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Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh
BACKGROUND: AmBisome 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....
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466346/ https://www.ncbi.nlm.nih.gov/pubmed/28558062 http://dx.doi.org/10.1371/journal.pntd.0005635 |
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author | Rahman, Ridwanur Goyal, Vishal Haque, Rashidul Jamil, Kazi Faiz, Abul Samad, Rasheda Ellis, Sally Balasegaram, Manica den Boer, Margriet Rijal, Suman Strub-Wourgaft, Nathalie Alves, Fabiana Alvar, Jorge Sharma, Bhawna |
author_facet | Rahman, Ridwanur Goyal, Vishal Haque, Rashidul Jamil, Kazi Faiz, Abul Samad, Rasheda Ellis, Sally Balasegaram, Manica den Boer, Margriet Rijal, Suman Strub-Wourgaft, Nathalie Alves, Fabiana Alvar, Jorge Sharma, Bhawna |
author_sort | Rahman, Ridwanur |
collection | PubMed |
description | BACKGROUND: AmBisome 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. METHODS: The 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. RESULTS: 601 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. CONCLUSION: None 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 REGISTRATION: ClinicalTrials.gov NCT01122771 |
format | Online Article Text |
id | pubmed-5466346 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54663462017-06-22 Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh Rahman, Ridwanur Goyal, Vishal Haque, Rashidul Jamil, Kazi Faiz, Abul Samad, Rasheda Ellis, Sally Balasegaram, Manica den Boer, Margriet Rijal, Suman Strub-Wourgaft, Nathalie Alves, Fabiana Alvar, Jorge Sharma, Bhawna PLoS Negl Trop Dis Research Article BACKGROUND: AmBisome 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. METHODS: The 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. RESULTS: 601 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. CONCLUSION: None 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 REGISTRATION: ClinicalTrials.gov NCT01122771 Public Library of Science 2017-05-30 /pmc/articles/PMC5466346/ /pubmed/28558062 http://dx.doi.org/10.1371/journal.pntd.0005635 Text en © 2017 Rahman et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Rahman, Ridwanur Goyal, Vishal Haque, Rashidul Jamil, Kazi Faiz, Abul Samad, Rasheda Ellis, Sally Balasegaram, Manica den Boer, Margriet Rijal, Suman Strub-Wourgaft, Nathalie Alves, Fabiana Alvar, Jorge Sharma, Bhawna Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh |
title | Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh |
title_full | Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh |
title_fullStr | Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh |
title_full_unstemmed | Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh |
title_short | Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh |
title_sort | safety and efficacy of short course combination regimens with ambisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (vl) in bangladesh |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466346/ https://www.ncbi.nlm.nih.gov/pubmed/28558062 http://dx.doi.org/10.1371/journal.pntd.0005635 |
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