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      Paromomycin for the Treatment of Visceral Leishmaniasis in Sudan: A Randomized, Open-Label, Dose-Finding Study

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          Abstract

          Background

          A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.

          Methods

          This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.

          Findings

          42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).

          Conclusion

          Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

          Trial Registration

          ClinicalTrials.gov NCT00255567

          Author Summary

          Visceral leishmaniasis (VL) is a parasitic disease transmitted through the bite of sandflies. The WHO estimates 500,000 new cases of VL each year, with more than 90% of cases occurring in Southeast Asia, East Africa, and South America. If left untreated, VL can be fatal. We had previously conducted a large multi-center study in Sudan, East Africa, to assess the efficacy of paromomycin (PM) alone or in combination with sodium stibogluconate. Clinical studies in India have shown that 15 mg/kg/day PM for 21 days was an effective cure. However, the same treatment regimen was not efficacious in two study sites in Sudan. Here, our aim was to assess two high-dose regimens of PM in Sudan: 15 mg/kg/day for 28 days and 20 mg/kg/day for 21 days. The results suggest that, at these total doses, PM is more efficacious than when given daily at 15 mg/kg for 21 days, and that high doses are required to treat VL in Sudan. Efficacy of 20 mg/kg/day PM for 21 days is currently being evaluated in a prospective, comparative phase III trial in East Africa.

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          Most cited references 8

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          Leishmaniasis. Public health aspects and control.

           P Desjeux (2015)
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            Quantitation of amastigotes of Leishmania donovani in smears of splenic aspirates from patients with visceral leishmaniasis.

             J Chulay,  A Bryceson (1983)
            During a 20-month period, more than 500 splenic aspirations were performed in 89 patients with suspected or proven visceral leishmaniasis. The two complications which occurred (intra-abdominal bleeding and penetration of the intestine in one patient each) both resolved with conservative management. Parasite density in splenic aspirate smears was graded on a logarithmic scale from 0 (no parasites in 1,000 microscopic fields) to 6+ (greater than 100 parasites per microscopic field). Among 46 newly diagnosed and 17 relapsed or drug-resistant patients with visceral leishmaniasis, the average initial parasite grade was 4.35 +/- 0.92 (mean +/- SD) and 4.15 +/- 1.37, respectively. The grading system was useful in measuring the speed of response to treatment, and in distinguishing slow responders from nonresponders. This was especially valuable for managing patients with drug-resistant visceral leishmaniasis. The system also provided a means of comparing the efficacy of different treatment regimens, and for calculating the optimum duration of treatment.
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              Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India.

              To assess the efficacy and tolerability of aminosidine compared with sodium stibogluconate for treating visceral leishmaniasis. Randomised, unblinded, controlled trial with 180 day follow up. Kala-Azar Research Centre, Brahmpura, Muzaffarpur, Bihar, India. People of either sex aged 6-50 years with symptoms and signs suggestive of visceral leishmaniasis (fever, loss of appetite, enlarged spleen) with leishmania amastigotes detected in Giemsa stained aspirates of spleen or bone marrow. Aminosidine at three daily doses (12, 16, and 20 mg/kg) for 21 days and sodium stibogluconate 20 mg/kg/day for 30 days. Laboratory measures of efficacy: parasite count, haemoglobin concentration, white cell count, platelet count, serum albumin concentration. Clinical measures of efficacy: spleen size, fever, body weight, and liver size. Measures of safety: liver and renal function tests, reports of adverse events. Of the 120 patients enrolled (30 per treatment arm), 119 completed treatment and follow up. Cure at end of follow up was achieved in 23 (77%), 28 (93%), and 29 (97%) patients treated with 12, 16, and 20 mg aminosidine/kg/day respectively, and in 19 (63%) patients given sodium stibogluconate. At 16 and 20 mg/kg/day, aminosidine was significantly more active than sodium stibogluconate in both clinical and laboratory measures of efficacy. No significant clinical or laboratory toxicity occurred in any treatment group. A 21 day course of aminosidine 16 or 20 mg/kg/day should be considered as first line treatment for visceral leishmaniasis in Bihar.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                October 2010
                26 October 2010
                : 4
                : 10
                Affiliations
                [1 ]Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan
                [2 ]Faculty of Medicine, Gedaref University, Gedaref, Sudan
                [3 ]Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland
                [4 ]Centre for Clinical Research, Kenya Medical Research Institute (KEMRI), Nairobi, Kenya
                [5 ]Addis Ababa University, Addis Ababa, Ethiopia
                [6 ]London School of Hygiene and Tropical Medicine, London, United Kingdom
                [7 ]Faculty of Pharmacy, University of Nairobi, Nairobi, Kenya
                [8 ]Consortium for National Health Research (CNHR), Nairobi, Kenya
                London School of Hygiene and Tropical Medicine, United Kingdom
                Author notes

                Conceived and designed the experiments: AMM CR MB MW AH GK AEH EK. Performed the experiments: AMM BY AF MM GK EK. Analyzed the data: AMM CR MB TE RO GK EK. Contributed reagents/materials/analysis tools: CR. Wrote the paper: AMM CR MB MW AH TE RO GK AEH EK.

                Article
                10-PNTD-RA-0869R3
                10.1371/journal.pntd.0000855
                2964291
                21049063
                Musa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 7
                Categories
                Research Article
                Infectious Diseases
                Infectious Diseases/Epidemiology and Control of Infectious Diseases
                Infectious Diseases/Neglected Tropical Diseases

                Infectious disease & Microbiology

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