Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study

Meghan R Perry; Vijay K Prajapati; Joris Menten; Andrea Raab; Joerg Feldmann; Dipankar Chakraborti; Shyam Sundar; Alan H Fairlamb; Marleen Boelaert; Albert Picado

doi:10.1371/journal.pntd.0003518

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study

Meghan R Perry, Vijay K Prajapati, Joris Menten, Andrea Raab, Joerg Feldmann, Dipankar Chakraborti, Shyam Sundar, Alan H Fairlamb, Marleen Boelaert, Albert Picado

Chemistry

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Abstract

BACKGROUND: In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites.

METHODS: A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic.

RESULTS: One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 μg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels ≥ 10 μg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected.

DISCUSSION/CONCLUSION: This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation.

Original language	English
Article number	e0003518
Journal	PLoS Neglected Tropical Diseases
Volume	9
Issue number	3
DOIs	https://doi.org/10.1371/journal.pntd.0003518
Publication status	Published - 2 Mar 2015

Bibliographical note

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

Adolescent
Adult
Antimony Sodium Gluconate
Antiprotozoal Agents
Arsenic
Child
Child, Preschool
Cohort Studies
Drug Resistance
Female
Humans
India
Leishmaniasis, Visceral
Logistic Models
Male
Middle Aged
Retrospective Studies
Treatment Failure

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pntd.0003518Licence: CC BY

Arsenic Exposure and Outcomes of Antimonial Treatment in Visceral Leishmaniasis Patients in Bihar, India
Copyright: © 2015 Perry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
Final published version, 4.44 MBLicence: CC BY

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Perry, M. R., Prajapati, V. K., Menten, J., Raab, A., Feldmann, J., Chakraborti, D., Sundar, S., Fairlamb, A. H., Boelaert, M., & Picado, A. (2015). Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study. PLoS Neglected Tropical Diseases, 9(3), Article e0003518. https://doi.org/10.1371/journal.pntd.0003518

Perry, MR, Prajapati, VK, Menten, J, Raab, A, Feldmann, J, Chakraborti, D, Sundar, S, Fairlamb, AH, Boelaert, M & Picado, A 2015, 'Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study', PLoS Neglected Tropical Diseases, vol. 9, no. 3, e0003518. https://doi.org/10.1371/journal.pntd.0003518

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title = "Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study",

abstract = "BACKGROUND: In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites.METHODS: A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic.RESULTS: One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 μg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels ≥ 10 μg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected.DISCUSSION/CONCLUSION: This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation.",

keywords = "Adolescent, Adult, Antimony Sodium Gluconate, Antiprotozoal Agents, Arsenic, Child, Child, Preschool, Cohort Studies, Drug Resistance, Female, Humans, India, Leishmaniasis, Visceral, Logistic Models, Male, Middle Aged, Retrospective Studies, Treatment Failure",

author = "Perry, {Meghan R} and Prajapati, {Vijay K} and Joris Menten and Andrea Raab and Joerg Feldmann and Dipankar Chakraborti and Shyam Sundar and Fairlamb, {Alan H} and Marleen Boelaert and Albert Picado",

note = "Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

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month = mar,

day = "2",

doi = "10.1371/journal.pntd.0003518",

language = "English",

volume = "9",

journal = "PLoS Neglected Tropical Diseases",

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TY - JOUR

T1 - Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India

T2 - a retrospective cohort study

AU - Perry, Meghan R

AU - Prajapati, Vijay K

AU - Menten, Joris

AU - Raab, Andrea

AU - Feldmann, Joerg

AU - Chakraborti, Dipankar

AU - Sundar, Shyam

AU - Fairlamb, Alan H

AU - Boelaert, Marleen

AU - Picado, Albert

N1 - Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2015/3/2

Y1 - 2015/3/2

N2 - BACKGROUND: In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites.METHODS: A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic.RESULTS: One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 μg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels ≥ 10 μg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected.DISCUSSION/CONCLUSION: This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation.

AB - BACKGROUND: In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites.METHODS: A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic.RESULTS: One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 μg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels ≥ 10 μg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected.DISCUSSION/CONCLUSION: This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation.

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KW - Adult

KW - Antimony Sodium Gluconate

KW - Antiprotozoal Agents

KW - Arsenic

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Drug Resistance

KW - Female

KW - Humans

KW - India

KW - Leishmaniasis, Visceral

KW - Logistic Models

KW - Male

KW - Middle Aged

KW - Retrospective Studies

KW - Treatment Failure

U2 - 10.1371/journal.pntd.0003518

DO - 10.1371/journal.pntd.0003518

M3 - Article

C2 - 25730310

SN - 1935-2735

VL - 9

JO - PLoS Neglected Tropical Diseases

JF - PLoS Neglected Tropical Diseases

IS - 3

M1 - e0003518

ER -

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study

Abstract

Bibliographical note

Keywords

UN SDGs

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