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

Abstract

BackgroundVisceral 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 FindingsIntravenous 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.SignificanceThis 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.

Nanoliposomal Buparvaquone Immunomodulates Leishmania infantum-Infected Macrophages and Is Highly Effective in a Murine Model

“…Phosphatidylserine-treated liposomes have proved an efficient tool for delivering drugs to Leishmania-infected macrophages (9,12). The association of negatively charged phosphatidylserine with liposomes improves the selective uptake by macrophages via scavenger receptors, resulting in higher in vitro (12) and in vivo efficacies against Leishmania parasites (13).…”

“…Amphotericin B has been used in clinical therapy for leishmaniasis for many years in the form of a safe liposomal formulation named Ambisome (9). However, liposomal formulations must be adequately designed for delivery or for a specific disease, and this requires includes previous knowledge of the target cells, as well as of the physicalchemical properties, including (i) the size, (ii) the surface charge, (iii) the phase transition temperature of phospholipids, (iv) the amount of cholesterol, and (v) the host cell surface receptors (10).…”

Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

“…Recently, oral miltefosine was approved by the U.S. Food and Drug Administration, while liposomal amphotericin B is in clinical trials for treatment against cutaneous and visceral leishmaniasis (4,5). In addition, the increasing incidence of drug resistance in Leishmania renders currently available treatment options ineffective and further drives the need for new therapeutic agents.…”

Short-Course Treatment Regimen of Indian Visceral Leishmaniasis with an Indian Liposomal Amphotericin B Preparation (Fungisome™)

“…Interestingly, the mean spleen size of our patients were much greater than recently reported literature. 26 This we believe is due to late presentation of rural patient in the metropolitan tertiary care centers that our study represents. However, despite such late presentation the excellent efficacy of the presented regimen brings hope.…”