Didanosine
| 證據等級: L5 | 預測適應症: 3 個 |
目錄
Didanosine: From HIV-1 Infection to Simian Immunodeficiency Virus Infection
One-Sentence Summary
Didanosine (ddI) is a nucleoside reverse transcriptase inhibitor (NRTI) originally developed for the treatment of HIV-1 infection, a drug that has since been withdrawn from most markets worldwide. The TxGNN model predicts it may be effective for Simian Immunodeficiency Virus (SIV) Infection, with 0 clinical trials and 12 publications (all preclinical animal or in vitro studies) currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | HIV-1 infection (withdrawn from market; no India registration on record) |
| Predicted New Indication | Simian Immunodeficiency Virus (SIV) Infection |
| TxGNN Prediction Score | 99.33% |
| Evidence Level | L3 |
| India Market Status | ✗ Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the current Evidence Pack. Based on the repurposing rationale and known pharmacology, Didanosine is a nucleoside reverse transcriptase inhibitor (NRTI). It exerts its antiviral effect by being incorporated into the viral DNA chain, competitively inhibiting reverse transcriptase (RT) and terminating further DNA strand elongation — thereby blocking viral replication at a critical early step.
Simian Immunodeficiency Virus (SIV) belongs to the same lentivirus genus as HIV-1 and HIV-2, sharing a highly conserved RT catalytic domain. This structural homology makes the mechanistic extension from HIV to SIV scientifically plausible. PMID 9923010 (1998) provides the strongest direct evidence: ddI pretreatment significantly reduced acute viral load in SIVmac251-infected cynomolgus macaques and modulated both pro-inflammatory and anti-inflammatory cytokine profiles. PMID 15040537 further confirmed ddI’s in vitro susceptibility against multiple SIV and SHIV strains, and PMID 9282812 showed that ddI — but not high-dose hydroxyurea — rescued pigtail macaques from a lethal SIV(smmpbj14) challenge.
However, significant counterevidence constrains translation. PMID 22013040 documented fatal pancreatitis in SIVmac251-infected rhesus macaques treated with ddI plus stavudine following immune modulation. Additionally, the target indication (SIV infection) is an animal disease with no direct human clinical counterpart, the drug has been commercially withdrawn, and a burden of 153 documented drug-drug interactions further narrows any viable therapeutic window.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 9923010 | 1998 | Animal in vivo (macaque) | Research in Virology | ddI pretreatment significantly reduced SIVmac251 acute viral load and remodeled cytokine profiles (IL-6, TNF-α, IL-10) in cynomolgus macaques — strongest direct evidence |
| 9282812 | 1997 | Animal in vivo (macaque) | AIDS Research and Human Retroviruses | ddI (not high-dose hydroxyurea) rescued pigtail macaques from lethal SIV(smmpbj14); combination therapy tested |
| 15040537 | 2004 | In vitro / Comparative | Antiviral Therapy | ddI showed antiviral activity against SIV mac251, SIV B670, and SHIV strains; provides cross-species susceptibility data relevant to treatment and PEP guidance |
| 22013040 | 2012 | Animal in vivo (macaque) — Safety | Journal of Virology | Fatal pancreatitis observed in SIVmac251-infected macaques on ddI + stavudine after CTLA-4/IDO blockade; critical safety signal for ddI use in lentiviral infection |
| 11090360 | 2000 | Animal RCT (macaque) | Science | Structured treatment interruption with HAART (including ddI) in acute SIV-infected macaques enhanced virus-specific T-cell responses and controlled viral rebound |
| 14965468 | 2004 | Animal — Biomarker | DNA and Cell Biology | TREC analysis in SHIV89.6p and SIVmac251 models treated with ART regimens including ddI; evaluates TREC as immune reconstitution surrogate marker |
| 15182307 | 2004 | Animal — Pathomechanism | European Journal of Neuroscience | A ddI-class nucleoside (6-Cl-ddG) lowered brain viral burden and IDO expression in lentivirus-infected rhesus monkeys; contextual evidence for CNS effects of NRTIs in SIV |
| 11435599 | 2001 | In vitro | Journal of Virology | Dideoxynucleosides (including ddI) tested against human foamy virus (a simian-origin retrovirus); only AZT showed equivalent activity against both HIV and HFV |
| 8554904 | 1995 | In vitro model | AIDS Research and Human Retroviruses | Human thymic organ culture model for HIV/SIV pathogenesis; ddI used as reference antiretroviral in validating the model system |
| 8870848 | 1996 | Animal — Pathomechanism | AIDS Research and Human Retroviruses | Cytokine mRNA expression across tissues during acute SIVmac251 infection; provides baseline immunological context for evaluating ddI treatment effects |
India Market Information
Didanosine is currently not marketed in India. No product registrations are on record.
Safety Considerations
Drug Interactions: Didanosine has 153 documented drug interactions in total. A representative sample is shown below:
| Severity | Interacting Drug(s) |
|---|---|
| Moderate | Acetylsalicylic acid, Metronidazole, Levofloxacin, Naltrexone, Nitisinone, Orlistat, Rosuvastatin, Simvastatin, Tinidazole |
| Minor | Ranitidine, Doxycycline, Minocycline, Tetracycline, Ranitidine (bismuth citrate) |
| Unknown | Levocarnitine, Amphotericin B, Pantoprazole, Glimepiride, Morphine, Metformin |
This high interaction burden (153 total) warrants thorough medication reconciliation in any proposed use. For complete warnings and contraindications, please refer to the original product package insert.
Conclusion and Next Steps
Decision: Hold
Rationale: Despite a high TxGNN score (99.33%) grounded in the conserved lentiviral RT structure, all supporting evidence is preclinical — no human or veterinary clinical trials exist — and a documented fatal pancreatitis signal in the SIV animal model, combined with the drug’s commercial withdrawal and 153 known drug-drug interactions, makes further clinical translation infeasible without substantial additional investigation.
To proceed, the following is needed:
- Clarification of clinical intent: SIV is an animal disease; if the goal is cross-species HIV research utility, reframe the research question accordingly
- Retrieval of full MOA and package insert data to characterize the pancreatitis risk and determine whether it is dose- or combination-dependent
- Assessment of whether a reformulated or lower-dose ddI regimen could reduce the pancreatitis risk observed in PMID 22013040
- A systematic review or meta-analysis of all NRTI activity across lentivirus strains to position ddI relative to current agents
- Regulatory feasibility assessment given the drug’s withdrawn status in most jurisdictions
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.