Darunavir

證據等級: L5

預測適應症: 10 個

Darunavir: From HIV-1 Infection to Congenital Human Immunodeficiency Virus

One-Sentence Summary

Darunavir is a second-generation HIV-1 protease inhibitor used as part of combination antiretroviral therapy (cART) for HIV-1 infection in adults and pediatric patients. The TxGNN model predicts it may be effective for Congenital Human Immunodeficiency Virus (perinatally transmitted HIV), with 23 clinical trials and 9 publications currently supporting this direction.

Prediction Landscape Note: Among the 10 TxGNN predictions in this report, Congenital HIV (Rank 5) carries the strongest clinical evidence (L1) and is the primary focus of this evaluation. The top-scoring predictions by TxGNN score — feline AIDS (Rank 1) and SIV infection (Rank 2) — reflect knowledge-graph topological proximity rather than direct clinical applicability; both are assessed in the Conclusion section.

Quick Overview

Item	Content
Original Indication	HIV-1 infection (combination antiretroviral therapy)
Predicted New Indication	Congenital Human Immunodeficiency Virus
TxGNN Prediction Score	98.97%
Evidence Level	L1
EU Market Status	Not marketed (0 authorizations on record)
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available in this Evidence Pack (Data Gap DG002). Based on well-established pharmacological knowledge, Darunavir is a second-generation HIV-1 protease inhibitor that competitively inhibits the viral aspartyl protease enzyme responsible for cleaving the Gag and Gag-Pol polyprotein precursors. This cleavage is essential for HIV-1 maturation; inhibiting it produces structurally immature, non-infectious viral particles. Darunavir binds the protease active site with exceptionally high affinity, maintaining activity against many drug-resistant variants. It is always co-administered with a pharmacokinetic booster — ritonavir or cobicistat — to slow hepatic metabolism and sustain therapeutic plasma concentrations.

Congenital HIV (perinatal HIV) results from mother-to-child transmission (MTCT) of HIV-1 during pregnancy, delivery, or breastfeeding. Because the causative pathogen is the same HIV-1 virus, Darunavir’s mechanism is directly applicable without any mechanistic extrapolation. Prevention of MTCT requires effective viral suppression in the mother and, in some protocols, prophylactic treatment of the neonate — both targets that Darunavir-based regimens address. The drug is already included in WHO, DHHS (US), and EACS (Europe) guidelines for treatment-experienced pregnant women, particularly when NNRTI resistance or prior therapy failure complicates first-line options.

The 23 clinical trials identified span Phase 2 to Phase 4, including large Phase 3 RCTs with up to 1,578 participants specifically in pregnant and perinatal populations. This depth of evidence places congenital HIV firmly at L1 and makes the TxGNN prediction score of 98.97% both mathematically high and biologically sound — unlike several other high-scoring predictions in this set that are topological artifacts of the knowledge graph.

Clinical Trial Evidence

Based on the congenital HIV indication (Rank 5), which carries the strongest evidence in this dataset.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02738502	Phase 2	Completed	91	Darunavir/ritonavir monotherapy as NRTI-sparing PMTCT strategy in treatment-experienced pregnant women; neonatal nevirapine prophylaxis assessed
NCT00855335	Phase 3	Completed	77	Pharmacokinetics of DRV/ritonavir and DRV/cobicistat in HIV-1 infected pregnant women; defines dose adjustment rationale for perinatal use
NCT04518228	N/A	Completed	205	PK of ARV and anti-TB drugs during pregnancy and postpartum; supports safety evidence base for perinatal Darunavir
NCT06747507	Phase 3	Recruiting	392	RCT: optimal management of dolutegravir resistance — switch to boosted Darunavir as comparator; includes perinatally infected adolescents
NCT02269917	Phase 3	Completed	1,149	D/C/F/TAF single-tablet switch vs boosted PI + FTC/TDF in virologically suppressed HIV-1; largest RCT in dataset, provides efficacy/safety floor
NCT02431247	Phase 3	Completed	725	D/C/F/TAF non-inferiority vs DRV/COBI + FTC/TDF in ARV-naïve HIV-1 patients; registrational trial for Symtuza
NCT02275780	Phase 3	Completed	769	Doravirine vs Darunavir/ritonavir (active comparator) in treatment-naïve HIV-1; 96-week double-blind RCT
NCT01281813	Phase 3	Completed	145	Continued access to DRV/rtv in adults, adolescents, and children ≥3 years in countries without commercial access; direct pediatric/congenital HIV data
NCT00042289	N/A	Completed	1,578	IMPAACT P1026s: prospective PK evaluation of ARV drugs in pregnant women and infants; largest perinatal ARV cohort
NCT04442737	Phase 4	Completed	103	Switch to D/C/F/TAF in virologically suppressed patients experiencing rapid weight gain on INI + TAF/FTC; metabolic safety data

Literature Evidence

PMID	Year	Type	Journal	Key Findings
38788744	2024	RCT	The Lancet HIV	D2EFT trial (Phase 3b/4): dolutegravir + boosted Darunavir vs standard second-line ART after NNRTI failure across diverse global settings
38864586	2024	Cohort Study	AIDS	First-trimester exposure to newer ARVs and congenital anomalies in US cohort of HIV-positive persons; Darunavir safety signal assessment
33048878	2021	Cohort Study	AIDS	INSTI exposure at conception and birth defects/perinatal outcomes in French national cohort; comparative safety benchmark for PI-based regimens
31595301	2020	Pharmacovigilance	Clin Infect Dis	Multi-database pharmacovigilance analysis of ARV safety in pregnancy, including PI class; neural tube defect signal investigation
25326090	2015	PK Cohort	J Antimicrob Chemother	Darunavir total and unbound PK in HIV-1 infected pregnant women in third trimester vs postpartum; pregnancy reduces exposure by ~30%
20587860	2010	Cohort Study	Antiviral Therapy	Darunavir + etravirine ± raltegravir in two highly treatment-experienced pregnant women; demonstrates feasibility of PI salvage regimens in PMTCT
35809963	2022	Case Report	Chest	28-year-old with congenital HIV presenting with bilateral pulmonary nodules; illustrates long-term disease complications in perinatally infected adults
34151853	2021	Case Report	J Neuromuscular Dis	Inflammatory myositis in a 5-year-old with congenital HIV on ARV therapy; highlights pediatric safety monitoring requirements
25172528	2015	Case Report	Arch Soc Esp Oftalmol	Retinal folds as previously unreported adverse effect of Darunavir in a 20-year-old HIV patient; ophthalmologic safety signal

EU Market Information

No EU authorization data is available in the current dataset (0 licenses recorded; regulatory field shows no marketing authorizations on file).

This likely reflects a data gap rather than true absence of regulatory approval. Darunavir (brand name Prezista®, Janssen-Cilag) has received EMA marketing authorization for HIV-1 treatment in adults and pediatric patients ≥3 years of age; EU authorization status should be verified directly through the EMA product database.

Safety Considerations

Please refer to the SmPC for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails (for Congenital HIV indication)

Rationale: Darunavir’s mechanism directly targets HIV-1 protease — the same pathogen responsible for congenital HIV — and multiple completed Phase 3 RCTs, along with extensive perinatal pharmacokinetic data, confirm both efficacy and feasibility in pregnant women and pediatric patients. The drug is already embedded in international PMTCT guidelines, making this a de facto indication extension rather than a novel repurposing hypothesis.

Full Prediction Landscape Assessment:

Rank	Indication	Evidence Level	Decision
5	Congenital Human Immunodeficiency Virus	L1	Proceed with Guardrails
6	AIDS Related Complex	L2	Research Question
2	Simian Immunodeficiency Virus Infection	L4	Research Question (animal model only)
1	Feline Acquired Immunodeficiency Syndrome	L5	Hold — false positive (human HIV trial mismatched by semantic similarity)
3	Neurodevelopmental disorder with ataxic gait / absent speech	L5	Hold — no biological rationale; graph topology artifact
4	Familial Combined Hyperlipidemia (obsolete term)	L5	Hold — obsolete ontology term; lipid effect is an adverse reaction, not a therapeutic target
7–10	Fibroma of prostate / Brenner tumor / Benign reproductive neoplasms	L5	Hold — cluster of graph diffusion false positives; no clinical data

To proceed, the following is needed:

EMA authorization verification: Confirm Darunavir (Prezista®) EU marketing authorization scope, including pediatric indications and boosted formulation (Symtuza® D/C/F/TAF), directly from EMA EPAR
TFDA SmPC: Retrieve contraindications, warnings, and DDI data from the Taiwan SmPC (Data Gap DG001 — currently Blocking for safety pre-screening)
MOA data: Query DrugBank API for Darunavir (DB01264) mechanism of action details (Data Gap DG002)
Perinatal dosing plan: Confirm current weight-based dosing recommendations for children ≥3 years and neonatal prophylaxis protocols (refer to IMPAACT P1026s data from NCT00042289)
AIDS Related Complex follow-up: For the L2 ARC indication, CNS penetration data for Darunavir is needed; NCT02503462 was terminated early (n=7) and cannot support conclusions — a new well-powered study is required before advancing this indication
Pharmacovigilance monitoring: Establish a post-authorization safety monitoring plan covering ophthalmologic (retinal fold signal PMID 25172528), musculoskeletal (myositis signal PMID 34151853), and metabolic parameters for long-term congenital HIV patients
Disclaimer

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