Risk factors for therapeutic failure to meglumine antimoniate and miltefosine in adults and children with cutaneous leishmaniasis in Colombia: A cohort study

Introduction Reports of therapeutic failure to meglumine antimoniate (MA) and miltefosine in cutaneous leishmaniasis (CL) varies between species, populations and geographic regions. This study aimed to determine the clinical, drug-related factors, and Leishmania species associated with treatment failure in children and adults with cutaneous leishmaniasis. Methods A cohort study was performed with children (2–12 years old) and adults (18–65 years old) with CL, who have participated in clinical studies at CIDEIM Cali, Tumaco and Chaparral. Incidence of therapeutic failure was estimated by treatment and age groups. Descriptive, bivariate, and multiple logistic regression analyses were performed for the complete cohort and pediatric patients. Results Two hundred and thirty patients were included (miltefosine: 112; MA: 118), of which 60.4% were children and 83.9% were infected with L.V. panamensis. Overall incidence of therapeutic failure was 15.65% (95%CI: 10.92–20.38), and was lower for miltefosine than for MA (8.92%, 95%CI: 3.59–14.26 versus 22.03%, 95%CI:14.48–29.58, p = 0.006). Treatment failure was associated with age ≤8 years (OR: 3.29; 95%CI: 1.37–7.89), disease duration ≤1 month (OR: 3.29; 95%CI: 1.37–7.89), regional lymphadenopathy (OR: 2.72; 95%CI: 1.10–6.70), treatment with MA (OR: 3.98; 95%CI: 1.66–9.50), and adherence <90% (OR: 3.59; 95%CI: 1.06–12.11). In children, higher Z-score of height/age was a protective factor (OR: 0.58; 95%CI: 0.36–0.93), while treatment with MA was a risk factor (OR: 40.82; 95%CI: 2.45–677.85), demonstrating significant interaction with age (p = 0.03). Conclusions Clinical and drug-related factors determine therapeutic failure in CL. High risk of failure in children treated with MA indicates the need to reconsider this drug as first line treatment in this population. Trial registration Clinical trial registration: NCT00487253 Clinical trial registration: NCT01462500 Clinical trial registration: NCT01464242


Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 5, 6 This is described in the introduction Objectives 3 State specific objectives, including any prespecified hypotheses 6 "This study sought to determine the clinical and drug-related factors, and Leishmania species associated with treatment failure in children and adults with cutaneous leishmaniasis"

Study design 4
Present key elements of study design early in the paper 6 Section "study design" Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection 7 Section "Study setting and participants" Participants 6 (a) Cohort study-Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Case-control study-Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study-Give the eligibility criteria, and the sources and methods of selection of participants Describe any efforts to address potential sources of bias 8, 9 Section: "Statistical analysis" Study size 10 Explain how the study size was arrived at As the number of patients was determined by the size of the original studies, all patients who met eligibility criteria were included in the analysis.
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why 8, 9 Section: "Statistical analysis" Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 8, 9 Section: "Statistical analysis" (b) Describe any methods used to examine subgroups and interactions 9 Section: "Statistical analysis" (c) Explain how missing data were addressed 7, 9 "Patients' records that did not include assessment of therapeutic response or have missing data regarding weight or treatment information (doses prescribed and received) were excluded." Additional information is described in the section of "Statistical analysis". (d) Cohort study-If applicable, explain how loss to follow-up was addressed Case-control study-If applicable, explain how matching of cases and controls was addressed Cross-sectional study-If applicable, describe analytical methods taking account of sampling strategy Not applicable: only participants with complete follow-up in the original studies were included in this analysis. See section "Study setting and participants" (e) Describe any sensitivity analyses 9 Section: "Statistical analysis"

Results
Participants 13* (a) Report numbers of individuals at each stage of study-eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed 9, 10 This is described in the results section and  Subgroup and sensitivity analysis were described in the results section, table 3 and S1

-21
Mentioned in the discussion, see: "…which allowed us to generalize our findings to CL patients from central and southwestern Colombia with predominance of L. V. panamensis."

Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based All sources of funding were declared *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.