Ritonavir
| Evidence Level: L4 | Predicted Indications: 3 |
Table of Contents
Ritonavir: Simian immunodeficiency virus infection
One-Sentence Summary
Ritonavir is an HIV protease inhibitor that is also widely used as a pharmacokinetic booster. Its original indications are HIV infection and AIDS, plus chronic hepatitis C as part of combination regimens. The TxGNN model predicts it may be effective for simian immunodeficiency virus (SIV) infection, but this is a non-human primate disease used as a research model. Support is limited to 0 clinical trials and 10 publications, mostly preclinical.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Simian immunodeficiency virus infection |
| TxGNN Prediction Score | 0.9992 |
| 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?
Currently, detailed mechanism of action data is not available. Based on known information, ritonavir is an HIV protease inhibitor and, at low doses, a CYP3A4 inhibitor used to boost other antivirals. Its efficacy in HIV infection is established, and mechanistically it may be applicable to SIV.
SIV is a lentivirus closely related to HIV, and its protease is inhibited by HIV protease inhibitors. An in vitro study found that ritonavir inhibited SIVmac239 with a half-maximal effective concentration (EC50) of about 13 nM, compared with about 25 nM against HIV-1. The high score (0.9992) comes from the TxGNN model (deep learning) and may reflect similarities the model learned between related diseases, not biological evidence.
SIV infection occurs in non-human primates and is a research model, not a human indication. The prediction therefore has little direct clinical applicability and is best read as support for ritonavir’s activity against lentiviruses.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
None of the publications is an RCT or human clinical study. The table lists the most relevant items and omits a few that are off-topic or have no abstract.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12709355 | 2003 | In vitro | Antimicrob Agents Chemother | SIVmac239 was inhibited by indinavir, saquinavir and ritonavir (ritonavir about 13 nM versus about 25 nM for HIV-1) |
| 15040537 | 2004 | In vitro | Antivir Ther | Compared 16 approved antivirals against HIV-2, SIV and SHIV to guide treatment and post-exposure prophylaxis |
| 22737073 | 2012 | Animal (macaque) | PLoS Pathog | A highly intensified multidrug ART regimen gave long-term viral suppression and restricted the viral reservoir in a simian AIDS model |
| 16973590 | 2006 | Animal (macaque) | J Virol | Quadruple ART produced rapid viral decay in SIVmac251-infected cynomolgus macaques |
| 25033210 | 2014 | Animal | PLoS One | Intensive cART plus the HDAC inhibitor SAHA in SIV-infected rhesus macaques, studying viral reservoirs |
| 34903055 | 2021 | Animal | mBio | Lentiviral infection persisted in the brain despite effective ART |
| 12951220 | 2003 | Animal | J Virol Methods | Oral HAART including lopinavir/ritonavir in SHIV-infected macaques, assessing effects on the CD8 subset |
| 17350308 | 2007 | Methods | Microbes Infect | Built a novel SHIV carrying the HIV-1 protease gene as a model for testing protease inhibitors in vivo |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 10273Q | Norvir | Tablet 100 mg | Not specified in the data compiled |
Safety Considerations
- Contraindication-related conditions (from the TxGNN knowledge graph, not label text): The graph links ritonavir to the following conditions. Several, such as long QT syndrome, pancreatitis, liver disease, cirrhosis, hyperglycaemia and diabetes, hyperlipidaemia and cardiac conduction disease, may warrant caution.
- Cardiac: long QT syndrome, torsades de pointes, sudden cardiac arrest, heart conduction disease, atrioventricular block, cardiomyopathy, coronary artery disease, myocardial ischaemia
- Hepatic and biliary: liver disease, cirrhosis, gallbladder disease, hyperbilirubinaemia, Gilbert syndrome, chronic hepatitis B
- Metabolic: diabetes mellitus, diabetic ketoacidosis, hyperglycaemia, hypertriglyceridaemia, familial combined hyperlipidaemia, gout, potassium deficiency
- Other: pancreatitis, haemophilia
- Drug interactions: 100 interactions are recorded, with the following examples.
- Major: loperamide, triamcinolone, budesonide
- Moderate: acarbose, metformin, alogliptin, canagliflozin, hydrocortisone, dexamethasone, betamethasone, bupropion, aprepitant, clarithromycin, metronidazole, alosetron, lorcaserin
Please also refer to the TGA-approved Product Information (PI) for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The predicted indication is an animal research model, with no registered clinical trials and only preclinical support (L4), so it is not a human repurposing opportunity. The very high score mainly reflects ritonavir’s known activity against lentiviral protease. Two other predictions in the same output are on-label extensions of the HIV indication. These are congenital HIV and AIDS-related complex, both at L1 and suitable for “Proceed with Guardrails”. They are worth reviewing separately.
To proceed, the following is needed:
- Re-prioritise the candidate list towards human indications, such as congenital HIV, rather than animal models
- Detailed mechanism of action data (MOA)
- The TGA Product Information (warnings, contraindications and approved indications) for the Norvir entry
- A review of the drug interaction burden before any new use
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.