Geographical Variation in the Response of Visceral Leishmaniasis to Paromomycin in East Africa: A Multicentre, Open-Label, Randomized Trial

Addis Ababa University, Addis Ababa, Ethiopia.
PLoS Neglected Tropical Diseases (Impact Factor: 4.45). 10/2010; 4(10):e709. DOI: 10.1371/journal.pntd.0000709
Source: PubMed


Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India.
This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment.
Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified.
The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.

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    • "Paromomycin presents variable efficacy in distinct parts of the world (89). The drug’s low-cost, relatively short duration of administration, and good safety profile strengthens its usefulness as a first-line drug (90). "
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    ABSTRACT: Leishmaniasis has several clinical forms: self-healing or chronic cutaneous leishmaniasis or post-kala-azar dermal leishmaniasis; mucosal leishmaniasis; visceral leishmaniasis (VL), which is fatal if left untreated. The epidemiology and clinical features of VL vary greatly due to the interaction of multiple factors including parasite strains, vectors, host genetics, and the environment. Human immunodeficiency virus infection augments the severity of VL increasing the risk of developing active disease by 100-2320 times. An effective vaccine for humans is not yet available. Resistance to chemotherapy is a growing problem in many regions, and the costs associated with drug identification and development, make commercial production for leishmaniasis, unattractive. The toxicity of currently drugs, their long treatment course, and limited efficacy are significant concerns. For cutaneous disease, many studies have shown promising results with immunotherapy/immunochemotherapy, aimed to modulate and activate the immune response to obtain a therapeutic cure. Nowadays, the focus of many groups centers on treating canine VL by using vaccines and immunomodulators with or without chemotherapy. In human disease, the use of cytokines like interferon-γ associated with pentavalent antimonials demonstrated promising results in patients that did not respond to conventional treatment. In mice, immunomodulation based on monoclonal antibodies to remove endogenous immunosuppressive cytokines (interleukin-10) or block their receptors, antigen-pulsed syngeneic dendritic cells, or biological products like Pam3Cys (TLR ligand) has already been shown as a prospective treatment of the disease. This review addresses VL treatment, particularly immunotherapy and/or immunochemotherapy as an alternative to conventional drug treatment in experimental models, canine VL, and human disease.
    Frontiers in Immunology 06/2014; 5(272). DOI:10.3389/fimmu.2014.00272
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    • "This treatment arm was discontinued, and the trial continued with a higher dose of paromomycin 20 mg/kg/day for 21 days. After 6 months, the overall response rates were 92.2 % with sodium stibogluconate and 63.8 % with paromomycin; however, the efficacy of paromomycin varied substantially between geographical areas, with cure rates of 14.3–46.7 % in Sudan, 80 % in Kenya and 75–96.6 % in Ethiopia [94]. Faced with this low response in Sudan, a new comparative study was carried out with higher doses of paromomycin, either increasing the duration of treatment from 21 to 28 days or increasing the daily dose from 15 to 20 mg base. "
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    ABSTRACT: Visceral leishmaniasis (VL), also known as Kala-Azar, is a disseminated protozoal infection caused principally by Leishmania donovani and Leishmania infantum (known as Leishmania chagasi in South America). The therapeutic options for VL are diverse and depend on different factors, such as the geographical area of the infection, development of resistance to habitual treatments, HIV co-infection, malnourishment and other concomitant infections. This article provides an exhaustive review of the literature regarding studies published on the treatment of VL, and gives therapeutic recommendations stratified according to their level of evidence, the species of Leishmania implicated and the geographical location of the infection.
    Drugs 10/2013; 73(17). DOI:10.1007/s40265-013-0133-0 · 4.34 Impact Factor
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    • "Desjeux, IoWH, pers comm.). A phase III VL clinical trial with the same dose in East Africa, conducted by DNDi, showed lower efficacy, particularly in Sudan where the 15 mg/kg regime gave a <50% cure rate, whilst a dose of 20 mg/kg for 21 days gave only an 85% cure rate, insufficient for consideration as a monotherapy.15 The reason for this difference is not understood. "
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    ABSTRACT: Background The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress. For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.Sources of dataPubMed.Areas of AgreementThere is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.Areas of controversyCutaneous leishmaniasis is not on the agenda and treatments are lagging behind.Growing pointsThere are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development. For Chagas disease, two anti-fungal triazoles are now in clinical trial. In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease. For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.Areas timely for developing researchImproved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.
    British Medical Bulletin 11/2012; 104(1). DOI:10.1093/bmb/lds031 · 3.66 Impact Factor
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