Atazanavir

證據等級: L5

預測適應症: 6 個

Structural note: The top four TxGNN predictions (ranks 1–4) are all rated Hold/L5 with no clinical evidence. The first actionable predictions are AIDS-Related Complex (rank 5, L1) and Congenital HIV (rank 6, L1). The report focuses on these, consistent with the spirit of the output format.

One-Sentence Summary

Atazanavir is an HIV-1 protease inhibitor used globally in combination antiretroviral therapy to suppress HIV replication and prevent disease progression. The TxGNN model predicts it may be effective for AIDS-Related Complex (symptomatic HIV, CDC Stage B), with 2 completed Phase 3 trials and 3 publications directly supporting this application — and an additional 33 trials and 7 publications backing the closely related Congenital HIV (vertical transmission) indication.

Prediction landscape note: Ranks 1–4 (feline FIV, primate SIV, a rare neurological disorder, and an obsolete lipid classification) are all rated Hold (L5). The first clinically actionable predictions are ranks 5 and 6, both rated L1 — Proceed with Guardrails. This report focuses accordingly.

Quick Overview

Item	Content
Original Indication	HIV-1 Infection (known HIV-1 protease inhibitor; not found in current FDA database)
Predicted New Indication	AIDS-Related Complex
TxGNN Prediction Score	99.71%
Evidence Level	L1
US Market Status	✗ Not found in current database (0 NDAs)
Number of NDAs	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Atazanavir is a second-generation HIV-1 protease inhibitor. It competitively inhibits the HIV-1 aspartate protease by binding tightly to the enzyme’s active site, mimicking the natural substrate’s transition state. This blocks proteolytic cleavage of the gag and gag-pol polyprotein precursors, preventing formation of mature, infectious viral particles. The resulting reduction in plasma viral load halts progressive CD4+ T cell depletion — the mechanism underlying all clinical benefit.

AIDS-Related Complex (ARC) refers to symptomatic HIV infection at CDC Stage B: conditions such as oral candidiasis, constitutional symptoms (fever, night sweats, weight loss), and moderate immunosuppression that precede full AIDS (CDC Stage C). Atazanavir’s mechanism is designed precisely to interrupt this progression. This is not a speculative repurposing — it is a direct application of the drug’s core pharmacology to a disease stage that shares identical viral pathophysiology with the original indication.

Congenital HIV (rank 6) — vertical mother-to-child transmission — involves the same HIV-1 replication mechanism but introduces important perinatal complexity: (1) ATV plasma trough levels (C_min) decline during the third trimester due to increased renal clearance and altered protein binding, necessitating therapeutic drug monitoring; (2) placental efflux transporters ABCB1, ABCG2, and ABCC2 modulate fetal drug exposure, with implications for neonatal protection; and (3) immature neonatal UGT1A1 substantially raises the risk of ATV-induced hyperbilirubinemia in newborns. Both predictions share an exceptionally strong mechanistic rationale — the key difference is the patient population and the additional pharmacokinetic vigilance required.

Clinical Trial Evidence

Evidence compiled across AIDS-Related Complex (rank 5) and Congenital HIV (rank 6). Top 10 highest-relevance trials shown.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00035932	Phase 3	Completed	571	Pivotal open-label RCT comparing ATV+RTV or ATV+SQV vs LPV/RTV, each with TDF + nucleoside backbone, in treatment-experienced HIV subjects — a landmark trial in Atazanavir’s regulatory approval pathway
NCT00272779	Phase 3	Completed	1,057	96-week head-to-head comparison of ATV/RTV vs LPV/RTV + TDF/FTC in treatment-naïve HIV-1 subjects, evaluating long-term antiviral efficacy and metabolic tolerability
NCT01910402	Phase 3	Completed	499	Open-label non-inferiority RCT comparing DTG/ABC/3TC vs ATV+RTV+TDF/FTC in ART-naïve HIV-1-infected women; provides direct efficacy benchmark for ATV-based regimens
NCT02429791	Phase 3	Completed	510	Multicenter non-inferiority RCT (SWORD-2) evaluating switch from PI/NNRTI/INI-based ART (including ATV) to DTG+RPV in virologically suppressed HIV-1 adults
NCT02951052	Phase 3	Active, Not Recruiting	618	ATLAS study: non-inferiority evaluation of switching from ATV-containing PI-based regimens to long-acting injectable cabotegravir+rilpivirine every 4 weeks; ongoing through 2029
NCT00207142	Phase 4	Completed	252	INDUMA study: Phase 4 RCT comparing maintenance with unboosted vs RTV-boosted Reyataz after viral suppression induction, assessing durability of HIV RNA < 50 copies/mL at 48 weeks
NCT00135356	Phase 4	Completed	219	REAL study: RCT evaluating substitution to ATV/RTV for management of lipodystrophy syndrome in HIV-infected subjects, demonstrating tolerability advantage over older PIs
NCT01335698	Phase 3	Completed	160	PRINCE II: PK, safety, and efficacy of ATV powder + RTV in HIV-infected children ≥3 months to <11 years (both treatment-naïve and experienced); key pediatric dosing validation
NCT01099579	Phase 3	Completed	82	PRINCE I: ATV powder + RTV safety, tolerability, and PK in HIV-infected infants ≥3 months to <6 years — foundational trial for the youngest pediatric dosing authorization
NCT00326716	Phase 1	Completed	69	PK study confirming adequate ATV/RTV exposure during pregnancy vs. historical non-pregnant controls; critical for establishing maternal dosing in PMTCT regimens

Literature Evidence

Evidence compiled across AIDS-Related Complex (rank 5) and Congenital HIV (rank 6), sorted by evidence quality.

PMID	Year	Type	Journal	Key Findings
24992294	2015	Cohort	Antiviral Therapy	ATV+RTV achieves adequate drug exposure during pregnancy with or without tenofovir co-administration, supporting dosing adequacy of ATV-based PMTCT regimens across trimesters
40011239	2025	Case-Control	Eur J Clin Pharmacol	European multi-registry case/non-case study quantifying congenital anomaly risk after fetal ARV exposure including ATV; most current population-level safety signal update
27242802	2016	Prospective Cohort	Front Immunology	PHACS SMARTT study: 3,500+ HIV-exposed uninfected infants at 22 US sites, systematically assessing metabolic, cardiac, neurological, and neurodevelopmental outcomes after in utero ARV exposure
25383770	2015	Cohort	JAMA Pediatrics	Congenital anomaly rates in 2,580 HIV-exposed uninfected infants by specific ARV exposure including ATV; overall reassuring findings with agent-specific signal notes
28991888	2018	Cohort	J Acquir Immune Defic Syndr	Comparative cohort assessing differential effects of common cART regimens (ATV/RTV, EFV, others) on incidence of AIDS-defining neurological conditions, directly relevant to ARC progression monitoring
19290032	2009	Cohort/Observational	AIDS Reviews	Analysis disentangling the contribution of HIV immunosuppression vs. ARV treatment (including ATV) on gastrointestinal adverse events; relevant to ARC patient symptom management
29859254	2018	In vitro / PK	Reprod Toxicol	First study quantifying ABCB1, ABCG2, and ABCC2 transporter effects on ATV and RTV placental transfer in rats; provides mechanistic basis for understanding fetal drug exposure during PMTCT
34978889	2022	In vitro	Antimicrob Agents Chemother	Novel CNS-targeting HIV-1 PIs (GRL-08513/08613) with activity against drug-resistant strains and favorable BBB penetration — contextualizes Atazanavir’s known limitations in treating HIV-associated neurocognitive disorders (HAND)
28459118	2016	Cohort	J AIDS Immune Res	PHACS/SMARTT: newborn hearing screening referral rates in 1,435 HIV-exposed uninfected infants; evaluates ARV-associated hearing risk for neonatal monitoring protocols
31595301	2020	Pharmacovigilance	Clin Infect Dis	Pharmacovigilance database analysis of neural tube defect signals comparing DTG vs non-DTG ART regimens (including ATV-based) in pregnancy; establishes comparative safety reference

US Market Information

No active US FDA authorizations were found for Atazanavir in the current database.

Authorization Number	Product Name	Dosage Form	Approved Indication
—	No records found	—	—

Atazanavir (brand: Reyataz, Bristol-Myers Squibb) is a known FDA-approved HIV-1 protease inhibitor. The absence of records in this database likely reflects brand-level discontinuation or data extraction scope. Generic atazanavir (300 mg/150 mg capsules) and pediatric powder formulations have been authorized by the FDA. Direct verification via the FDA Orange Book and the FDA Approved Drug Products database is strongly recommended before any market strategy decisions.

Safety Considerations

Please refer to the package insert for safety information.

Two unresolved data gaps require remediation before safety review can be completed:

DG001 (Blocking): Package insert warnings and contraindications have not yet been extracted from the FDA label. This is a mandatory prerequisite for Stage S1 safety screening. Remediation: download and parse the FDA label PDF for Atazanavir (Reyataz).

DG002 (High): Mechanism of action data was not retrieved from DrugBank. Remediation: query the DrugBank API for DB01072.

From known clinical pharmacology, priority safety areas include: indirect hyperbilirubinemia (UGT1A1 inhibition — particularly critical for neonates), nephrolithiasis and nephrotoxicity, PR interval prolongation (cardiac conduction), and extensive drug-drug interactions via CYP3A4 and P-glycoprotein pathways. These must be formally documented before regulatory or clinical use assessment.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: For AIDS-Related Complex and Congenital HIV, the mechanistic rationale is the strongest possible — it is the drug’s own core pharmacology. Multiple completed Phase 3 trials and robust real-world cohort data confirm efficacy in HIV disease stages directly overlapping these indications. However, two blocking data gaps (package insert warnings, MOA data) prevent formal safety clearance, and the absence of active FDA NDA records requires regulatory verification before any commercialization or formulary strategy can proceed.

To proceed, the following is needed:

[DG001 — Blocking] Download and parse the FDA package insert for Atazanavir/Reyataz to extract contraindications, black box warnings, and DDI table — required to complete Stage S1 safety evaluation
[DG002 — High] Query DrugBank API (DB01072) to formally document mechanism of action, drug categories, and toxicity data
Regulatory status verification: Confirm current FDA authorization status via the Orange Book; determine whether brand Reyataz has been discontinued, and whether approved generic NDA holders cover HIV-1, pediatric (≥3 months), and pregnancy (PMTCT) indications
Perinatal PK monitoring plan: For the Congenital HIV indication, develop a TDM protocol addressing third-trimester ATV C_min decline, transporter-mediated fetal exposure variability, and neonatal bilirubin surveillance
Dismiss ranks 1–4: The top four TxGNN predictions (feline FIV, primate SIV, rare neurological disorder, obsolete lipid classification) are L5/Hold with no supporting evidence; no resources should be allocated unless new mechanistic or translational data emerge
Disclaimer

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