Darunavir

證據等級: L5

預測適應症: 10 個

Darunavir: From HIV-1 Infection to Congenital HIV

One-Sentence Summary

Darunavir is a second-generation HIV-1 protease inhibitor used to treat HIV-1 infection in adults and children, with a well-established role in combination antiretroviral therapy (cART) regimens globally. The TxGNN model predicts it may be effective for Congenital HIV (prevention of mother-to-child transmission and treatment of perinatally infected individuals), with 23 clinical trials and 9 publications currently supporting this direction.

Note on prediction ranking: The highest-ranked TxGNN prediction (Rank 1: feline acquired immunodeficiency syndrome, 99.97%) is a veterinary condition with no direct clinical applicability to human patients — the sole trial retrieved was flagged as a data mapping error in the evidence review. This report therefore focuses on Congenital HIV (Rank 5, 98.97%), which carries the strongest human clinical evidence (L1) and the highest actionability recommendation among all predicted indications.

Quick Overview

Item	Content
Original Indication	HIV-1 infection (treatment-experienced adults and children ≥3 years)
Predicted New Indication	Congenital HIV (Mother-to-Child Transmission Prevention and Paediatric Treatment)
TxGNN Prediction Score	98.97%
Evidence Level	L1
Australia Market Status	Not marketed in Australia
Number of ARTG Entries	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data was not available in this Evidence Pack. Based on well-established medical literature, Darunavir is a nonpeptidic HIV-1 protease inhibitor (part of the second-generation protease inhibitor class) that binds with very high affinity to the active site of the HIV-1 protease enzyme. Its efficacy in HIV-1 infection has been extensively proven across numerous Phase 3 clinical trials, and it is approved by the US FDA, EMA, and WHO as an essential medicine. Mechanistically, darunavir prevents the cleavage of HIV Gag and Gag-Pol polyprotein precursors, blocking viral maturation and the production of infectious viral particles — and this mechanism is directly applicable to any HIV-1-related indication.

The connection between darunavir’s established adult HIV-1 indication and congenital HIV is mechanistically direct: both involve the same pathogen (HIV-1). Congenital HIV refers to vertical (mother-to-child) transmission occurring in utero, during labour and delivery, or through breastfeeding. Darunavir’s role in this context operates on two fronts: first, as part of the mother’s Prevention of Mother-to-Child Transmission (PMTCT) regimen to maximally suppress maternal viral load before and during delivery; and second, as a component of treatment regimens for perinatally infected infants and children. The dedicated Phase 2 PMTCT trial NCT02738502 directly evaluated a darunavir/ritonavir-based strategy without NRTIs in pretreated pregnant women.

A clinically important consideration is that darunavir plasma concentrations are meaningfully reduced during pregnancy — particularly in the third trimester — compared with postpartum levels. Pharmacokinetic studies in HIV-positive pregnant women (PMID 25326090; NCT00855335; NCT00042289) have quantified this effect and provide the evidence base for dose adjustment guidance. The TxGNN prediction score of 98.97% aligns with this rich clinical evidence base and represents a clinically meaningful extension of the drug’s known indication into the PMTCT and paediatric HIV treatment space.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrolment	Key Findings
NCT02738502	Phase 2	Completed	91	Feasibility study of darunavir/ritonavir monotherapy as a PMTCT strategy without any NRTIs in pretreated pregnant women, combined with neonatal nevirapine prophylaxis; directly addresses congenital HIV prevention
NCT00855335	Phase 3	Completed	77	Characterised the pharmacokinetics of darunavir/ritonavir and darunavir/cobicistat in HIV-1 infected pregnant women; demonstrated reduced exposure in the third trimester, supporting the need for dose adjustment
NCT00042289	Phase 4	Completed	1,578	Prospective PK evaluation of ARVs including darunavir in pregnant women and their infants (IMPAACT P1026s); the largest maternal ARV pharmacokinetic dataset available
NCT04518228	N/A	Completed	205	Evaluated PK of ARV and anti-TB drugs during pregnancy and postpartum, including darunavir-containing regimens in co-infected women
NCT02269917	Phase 3	Completed	1,149	Large RCT demonstrating non-inferiority of switching to D/C/F/TAF single-tablet regimen in virologically suppressed HIV-1 adults; establishes robust efficacy of the boosted darunavir backbone
NCT02431247	Phase 3	Completed	725	D/C/F/TAF vs darunavir/cobicistat + FTC/TDF in ARV-naive adults; confirms the efficacy of darunavir as a foundation agent for treatment initiation
NCT02275780	Phase 3	Completed	769	Double-blind RCT of doravirine vs darunavir/ritonavir in treatment-naive HIV-1 infection; darunavir/r served as active comparator, reinforcing its role as a benchmark first-line agent
NCT01281813	Phase 3	Completed	145	Continued access to darunavir/ritonavir in adults and paediatric patients (≥3 years) in countries where darunavir was commercially unavailable; includes paediatric dosing and safety data
NCT06747507	Phase 3	Recruiting	392	Randomised trial of maintaining dolutegravir vs switching to ritonavir-boosted darunavir in patients with DTG-associated resistance mutations; supports darunavir’s role as a second-line and salvage option
NCT02429791	Phase 3	Completed	510	Non-inferiority RCT of DTG+RPV switch from PI-based regimens (including darunavir); reinforces the breadth of the evidence ecosystem supporting antiretroviral sequencing decisions

Literature Evidence

PMID	Year	Type	Journal	Key Findings
38788744	2024	RCT	The Lancet HIV	D2EFT trial: dolutegravir plus boosted darunavir demonstrated non-inferiority to standard second-line ART after NNRTI failure across diverse global settings; highest-tier evidence for darunavir in second-line use
38864586	2024	Cohort	AIDS	US cohort characterising congenital anomaly rates following first-trimester exposure to newer ARVs including darunavir; key safety data for PMTCT regimen selection
25326090	2015	PK Study	J Antimicrobial Chemotherapy	Total and unbound darunavir pharmacokinetics in HIV-infected pregnant women in the third trimester and postpartum; demonstrates significant reduction in exposure during pregnancy
20587860	2010	Case Series	Antiviral Therapy	Two cases of darunavir (with etravirine and/or raltegravir) use in treatment-experienced pregnant women; earliest published evidence of darunavir feasibility in pregnancy
35809963	2022	Case Report	Chest	28-year-old man with congenital HIV presenting with bilateral pulmonary nodules; illustrates long-term clinical complexity in perinatally infected adults receiving ART throughout life
34151853	2021	Case Report	J Neuromuscular Diseases	Inflammatory myositis secondary to ART in a 5-year-old child with congenital HIV on a darunavir-containing regimen; important paediatric safety signal for musculoskeletal monitoring
33048878	2021	Cohort	AIDS	Risk of birth defects and adverse perinatal outcomes with integrase inhibitor exposure at conception; provides comparative safety context relevant to PMTCT regimen selection
31595301	2020	Pharmacovigilance	Clinical Infectious Diseases	Pharmacovigilance database analysis of dolutegravir safety signals in pregnancy (neural tube defect concern); contextualises the clinical rationale for darunavir-based alternatives in PMTCT
25172528	2015	Case Report	Arch Soc Esp Oftalmol	Retinal folds as a previously unreported adverse effect of darunavir in a 20-year-old HIV patient; highlights the importance of ophthalmological monitoring in young patients on long-term darunavir therapy

Australia Market Information

Darunavir has no current ARTG entries and is not registered with the Therapeutic Goods Administration (TGA) in Australia.

Use in Australian patients would require access through one of the following TGA pathways:

Special Access Scheme (SAS) – Category B: For individual patients where a clinician determines the drug is appropriate. Application submitted to TGA.
Authorised Prescriber Scheme: For clinicians treating a class of patients on a recurring basis.
Clinical Trial Import: For research use under a Clinical Trial Notification or Approval.

Darunavir (brand name Prezista®; also available as Symtuza® as a fixed-dose combination with cobicistat/emtricitabine/tenofovir alafenamide) is approved in the United States (FDA), European Union (EMA), and is included on the WHO Model List of Essential Medicines. Clinicians seeking access should contact the TGA at www.tga.gov.au or the manufacturer (Janssen-Cilag Pty Ltd) for the current Australian access pathway.

Safety Considerations

No safety data was available in this Evidence Pack for the Australian context. Please refer to the TGA-approved Product Information (PI) once registered, or consult the current FDA prescribing information (Prezista®) or EMA Summary of Product Characteristics for comprehensive safety data.

The following considerations are particularly relevant to the congenital HIV indication:

Pregnancy pharmacokinetics: Darunavir plasma exposure is significantly reduced in the third trimester; dose adjustment (e.g., twice-daily dosing) may be required and should be guided by therapeutic drug monitoring
Paediatric use: Weight-based dosing is required for children; minimum age and weight thresholds apply — consult current product labelling for specific paediatric dosing tables
Drug interactions: Darunavir requires a pharmacokinetic booster (ritonavir 100 mg or cobicistat 150 mg); as a potent CYP3A4 inhibitor and substrate, it has numerous clinically significant interactions with other medications commonly used in pregnancy and paediatric care
Sulfonamide allergy: Darunavir contains a sulfonamide moiety; use with caution in patients with known sulfonamide allergy

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Multiple completed Phase 2/3 clinical trials — including a dedicated PMTCT study (NCT02738502, n=91) and large Phase 3 RCTs establishing the darunavir backbone (NCT02269917, n=1,149; NCT02275780, n=769) — combined with robust pharmacokinetic data in pregnant women, provide a strong foundation for darunavir’s use in congenital HIV prevention and treatment. The TxGNN prediction score (98.97%) is consistent with this clinical evidence base. The principal barrier to use in Australia is the absence of TGA registration, not a lack of clinical evidence.

To proceed, the following is needed:

Submit a TGA Special Access Scheme (SAS Category B) application for darunavir, or explore the Authorised Prescriber pathway via an appropriate HIV specialist or clinical network
Obtain the complete manufacturer Product Information (PI) for safety, contraindication, and paediatric dosing details
Develop a pharmacokinetic monitoring plan for pregnant patients, including third-trimester dose adjustment protocols
Establish a paediatric dosing and monitoring protocol for perinatally infected infants and children, aligned with current WHO and PENTA (Paediatric European Network for Treatment of AIDS) guidelines
Consult ASHM (Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine) for local clinical pathway guidance and expert endorsement
Confirm reliable supply chain access to cobicistat or ritonavir as required pharmacokinetic boosters
Address the formal MOA data gap (DrugBank DB01264 query) to complete the mechanism of action documentation for regulatory submissions

Disclaimer: This report is for research reference only and does not constitute medical advice. Drug repurposing candidates require clinical validation before application. All predictions should be interpreted in the context of individual patient assessment by qualified healthcare professionals.

Disclaimer

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