In a proof‐of‐concept (POC) study, the oral prenylation inhibitor, lonafarnib (LNF), decreased hepatitis D virus (HDV) RNA during 4 weeks of treatment. Here, we explored optimal LNF regimens. Fifteen patients (five groups; 3 per group) completed dosing as follows: (1) LNF 200 mg twice‐daily (BID; 12 weeks); (2) LNF 300 mg BID (12 weeks); (3) LNF 100 mg thrice‐daily (5 weeks); (4) LNF 100 mg BID + pegylated interferon alfa (PEG‐IFNα) 180 μg once‐weekly (QW; 8 weeks); and (5) LNF 100 mg BID + ritonavir (RTV) 100 mg once‐daily (QD; 8 weeks). Tolerability and efficacy were assessed. Higher LNF monotherapy doses had greater decreases in HDV viral load than achieved in the original POC study. However, this was associated with increased gastrointestinal adverse events. Addition of RTV 100 mg QD to a LNF 100 mg BID regimen yielded better antiviral responses than LNF 300 mg BID monotherapy and with less side effects. A similar improvement was observed with LNF 100 mg BID + PEG‐IFNα 180 μg QW. Two of 6 patients who received 12 weeks of LNF experienced transient posttreatment alanine aminotransferase (ALT) increases resulting in HDV‐RNA negativity and ALT normalization. Conclusion: The cytochrome P450 3A4 inhibitor, RTV, allows a lower LNF dose to be used while achieving higher levels of postabsorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG‐IFNα achieved more substantial and rapid HDV‐RNA reduction, compared to historical responses with PEG‐IFNα alone. Twelve weeks of LNF can result in posttreatment HDV‐RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG‐IFN. (Hepatology 2018;67:1224‐1236)

中文翻译：

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优化 lonafarnib 治疗慢性丁型肝炎：低 HDV - 1 研究

在概念验证 (POC) 研究中，口服异戊二烯化抑制剂 lonafarnib (LNF) 在 4 周的治疗期间降低了丁型肝炎病毒 (HDV) RNA。在这里，我们探索了最佳 LNF 方案。15 名患者（5 组；每组 3 名）完成给药如下：（1）LNF 200 mg 每天两次（BID；12 周）；(2) LNF 300 毫克 BID（12 周）；(3) LNF 100 毫克，每天三次（5 周）；(4) LNF 100 mg BID + 聚乙二醇化干扰素α (PEG-IFNα) 180 μg，每周一次（QW；8 周）；(5) LNF 100 mg BID + ritonavir (RTV) 100 mg，每天一次（QD；8 周）。评估了耐受性和有效性。与最初的 POC 研究相比，较高的 LNF 单药治疗剂量对 HDV 病毒载量的降低幅度更大。然而，这与胃肠道不良事件增加有关。将 RTV 100 mg QD 添加到 LNF 100 mg BID 方案可产生比 LNF 300 mg BID 单药治疗更好的抗病毒反应，并且副作用更少。使用 LNF 100 mg BID + PEG-IFNα 180 μg QW 观察到类似的改善。接受 12 周 LNF 治疗的 6 名患者中有 2 名经历了短暂的治疗后丙氨酸氨基转移酶 (ALT) 升高，导致 HDV-RNA 阴性和 ALT 正常化。结论：细胞色素 P450 3A4 抑制剂 RTV 允许使用较低的 LNF 剂量，同时实现更高水平的吸收后 LNF，产生更好的抗病毒反应和耐受性。此外，与单独使用 PEG-IFNα 的历史反应相比，将 LNF 与 PEG-IFNα 组合实现了更大量和更快速的 HDV-RNA 减少。12 周的 LNF 可导致某些患者的治疗后 HDV-RNA 阴性，我们推测这是恢复有利的免疫反应的结果。这些结果支持进一步开发具有 RTV 增强的 LNF 和探索 LNF 与 PEG-IFN 的组合。（肝病学 2018 年；67：1224-1236）