A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia
A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia
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DOI：
10.1371/journal.pntd.0006988
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Alvar, Jorge
中科院分区：
文献类型：
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作者：
Diro, Ermias;Blesson, Severine;Alvar, Jorge
背景 人类免疫缺陷病毒 (HIV) 合并感染患者的内脏利什曼病 (VL) 需要特殊的病例管理。世界卫生组织推荐 40 mg/kg AmBisome 单药治疗。该研究的目的是评估较低剂量的 AmBisome 与米替福辛的组合在治疗结束时是否会显示出可接受的疗效。 方法/主要结果 在埃塞俄比亚 VL 合并感染 HIV 的患者中进行了一项开放标签、非比较性随机试验，AmBisome (30 mg/kg) 与米替福辛 (100 mg/天，持续 28 天)，以及 AmBisome 单药治疗 (40 mg/kg) （NCT02011958）。使用具有三角形连续区域的顺序设计。主要结果是第一轮治疗后第 29 天的寄生虫清除情况。第 29 天临床改善但寄生虫未清除的患者接受了第二轮分配的治疗。治疗完成后第58天再次评估疗效。根据预先指定的停止规则，在单药治疗组和联合治疗组分别纳入 19 名和 39 名患者后，招募被停止。在第 29 天，AmBisome 组的意向治疗疗效在未经调整的分析中为 70% (95% CI 45-87%)，在调整分析中为 50% (95% CI 27-73%)，而在联合治疗组中，分别为 81% (95% CI 67-90%) 和 67% (95% CI 48-82%)。在第 58 天，单药治疗组的调整后疗效为 55%（95% CI 32-78%），联合治疗组为 88%（95% CI 79-98%）。没有发现与研究药物相关的重大安全问题。治疗期间观察到 10 例 SAE，其中 4 例与研究药物无关的死亡。 结论/意义 采用联合方案的扩展治疗策略在 HIV-VL 患者中显示出最高的记录疗效；这些结果支持建议将该方案作为东非 HIV-VL 患者的一线治疗策略。试验注册号 www.clinicaltrials.gov NCT02011958。作者摘要 内脏利什曼病是一种复杂的寄生虫病，对于同时感染人类免疫缺陷病毒 (HIV) 的患者来说治疗起来尤其具有挑战性。在东非，用于免疫功能正常患者一线治疗的锑药物对免疫功能低下患者的毒性更大。 2010年，世界卫生组织专家委员会根据在西班牙进行的一项临床试验以及从使用AmBisome（脂质体两性霉素B）的分散病例报告中获得的经验信息，推荐将两性霉素B脂质制剂作为HIV/VL合并感染患者的一线治疗。此外，无国界医生组织在埃塞俄比亚西北部的一个治疗中心开始了一项结合 AmBisome 和米替福辛 a 的同情用药方案，取得了令人鼓舞的结果。在此，我们报告了一项试验的结果，该试验旨在评估目前国际推荐的 AmBisome 单一疗法和新的 AmBisome-米替福辛联合疗法在埃塞俄比亚患者中的有效性和安全性。该试验的结果表明，任一方案的一个疗程可能不足以清除大部分患者的寄生虫，而进行第二个疗程的扩展治疗策略可能会导致接受联合方案治疗的患者的寄生虫清除率较高。
Background Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment.Methodology/Principal findings An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment. Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45-87%) in the unadjusted analysis, and 50% (95% CI 27-73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67-90%) and 67% (95% CI 48-82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32-78%) in the monotherapy arm, and 88% (95% CI 79-98%) in the combination arm. No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication.Conclusions/Significance The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa.Trial registration number www.clinicaltrials.gov NCT02011958.Author summary Visceral Leishmaniasis is a complex parasitological disease and is particularly challenging to treat in patients coinfected with human immunodeficiency virus (HIV). Antimonial drugs used in first-line treatments for immunocompetent patients in eastern Africa are more toxic in immunocompromised patients. In 2010, a WHO expert committee recommended a lipid formulation of amphotericin B as first line treatment for HIV/VL co-infected patients, based on a single clinical trial conducted in Spain and empirical information obtained from scattered case reports using AmBisome (liposomal amphotericin B). In addition, Medecins Sans Frontieres began a compassionate use regimen combining AmBisome and miltefosine a in a treatment centre in Northwest Ethiopia with encouraging results. Here, we report the results of a trial to assess the efficacy and safety of both the currently internationally recommended treatment of AmBisome monotherapy and the new AmBisome-miltefosine combination regimen, in Ethiopian patients. The results of this trial show that one course of treatment with either regimen could be insufficient to clear parasites in a high proportion of patients and that an extended treatment strategy, of administrating a second course of treatment, could lead to a high parasite clearance rate in patients treated with the combination regimen.