AASLD2016[1875]甲型肝炎患者Prenylation抑制剂Lonafarnib可以诱导 治

StephenW

The Prenylation Inhibitor Lonafarnib Can Induce
Post-Treatment Alt Flares With Viral Clearance In
Patients With Chronic Delta Hepatitis
Cihan Yurdaydin1, Ramazan Idilman1, Cagdas Kalkan1, Fatih
Karakaya1, Aysun Caliskan Kartal1, Onur Keskin1, Ersin Karatayli1,
Senem C. Karatayli1, A Mithat Bozdayi1, Christopher
Koh2, Theo Heller2, Jeffrey Glenn3; 1Gastroenterology Section,
Ankara University Medical School, Ankara, Turkey; 2Liver Diseases
Branch, NIDDK, Bethesda, MD; 3Division of Gastroenterology and
Hepatology, Stanford University School of Medicine, Stanford, CA
Background/Aims: Chronic delta hepatitis (CDH) is the most
severe form of viral hepatitis. There is currently no approved
therapy for CDH. The only established treatment is with interferons,
effective in only 25 to 30% of patients. New treatment
options are needed in CDH. The prenylation inhibitor
lonafarnib (LNF) is the first pharmacological investigational
treatment specific for hepatitis D virus (Koh et al, Lancet Infect
Dis 2015). Here we report for the first time post-treatment ALT
flares and their outcomes in patients treated with 12 or 24 wks
of LNF in various treatment regimens. Methods: 27 patients
were analyzed who had detectable HDV RNA after receiving
LNF for 12 or 24 wks in the LOWR HDV-1 and LOWR
HDV-2 trials. A post-treatment ALT flare was defined as elevation
of ALT to >2x baseline ALT level. Results: To date, 5 of 27
(18.5%) patients have experienced post-treatment ALT flares.
These post-treatment flares (median ALT 190 U/mL, range 110-
1355 U/mL) led to ALT normalization and HDV RNA became
negative within 12-24 wks. These patients came from a variety
of LNF treatment cohorts: LNF 200mg bid, 12 wks; LNF 300
mg bid, 12 wks, LNF 100mg bid/RTV 50mg bid, 12 wks; LNF
75 mg bid/RTV 100mg bid, 12 wks, followed by addition of
pegylated interferon alfa (PEG IFN α) for 12 wks; LNF 50mg
bid/RTV 100mg bid, 24 wks. One patient cleared HBV DNA
and subsequently cleared HBsAg; the others did not, although
2 other patients exhibited declines in HBV DNA of 2 logs or
greater. All five patients exhibited rapid initial declines of HDV
RNA with initiation of LNF that were eventually followed by
more gradual rises on therapy associated with decreased LNF
exposure (due to dose reductions or excessive GI side effects).
Conclusion: The data suggest that a short course of LNF may
contribute to an effective reset and activation of the immune
reactivity in CDH, which in some cases my spread to HBV.
Thus, there appear to be at least two pathways for achieving
HDV negativity with LNF therapy: On treatment LNF-induced
progressive suppression to HDV negativity with ALT normalization
(more classical antiviral approach, e.g. exemplified in
the ongoing LOWR 2 study), and LNF-induced post-treatment
anti-HDV ALT flares (described here). The mechanisms of this
latter immune restoration are being explored and may lead
to the prospective identification of patients who are likely to
experience this remarkable outcome.
Disclosures:
Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche,
Merck, Gilead, AbbVie; Speaking and Teaching: BMS
Jeffrey Glenn - Board Membership: Eiger Biopharmaceuticals; Consulting: Gilead,
Romark Laboratories; Grant/Research Support: Roche, Sundise; Stock
Shareholder: Riboscience LLC, Eiger Biopharmaceuticals, Eiger Group International
The following people have nothing to disclose: Ramazan Idilman, Cagdas
Kalkan, Fatih Karakaya, Aysun Caliskan Kartal, Onur Keskin, Ersin Karatayli,
Senem C. Karatayli, A Mithat Bozdayi, Christopher Koh, Theo Heller

StephenW

AASLD2016甲型肝炎患者Prenylation抑制剂Lonafarnib可以诱导
治疗后火焰与病毒清除
慢性甲型肝炎患者
Prenylation抑制剂Lonafarnib可以诱导
治疗后火焰与病毒清除
慢性甲型肝炎患者
Cihan Yurdaydin1，Ramazan Idilman1，Cagdas Kalkan1，Fatih
Karakaya1，Aysun Caliskan Kartal1，Onur Keskin1，Ersin Karatayli1，
Senem C. Karatayli1，A Mithat Bozdayi1，Christopher
Koh2，Theo Heller2，Jeffrey Glenn3; 1胃肠病科，
安卡拉大学医学院，安卡拉，土耳其; 2肝病
Branch，NIDDK，Bethesda，MD;胃肠病学
肝脏病学，斯坦福大学医学院，斯坦福，加利福尼亚州
背景/目的：慢性δ型肝炎（CDH）是最多的
严重形式的病毒性肝炎。目前没有批准
治疗CDH。唯一建立的治疗是用干扰素，
仅在25％至30％的患者中有效。新治疗
CDH中需要选项。异戊烯化抑制剂
lonafarnib（LNF）是第一个药理研究
治疗特异于丁型肝炎病毒（Koh等人，Lancet Infect
Dis 2015）。在这里我们报告第一次治疗后ALT
耀斑和他们的结果在治疗12或24周的患者
的LNF在各种治疗方案。方法：27例
分析了在接受后具有可检测的HDV RNA的人
LNF在LOWR HDV-1和LOWR中为12或24周
HDV-2试验。治疗后ALT flare定义为升高
的ALT至> 2x基线ALT水平。结果：迄今为止，27/27
（18.5％）患者经历了治疗后ALT发作。
这些后处理突出（中位ALT 190U / mL，范围110-
1355 U / mL）导致ALT正常化，HDV RNA变为
在12-24周内消极。这些患者来自一个品种
的LNF治疗组：LNF 200mg bid，12周; LNF 300
mg bid，12周，LNF 100mg bid / RTV 50mg bid，12周; LNF
75mg bid / RTV 100mg bid，12周，然后加入
聚乙二醇化干扰素α（PEG IFNα）12周; LNF 50mg
bid / RTV 100mg bid，24周。一名患者清除了HBV DNA
并随后清除HBsAg;其他人没有，虽然
2例其他患者的HBV DNA水平下降2 log或
更大。所有五个患者表现出HDV的快速初始下降
RNA，其最终随后是LNF起始
与LNF降低相关的治疗的更逐渐的上升
暴露（由于剂量减少或过度的GI副作用）。
结论：数据表明短期LNF可能
有助于有效重置和激活免疫
CDH中的反应性，在一些情况下，我的传播到HBV。
因此，似乎有至少两个途径实现
HDF阴性与LNF治疗：治疗LNF诱导
进行性抑制与HDV阴性与ALT正常化
（更经典的抗病毒方法，例如，
正在进行的LOWR 2研究）和LNF诱导的后处理
抗HDV ALT突发（如本文所述）。这种机制
后者的免疫恢复正在被探索和可能导致
到可能的患者的预期识别
体验这一显着的成果。
披露：
Cihan Yurdaydin - 咨询委员会或审查小组：Janssen，Roche，
默克，吉利德，艾伯维口语和教学：BMS
Jeffrey Glenn - 董事会成员：Eiger Biopharmaceuticals;咨询：Gilead，
Romark实验室;资助/研究支持：罗氏，Sundise;股票
股东：Riboscience LLC，Eiger生物制药，艾格集团国际
以下人没有什么可披露：Ramazan Idilman，Cagdas
Kalkan，Fatih Karakaya，Aysun Caliskan Kartal，Onur Keskin，Ersin Karatayli，
Senem C. Karatayli，A Mithat Bozdayi，Christopher Koh，Theo Heller