Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
HIV Med. 2019 Jan;20(1):1-10. doi: 10.1111/hiv.12676. Epub 2018 Oct 25.
The aim of this work was to review current treatment options and propose alternatives for immune reconstitution inflammatory syndrome (IRIS) in HIV-infected individuals with cryptococcal meningitis (CM) (termed 'HIV-CM IRIS'). As a consequence of the immunocompromised state of these individuals, the initial immune response to CM is predominantly type 2 T helper (Th2) /Th17 rather than Th1, leading to inefficient fungal clearance at the time of antiretroviral initiation, and a subsequent overexaggeration of the Th1 response and life-threatening IRIS development.
An article-based and clinical trial-based search was conducted to investigate HIV-CM IRIS pathophysiology and current treatment practices.
Guidelines for CM treatment, based on the Cryptococcal Optimal Antiretroviral Timing (COAT) trial, recommend delayed antiretroviral therapy (ART) following antifungal treatment. The approach aims to decrease fungal burden and allow immune balance restoration prior to ART initiation. If the initial immune balance is not restored, the fungal burden is not sufficiently reduced and there is a risk of developing IRIS post-ART, highlighted by a Th1 immune overcompensation, leading to increased mortality. The mainstay treatment for Th1-biased IRIS is corticosteroids; however, this treatment has been shown to correlate with increased mortality and significant associated adverse events. We emphasize targeting a more specific Th1 mechanism via the tumour necrosis factor (TNF)-α cytokine antagonist thalidomide, as it is the only TNF-α antagonist currently approved for use in infectious disease settings and has been shown to decrease Th1 overreaction, restoring immune balance in HIV-CM IRIS.
Although the side effects and limitations of thalidomide must be considered, it is currently being successfully used in infectious disease settings and warrants mainstream application as a therapeutic option for treatment of IRIS in HIV-infected patients with CM.
本研究旨在回顾目前针对 HIV 合并隐球菌性脑膜炎（CM）患者免疫重建炎症综合征（IRIS）的治疗选择，并提出替代方案（简称“HIV-CMIRIS”）。由于这些患者免疫功能低下，最初对 CM 的免疫反应主要是 2 型辅助性 T 细胞（Th2）/Th17，而不是 Th1，导致在开始抗逆转录病毒治疗（ART）时真菌清除效率低下，并随后出现 Th1 反应过度和危及生命的 IRIS 发展。
通过文献综述和临床试验搜索，研究 HIV-CMIRIS 的病理生理学和当前治疗实践。
基于隐球菌最佳抗逆转录病毒时机（COAT）试验的 CM 治疗指南建议在抗真菌治疗后延迟 ART。该方法旨在降低真菌负荷并在开始 ART 之前恢复免疫平衡。如果最初的免疫平衡没有恢复，真菌负荷没有充分降低，并且存在 ART 后发生 IRIS 的风险，这突出表现为 Th1 免疫过度补偿，导致死亡率增加。针对 Th1 偏向性 IRIS 的主要治疗方法是皮质类固醇；然而，这种治疗方法与死亡率增加和相关不良事件显著相关。我们强调通过肿瘤坏死因子（TNF）-α细胞因子拮抗剂沙利度胺靶向更特定的 Th1 机制，因为它是目前唯一在感染性疾病环境中批准用于 TNF-α拮抗剂的药物，并且已被证明可降低 Th1 过度反应，恢复 HIV-CMIRIS 中的免疫平衡。
尽管必须考虑到沙利度胺的副作用和局限性，但它目前正在感染性疾病环境中成功使用，并值得作为治疗 HIV 合并 CM 患者 IRIS 的治疗选择进行主流应用。
