Five-Year Field Results and Long-Term Effectiveness of 20 mg/kg Liposomal Amphotericin B (Ambisome) for Visceral Leishmaniasis in Bihar, India

Background
Visceral Leishmaniasis (VL; also known as Kala-azar) is an ultimately fatal disease endemic in Bihar. A 2007 observational cohort study in Bihar of 251 patients with VL treated with 20 mg/Kg intravenous liposomal amphotericin B (Ambisome) demonstrated a 98% cure rate at 6-months. Between July 2007 and August 2012, Médecins Sans Frontières (MSF) and the Rajendra Memorial Research Institute (RMRI) implemented a VL treatment project in Bihar, India—an area highly endemic for Leishmania donovani—using this regimen as first-line treatment.
Methods and Principal Findings
Intravenous Ambisome 20 mg/kg was administered in four doses of 5 mg/kg over 4–10 days, depending on the severity of disease. Initial clinical cure at discharge was defined as improved symptoms, cessation of fever, and recession of spleen enlargement. This observational retrospective cohort study describes 8749 patients with laboratory-confirmed primary VL treated over a 5-year period: 1396 at primary healthcare centers, 7189 at hospital, and 164 at treatment camps. Initial clinical cure was achieved in 99.3% of patients (8692/8749); 0.3% of patients (26/8749) defaulted from treatment and 0.4% (31/8749) died. Overall, 1.8% of patients (161/8749) were co-infected with HIV and 0.6% (51/8749) with tuberculosis. Treatment was discontinued because of severe allergic reactions in 0.1% of patients (7/8749). Overall, 27 patients (0.3%) were readmitted with post Kala-azar dermal leishmaniasis (PKDL). Risk factors for late presentation included female sex, age >15 years and being from a scheduled caste.
In 2012, a long-term efficacy survey in the same area of Bihar determined relapse rates of VL after 5 years' intervention with Ambisome. Of 984 immunocompetent patients discharged between September 2010 and December 2011, 827 (84.0%) were traced in order to determine their long-term outcomes. Of these, 20 patients (2.4%) had relapsed or received further treatment for VL. Of those completing 6, 12, and 15 month follow-up, 0.3% (2/767), 3.7% (14/383), and 2.4% (4/164), respectively, had relapsed. The mean ±SD time-to-relapse was 9.6±3.0 months.
Significance
This is the largest cohort of VL patients treated with 20 mg/kg Ambisome worldwide. The drug has high initial and long-term efficacy, and a low rate of adverse reactions when administered under field conditions in Bihar, India. Although challenging, its use as first line treatment in rural settings in Bihar is safe and feasible.

### 背景
内脏利什曼病（Visceral Leishmaniasis，VL，又称黑热病Kala-azar）是一种最终可致命的地方性疾病，在印度比哈尔邦广泛流行。2007年一项在比哈尔邦开展的观察性队列研究纳入251例VL患者，给予20 mg/kg静脉输注脂质体两性霉素B（liposomal amphotericin B，Ambisome）治疗，结果显示患者在6个月时的治愈率达98%。2007年7月至2012年8月期间，无国界医生（Médecins Sans Frontières，MSF）与拉金德拉纪念研究所（Rajendra Memorial Research Institute，RMRI）在印度比哈尔邦——杜氏利什曼原虫（Leishmania donovani）的高流行区域——开展了一项VL治疗项目，将上述给药方案作为一线治疗方案。

### 方法与主要研究结果
安必素（Ambisome）以20 mg/kg的总剂量静脉输注，分4次给予5 mg/kg，给药周期为4至10天，具体根据疾病严重程度调整。出院时的初始临床治愈定义为症状改善、发热停止以及脾脏肿大消退。本观察性回顾性队列研究纳入了8749例经实验室确诊的原发性VL患者，这些患者在5年期间内接受治疗，其中1396例在初级医疗中心接受治疗，7189例在医院接受治疗，164例在治疗营地接受治疗。99.3%的患者（8692/8749）实现了初始临床治愈；0.3%的患者（26/8749）中途放弃治疗，0.4%的患者（31/8749）死亡。整体而言，1.8%的患者（161/8749）合并人类免疫缺陷病毒（HIV）感染，0.6%的患者（51/8749）合并结核病。0.1%的患者（7/8749）因严重过敏反应终止治疗。总计27例患者（0.3%）因黑热病后皮肤利什曼病（Post Kala-azar Dermal Leishmaniasis，PKDL）再次入院。就诊延迟的危险因素包括女性性别、年龄大于15岁以及来自在册种姓群体。

2012年，研究团队在比哈尔邦同一区域开展了一项长期疗效调查，旨在评估安必素（Ambisome）干预5年后VL的复发率。在2010年9月至2011年12月期间出院的984例免疫功能正常患者中，研究人员成功追踪到827例（84.0%）以评估其长期转归。其中20例患者（2.4%）出现VL复发或需接受后续VL治疗。在完成6个月、12个月和15个月随访的患者中，复发率分别为0.3%（2/767）、3.7%（14/383）和2.4%（4/164）。复发的平均时间±标准差为9.6±3.0个月。

### 研究意义
本研究是全球范围内纳入接受20 mg/kg安必素治疗的VL患者规模最大的队列研究。在印度比哈尔邦的现场条件下给药时，该药物具有较高的初始及长期疗效，且不良反应发生率较低。尽管存在挑战，但在比哈尔邦的农村地区将其作为一线治疗方案是安全且可行的。