VAIL, Colorado (EGMN) – Much needed help in treating pandemic 2009 H1N1 influenza may be on the way in the form of two promising investigational drugs that could become commercially available within the next several flu seasons.
Favipiravir and laninamivir are in phase III clinical trials abroad, where to date both appear to be performing very well, Dr. Adriana Weinberg said at the annual conference on pediatric infectious diseases sponsored by the Children’s Hospital, Denver.
Favipiravir is an oral RNA polymerase inhibitor effective against both influenza A and B as well as other RNA viruses. It is in Phase III testing in Japan. Importantly, it has no cross-resistance with the neuraminidase inhibitors or amantadines.
Laninamivir is a neuraminidase inhibitor administered only by inhalation. However, the drug has an extremely long half-life such that a single inhalation constitutes an entire course of treatment. Laninamivir is effective against oseltamivir-resistant isolates. It is in Phase III trials in Australia, where it is establishing a very favorable safety profile, according to Dr. Weinberg, professor of medicine, pediatrics, and pathology of the University of Colorado, Denver, and medical director of the clinical virology laboratory at University of Colorado Hospital.
Current treatment options for pandemic H1N1 flu are quite limited, so these two new drugs are badly needed, she added.
More than 90% of H1N1 isolates from the 2009 pandemic were resistant to adamantanes. So basically all that physicians had available early on were the oral neuraminidase inhibitor oseltamivir and the inhalation-only formulation of zanamivir, another neuraminidase inhibitor.
These were supplemented during the pandemic by intravenous peramivir, a drug that was in Phase III trials but was decreed available for use in critically ill patients as a result of an Emergency Use Authorization. The Emergency Use Authorization was terminated in June 2010. Peramivir has a resistance profile and efficacy similar to oseltamivir. Thus, its sole advantage is that it can be given intravenously. The recommended dosing is 6 mg/kg in neonates, 8 mg/kg for infants aged 31-90 days, 10 mg/kg for 91- to 180-day-olds, 12 mg/kg for children aged 181 days through 5 years, 10 mg/kg for 6- to 17-year-olds, and 600 mg for patients aged 18 years and older. The infusion is given over 30-60 minutes.
Intravenous zanamivir became available on a compassionate use basis during the pandemic. Unlike peramivir, it is effective against oseltamivir-resistant isolates.
Ribavirin is commercially available for indications other than influenza. However, it does have in vitro activity against influenza, and although it’s not a very good anti-influenza drug by itself, it may have a future in combination therapy for severe pandemic H1N1 disease.
Combo therapy with neuraminidase inhibitors, ribavirin, adamantanes, and interferon was widely used for avian influenza A(H5N1), but due to the lack of controls it’s hard to draw any conclusions as to whether this resulted in enhanced efficacy. In animal models, two drugs for pandemic H1N1 disease are more effective than one, regardless of the drugs tested, provided the virus is susceptible to both drugs. Results thus far are conflicting when the virus is resistant, according to Dr. Weinberg.
Oseltamivir performed well last season against pandemic H1N1. When started within 2 days following symptom onset, it reduced mortality by 50%. It also reduced the duration of symptoms. There is some evidence that if the drug is given within the first 3 days, it reduces duration of viral shedding, which is 14 days without treatment compared with 7 days for seasonal influenza. Oseltamivir did a good job of limiting disease transmission during outbreaks in nursing homes and other closed communities.
Under an Emergency Use Authorization issued during last year’s pandemic, oseltamivir became available for the treatment of patients of all ages with H1N1 flu. Recent interim data from a National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial suggest the best dose in infants is 3 mg/kg/dose twice daily. In premature babies, the optimal dose appears to be 1 mg/kg/dose twice daily (J. Infect. Dis. Aug. 15, 2010;202:563-6).
In the middle of last year’s pandemic, the World Health Organization recommended that the standard 75-mg b.i.d adult and adolescent dose of oseltamivir could be doubled in severe cases of H1N1 disease, an announcement Dr. Weinberg dismissed as “weirdness that made little sense” since the pharmacokinetics of the drug are linear up to 500 mg/dose.
“Why would you go from 75 mg to 150 and not to 300 mg/dose?” she asked. Her advice: Consider quadrupling the standard dose in severe cases.
Prophylactic administration of oseltamivir is a common inducer of resistance in immunocompetent patients, which is why the WHO recommends not using the drug for prophylaxis. Resistance also develops quickly in lung transplant recipients.
There was concern that oseltamivir resistance would spread widely through communities, but that didn’t prove to be the case. All documented cases have occurred in patients on oseltamivir or in close contacts of patients treated with the drug, according to Dr. Weinberg.
Two recent animal studies reached dead opposite conclusions regarding the pathogenicity of oseltamivir-resistant H1N1 strains. One study showed the drug-resistant strains were less pathogenic than wild-type virus, whereas the other study found that the drug-resistant and wild-type viruses had similar pathogenicity. Clearly, more work is needed in this area, she noted.
Dr. Weinberg disclosed serving as a consultant to MedImmune, Astellas, GlaxoSmithKline, and Merck.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
科罗拉多州维尔(EGMN)——在治疗大流行性2009 H1N1流感方面，目前有两种具治疗前景的试验药即将在下几季流感季节上市，这对解决当下的亟需现状将大有助益。
Favipiravir和 laninamivir在国外均处于III期临床试验阶段，目前看来效果极好，Adriana Weinberg博士在丹佛儿科医院主办的儿科传染病年会上说。
Favipiravir是一种能有效对抗甲型和乙型流感以及其他RNA病毒的口服RNA多聚酶抑制剂，在日本处于III期试验阶段。重要的是，该药与神经氨酸酶抑制剂或金刚烷胺类药物无交叉耐药性。
Laninamivir是一种仅通过吸入给药的神经氨酸酶抑制剂，但该药半衰期极长，单次吸入即构成一个完整的疗程。Laninamivir可有效对抗奥司他韦耐药分离株，在澳大利亚处于III期临床试验阶段，经证实其安全性极优，据科罗拉多大学丹佛校区医学、儿科学及病理学教授Weinberg博士说。
当前大流行性H1N1流感的治疗选择相当有限，因此这两种新药的上市可解燃眉之急，她说。
由2009年度大流行中分离出的H1N1分离株中有90%以上对金刚烷胺类药物耐药，因此基本上所有的医生早先有的治疗药为口服神经氨酸酶抑制剂奥司他韦和另一种神经氨酸酶抑制剂、仅经吸入用药的扎那米韦。
大流行期间的新增疗法为静脉注射peramivir，该药在III期临床试验中获准用于治疗危重患者，此为紧急使用授权的结果。紧急使用授权终止于2010年6月。Peramivir有耐药谱，疗效类似于奥司他韦。因此，其惟一的优势为可静脉给药。新生儿的推荐剂量为6 mg/kg，31~90天的婴儿为8 mg/kg，91~180天的婴儿为10 mg/kg，181天~5岁的孩子为12 mg/kg，均在30~60 min内输完。
大流行期间可少量应用静脉扎那米韦。与peramivir不同，该药可有效对抗奥司他韦耐药分离株。
市售的利巴韦林适应证不仅限于流感。但该药在体外确实具有对抗流感病毒的活性，尽管其本身并不是一种非常好的抗流感药，不过今后可能会用于重度流行性H1N1流感的联合治疗。
神经氨酸酶抑制剂、利巴韦林、金刚烷胺及干扰素联合治疗被广泛用于甲型禽流感的治疗中，但由于缺乏对照，很难界定这种联合治疗方案是否能增加疗效。在动物模型中，应用两种抗大流行性H1N1流感药物的疗效优于应用一种，无论是什么试验药，前提是病毒对这两种药均敏感。因此若病毒耐药，则结果就会颇具争议，Weinberg博士说。
奥司他韦在对抗上季大流行性H1N1流感是疗效很好。若在起病后的2天内使用该药开始治疗，则死亡率会减少50%，此外，还可以减少症状的持续时间。有证据显示，若在3天内给予此药，则会减少季节性流感病毒的脱落时间：无治疗的情况下为14天，治疗后为7天。在养老院或其他封闭的社区中，应用奥司他韦在限制流感暴发期间的疾病传播性方面成效卓著。
在去年大流行期间，在紧急使用授权下，奥司他韦用于治疗各年龄段的H1N1流感患者。近期的国家过敏和传染性疾病研究所联合抗病毒研究组试验的中期数据显示，婴幼儿的最佳剂量为3 mg/kg/剂，2次/天。在早产儿中，最佳剂量看似为1 mg/kg/剂，2次/天(J. Infect. Dis. Aug. 15, 2010;202:563-6)。
在去年大流行的中期，世界卫生组织(WHO)推荐对于重度H1N1流感，可以将成人和青少年奥司他韦的剂量——75 mg，3次/天——加倍应用，Weinberg博士将此声明以“几无意义的古怪做法”予以驳回，因为该药的药代动力学的线性关系达500 mg/剂。
“你为什么会由75 mg升至150 mg，而不是300 mg/剂？”她问道。她的建议是：对重度流感病例可考虑应用4倍的标准剂量。
对于有免疫力的患者预防性应用奥司他韦常导致耐药性的产生，这是WHO不推荐将该药用于预防的原因。肺移植患者耐药性的产生速度很快。
令人担忧的是，奥司他韦耐药性可能会在社区广泛蔓延，但这还没有得到证实。所有的确诊病例均发生于奥司他韦治疗者或与接受该药治疗者的密切接触者之中，Weiberg博士说。
在对奥司他韦耐药的H1N1流感毒株的致病性方面，近期有两项结果得出了截然相反的结论。一项研究表明，耐药毒株的致病性小于野生型病毒，而另一研究发现耐药毒株与野生型病毒的致病性相近。显而易见，在这方面还需要进行更多的工作，她指出。
Weinberg博士披露担任医学免疫公司、安斯泰来公司、葛兰素史克公司以及默克公司的顾问。
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