Atazanavir

證據等級: L5

預測適應症: 10 個

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

One-Sentence Summary

Atazanavir (ATV) is a selective HIV-1 protease inhibitor, internationally approved for treatment of HIV-1 infection in adults and paediatric patients, though it is not currently registered in Australia. The TxGNN model predicts it may be effective for Congenital Human Immunodeficiency Virus (HIV acquired through mother-to-child vertical transmission), supported by multiple completed Phase 3 RCTs and 7 publications — including dedicated paediatric trials (PRINCE I & II) and pregnancy pharmacokinetic studies, placing overall evidence at L1.

Note on TxGNN ranking: The highest-scoring TxGNN predictions for this drug include veterinary or animal-model diseases (feline AIDS, SIV infection) and clinically obsolete terms, all assessed as Hold (L5). This report focuses on Congenital Human Immunodeficiency Virus (TxGNN Rank #5), which is the highest-ranked human disease indication with substantive clinical evidence and a Proceed with Guardrails recommendation.

Quick Overview

Item	Content
Original Indication	HIV-1 Infection (internationally approved; not registered in Australia)
Predicted New Indication	Congenital Human Immunodeficiency Virus
TxGNN Prediction Score	99.71%
Evidence Level	L1
Australia Market Status	Not marketed
Number of ARTG Entries	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Atazanavir is a highly selective inhibitor of HIV-1 aspartyl protease — an enzyme that cleaves viral polyproteins into functional structural components during the final stage of HIV replication. Without functional protease activity, HIV produces immature, non-infectious viral particles. ATV is typically co-administered with a pharmacokinetic booster (ritonavir or cobicistat) to achieve adequate and sustained plasma concentrations. While detailed mechanism of action data was not available in this Evidence Pack, ATV’s role as an HIV-1 protease inhibitor is extensively documented in international literature and regulatory submissions.

Congenital HIV refers to HIV-1 infection acquired through mother-to-child transmission (MTCT) — occurring in utero, perinatally during delivery, or postnatally through breastfeeding. The mechanistic case is direct: the HIV-1 protease targeted by ATV is identical regardless of whether the patient is an adult, a neonate, or a child with vertically acquired infection. Suppressing maternal viral load through effective antiretroviral therapy (ART) is the cornerstone of MTCT prevention, placing ATV squarely within this clinical pathway. Additionally, once a child acquires HIV congenitally, treatment with protease inhibitor-containing regimens follows the same virological principles as adult therapy.

The evidence base specifically supporting ATV in this population is notably robust. The PRINCE I (NCT01099579) and PRINCE II (NCT01335698) paediatric trials evaluated ATV powder plus ritonavir in children as young as 3 months, providing both safety and pharmacokinetic data for neonatal and infant populations. Dedicated pregnancy PK studies (NCT00326716; the large IMPAACT P1026s cohort, NCT00042289) characterise drug exposure across gestational trimesters, and SMARTT prospective cohort data (PMID 27242802) assess safety across multiple developmental domains in over 3,500 HIV-exposed uninfected infants. The TxGNN prediction reflects genuine mechanistic and clinical alignment between ATV’s established antiviral activity and the congenital HIV disease context.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrolment	Key Findings
NCT00272779	Phase 3	Completed	1,057	96-week head-to-head comparison of ATV/r vs LPV/r, each with TDF/FTC, in treatment-naïve HIV-1 subjects; established non-inferiority and confirmed ATV/r as a standard-of-care first-line regimen
NCT01335698	Phase 3	Completed	160	PRINCE II: safety, efficacy, and pharmacokinetics of ATV oral powder + ritonavir in HIV-infected children aged 3 months to under 11 years; directly informs paediatric/congenital HIV dosing
NCT01099579	Phase 3	Completed	82	PRINCE I: safety, tolerability, and PK of ATV oral powder + ritonavir in HIV-infected paediatric patients aged 3 months to under 6 years, including the youngest age cohort relevant to congenital HIV
NCT01691794	Phase 4	Completed	108	Prospective safety evaluation of ATV capsule + ritonavir in HIV-infected adolescents aged 6–18 years (≥15 kg); confirmed safety profile across the paediatric weight spectrum
NCT00326716	Phase 1	Completed	69	PK of ATV/r as part of HAART in HIV-1-infected pregnant women across trimesters; established dose adjustment guidance to ensure adequate foetal and maternal drug exposure
NCT00042289	N/A	Completed	1,578	IMPAACT P1026s: large prospective PK study of ARV drugs (including ATV) in pregnant women and their infants across multiple sites; the most comprehensive ARV pregnancy PK dataset available
NCT01910402	Phase 3	Completed	499	DTG/ABC/3TC vs ATV+RTV+TDF/FTC in HIV-1-infected ART-naïve women; ATV/r arm provides 48-week efficacy and safety data specifically in women of childbearing age
NCT02422797	Phase 3	Completed	518	Phase 3 RCT evaluating switch from PI-based regimen (including ATV/r) to dolutegravir + rilpivirine; validates ATV/r as the established PI comparator backbone for virological suppression
NCT02269917	Phase 3	Completed	1,149	D/C/F/TAF vs boosted PI + FTC/TDF (boosted PI class includes ATV/r) in virologically suppressed HIV-1 adults; largest switch trial contextualising ATV/r within current PI-based therapy
NCT02227238	Phase 3b	Completed	627	Dolutegravir vs LPV/r (with ATV/r as permitted active comparator) in treatment-failure HIV-1 adults on first-line therapy; reinforces ATV/r as an established second-line standard

Literature Evidence

PMID	Year	Type	Journal	Key Findings
27242802	2016	Prospective cohort	Frontiers in Immunology	PHACS SMARTT study: comprehensive safety assessment of in utero ARV exposure (including ATV) across metabolic, cardiac, neurological, and neurodevelopmental domains in >3,500 HIV-exposed uninfected infants at 22 US sites
25383770	2015	Cohort	JAMA Pediatrics	Congenital anomalies and prenatal ARV exposure in HIV-exposed uninfected infants; provides reassuring safety data for most antiretrovirals including ATV when used during pregnancy
40011239	2025	Case-control	European Journal of Clinical Pharmacology	Most recent European congenital anomaly registry analysis of fetal ARV exposure; evaluates teratogenicity signals using population-level surveillance data
24992294	2015	Cohort/PK study	Antiviral Therapy	ATV exposure remains therapeutically adequate during pregnancy irrespective of concurrent tenofovir use; supports current standard dosing recommendations in pregnant women
28459118	2016	Cross-sectional	Journal of AIDS and Immune Research	Newborn hearing screening outcomes in HIV-exposed uninfected infants from the SMARTT cohort; evaluates auditory safety of in utero ARV exposures
29859254	2018	In vitro/mechanistic	Reproductive Toxicology	ATV and ritonavir interactions with placental efflux transporters (ABCB1, ABCG2, ABCC2) in rats; first mechanistic study characterising transplacental transfer and foetal ATV exposure
31595301	2020	Pharmacovigilance/Review	Clinical Infectious Diseases	Pharmacovigilance database analysis of ARV safety in pregnancy; contextualises ATV within the broader landscape of antiretroviral teratogenicity and adverse event reporting

Australia Market Information

Atazanavir is not currently registered on the Australian Register of Therapeutic Goods (ARTG) and has no commercial availability in Australia.

ARTG Number	Product Name	Dosage Form	Approved Indication
—	Not registered	—	No ARTG entries exist for atazanavir

Clinicians in Australia requiring access to atazanavir may apply through the TGA Special Access Scheme (SAS Category B for individual patients, or Category C for unapproved use in clinical contexts). International product information — including the FDA-approved Reyataz® label and the EMA-approved summary of product characteristics — serves as the primary reference for dosing, safety, and monitoring guidance.

Safety Considerations

No specific safety data (key warnings, contraindications, or drug interaction records) were available in this Evidence Pack.

Please refer to the international Product Information (PI) for Atazanavir/Reyataz® (FDA or EMA-approved) for comprehensive safety information, and consult the TGA Special Access Scheme requirements for unapproved therapeutic goods.

Important clinical note for Australian prescribers: Atazanavir is internationally recognised to carry significant drug–drug interaction potential, including with proton pump inhibitors (PPIs; may reduce ATV absorption substantially), H₂-receptor antagonists (require dose separation and timing adjustments), antacids, and medications metabolised by CYP3A4 or UGT1A1. ATV also commonly causes asymptomatic unconjugated hyperbilirubinaemia (indirect bilirubin elevation), which is generally benign but can lead to jaundice. These interactions are particularly relevant in the congenital/neonatal setting given the polypharmacy frequently encountered in HIV-positive mothers and in co-managed paediatric patients.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Multiple completed Phase 3 RCTs — including the dedicated PRINCE I and PRINCE II paediatric trials, large-scale pregnancy pharmacokinetic studies, and head-to-head adult trials establishing ATV/r as a standard-of-care regimen — provide L1 evidence directly relevant to the congenital HIV clinical context. The mechanistic link is unambiguous: ATV’s HIV-1 protease inhibition addresses the same viral pathway in vertically acquired infection as in adult disease.

To proceed, the following is needed:

TGA Special Access Scheme (SAS) application to access atazanavir for individual patients in Australia
Full international prescribing information (FDA Reyataz® PI or EMA SmPC) to substitute for unavailable TGA-approved PI
Comprehensive drug–drug interaction assessment for the patient’s concurrent medications, with particular attention to acid-suppressing agents (PPIs, H₂ blockers), rifamycins, and CYP3A4-active drugs
Weight-band and age-appropriate paediatric dosing confirmation using PRINCE I/II pharmacokinetic data
Baseline and on-treatment monitoring plan: HIV-1 RNA viral load, CD4+ T-cell count, liver function tests (ALT, AST), total and unconjugated bilirubin, serum creatinine, and urinalysis
For pregnant patients: trimester-specific PK guidance per IMPAACT P1026s and NCT00326716 data to ensure adequate maternal plasma levels
Specialist infectious diseases consultation (or paediatric HIV service referral) prior to initiation
Disclaimer

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