Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
Front Immunol. 2018 Feb 7;9:146. doi: 10.3389/fimmu.2018.00146. eCollection 2018.
Recent introduction of all-oral direct-acting antiviral (DAA) treatment has revolutionized care of patients with chronic hepatitis C virus (HCV) infection. Regrettably, the high cost of DAA treatment is burdensome for healthcare systems and may be prohibitive for some patients who would otherwise benefit. Understanding how patient-related factors influence individual responses to DAA treatment may lead to more efficient prescribing. In this observational study, patients with chronic HCV infection were comprehensively monitored by flow cytometry to identify pretreatment immunological variables that predicted HCV RNA negativity within 4 weeks of commencing DAA treatment. Twenty-three patients [genotype 1a ( = 10), 1b ( = 9), and 3 ( = 4)] were treated with daclatasvir plus sofosbuvir (SOF) ( = 15), ledipasvir plus SOF ( = 4), or ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir ( = 4). DAA treatment most prominently altered the distribution of CD8 memory T cell subsets. Knowing only pretreatment frequencies of CD3 and naive CD8 T cells allowed correct classification of 83% of patients as "fast" (HCV RNA-negative by 4 weeks) or "slow" responders. In a prospective cohort, these parameters correctly classified 90% of patients. Slow responders exhibited higher frequencies of CD3 T cells, CD8 T cells, and CD5 CD27 CD57 CD8 chronically activated T cells, which is attributed to bystander hyperactivation of virus-non-specific CD8 T cells. Taken together, non-specific, systemic CD8 T cell activation predicted a longer time to viral clearance. This discovery allows pretreatment identification of individuals who may not require a full 12-week course of DAA therapy; in turn, this could lead to individualized prescribing and more efficient resource allocation.
最近，所有口服直接作用抗病毒（DAA）治疗的引入彻底改变了慢性丙型肝炎病毒（HCV）感染患者的治疗模式。遗憾的是，DAA 治疗的高成本给医疗系统带来了负担，而且对于一些本应受益的患者来说，可能是无法承受的。了解患者相关因素如何影响个体对 DAA 治疗的反应，可能会导致更有效的处方。在这项观察性研究中，通过流式细胞术对慢性 HCV 感染患者进行全面监测，以确定在开始 DAA 治疗后 4 周内预测 HCV RNA 阴性的预处理免疫变量。23 例患者[基因型 1a（ = 10）、1b（ = 9）和 3（ = 4）]接受了达卡他韦联合索非布韦（SOF）（ = 15）、来迪派韦联合 SOF（ = 4）或利托那韦增强的泊沙康唑、奥比他韦和达沙布韦（ = 4）治疗。DAA 治疗最显著地改变了 CD8 记忆 T 细胞亚群的分布。仅知道预处理 CD3 和幼稚 CD8 T 细胞的频率，就可以正确地将 83%的患者分类为“快速”（4 周内 HCV RNA 阴性）或“缓慢”反应者。在一项前瞻性队列研究中，这些参数正确地将 90%的患者分类。缓慢反应者表现出更高频率的 CD3 T 细胞、CD8 T 细胞和 CD5 CD27 CD57 CD8 慢性激活 T 细胞，这归因于病毒非特异性 CD8 T 细胞的旁观者过度激活。总的来说，非特异性、全身性 CD8 T 细胞激活预测了清除病毒所需的时间更长。这一发现允许在治疗前识别可能不需要 12 周全疗程 DAA 治疗的个体；反过来，这可能会导致个体化处方和更有效地分配资源。
