萨拉萨尔与诺维尔有效地延缓HDV进展，可能会清除病毒

StephenW

Sarasar with Norvir effectively delays HDV progression, may clear virus
October 22, 2017

Combination therapy with Sarasar and Norvir in patients with hepatitis D effectively blocked hepatitis D virus production, regardless of Sarasar dose, according to a presentation at The Liver Meeting 2017. Longer treatment duration may clear the virus.

“Up to 20 million people worldwide are infected with hepatitis delta and the majority of them will develop cirrhosis within 5 to 10 years,” Harel Dahari, PhD, from the division of hepatology at the Loyola University Medical Center, Illinois, said in his presentation. “And compared to HBV mono-infected patients, HDV-infected patients will have a higher risk for hepatic decompensation and the development of liver disease.”

To confirm the efficacy of Sarasar (lonafarnib, Eiger BioPharmaceuticals) combined with Norvir (ritonavir, AbbVie) for HDV, the researchers conducted a study with a mathematical model that included data from the phase 2 LOWR HDV-3 study. The model also included hepatocyte proliferation to estimate HDV kinetic parameters and treatment efficacy in blocking viral production.

The researchers randomized 21 patients into six groups that received 50, 75, or 100 mg of Sarasar with 100 mg of Norvir daily for 24 weeks (n = 12) or 12 weeks of placebo followed by 12 weeks of treatment with Sarasar and Norvir (n = 9). Additionally, all patients received hepatitis B nucleos(t)ide analogue therapy.

Median patient age was 40, 60% of patients were men, and most patients were Caucasian and Asian, had elevated alanine aminotransferase levels, and had mild fibrosis.

The researchers observed the following viral kinetic patterns among the groups:

    a rapid virus load decline that was followed by a phase in which the virus load decayed slowly or remained constant and a third phase of renewed viral decay;
    a flat partial response that consisted of rapid virus load decline followed by a lower set point of viral load;
    a pattern of virus rebound, in which the flat partial response or the three-point phase were followed by a rebound in viral load due to a varying effectiveness of the drug; and
    non-response (patients were excluded from modeling).

Results of the model showed a delay of HDV production (median, 8.5 days), in which viral load remained at pre-treatment levels, and that Sarasar with Norvir had a 95% efficacy in blocking HDV production, regardless of Sarasar dose. Viral rebound was due to a decline in treatment efficacy from approximately 95% to approximately 50% after 28 to 137 days after treatment started.

According to Dahari, the model suggests treatment for 51 weeks in those with the three-phase response, treatment for 52 weeks in those with the flat partial response, and treatment for 94 weeks in those with a pattern of virus rebound.

“Lonafarnib and rotanovir were safe and generally well-tolerated,” Dahari said. “The model was able to reproduce the observed viral HBS antigen and ALT kinetics in each patient and provide an insight into viral response to the drug.” – by Talitha Bennett

Reference:

Dahari H, et al. Abstract 38. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.

Disclosure: Dahari reports he received grants or research support from Eiger BioPharmaceuticals.

StephenW

萨拉萨尔与诺维尔有效地延缓HDV进展，可能会清除病毒
2017年10月22日

根据2011年肝病会议的介绍，不论Sarasar剂量如何，联合治疗甲型肝炎患者的Sarasar和Norvir均有效地阻断了丙型肝炎病毒的产生。较长的治疗时间可能会清除病毒。

来自伊利诺斯州洛约拉大学医学中心肝病学部门的Harel Dahari博士在演讲中表示：“全球多达2000万人感染了三角洲，大多数人将在5到10年内发展成肝硬化。” 。 “与HBV单感染患者相比，HDV感染患者肝脏代偿失调和肝脏疾病发展风险更高。”
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为了证实Sarasar（lonafarnib，Eiger BioPharmaceuticals）与Norvir（利托那韦，AbbVie）联合用于HDV的疗效，研究人员进行了一项数学模型的研究，其中包括第2期LOWR HDV-3研究的数据。该模型还包括肝细胞增殖以估计HDV动力学参数和阻断病毒生产的治疗效果。

研究人员将21名患者随机分为6组，每组接受50,75或100 mg的Sarasar，每天用100mg Norvir进行24周（n = 12）或12周安慰剂，然后用Sarasar和Norvir（n = 9）。此外，所有患者都接受了乙型肝炎核苷类似物治疗。

中位患者年龄40岁，60％为男性，大多数患者为白种人和亚洲人，具有升高的丙氨酸氨基转移酶水平，并具有轻度纤维化。

研究人员观察到以下病毒动力学模式：

    病毒载量快速下降，其后是病毒载量缓慢或保持不变的阶段，再次病毒衰退的第三阶段;
    平坦的部分反应包括病毒载量迅速下降，病毒载量设定点较低;
    病毒反弹的模式，其中平坦部分反应或三点阶段由于药物的有效性而在病毒载量中反弹;和
    无反应（患者被排除在建模之外）。

该模型的结果显示HDV生产延迟（中位数为8.5天），其中病毒载量保持在治疗前水平，并且与Norvir的Sarasar在阻断HDV生产中具有95％的功效，而不考虑Sarasar剂量。病毒反弹是由于治疗开始后28至137天，治疗效果从约95％降至约50％。

据Dahari介绍，该模型表明，对于具有三期反应的患者，治疗51周，平均偏瘫患者治疗52周，病毒反弹模式治疗94周。

“Lonafarnib和rotanovir是安全的，普遍耐受性很好，”达哈里说。 “该模型能够重现每个患者中观察到的病毒HBS抗原和ALT动力学，并提供对药物的病毒反应的洞察。” - 由Talitha Bennett

参考：

Dahari H，et al。摘要38.介绍：肝病会议; 2017年10月20日至24日华盛顿特区。

披露：达哈里报告他获得了Eiger BioPharmaceuticals的资助或研究支持。