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Abstract：
BACKGROUND: Severe malaria is a life-threatening infection, particularly affecting children under the age of 5 years in Africa. Current treatment with parenteral artemisinin derivatives is highly efficacious. However, artemisinin partial resistance is widespread in Southeast Asia, resulting in delayed parasite clearance after therapy, and has emerged independently in South America, Oceania, and Africa. Hence, new treatments for severe malaria are needed, and it is prudent to define their characteristics now. This manuscript focuses on the target product profile (TPP) for new treatments for severe malaria. It also highlights preparedness when considering ways of protecting the utility of artemisinin-based therapies.
UNASSIGNED: Severe malaria treatments must be highly potent, with rapid onset of antiparasitic activity to clear the infection as quickly as possible to prevent complications. They should also have a low potential for drug resistance selection, given the high parasite burden in patients with severe malaria. Combination therapies are needed to deter resistance selection and dissemination. Partner drugs which are approved for uncomplicated malaria treatment would provide the most rapid development pathway for combinations, though new candidate molecules should be considered. Artemisinin combination approaches to severe malaria would extend the lifespan of current therapy, but ideally, completely novel, non-artemisinin-based combination therapies for severe malaria should be developed. These should be advanced to at least phase 2 clinical trials, enabling rapid progression to patient use should current treatment fail clinically. New drug combinations for severe malaria should be available as injectable formulations for rapid and effective treatment, or as rectal formulations for pre-referral intervention in resource-limited settings.
CONCLUSIONS: Defining the TPP is a key step to align responses across the community to proactively address the potential for clinical failure of artesunate in severe malaria. In the shorter term, artemisinin-based combination therapies should be developed using approved or novel drugs. In the longer term, novel combination treatments should be pursued. Thus, this TPP aims to direct efforts to preserve the efficacy of existing treatments while improving care and outcomes for individuals affected by this life-threatening disease.
UNASSIGNED: Severe malaria treatments must be highly potent, with rapid onset of antiparasitic activity to clear the infection as quickly as possible to prevent complications. They should also have a low potential for drug resistance selection, given the high parasite burden in patients with severe malaria. Combination therapies are needed to deter resistance selection and dissemination. Partner drugs which are approved for uncomplicated malaria treatment would provide the most rapid development pathway for combinations, though new candidate molecules should be considered. Artemisinin combination approaches to severe malaria would extend the lifespan of current therapy, but ideally, completely novel, non-artemisinin-based combination therapies for severe malaria should be developed. These should be advanced to at least phase 2 clinical trials, enabling rapid progression to patient use should current treatment fail clinically. New drug combinations for severe malaria should be available as injectable formulations for rapid and effective treatment, or as rectal formulations for pre-referral intervention in resource-limited settings.
CONCLUSIONS: Defining the TPP is a key step to align responses across the community to proactively address the potential for clinical failure of artesunate in severe malaria. In the shorter term, artemisinin-based combination therapies should be developed using approved or novel drugs. In the longer term, novel combination treatments should be pursued. Thus, this TPP aims to direct efforts to preserve the efficacy of existing treatments while improving care and outcomes for individuals affected by this life-threatening disease.
摘要：
背景：严重疟疾是一种危及生命的感染，特别影响非洲5岁以下儿童。目前使用肠胃外青蒿素衍生物的治疗是非常有效的。然而,青蒿素部分耐药性在东南亚普遍存在，导致治疗后寄生虫清除延迟，并在南美独立出现，大洋洲,和非洲。因此，需要治疗严重疟疾的新疗法，现在确定它们的特征是谨慎的。该手稿着重于针对严重疟疾的新疗法的目标产品概况（TPP）。它还强调了在考虑保护青蒿素疗法效用的方法时的准备。
■重症疟疾治疗必须非常有效，具有快速起效的抗寄生虫活性，以尽快清除感染，以防止并发症。它们还应该具有低的耐药性选择潜力，鉴于严重疟疾患者的高寄生虫负担。需要联合疗法来阻止抗性选择和传播。批准用于简单疟疾治疗的伙伴药物将为联合用药提供最快速的发展途径，尽管应该考虑新的候选分子。青蒿素联合治疗严重疟疾的方法将延长目前治疗的寿命，但理想情况下，完全新颖,应开发针对严重疟疾的非青蒿素类联合疗法。这些应该推进到至少2期临床试验，如果当前治疗在临床上失败，则能够快速进展为患者使用。治疗严重疟疾的新药组合应作为可注射制剂提供，以便快速有效地治疗。或在资源有限的情况下作为转诊前干预的直肠制剂。
结论：确定TPP是调整整个社区反应的关键步骤，以积极应对青蒿琥酯在严重疟疾中临床失败的可能性。从短期来看,以青蒿素为基础的联合疗法应使用批准的药物或新药开发。从长远来看，应该寻求新的联合治疗。因此，该TPP旨在指导努力保持现有治疗的疗效，同时改善受这种危及生命的疾病影响的个体的护理和结果。
■重症疟疾治疗必须非常有效，具有快速起效的抗寄生虫活性，以尽快清除感染，以防止并发症。它们还应该具有低的耐药性选择潜力，鉴于严重疟疾患者的高寄生虫负担。需要联合疗法来阻止抗性选择和传播。批准用于简单疟疾治疗的伙伴药物将为联合用药提供最快速的发展途径，尽管应该考虑新的候选分子。青蒿素联合治疗严重疟疾的方法将延长目前治疗的寿命，但理想情况下，完全新颖,应开发针对严重疟疾的非青蒿素类联合疗法。这些应该推进到至少2期临床试验，如果当前治疗在临床上失败，则能够快速进展为患者使用。治疗严重疟疾的新药组合应作为可注射制剂提供，以便快速有效地治疗。或在资源有限的情况下作为转诊前干预的直肠制剂。
结论：确定TPP是调整整个社区反应的关键步骤，以积极应对青蒿琥酯在严重疟疾中临床失败的可能性。从短期来看,以青蒿素为基础的联合疗法应使用批准的药物或新药开发。从长远来看，应该寻求新的联合治疗。因此，该TPP旨在指导努力保持现有治疗的疗效，同时改善受这种危及生命的疾病影响的个体的护理和结果。
