Cummings Tammy H, Magagnoli Joseph, Sikirzhytskaya Aliaksandra, Tyagin Ilya, Safro Ilya, Wyatt Michael D, Shtutman Michael S, Sutton S Scott
Dorn Research Institute, Columbia Veterans Affairs Healthcare System.
Department of Clinical Pharmacy & Outcomes Sciences.
AIDS. 2024 Dec 1;38(15):1999-2009. doi: 10.1097/QAD.0000000000004009. Epub 2024 Sep 9.
The decreased mortality of people with HIV (PWH) has revealed non-HIV-associated comorbidities such as neurocognitive disorders (e.g., dementia). There is an urgency to discover therapeutics to prevent or delay neurocognitive decline among PWH.
The artificial intelligence platform Automatic Graph-mining And Transformer based Hypothesis Generation Approach (AGATHA) was utilized to seek potential drugs to be repurposed for the management of non-HIV-associated dementia. AGATHA revealed angiotensin-converting enzyme inhibitors that cross the blood-brain barrier (BBB ACEi) as a target for decreasing dementia. Subsequently, we conducted a retrospective study evaluating incident dementia using the Veterans Affairs Informatics and Computing Infrastructure (VINCI) evaluating ACE inhibitors. Cox proportional hazards models were fit and hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) are presented.
A total 9419 PWH exposed to an BBB ACE inhibitor (ACEi) and 8831 PWH unexposed demonstrated that PWH exposed to BBB ACEi had a 21.4% (univariate) and 15.2% (multivariate) lower hazard of dementia. The propensity score matched analysis demonstrated a 14.3% lower hazard of incident dementia compared to BBB ACEi unexposed (HR 0.857, 95% CI 0.747-0.984).
An artificial intelligence-based literature mining system (AGATHA) was utilized to uncover a medication with potential to be repurposed. AGATHA demonstrated that BBB ACEi as a target for decreasing dementia among PWH. Additionally, we conducted a retrospective study demonstrating a decrease in incident dementia among PWH exposed to BBB ACEi. Future research is needed to explore further and understand the relationship of dementia among PWH exposed to ACEi.
感染人类免疫缺陷病毒者（PWH）死亡率的下降揭示了诸如神经认知障碍（如痴呆症）等与HIV无关的合并症。迫切需要发现能够预防或延缓PWH神经认知衰退的治疗方法。
利用人工智能平台自动图挖掘和基于Transformer的假设生成方法（AGATHA）来寻找可重新用于治疗与HIV无关的痴呆症的潜在药物。AGATHA显示，能够穿过血脑屏障的血管紧张素转换酶抑制剂（BBB ACEi）是降低痴呆症的一个靶点。随后，我们进行了一项回顾性研究，使用退伍军人事务信息学和计算基础设施（VINCI）评估ACE抑制剂，以评估新发痴呆症情况。拟合了Cox比例风险模型，并给出了风险比（HR）及相应的95%置信区间（CI）。
共有9419名接触BBB ACE抑制剂（ACEi）的PWH和8831名未接触的PWH，结果显示，接触BBB ACEi的PWH患痴呆症的风险单变量分析降低了21.4%，多变量分析降低了15.2%。倾向评分匹配分析显示，与未接触BBB ACEi的PWH相比，新发痴呆症风险降低了14.3%（HR 0.857，95%CI 0.747-0.984）。
利用基于人工智能的文献挖掘系统（AGATHA）发现了一种有重新用途潜力的药物。AGATHA表明，BBB ACEi是降低PWH痴呆症的一个靶点。此外，我们进行的一项回顾性研究表明，接触BBB ACEi的PWH新发痴呆症有所减少。未来需要进一步研究，以探索并了解接触ACEi的PWH患痴呆症的关系。
