[Show abstract][Hide abstract]ABSTRACT: Anti-leishmanial drug regimens that include a single dose AmBisome® could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown.
A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome® for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome® 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1-5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR.
The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73-93%), 40% (95%CI 19-64%), and 58% (95%CI 41-73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label.
The tested AmBisome® regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified.
Full-text Article · Jan 2014 · PLoS Neglected Tropical Diseases
[Show abstract][Hide abstract]ABSTRACT: Unlabelled:
Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis that affects more than 50% of successfully treated visceral leishmaniasis (VL) patients in Sudan. PKDL is considered an important reservoir for the parasite and its treatment may help in the control of VL. Currently, treatment is mainly with sodium stibogluconate (SSG), an expensive and fairly toxic drug and without universally in treatment protocols used. A literature review, a consensus of a panel of experts, and unpublished data formed the basis for the development of guidelines for the treatment of PKDL in the Sudan. Six treatment modalities were evaluated. Experts were asked to justify their choices based on their experience regarding of drug safety, efficacy, availability, and cost. The consensus was defined by assigning a categorical rank (first line, second line, third line) to each option. Regarding the use of AmBisome the presence of the drug in the skin was confirmed in smears from PKDL lesions.
AmBisome at 2.5 mg/kg/day/20 days or SSG at 20 mg/kg/day/40 days plus four/weekly intradermal injection of alum-precipitated autoclave L. major vaccine are suggested as first- and second-treatment options for PKDL in the Sudan, respectively. SSG at 20 mg/Kg/day/60 or more days can be used if other options are not available.
Full-text Article · Apr 2013 · Journal of Tropical Medicine
[Show abstract][Hide abstract]ABSTRACT: Visceral leishmaniasis (VL) is a parasitic disease characterized by immune suppression. Successful treatment is usually followed by immune reconstitution and a dermatosis called post-Kala-azar dermal leishmaniasis (PKDL). Recently, PKDL was described as one of the immune reconstitution syndromes (IRISs) in HIV/VL patients on HAART. This study aimed to present PKDL as a typical example of paradoxical IRIS in non-HIV/AIDS individuals. Published and new data on the pathogenesis and healing of PKDL was reviewed and presented. The data suggested that PKDL is a typical example of paradoxical IRIS, being a new disease entity that follows VL successful treatment and immune recovery. PKDL lesions are immune inflammatory in nature with granuloma, adequate response to immunochemotherapy, and an ensuing hypersensitivity reaction, the leishmanin skin test (LST). The data also suggested that the cytokine patterns of PKDL pathogenesis and healing are probably as follows: an active disease state dominated by IL-10 followed by spontaneous/treatment-induced IL-12 priming, IL-2 stimulation, and INF-
-activated macrophages eliminate the
parasites/antigen to be followed by LST conversion and healing. In conclusion, PKDL is a typical example of paradoxical IRIS in non-HIV/AIDS individuals with anti-inflammatory cytokine patterns that are superseded by treatment-induced proinflammatory cytokines and lesions healing.
Full-text Article · Mar 2013 · Journal of Tropical Medicine
[Show abstract][Hide abstract]ABSTRACT: Visceral leishmaniasis (VL) is a serious parasitic disease for which control measures are limited and drug resistance is increasing. First and second generation vaccine candidates have not been successful. The goal of the present study was to select possibly immunogenic L. donovani donovani GP63 peptides using immunoinformatics tools and to test their immunogenicity in vitro. The amino acid sequence of L. donovani donovani GP63 [GenBank accession: ACT31401] was screened using the EpiMatrix algorithm for putative T cell epitopes that would bind to the most common HLA class II alleles (DRB1*1101 and DRB1*0804) among at-risk populations. Four T cell epitopes were selected from nine potential candidates. Stimulation of whole blood from healthy volunteers using the peptides separately produced mean IFN-γ and IL-4 levels that were not significantly different from negative controls, while the pooled peptides produced a moderate IFN-γ increase in some volunteers. However, mean IL-10 levels were significantly reduced for all individuals compared with controls. The immunogenicity of these epitopes may be harnessed most effectively in a vaccine delivered in combination with immune-modulating adjuvants.
Full-text Article · Aug 2012 · Human Vaccines & Immunotherapeutics
[Show abstract][Hide abstract]ABSTRACT: Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.
A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4-60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.
The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: -1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.
The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.
Full-text Article · Jun 2012 · PLoS Neglected Tropical Diseases
[Show abstract][Hide abstract]ABSTRACT: The horn of Africa bears the prunt of Leishmaniasis in the world where both Phlebotomus orientalis, the vector of Leishmania donovani and Phlebotomus papatasi, the vector of Leishmania major, exist. Visceral leishmaniasis (VL) caused by L. donovani is a major cause of morbidity and mortality in east Africa. The populations of east Africa are very dynamic in continuous movements between endemic areas of different leishmaniasis clinical forms. Molecular epidemiological studies have provided indirect evidence for genetic exchange between different strains of one Leishmania species. Only recently, genetic exchange between different Leishmania strains of one species was definitively demonstrated in vitro. Genetic exchange between different Leishmania species is probably an even rarer event. In this study, one hundred and seven L. donovani isolates were collected from lymph nodes/bone marrow aspirates, from patients from Sudan and Ethiopia. DNA was isolated from leishmania parasites using the High Pure PCR Template Preparation Kit. PCR products were sequenced using BigDye Terminator chemistry and analyzed using the ABI 3100 or 3730 Genetic Analyzers. Sequences were analyzed using CodonCode program (CodonCode Corporation) and MEGA. Sequences were submitted to Genbank and are accessible under accession numbers HM117696-HM117699. Our data showed hybridization between two divergent Leishmania species, L. donovani and L. major, possibly due to migration. Such hybridization may have clinical implications with respect to parasite fitness, vector adaptation and response to treatment.
[Show abstract][Hide abstract]ABSTRACT: This prospective study aimed to determine the safety and efficacy of itraconazole for the treatment of patients with mycetoma due to Madurella mycetomatis. The study consisted of 13 patients with confirmed disease; all were treated with oral itraconazole in a dose of 400mg daily for three months after which the dose was reduced to 200mg daily for nine months. All patients showed good clinical response to 400mg itraconazole daily, but when the dose was reduced to 200mg daily, the clinical response was gradual and slow. Post-treatment surgical exploration showed that, in all patients, the lesions were well localized, encapsulated with thick capsule and they were easily removed surgically. In all these lesions, grains colonies were encountered and they were viable on culture. Post-operative biopsies showed no significant changes in the morphology of the grains. A constant finding was the presence of between 5-7 grains in a single cavity walled by fibrous tissue. The reaction surrounding the grains was a Type I tissue reaction characterized by a neutrophil zone around grains. Patients were followed up post-operatively for variable periods (range 18-36 months) and only one patient had recurrence. Initial pre-operative treatment with itraconazole may be recommended for eumycetoma patients to enhance lesions encapsulation and localization which can facilitate wide local excision to avoid unnecessary massive mutilating surgery and recurrence.
Full-text Article · Mar 2011 · Transactions of the Royal Society of Tropical Medicine and Hygiene
[Show abstract][Hide abstract]ABSTRACT: 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.
Full-text Article · Oct 2010 · PLoS Neglected Tropical Diseases
[Show abstract][Hide abstract]ABSTRACT: 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.
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.
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).
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.
Full-text Article · Oct 2010 · PLoS Neglected Tropical Diseases
[Show abstract][Hide abstract]ABSTRACT: Sudanese visceral leishmaniasis (VL) is a disease of children that is characterized by fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, and renal injury. Microalbuminuria (MA) and urinary retinol binding protein (urRBP) are useful markers for glomerular and tubular dysfunctions, respectively. We report the prevalence of subtle renal injury in 88 parasitologically confirmed VL patients in a cross-sectional and hospital-based study. Blood and urine were collected before treatment for hematological, biochemical profiles in addition to MA and urRBP measurement using competitive solid phase, sandwich enzyme-linked immune sorbent assay (ELISA), and immunoturbidometry. All the patients had normal serum urea and creatinine levels and no detectable urRBP. However, 40% of the patients had MA detected by ELISA, and 42% were reactive with turbidometry. The sensitivity, specificity, positive and negative predictive values for MA turbidometric technique were calculated as 100%; 96%; 95% and 100%, respectively. In conclusion; subtle renal injury in VL is mainly glomerular. Turbidometry for MA measurement is a simple, inexpensive, sensitive, and specific technique with high predictive values.
Article · Sep 2010 · Saudi journal of kidney diseases and transplantation: an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia
[Show abstract][Hide abstract]ABSTRACT: Drug unresponsiveness in patients with visceral leishmaniasis (VL) is a problem in many endemic areas. This study aimed to determine genetic diversity of Leishmania donovani isolates from a VL endemic area in Sudan as a possible explanation for drug unresponsiveness in some patients. Thirty clinically stibogluconate (SSG)-sensitive isolates were made SSG-unresponsive in vitro by gradually increasing SSG concentrations. The sensitive isolates and their SSG-unresponsive counterparts were typed using mini-circle kDNA and categorized using PCR-RAPD. All the isolates were typed as L. donovani, the resulting PCR-RAPD characterization of the SSG-sensitive isolates gave three distinct primary genotypes while, the SSG-unresponsive isolates showed only a single band. L. donovani isolates from eastern Sudan are diverse; this probably resulted from emergence of new L. donovani strains during epidemics due to the pressure of widespread use of antimonials. In this communication the possible role of isolates diversity in antimonial unresponsiveness and the in vitro changing PCR-RAPD band pattern in SSG-unresponsive strains were discussed.
[Show abstract][Hide abstract]ABSTRACT: Sickle cell disease is a heterogenous disorder characterized by an abnormal haemoglobin and sickling phenomena of red cells. It is prevalent among certain nomadic tribes in Sudan. Painful, aplastic and haemolytic crises mark sickle cell anaemia. Haemoglobin S (HbS) is detected using haemoglobin electrophoresis, iso-electric focusing and/or high-performance liquid chromatography techniques with high sensitivity, but entails cost and expertise. This study aimed to determine the sensitivity, specificity and positive predictive values (PPV) of the ID-particle gel diffusion technique for screening, diagnosis and phenotyping of HbS in patients with a provisional diagnosis of abnormal haemoglobin.
Following informed consent, 100 sequential individuals who reported to a central referral haemoglobinopathy clinic were enrolled. ID-particle gel diffusion technique was compared with cellulose acetate electrophoresis to determine haemoglobin phenotypes.
The ID-particle gel test detected HbAA with 100% sensitivity and 100% specificity. Sensitivity for HbS was 100%, whether as HbSS or as a mixed pattern. HbSS was identified in all cases where this is the only haemoglobin present. Other patterns were detected with <100% specificity and these would require further testing by other means to definitively identify abnormal haemoglobins.
Although the ID-particle technique is a simple and cheap technique with high sensitivity, specificity and PPV compared with cellulose acetate electrophoresis in detecting HbSS, it could not differentiate HbAS from HbSS with high levels of HbF. High environmental temperatures could melt the test microtubes. Cellulose acetate electrophoresis remains the technique of choice for the screening of abnormal haemoglobins in the Sudan.
Article · Jan 2009 · Annals of Clinical Biochemistry
[Show abstract][Hide abstract]ABSTRACT: Histoplasmosis is a fungal infection caused by Histoplasma capsulatum. In the normal individual, both disseminated histoplasmosis and symptomatic adrenal histoplasmosis are rare. Herein, we describe the case of a 50-year-old gentleman residing in western Sudan who presented with a 7-month history of generalized body weakness, easy fatigue, and frequent attacks of vomiting and diarrhea. Physical examination and laboratory investigations confirmed the diagnosis of Addison's disease due to Histoplasma capsulatum var duboisii infection of the adrenal glands. He was treated with intravenous hydrocortisone, followed by oral prednisolone and itraconazole.