Arsenic Exposure and Outcomes of Antimonial Treatment in Visceral Leishmaniasis Patients in Bihar, India

A Retrospective Cohort Study

Citation: Perry MR, Prajapati VK, Menten J, Raab A, Feldmann J, et al. (2015) Arsenic Exposure and Outcomes of Antimonial Treatment in Visceral Leishmaniasis Patients in Bihar, India: A Retrospective Cohort Study. PLoS Negl Trop Dis 9(3): e0003518. doi:10.1371/journal.pntd.0003518
Published: March 2, 2015

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.

Author Summary: The parasitic disease visceral leishmaniasis (VL) causes a significant burden of illness and death in India. The main drug used to treat VL, which is based on the chemical element antimony, stopped working well in about half of all patients in the late twentieth century. We hypothesised that arsenic exposure of the Indian population, through contaminated groundwater, was contributing to treatment failure with antimony based drugs. Arsenic and antimony are similar chemical elements and exposure of the parasite to arsenic within the liver of arsenic-exposed patients could allow the parasite to become resistant to treatment with antimony. Using a field-based questionnaire study we retrospectively evaluated whether arsenic exposure was linked to antimonial treatment failure in a cohort of 110 antimonial treated patients. No significant association was found, although this may be because the number of patients in the study was low as antimony use was officially discontinued in 2005 due to high rates of treatment failure. However, arsenic exposure was found to increase risk of mortality from VL particularly if death occurred more than 3 months after the symptoms of VL developed. More research into the relationship between arsenic exposure and mortality in VL is warranted.

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