title: Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia.
abstract: BACKGROUND
  High frequency of relapse in miltefosine-treated visceral leishmaniasis (VL) patients in India and Nepal followed up for twelve months.
  
  
  OBJECTIVE
  To identify epidemiological and clinical risk factors for relapse of VL in patients recently treated with standard dosing of miltefosine in India and Nepal.
  
  
  METHODS
  Prospective observational study in three Primary Health Centers and one reference center in Muzaffarpur district, Bihar, India; and two zonal hospitals and a university hospital in South-east Nepal; records of all consenting patients diagnosed with VL and treated with miltefosine according to the current treatment guidelines of the Kala azar elimination program between 2009 and 2011.
  
  
  RESULTS
  We compared the clinical records of 78 cases of relapse with those of 775 patients who had no record of subsequent relapse. Relapse was 2 times more common amongst male patients (IRR 2.14, 95% CI 1.27-3.61), and 2 to 3 times more frequent in the age groups below 15 compared to the over 25 year olds (age 10 to 14: IRR 2.53; 95% CI 1.37-4.65 and Age 2 to 9: IRR 3.19; 95% CI 1.77-5.77). History of earlier VL episodes, or specific clinical features at time of diagnosis such as duration of symptoms or spleen size were no predictors of relapse.
  
  
  CONCLUSIONS
  Young age and male gender were associated with increased risk of VL relapse after miltefosine, suggesting that the mechanism of relapse is mainly host-related i.e. immunological factors and/or drug exposure (pharmacokinetics). The observed decrease in efficacy of miltefosine may be explained by the inclusion of younger patients compared to the earlier clinical trials, rather than by a decreased susceptibility of the parasite to miltefosine. Our findings highlight the importance of proper clinical trials in children, including pharmacokinetics, to determine the safety, efficacy, drug exposure and therapeutic response of new drugs in this age group.
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ostyn
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Epco
authors.initials: E
authors.lastname: Hasker
authors.affiliation: Division of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Thomas P C
authors.initials: TP
authors.lastname: Dorlo
authors.affiliation: Department of Internal Medicine, B. P. Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Suman
authors.initials: S
authors.lastname: Rijal
authors.affiliation: Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Boelaert
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007194:India; D007893:Leishmania donovani / Q000187:drug effects / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D009390:Nepal; D021261:Parasitic Sensitivity Tests; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017410:Practice Guidelines as Topic; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D012737:Sex Factors; D017211:Treatment Failure
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine