title: Arsenic, antimony, and Leishmania: has arsenic contamination of drinking water in India led to treatment- resistant kala-azar?
abstract: BACKGROUND
  In Bihar state, India, the cure rate of antimonial compounds (eg, sodium stibogluconate) in the treatment of visceral leishmaniasis (VL) has fallen from more than 85% to less than 50%. This reduction has been attributed to long-term, widespread misuse of antimonial drugs within the Indian private health-care system. We aimed to test the hypothesis that exposure to arsenic in drinking water in this region has resulted in antimony-resistant Leishmania parasites.
  
  
  METHODS
  L donovani parasites were serially passaged in mice exposed to environmentally relevant concentrations of arsenic in drinking water. Arsenic concentrations in murine organs were quantified and the sensitivity of L donovani to sodium stibogluconate assessed at each passage. A retrospective field study on a cohort of antimony-treated patients with VL was performed in an arsenic-contaminated area of Bihar to assess risk of treatment failure and death in people exposed to arsenic.
  
  
  RESULTS
  Arsenic accumulation in organs of exposed mice was proportional to exposure level. After five passages, isolated parasites were refractory to sodium stibogluconate in in-vitro drug sensitivity assays. Treatment of arsenic exposed, infected mice with this drug confirmed that these parasites retained resistance in vivo. In the field work study, 110 patients with VL treated with sodium stibogluconate, failure rate was 59%. Patients using well water with high mean arsenic concentrations had a higher risk of treatment failure than patients using wells with arsenic levels of less than 10 μg/L (odds ratio 1·78, 95% CI 0·7-4·6, p=0·23). 21 patients died, 16 directly as a result of their disease. Mean arsenic concentrations of more than 10 μg/L increased the risk of all-cause and VL-related mortality (hazard ratio 3·27, 95% CI 1·4-8·1, and 2·65, 0·96-7·65, respectively).
  
  
  CONCLUSIONS
  These data suggest that arsenic contamination might have contributed to the development of antimonial resistance in Leishmania parasites in Bihar. Our epidemiological study was underpowered and retrospective in nature, so firm conclusions cannot be made. Further research into the associations between arsenic exposure and antimonial treatment failure and death in the leishmaniases is warranted.
  
  
  BACKGROUND
  Wellcome Trust.
authors: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK. Electronic address: meghanperry79@yahoo.co.uk.
authors: Meghan
authors: M
authors: Perry
authors: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
authors: Susan
authors: S
authors: Wyllie
authors: Department of Biochemistry, Central University of Rajasthan, Rajasthan, India.
authors: Vijay
authors: V
authors: Prajapati
authors: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors: Joris
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authors: Menten
authors: College of Physical Sciences - Chemistry, Trace Element Speciation Laboratory, University of Aberdeen, Aberdeen, UK.
authors: Andrea
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authors: Raab
authors: College of Physical Sciences - Chemistry, Trace Element Speciation Laboratory, University of Aberdeen, Aberdeen, UK.
authors: Joerg
authors: J
authors: Feldmann
authors: School of Environmental Studies, Jadavpur University, Kolkata, India.
authors: Dipankar
authors: D
authors: Chakraborti
authors: Infectious Disease Research Laboratory, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors: Shyam
authors: S
authors: Sundar
authors: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors: Marleen
authors: M
authors: Boelaert
authors: Barcelona Centre for International Health Research, Hospital Clinic Universitat de Barcelona, Barcelona, Spain.
authors: Albert
authors: A
authors: Picado
authors: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
authors: Alan
authors: A
authors: Fairlamb