Atazanavir

證據等級: L5

預測適應症: 6 個

Atazanavir: From HIV Infection to Simian Immunodeficiency Virus Infection

One-Sentence Summary

Atazanavir is an HIV protease inhibitor used internationally for the treatment of HIV-1 and HIV-2 infection, though it is not currently registered in Saudi Arabia. The TxGNN model predicts it may be effective for Simian Immunodeficiency Virus (SIV) Infection, with 0 clinical trials and 1 publication currently supporting this direction. Of note, two additional predictions within the HIV disease spectrum — AIDS Related Complex (rank 5) and Congenital HIV Infection (rank 6) — carry L1 evidence backed by multiple completed Phase 3 trials, representing substantially more actionable repurposing opportunities.

Quick Overview

Item	Content
Original Indication	HIV-1/HIV-2 infection (internationally approved; not registered in Saudi Arabia)
Predicted New Indication	Simian Immunodeficiency Virus Infection
TxGNN Prediction Score	99.98%
Evidence Level	L4
Saudi Arabia Market Status	Not marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Atazanavir is an azapeptide-class HIV protease inhibitor (PI). It selectively binds to and inhibits HIV-1/HIV-2 protease — the enzyme responsible for cleaving the Gag-Pol polyprotein precursor into structural proteins and enzymes required for mature, infectious virion assembly. Without active protease, newly budded viral particles remain immature and non-infectious. In clinical practice, atazanavir is pharmacokinetically boosted with ritonavir (300/100 mg once daily) or cobicistat and deployed as part of combination antiretroviral therapy (cART). It carries a distinct metabolic advantage over earlier PIs in that it causes less dyslipidaemia.

SIV (Simian Immunodeficiency Virus) is a lentivirus closely related to HIV that naturally infects non-human primates — chimpanzees, sooty mangabeys, and macaques. The SIV protease shares considerable structural and sequence homology with HIV-1 protease, making it a biologically plausible target for PI-class agents. Indeed, SIV-infected rhesus macaque models are the standard preclinical platform for testing HIV/AIDS therapeutics, and PI-containing HAART regimens have been evaluated in these models to study viral suppression, CNS reservoir dynamics, and immune reconstitution.

However, it is important to contextualise this prediction: SIV is not a human pathogen. Any repurposing application would be confined to veterinary or preclinical research settings rather than a human clinical indication. The TxGNN model likely generated this high-scoring prediction through structural homology propagation within its lentivirus knowledge-graph node cluster. The single supporting publication (a primate HAART model study) confirms biological plausibility but does not establish a human therapeutic pathway.

Clinical Trial Evidence

Currently no related clinical trials registered for simian immunodeficiency virus infection.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
20497048	2010	Animal Study (Primate Model)	The Journal of Infectious Diseases	SIV-infected macaques treated with HAART showed reduced CNS viral replication and neuroinflammation, but viral DNA persisted in the CNS despite effective plasma viremia suppression — highlighting the CNS reservoir problem relevant to both SIV and HIV

Saudi Arabia Market Information

Atazanavir has no regulatory authorisations in Saudi Arabia. It is not currently marketed.

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: Simian immunodeficiency virus infection is a non-human primate disease with no established human clinical indication pathway; the sole supporting publication is a primate animal model study (evidence tier 3, L4), and no clinical trials exist. While the mechanistic extrapolation from HIV to SIV is biologically reasonable, this prediction does not translate into a viable human drug repurposing candidate.

To proceed with SIV-related research, the following is needed:

Clarify the research question: Is the goal to use atazanavir in SIV macaque models to study CNS penetration and HIV-associated neurocognitive disorders (HAND)?
If targeting HAND or CNS reservoir research: redesign as a dedicated CNS-HIV translational study
Obtain full mechanism of action data for atazanavir (currently a data gap)
Assess regulatory pathway in Saudi Arabia before any clinical application

Higher-Priority Predictions Warranting Immediate Attention

Two TxGNN predictions within the HIV disease spectrum carry L1 evidence and a "Proceed with Guardrails" recommendation — far stronger than the rank-1 SIV prediction:

AIDS Related Complex (rank 5, score 99.71%, L1)

2 completed Phase 3 trials directly assessing atazanavir: NCT00035932 (n=571, ATV+RTV vs LPV/r) and NCT01099579 (n=82, paediatric Phase 3)
AIDS Related Complex represents the mid-spectrum stage of HIV infection; atazanavir's direct mechanism (HIV protease inhibition) applies throughout the entire HIV disease continuum, including ARC
3 supporting publications including retrospective cohort and in vitro mechanistic studies

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00035932	Phase 3	Completed	571	ATV+RTV or ATV+SQV combined with LPV/r, TDF and nucleoside backbone in treatment-experienced HIV subjects; head-to-head virologic suppression and safety data
NCT01099579	Phase 3	Completed	82	ATV powder boosted with RTV in HIV-infected children ≥3 months to <6 years (PRINCE I); international multicentre PK, safety, and efficacy

PMID	Year	Type	Journal	Key Findings
19290032	2009	Cohort/Observational	AIDS Reviews	Risk factors for GI adverse events in HIV-treated patients; atazanavir-related tolerability profile in ARC/AIDS continuum
28991888	2018	Retrospective Cohort	J Acquir Immune Defic Syndr	Differential effects of cART regimens including PI-based therapy on AIDS-defining neurological conditions (neuroAIDS)
34978889	2022	Medicinal Chemistry / In Vitro	Antimicrobial Agents and Chemotherapy	CNS-targeting HIV protease inhibitors with enhanced blood-brain barrier penetration — context for next-generation PI design beyond atazanavir

Congenital HIV / Prevention of Mother-to-Child Transmission (rank 6, score 99.71%, L1)

33 clinical trials retrieved; 7 publications covering pregnancy PK, congenital anomaly surveillance, and placental drug transport

Selected key trials (top 10 by relevance):

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00272779	Phase 3	Completed	1,057	ATV/r vs LPV/r each with TDF/FTC over 96 weeks in treatment-naïve HIV-1 subjects; largest head-to-head PI comparison trial
NCT02269917	Phase 3	Completed	1,149	Switch from boosted PI (including ATV/r) to D/C/F/TAF single-tablet regimen; largest completed randomised switch trial
NCT01691794	Phase 4	Completed	108	ATV capsule + RTV in HIV-infected paediatric patients aged 6–<18 years; dedicated safety data collection in specific paediatric populations
NCT04518228	N/A	Completed	205	PK of ARV and anti-TB drugs during pregnancy and postpartum; core dataset for ATV dosing adjustments in pregnancy
NCT00042289	N/A	Completed	1,578	IMPAACT P1026s — the definitive prospective PK study of ARVs including ATV in pregnant women and their infants
NCT02951052	Phase 3	Active, not recruiting	618	ATLAS study — long-acting CAB+RPV vs PI-based (including ATV) regimens in virologically suppressed adults
NCT00135356	Phase 4	Completed	219	REAL study — ATV/r substitution for lipodystrophy management in HIV-infected patients on HAART
NCT01003990	Phase 3	Completed	710	Extended access study providing long-term safety data across ATV clinical trial completers
NCT01335698	Phase 3	Completed	160	PRINCE II — ATV powder + RTV in paediatric patients 3 months to <11 years; safety, efficacy and PK
NCT01910402	Phase 3	Completed	499	DTG/ABC/3TC vs ATV+RTV+TDF/FTC in HIV-1 infected ART-naïve women over 48 weeks

Key literature for congenital HIV / PMTCT:

PMID	Year	Type	Journal	Key Findings
27242802	2016	Prospective Cohort (PHACS SMARTT)	Frontiers in Immunology	Comprehensive surveillance of in utero ARV toxicities across >3,500 HIV-exposed uninfected infants; metabolic, cardiac, neurological, and developmental outcomes assessed
24992294	2015	Prospective PK Study	Antiviral Therapy	ATV exposure remains adequate during pregnancy regardless of tenofovir co-use; informs dosing strategy for PMTCT
25383770	2015	Prospective Observational	JAMA Pediatrics	Congenital anomaly rates in HIV-exposed uninfected infants with in utero ARV exposure including ATV; safety signal assessment
40011239	2025	Case/Non-case (Pharmacovigilance)	European Journal of Clinical Pharmacology	European congenital anomaly registry analysis of ARV-exposed pregnancies; most recent pharmacovigilance dataset on ATV fetal safety
29859254	2018	In Vitro / Mechanistic	Reproductive Toxicology	ATV and RTV interactions with placental ABC transporters (ABCB1, ABCG2, ABCC2); explains moderate placental transfer and informs fetal exposure modelling
28459118	2016	Prospective Observational	Journal of AIDS and Immune Research	Newborn hearing screening outcomes in HIV-exposed uninfected infants from PHACS SMARTT; safety surveillance data
31595301	2020	Pharmacovigilance Database Analysis	Clinical Infectious Diseases	Pharmacovigilance database analysis of ARV safety signals in pregnancy; comparative context for ATV vs newer agents

Guardrails for congenital HIV / PMTCT indication:

Monitor for maternal nephrolithiasis (urinary crystal risk elevated in pregnancy)
Neonatal hyperbilirubinaemia risk (UGT1A1 inhibition → indirect bilirubin accumulation)
ATV AUC decreases ~17–28% during second/third trimester when co-administered with TDF; dose adjustment to ATV/r 400/100 mg may be required
Placental transfer is moderate; neonatal exposure should be monitored
Disclaimer

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