Treatment failure of pentavalent antimonial therapy for human visceral leishmaniasis: a meta-analysis

Abstract

Background Visceral leishmaniasis is found primarily in developing countries and is a neglected tropical disease that causes approximately 300,000 new cases and 20,000 deaths annually and is often fatal if untreated. Monotherapy with pentavalent antimonials (SSG or MA) is a second-line treatment option in many endemic areas. This meta-analysis provides regional and national analyses of the proportions of antimonial treatment failures at the end-of-treatment and at follow-up according to the drug used. Methods This meta-analysis was conducted in accordance with the PRISMA guidelines. Studies were identified by systematic searches of five electronic databases. Studies in English that reported the outcomes of 10 or more patients treated according to the World Health Organization (WHO) pentavalent antimonial regimen (20 mg/kg/day for 28-30 days) were included. Random-effects meta-analyses and funnel plots were performed, and bias was assessed using tools from the Cochrane collaboration. Results 33 articles were included in the final per protocol analyses, 16 from the Indian subcontinent (India and Nepal), 15 from East Africa and one from each of Iran and Turkey. Data were analysed by drug type regionally, nationally and temporally. Six-month follow-up data from 13 studies (n=797) on the Indian subcontinent gave a sodium stibogluconate (SSG) failure rate of 11.34% (95% confidence interval (CI)=7.05-16.48%). Nationally, the SSG failure rate across 11 studies from northern India greatly exceeded that identified from two Nepalese studies. Six-month follow-up data from three studies (n=638) from East Africa gave an SSG failure rate of 6.25% (95% CI=4.51-8.25%). End-of-SSG-treatment failure rates across the Indian subcontinent (n=1,135), northern India (n=990) and Nepal (n=145) were 39.82% (95% CI=31.67-48.27%), 45.21% (95% CI=39.31-51.17%) and 12.17% (95% CI=7.40-17.93%) respectively. A lower end-of-SSG-treatment failure rate was recorded in East Africa (n=53,335), 6.60% (95% CI=2.94-11.58%). No studies contained six-month follow-up data regarding meglumine antimoniate (MA), and only four studies (n=257) contained end-of-MA-treatment data with a failure rate of 5.01% (95% CI=2.70-7.98%). Conclusions Sb(V) remains an important second-line therapy in many areas. Knowledge of failure rates can inform policy decisions at all levels. The findings of this study are most applicable to SSG therapy, confirm the known patterns of resistance and reflect current policies.