Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh

Abstract

BackgroundAmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh.MethodsThe safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually randomized clinical trial. Patients from 5 to 60 years with uncomplicated primary VL were recruited from the Community Based Medical College Bangladesh (CBMC,B) and the Upazila Health Complexes of Trishal, Bhaluka and Fulbaria (all located in Mymensingh district), and randomly assigned to one of the treatments. The objective was to assess safety and definitive cure at 6 months after treatment.Results601 patients recruited between July 2010 and September 2013 received either AmBisome monotherapy (n = 158), AmBisome + paromomycin (n = 159), AmBisome + miltefosine (n = 142) or paromomycin + miltefosine (n = 142). At 6 months post- treatment, final cure rates for the intention-to-treat population were 98.1% (95%CI 96.0–100) for AmBisome monotherapy, 99.4% (95%CI 98.2–100) for the AmBisome + paromomycin arm, 94.4% (95%CI 90.6–98.2) for the AmBisome + miltefosine arm, and 97.9% (95%CI 95.5–100) for paromomycin + miltefosine arm. There were 12 serious adverse events in the study in 11 patients that included 3 non-study drug related deaths. There were no relapses or PKDL up to 6 months follow-up. All treatments were well tolerated with no unexpected side effects. Adverse events were most frequent during treatment with miltefosine + paromomycin, three serious adverse events related to the treatment occurred in this arm, all of which resolved.ConclusionNone of the combinations were inferior to AmBisome in both the intention-to-treat and per-protocol populations. All the combinations demonstrated excellent overall efficacy, were well tolerated and safe, and could be deployed under field conditions in Bangladesh. The trial was conducted by the International Centre for Diarrhoeal Disease Research (ICDDR,B) and the Shaheed Suhrawardy Medical College (ShSMC), Dhaka, in collaboration with the trial sites and sponsored by the Drugs for Neglected Diseases initiative (DNDi).Trial registrationClinicalTrials.gov NCT01122771

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…In an open-label, randomized trial of AmBisome ® alone or in combination with miltefosine to treat VL in HIV co-infected Ethiopian patients (NCT02011958), the combination regimen presented the highest documented efficacy and was recommended as first-line therapy for VL in East African HIV patients [252]. Short course combination regimens including AmBisome ® , miltefosine, and paromycin for the treatment of VL have proved to be safe, well-tolerated, and not inferior in efficacy to AmBisome ® monotherapy in phase III clinical trials conducted in India (NCT00696969) and Bangladesh (NCT01122771) enrolling 634 and 601 patients, respectively, with no relapses or PKDL observed up to six months follow-up [253,254].…”

Genomic and Metabolomic Polymorphism among Experimentally Selected Paromomycin-Resistant Leishmania donovani Strains

“…Paromomycin (PMM) is an aminoglycoside antibiotic that has been shown to have activity against Leishmania and that is increasingly tested in combination regimens (6). In Bangladesh, in combination with MIL or AmBisome, PMM showed efficacy similar to that of AmBisome monotherapy for the treatment of VL (7). A study has shown that combined sodium stibogluconate (SSG) and PMM treatment in Sudan, Kenya, Uganda, and Ethiopia was an effective first-line option for VL chemotherapy (8).…”

Visceral Leishmaniasis in a Non-Endemic Region of India- Investigation of an Outbreak

“…Various combinations containing both amphotericin and miltefosine are widely used in the management of visceral leishmaniasis. 8 But the recent evidences of lab-confirmed miltefosine resistant visceral leishmaniasis should be a pointer in the adoption of comprehensive treatment strategies for the disease. 9 The longer duration of illness in this patient and in other non-endemic areas are mostly due to the delay in diagnosis.…”

“…2,7 Also, the clinical management of VL is undergoing rapid changes with the use of liposomal forms of Amphotericin B and also due to the use of various combinations of miltefosine, amphotericin B, paromomycin etc. 8 But the healthcare professionals are facing newer challenges due to the emergence of miltefosine resistant forms of VL. 9 This points to the need for early identification and management of suspicious cases by healthcare professionals.…”