Flow diagram for study selection.

<p>Flow diagram for study selection.</p

Failure of Miltefosine Treatment for Visceral Leishmaniasis in Children and Men in South-East Asia

<div><p>Background</p><p>High frequency of relapse in miltefosine-treated visceral leishmaniasis (VL) patients in India and Nepal followed up for twelve months.</p><p>Objective</p><p>To identify epidemiological and clinical risk factors for relapse of VL in patients recently treated with standard dosing of miltefosine in India and Nepal.</p><p>Design</p><p>Prospective observational study in three Primary Health Centers and one reference center in Muzaffarpur district, Bihar, India; and two zonal hospitals and a university hospital in South-east Nepal; records of all consenting patients diagnosed with VL and treated with miltefosine according to the current treatment guidelines of the Kala azar elimination program between 2009 and 2011.</p><p>Results</p><p>We compared the clinical records of 78 cases of relapse with those of 775 patients who had no record of subsequent relapse. Relapse was 2 times more common amongst male patients (IRR 2.14, 95% CI 1.27–3.61), and 2 to 3 times more frequent in the age groups below 15 compared to the over 25 year olds (age 10 to 14: IRR 2.53; 95% CI 1.37–4.65 and Age 2 to 9: IRR 3.19; 95% CI 1.77–5.77). History of earlier VL episodes, or specific clinical features at time of diagnosis such as duration of symptoms or spleen size were no predictors of relapse.</p><p>Conclusions</p><p>Young age and male gender were associated with increased risk of VL relapse after miltefosine, suggesting that the mechanism of relapse is mainly host-related i.e. immunological factors and/or drug exposure (pharmacokinetics). The observed decrease in efficacy of miltefosine may be explained by the inclusion of younger patients compared to the earlier clinical trials, rather than by a decreased susceptibility of the parasite to miltefosine. Our findings highlight the importance of proper clinical trials in children, including pharmacokinetics, to determine the safety, efficacy, drug exposure and therapeutic response of new drugs in this age group.</p></div

Percentage of Relapse per age and gender.

<p>Percentage of Relapse per age and gender.</p

Evaluation of feasibility of all methods according to ASSURED criteria.

<p>1† = specificity of these techniques is assumed to be 100%.</p

Summary of published sensitivity and specificity estimates of several molecular methods techniques for HAT.

<p>Summary of published sensitivity and specificity estimates of several molecular methods techniques for HAT.</p

Factors associated with relapse in a multivariate model.

<p>Factors associated with relapse in a multivariate model.</p

Cure rates and relapse rates at various time points under ITT, ITT worst case, and per protocol analysis.

<p>Cure rates and relapse rates at various time points under ITT, ITT worst case, and per protocol analysis.</p

Factors associated with relapse in a ‘bi-variate’ model (controlled for treatment facility).

<p>Factors associated with relapse in a ‘bi-variate’ model (controlled for treatment facility).</p

Case definitions for the treatment outcome recording of VL patients.

<p><b>Note:</b> Treatment Failure: includes both non-response and relapse.</p><p>Adapted from TDR/WHO. Indicators for monitoring and evaluation of the kala-azar elimination programme. 2010.</p

Number of cases and completeness of follow-up per health facility.

<p>* = Treatment not completed = defaulter, transfer out, death during treatment, adverse event-related switch.</p