title: Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance.
abstract: BACKGROUND
  Miltefosine (MIL), the only oral drug for visceral leishmaniasis (VL), is currently the first-line therapy in the VL elimination program of the Indian subcontinent. Given the paucity of anti-VL drugs and the looming threat of resistance, there is an obvious need for close monitoring of clinical efficacy of MIL.
  
  
  METHODS
  In a cohort study of 120 VL patients treated with MIL in Nepal, we monitored the clinical outcomes up to 12 months after completion of therapy and explored the potential role of drug compliance, parasite drug resistance, and reinfection.
  
  
  RESULTS
  The initial cure rate was 95.8% (95% confidence interval [CI], 92.2-99.4) and the relapse rate at 6 and 12 months was 10.8% (95% CI, 5.2-16.4) and 20.0% (95% CI, 12.8-27.2) , respectively. No significant clinical risk factors of relapse apart from age <12 years were found. Parasite fingerprints of pretreatment and relapse bone marrow isolates within 8 patients were similar, suggesting that clinical relapses were not due to reinfection with a new strain. The mean promastigote MIL susceptibility (50% inhibitory concentration) of isolates from definite cures was similar to that of relapses. Although more tolerant strains were observed, parasite resistance, as currently measured, is thus not likely involved in MIL treatment failure. Moreover, MIL blood levels at the end of treatment were similar in cured and relapsed patients.
  
  
  CONCLUSIONS
  Relapse in one-fifth of the MIL-treated patients observed in our study is an alarming signal for the VL elimination campaign, urging for further review and cohort monitoring.
authors: B. P. Koirala Institute of Health Sciences, Dharan, Nepal. sumanrijal2@yahoo.com
authors: Suman
authors: S
authors: Rijal
authors: Bart
authors: B
authors: Ostyn
authors: Surendra
authors: S
authors: Uranw
authors: Keshav
authors: K
authors: Rai
authors: Narayan Raj
authors: NR
authors: Bhattarai
authors: Thomas P C
authors: TP
authors: Dorlo
authors: Jos H
authors: JH
authors: Beijnen
authors: Manu
authors: M
authors: Vanaerschot
authors: Saskia
authors: S
authors: Decuypere
authors: Subodh S
authors: SS
authors: Dhakal
authors: Murari Lal
authors: ML
authors: Das
authors: Prahlad
authors: P
authors: Karki
authors: Rupa
authors: R
authors: Singh
authors: Marleen
authors: M
authors: Boelaert
authors: Jean-Claude
authors: JC
authors: Dujardin
mesh_terms: D000293:Adolescent; D000328:Adult; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007893:Leishmania donovani / Q000187:drug effects / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology; D008297:Male; D009390:Nepal / Q000453:epidemiology; D059208:Parasite Load; D010349:Patient Compliance; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011446:Prospective Studies; D012008:Recurrence; D017211:Treatment Failure
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine
keywords: Nepal; miltefosine; parasite drug resistance; relapse; visceral leishmaniasis