preclinical (in vitro/animal) | Retrovirology | An antiretroviral regimen of two NRTIs plus raltegravir was developed for SIVmac251-infected macaques, providing a simian AIDS treatment and a model of viral persistence |
| 22737073 | 2012 | Preclinical | PLoS Pathogens | Highly intensified multidrug ART induced long-term viral suppression and restricted the viral reservoir in SIV-infected macaques |
| 29643246 | 2018 | Preclinical (animal model) | Journal of Virology | Studied 2-LTR circle dynamics in SIV-infected macaques treated with an integrase inhibitor, with and without CD8+ cells |
| 29466356 | 2018 | Preclinical (animal model) | PLoS One | Two SIV-infected macaques on tenofovir/emtricitabine intensified with raltegravir showed viral rebound and multiple resistance mutations under non-suppressive ART |
| 24622515 | 2014 | Preclinical (animal model) | Science Translational Medicine | Topical integrase inhibitors given after exposure protected macaques from vaginal SHIV infection |
| 24920794 | 2014 | Preclinical (in vitro) | Journal of Virology | Tested how HIV integrase resistance mutations, once introduced into SIVmac239, change susceptibility to INSTIs |
| 26378179 | 2015 | Preclinical (in vitro) | Journal of Virology | Characterized the resistance profiles of INSTIs in SIVmac239 |
| 25583721 | 2015 | Preclinical (in vitro) | Antimicrobial Agents and Chemotherapy | Used simian-tropic HIV as a model to study resistance to integrase inhibitors |
| 34903055 | 2021 | Preclinical (animal model) | mBio | Lentiviral infection persisted in the brain despite effective ART in human and animal models |
| 32166319 | 2020 | Preclinical (in vitro) | Clinical Infectious Diseases | Dolutegravir and raltegravir showed proadipogenic and profibrotic effects and induced insulin resistance in human and simian adipose tissue (a safety-related finding) |
US Market Information
The approved indication text is not available in the compiled data. All three licenses are cancelled.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA203045 | ISENTRESS (Merck Sharp & Dohme LLC) | Chewable tablet | Not available (status: cancelled) |
| NDA022145 | ISENTRESS (Proficient Rx LP) | Film-coated tablet | Not available (status: cancelled) |
| NDA205786 | ISENTRESS (Merck Sharp & Dohme LLC) | Granules for suspension | Not available (status: cancelled) |
Safety Considerations
- Knowledge-graph contraindication signals (not from label text): myopathy, muscular disease, skeletal muscle disease, familial periodic paralysis, rhabdomyolysis, and nodular fasciitis.
- Drug Interactions: 36 interactions were identified in total. The 20 listed in the compiled data are summarized below.
- Major: zinc sulfate, zinc acetate, aluminum hydroxide, calcium carbonate. These are polyvalent cation products and antacids, which can chelate integrase inhibitors and reduce absorption.
- Moderate: magnesium oxide, magnesium sulfate, magnesium chloride, orlistat.
- Minor: acid-suppressing agents (famotidine, ranitidine, cimetidine, nizatidine, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole), pioglitazone, and dexamethasone.
- A preclinical study also suggested possible adipose tissue and insulin resistance effects (PMID 32166319).
Please refer to the package insert for label warnings and contraindications, which are not available in the compiled data.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The evidence is limited to preclinical studies (L4), with no clinical trials. SIV is an animal-model virus, not a human disease, so this prediction does not translate into a human repurposing opportunity. Raltegravir’s marketed HIV use is already established, and all of its US licenses in the data are cancelled.
To proceed, the following is needed:
- Redefine the goal. SIV-related findings are best used to support preclinical HIV research models, not a new human indication.
- Obtain the FDA package insert warnings and contraindications. This is a blocking gap for safety screening.
- Obtain the mechanism of action data from DrugBank.
- Confirm current US marketing status, since all three listed licenses are cancelled.
- Do not pursue feline AIDS or the neurodevelopmental disorder prediction without new evidence, since no supporting data or credible mechanism was found.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.