Outpatient Treatment for Cutaneous Leishmaniasis in Children
Outpatient Treatment for Cutaneous Leishmaniasis in Children
The Cochrane review on interventions for Old World CL had a search date up to April 2008 and included 49 RCTs covering 19 different interventions. Nonpainful treatments included in the review that might be suitable for children were oral ketoconazole, oral itraconazole, oral fluconazole, dapsone, allopurinol, oral rifampicin, miltefosine, topical antifungals and topical paromomycin. Of these options, the review concluded there was some evidence to support the use of oral fluconazole and topical paromomycin in L. major infection, and oral itraconazole in L. tropica.
The Cochrane review on interventions for American cutaneous and mucocutaneous leishmaniasis had a search date up to January 2009 and included 38 RCTs covering 16 different interventions. Of these trials, 32 dealt with cutaneous rather than mucocutaneous leishmaniasis. Nonpainful treatments included in the review were oral ketoconazole, allopurinol, miltefosine, topical paromomycin and the topical aminoglycoside WR279396. The review concluded there was little evidence to support nonantimonial treatments. In L. panamensis infection, oral ketoconazole, miltefosine and topical paromomycin were found to be more effective than placebo.
The study design and reporting quality in most of the trials included in both Cochrane reviews were found to be poor. Trials often lacked adequate randomization, allocation concealment and blinding. Some trials did not address their stated primary outcome. Neither Cochrane review investigated the effect of patient age on response to treatment, making it very difficult to establish whether the conclusions drawn are applicable to children.
Topical Paromomycin. We found two RCTs investigating topical paromomycin (n = 467), one from Tunisia and France and the second from Tunisia alone. The two studies formed phase 2 and phase 3 trials investigating a topical agent named WR279396 (15% paromomycin and 0·5% gentamicin), and are summarized in Table 1.
Ben Salah et al. compared WR279396 with placebo applied twice daily for 20 days. The study included 92 patients aged 5–75 years who were allocated in a 1 : 1 ratio. All participants had lesions parasitologically confirmed and L. major was identified in 97% of the 68 patients typed. The primary end point was complete clinical response. Overall 94% of patients in the WR 279396 group vs. 71% in the placebo group met the definition for complete clinical response (P = 0·0045). Adjustment for age < 18 years lessened the treatment effect. The most commonly reported adverse event was erythema at the site of application, which was not statistically significant between the two groups. No treatment-related serious adverse events were reported. Randomization was well described, the placebo was matched to the active cream and the evaluators were reported to be blinded. Intention-to-treat analysis was performed. The reduced treatment effect in patients aged < 18 years was briefly discussed and requires further investigation.
Ben Salah et al. compared WR279396, 15% paromomycin and placebo in a three-arm trial. The topical agents were applied once daily for 20 days. In total, 375 patients were divided in a ratio of 1 : 1 : 1; 50% of patients in two of the three treatment arms were under the age of 17 years. The species in this study was L. major. The primary end point was final clinical cure. Overall, 81% of patients in the WR279396 group, 82% treated with paromomycin alone and 58% in the placebo control group achieved final clinical cure. There was a statistically significant response when comparing the active groups against placebo (P < 0·001), but not between WR279396 and paromomycin alone. The majority of treatment-related adverse events were application-site reactions, with vesicle formation more common in the active treatment groups.
This was a large study and power calculations were performed based on the results of the phase 2 trial. At follow-up all lesions were examined and the index lesion photographed. All study personnel were reported to be blinded. The WR279396, 15% paromomycin and placebo were packaged identically and matched as closely as possible in appearance. The method of randomization was fully described in the published study protocol. A modified intention-to-treat analysis was performed in which patients who were randomized but had not yet received one dose of the treatment were excluded from the analysis. This led to a removal of eight patients from the analysis. However, all patients who were lost to follow-up (n = 6) and had clinical failure (n = 93) were included in the analysis.
Miltefosine. We found three RCTs investigating miltefosine (n = 296), one based in Colombia and two from Brazil, which are summarized in Table 1.
Rubiano et al. compared oral miltefosine with intramuscular meglumine antimoniate. This study included only children (n = 116), aged 2–12 years, allocated in a 1 : 1 ratio. The Leishmania species was identified in 51·7% of participants, the majority of whom had L. panamensis, followed by L. guyanensis. The study was designed as a noninferiority trial with a primary end point of therapeutic failure (inflammation, ulceration or new lesions) at or before 26 weeks. The failure rate was higher in the antimony group (31%) than in patients treated with miltefosine (18%), which fulfilled the prespecified noninferiority criteria of miltefosine being potentially 15% worse than antimony. Subgroup analysis of patients under the age of 7 years showed 90% and 57% response in the miltefosine and antimony groups, respectively (P = 0·008). Adverse effects were observed in 91 of the 116 patients, split equally between the two groups, and were graded as mild in 95% of patients. Gastrointestinal symptoms and elevated hepatic enzymes were more common in the miltefosine group, including nausea and vomiting, whereas fever and loss of appetite were more common in the antimony group. This study was well designed with a clear description of randomization, allocation concealment, blinded evaluation (masked evaluator using standardized photographs of the lesions) and intention-to-treat analysis. Power calculations were performed to determine the sample size.
Machado et al. compared miltefosine with intravenous meglumine antimoniate, and patients were allocated in a 2 : 1 ratio. The study included 90 patients aged 2–65 years, who for analysis were divided into two groups according to age: 2–12 years (n = 32) and 13–65 years (n = 58). A positive culture for Leishmania was obtained in 52 of the 90 patients, and L. braziliensis was identified in 41 samples. The primary end point was cure at 6 months after the end of treatment. Overall, complete re-epithelialization was higher in the miltefosine group than in the antimony group, 75% vs. 53% (P = 0·04). In patients aged 2–12 years there was no statistically significant difference in response between the miltefosine and antimony treatment groups, 68% vs. 70% (P = 1·0). Adverse events were common in both groups (78% vs. 77%), and the type of side effect varied widely between treatment arms, but did not lead to patient withdrawal from the trial. Vomiting, nausea and abdominal pain were significantly more common in the miltefosine arm, whereas arthralgias, myalgias and fever were significantly more common in the antimony group. The study included a clear description of randomization and blinding of evaluators. Intention-to-treat analysis was performed. The main limitation in the subgroup analysis on age was the small size of the 2–12-year group, and therefore the study may have been underpowered to detect a clinically important but small difference in this younger age group.
Chrusciak-Talhari et al. compared miltefosine with intravenous glutamine, and patients were allocated in a 2 : 1 ratio. The study included 90 patients aged 2–65 years, who were divided into two groups according to age: 2–12 years (n = 30) and 13–65 years (n = 60). The Leishmania species was identified by polymerase chain reaction in all patients, and in the majority of patients was confirmed as L. guyanensis. The primary end point was definitive cure at 6 months. Overall, complete re-epithelialization was higher in the miltefosine group than in the antimony group, 71% vs. 54% (P = 0·05). In the patients aged 2–12 years there was no statistically significant difference in response between the miltefosine and antimony groups, 63% vs. 55% (P = 0·65). There were no serious adverse events in the trial and no withdrawals secondary to adverse events. The patients were randomly allocated, but it is not clear whether the evaluators were blinded. Intention-to-treat analysis was not performed, as six randomized patients were not included in the analysis. The 2–12-year age group was small, and again may have been underpowered to detect a difference.
Critical Appraisal of the Evidence
Cochrane Reviews
The Cochrane review on interventions for Old World CL had a search date up to April 2008 and included 49 RCTs covering 19 different interventions. Nonpainful treatments included in the review that might be suitable for children were oral ketoconazole, oral itraconazole, oral fluconazole, dapsone, allopurinol, oral rifampicin, miltefosine, topical antifungals and topical paromomycin. Of these options, the review concluded there was some evidence to support the use of oral fluconazole and topical paromomycin in L. major infection, and oral itraconazole in L. tropica.
The Cochrane review on interventions for American cutaneous and mucocutaneous leishmaniasis had a search date up to January 2009 and included 38 RCTs covering 16 different interventions. Of these trials, 32 dealt with cutaneous rather than mucocutaneous leishmaniasis. Nonpainful treatments included in the review were oral ketoconazole, allopurinol, miltefosine, topical paromomycin and the topical aminoglycoside WR279396. The review concluded there was little evidence to support nonantimonial treatments. In L. panamensis infection, oral ketoconazole, miltefosine and topical paromomycin were found to be more effective than placebo.
The study design and reporting quality in most of the trials included in both Cochrane reviews were found to be poor. Trials often lacked adequate randomization, allocation concealment and blinding. Some trials did not address their stated primary outcome. Neither Cochrane review investigated the effect of patient age on response to treatment, making it very difficult to establish whether the conclusions drawn are applicable to children.
New Randomized Controlled Trials Published Since the Cochrane Review
Topical Paromomycin. We found two RCTs investigating topical paromomycin (n = 467), one from Tunisia and France and the second from Tunisia alone. The two studies formed phase 2 and phase 3 trials investigating a topical agent named WR279396 (15% paromomycin and 0·5% gentamicin), and are summarized in Table 1.
Ben Salah et al. compared WR279396 with placebo applied twice daily for 20 days. The study included 92 patients aged 5–75 years who were allocated in a 1 : 1 ratio. All participants had lesions parasitologically confirmed and L. major was identified in 97% of the 68 patients typed. The primary end point was complete clinical response. Overall 94% of patients in the WR 279396 group vs. 71% in the placebo group met the definition for complete clinical response (P = 0·0045). Adjustment for age < 18 years lessened the treatment effect. The most commonly reported adverse event was erythema at the site of application, which was not statistically significant between the two groups. No treatment-related serious adverse events were reported. Randomization was well described, the placebo was matched to the active cream and the evaluators were reported to be blinded. Intention-to-treat analysis was performed. The reduced treatment effect in patients aged < 18 years was briefly discussed and requires further investigation.
Ben Salah et al. compared WR279396, 15% paromomycin and placebo in a three-arm trial. The topical agents were applied once daily for 20 days. In total, 375 patients were divided in a ratio of 1 : 1 : 1; 50% of patients in two of the three treatment arms were under the age of 17 years. The species in this study was L. major. The primary end point was final clinical cure. Overall, 81% of patients in the WR279396 group, 82% treated with paromomycin alone and 58% in the placebo control group achieved final clinical cure. There was a statistically significant response when comparing the active groups against placebo (P < 0·001), but not between WR279396 and paromomycin alone. The majority of treatment-related adverse events were application-site reactions, with vesicle formation more common in the active treatment groups.
This was a large study and power calculations were performed based on the results of the phase 2 trial. At follow-up all lesions were examined and the index lesion photographed. All study personnel were reported to be blinded. The WR279396, 15% paromomycin and placebo were packaged identically and matched as closely as possible in appearance. The method of randomization was fully described in the published study protocol. A modified intention-to-treat analysis was performed in which patients who were randomized but had not yet received one dose of the treatment were excluded from the analysis. This led to a removal of eight patients from the analysis. However, all patients who were lost to follow-up (n = 6) and had clinical failure (n = 93) were included in the analysis.
Miltefosine. We found three RCTs investigating miltefosine (n = 296), one based in Colombia and two from Brazil, which are summarized in Table 1.
Rubiano et al. compared oral miltefosine with intramuscular meglumine antimoniate. This study included only children (n = 116), aged 2–12 years, allocated in a 1 : 1 ratio. The Leishmania species was identified in 51·7% of participants, the majority of whom had L. panamensis, followed by L. guyanensis. The study was designed as a noninferiority trial with a primary end point of therapeutic failure (inflammation, ulceration or new lesions) at or before 26 weeks. The failure rate was higher in the antimony group (31%) than in patients treated with miltefosine (18%), which fulfilled the prespecified noninferiority criteria of miltefosine being potentially 15% worse than antimony. Subgroup analysis of patients under the age of 7 years showed 90% and 57% response in the miltefosine and antimony groups, respectively (P = 0·008). Adverse effects were observed in 91 of the 116 patients, split equally between the two groups, and were graded as mild in 95% of patients. Gastrointestinal symptoms and elevated hepatic enzymes were more common in the miltefosine group, including nausea and vomiting, whereas fever and loss of appetite were more common in the antimony group. This study was well designed with a clear description of randomization, allocation concealment, blinded evaluation (masked evaluator using standardized photographs of the lesions) and intention-to-treat analysis. Power calculations were performed to determine the sample size.
Machado et al. compared miltefosine with intravenous meglumine antimoniate, and patients were allocated in a 2 : 1 ratio. The study included 90 patients aged 2–65 years, who for analysis were divided into two groups according to age: 2–12 years (n = 32) and 13–65 years (n = 58). A positive culture for Leishmania was obtained in 52 of the 90 patients, and L. braziliensis was identified in 41 samples. The primary end point was cure at 6 months after the end of treatment. Overall, complete re-epithelialization was higher in the miltefosine group than in the antimony group, 75% vs. 53% (P = 0·04). In patients aged 2–12 years there was no statistically significant difference in response between the miltefosine and antimony treatment groups, 68% vs. 70% (P = 1·0). Adverse events were common in both groups (78% vs. 77%), and the type of side effect varied widely between treatment arms, but did not lead to patient withdrawal from the trial. Vomiting, nausea and abdominal pain were significantly more common in the miltefosine arm, whereas arthralgias, myalgias and fever were significantly more common in the antimony group. The study included a clear description of randomization and blinding of evaluators. Intention-to-treat analysis was performed. The main limitation in the subgroup analysis on age was the small size of the 2–12-year group, and therefore the study may have been underpowered to detect a clinically important but small difference in this younger age group.
Chrusciak-Talhari et al. compared miltefosine with intravenous glutamine, and patients were allocated in a 2 : 1 ratio. The study included 90 patients aged 2–65 years, who were divided into two groups according to age: 2–12 years (n = 30) and 13–65 years (n = 60). The Leishmania species was identified by polymerase chain reaction in all patients, and in the majority of patients was confirmed as L. guyanensis. The primary end point was definitive cure at 6 months. Overall, complete re-epithelialization was higher in the miltefosine group than in the antimony group, 71% vs. 54% (P = 0·05). In the patients aged 2–12 years there was no statistically significant difference in response between the miltefosine and antimony groups, 63% vs. 55% (P = 0·65). There were no serious adverse events in the trial and no withdrawals secondary to adverse events. The patients were randomly allocated, but it is not clear whether the evaluators were blinded. Intention-to-treat analysis was not performed, as six randomized patients were not included in the analysis. The 2–12-year age group was small, and again may have been underpowered to detect a difference.
Source...