Rilpivirine

Evidence Level: L4

Predicted Indications: 3

Rilpivirine

Pharmacist Assessment Report

Rilpivirine: From HIV Infection to Simian Immunodeficiency Virus Infection

One-Sentence Summary

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) originally used to treat HIV infection and AIDS. The TxGNN model predicts it may be effective for simian immunodeficiency virus infection, a macaque model of HIV. Support is limited to 0 clinical trials and 5 preclinical or review publications. This is essentially a confirmation of the existing HIV indication, not a new human indication.

Quick Overview

Item	Content
Original Indication	HIV infectious disease; AIDS (the Health Canada licence records contain no indication text)
Predicted New Indication	Simian immunodeficiency virus infection
TxGNN Prediction Score	0.9997
Evidence Level	L4 (preclinical studies only)
Canada Market Status	Marketed (marketed DINs: 6 of 6)
Number of DINs	6 (marketed: 6)
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, rilpivirine is an NNRTI that inhibits HIV-1 reverse transcriptase. Its efficacy in HIV infection is established, and it is marketed alone and in combination products in Canada.

Simian immunodeficiency virus (SIV) and chimeric SHIV infections in macaques are the standard preclinical surrogates for HIV. A prediction here is therefore expected, but it supports the original indication rather than a genuinely new one. SIV is naturally resistant to NNRTIs, so these models use SHIV carrying HIV reverse transcriptase. The macaque studies of long-acting rilpivirine with cabotegravir report sustained virologic suppression, remission after early treatment, and a low frequency of resistant variants. This is preclinical animal evidence, not a human repurposing indication.

The other predictions are weaker:

Feline acquired immunodeficiency syndrome: only in vitro and structural comparisons of NNRTIs against feline immunodeficiency virus reverse transcriptase, which is generally less sensitive to NNRTIs. There are no clinical data in cats, and the relevance to human use is limited.
A rare neurodevelopmental disorder (ataxic gait, absent speech): no mechanistic link, no trials and no literature. The score of 0.9997 comes from the TxGNN model (deep learning) and may reflect similarities the model learned between related diseases, not biological evidence.
AIDS related complex and congenital HIV: both overlap with the existing HIV indication.

Clinical Trial Evidence

Currently no related clinical trials registered for the top predicted indication.

(For the fifth-ranked prediction, congenital HIV, one completed Phase 4 trial is listed, NCT04340388, with 10 participants. It studies dolutegravir and obesity or cardiovascular disease, not rilpivirine, and its relevance is low.)

Literature Evidence

PMID	Year	Type	Journal	Key Findings
39632836	2024	Preclinical (macaque SHIV)	Nature Communications	Early treatment with long-acting cabotegravir/rilpivirine plus oral emtricitabine/tenofovir alafenamide was studied for SHIV remission in macaques
26438501	2015	Preclinical (macaque)	Antimicrobial Agents and Chemotherapy	Long-acting rilpivirine selected drug-resistant variants at a low frequency in macaques infected with SIV containing HIV-1 reverse transcriptase
41370971	2026	Preclinical (PEP model)	EBioMedicine	Evaluated whether a single injection of long-acting cabotegravir/rilpivirine could serve as post-exposure prophylaxis in macaques
42040962	2026	Preclinical (macaque)	Research Square	Long-acting antiretrovirals (lenacapavir with cabotegravir) were studied in early-life SIV infection in newborn macaques; this is a preprint and rilpivirine is not the focus
29746267	2018	Review	Current Opinion in HIV and AIDS	Review of cabotegravir for antiretroviral therapy and prevention; focused on cabotegravir rather than rilpivirine

Canada Market Information

DIN	Product Name	Dosage Form	Approved Indication
02370603	EDURANT	Not specified	Not specified
02497247	CABENUVA	Not specified	Not specified
02497220	CABENUVA	Not specified	Not specified
02475774	JULUCA	Not specified	Not specified
02374129	COMPLERA	Not specified	Not specified

A sixth authorization, ODEFSEY (DIN 02461463), is also valid.

Safety Considerations

Contraindications recorded in the knowledge graph (not taken from label text): long QT syndrome, familial long QT syndrome, torsades de pointes, liver failure, liver disease, fatty liver disease, non-alcoholic steatohepatitis, kidney disease, chronic hepatitis B virus infection, lactic acidosis, Fanconi renotubular syndrome, hypophosphatemia, osteomalacia, rickets, gallbladder disease, pyoureter, obesity disorder, monogenic obesity and pathologic fracture. Several of these probably reflect other components of combination products (for example tenofovir) rather than rilpivirine alone.
Drug interactions: 100 interactions were found. The main Major interactions are acid-reducing agents (famotidine, ranitidine, cimetidine, omeprazole, esomeprazole, rabeprazole, dexlansoprazole), dexamethasone, and QT-related drugs (cisapride, dolasetron). Moderate interactions include clarithromycin, aprepitant, loperamide, antacids (aluminum hydroxide, calcium carbonate, magnesium oxide), clotrimazole, and several laxatives.
Pregnancy: the literature on long-acting cabotegravir/rilpivirine in pregnancy includes a case report in which rilpivirine concentrations were 70–75% lower than in non-pregnant individuals, so monitoring is warranted.

Please refer to the package insert for label warnings and contraindications.

Conclusion and Next Steps

Decision: Hold

Rationale: The top prediction is an animal model of HIV, the disease rilpivirine already treats, so it offers no new human indication. Evidence is preclinical only (L4) and there are no registered trials. The other predicted indications are either overlapping with HIV, veterinary, or unsupported.

To proceed, the following is needed:

A clear human indication that differs from existing HIV approvals; none is currently identified
Mechanism of action data
Package insert warnings and contraindications from Health Canada, which are currently missing and block safety screening
Product details (dosage form and approved indication text) for the Canadian licences
A dedicated analysis of QT prolongation risk and the major interactions with acid-reducing agents
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.