Background&aims

With the introduction of DAA's, the majority of treated chronic hepatitis C patients (CHC) achieve a viral cure. The exact mechanisms by which the virus is cleared after successful therapy, is still unknown. The aim was to assess the role of the immune system and miRNA levels in acquiring a sustained virological response after DAA treatment in CHC patients with and without prior RG-101 (anti-miR-122) dosing.

Methods

In this multicenter, investigator-initiated study, 29 patients with hepatitis C virus (HCV) genotype 1 (n = 11), 3 (n = 17), or 4 (n = 1) infection were treated with sofosbuvir and daclatasvir ± ribavirin. 18 patients were previously treated with RG-101. IP-10 levels were measured by ELISA. Ex vivo HCV-specific T cell responses were quantified in IFN-γ-ELISpot assays. Plasma levels of miR-122 were measured by qPCR.

Results

All patients had an SVR12. IP-10 levels rapidly declined during treatment, but were still elevated 24 weeks after treatment as compared to healthy controls (median 53.82 and 39.4 pg/mL, p = 0.02). Functional IFN-γ HCV-specific T cell responses did not change by week 12 of follow-up (77.5 versus 125 SFU/10⁶ PBMC, p = 0.46). At follow-up week 12, there was no difference in plasma miR-122 levels between healthy controls and patients with and without prior RG-101 dosing.

Conclusions

Our data shows that successful treatment of CHC patients with and without prior RG-101 dosing results in reduction of broad immune activation, and normalisation of miR-122 levels (EudraCT: 2014-002808-25).

Trial registration

EudraCT: 2014-002808-25.

中文翻译：

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DAA 治疗的慢性丙型肝炎患者的免疫反应有和没有先前 RG-101 给药

背景&目标

随着 DAA 的引入，大多数接受治疗的慢性丙型肝炎患者 (CHC) 实现了病毒治愈。成功治疗后清除病毒的确切机制仍然未知。目的是评估免疫系统和 miRNA 水平在接受和不接受 RG-101（抗 miR-122）给药的 CHC 患者 DAA 治疗后获得持续病毒学应答中的作用。

方法

在这项由研究者发起的多中心研究中，29 名丙型肝炎病毒 (HCV) 基因型 1 (n = 11)、3 (n = 17) 或 4 (n = 1) 感染患者接受了索非布韦和达卡他韦±利巴韦林治疗。18 名患者先前接受了 RG-101 治疗。通过ELISA测量IP-10水平。在 IFN-γ-ELISpot 测定中量化离体 HCV 特异性 T 细胞反应。通过qPCR测量miR-122的血浆水平。

结果

所有患者都有 SVR12。IP-10 水平在治疗期间迅速下降，但与健康对照组相比，治疗后 24 周仍升高（中位数 53.82 和 39.4 pg/mL，p = 0.02）。功能性 IFN-γ HCV 特异性 T 细胞反应在随访的第 12 周没有改变（77.5 对 125 SFU/10 ⁶ PBMC，p = 0.46）。在第 12 周的随访中，健康对照组和既往服用或未服用 RG-101 的患者的血浆 miR-122 水平没有差异。

结论

我们的数据显示，成功治疗有和没有之前 RG-101 给药的 CHC 患者会导致广泛的免疫激活减少，并使 miR-122 水平正常化（EudraCT：2014-002808-25）。

试用注册

EudraCT：2014-002808-25。