Interventions for Old World cutaneous leishmaniasis

Abstract

Background: Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008.

Objectives: To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis.

Search methods: We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE.

Selection criteria: Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound.

Data collection and analysis: Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search.

Main results: We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons.

Authors' conclusions: There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.

Figure 1

Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

Figure 3

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.

Figure 4

Forest Plot of Primary Outcome: Lesions Cured (Various comparisons)

Figure 5

Forest plot of primary outcome: 1.2 Participants cured (Various comparisons)

Analysis 1.1

Comparison 1 ILMA weekly versus ILMA fortnightly for up to 8 weeks, Outcome 1 Lesions cured.

Analysis 2.1

Comparison 2 ILMA (every other day) versus IMMA (6 d/week) for up to 4 weeks, Outcome 1 Lesions cured.

Analysis 3.1

Comparison 3 IMMA (30 mg/kg/d for 3 weeks) + cimetidine versus IMMA (30 mg/kg/d for 3 weeks) + placebo, Outcome 1 Lesions cured.

Analysis 4.1

Comparison 4 IMMA (30 mg/kg/d for 3 weeks) + cimetidine versus IMMA (60 mg/kg/d for 3 weeks) + placebo, Outcome 1 Lesions cured.

Analysis 5.1

Comparison 5 IMMA (60 mg/kg/d for 3 weeks) + placebo versus IMMA (30 mg/kg/d for 3 weeks) + placebo, Outcome 1 Lesions cured.

Analysis 6.1

Comparison 6 IMMA (30 mg/kg/d for 3 weeks) + placebo versus IMMA (60 mg/kg/d for 3 weeks) + placebo, Outcome 1 Participants complete cure.

Analysis 6.2

Comparison 6 IMMA (30 mg/kg/d for 3 weeks) + placebo versus IMMA (60 mg/kg/d for 3 weeks) + placebo, Outcome 2 Adverse effects.

Analysis 7.1

Comparison 7 IMMA (30 mg/kg/d for 3 weeks) + 40 mg omeprazole versus IMMA (60 mg/kg/d for 3 weeks) + placebo, Outcome 1 Participants complete cure.

Analysis 8.1

Comparison 8 IMMA (30 mg/kg/d for 3 weeks) + placebo versus IMMA (60 mg/kg/d for 3 weeks) + placebo, Outcome 1 Participants complete cure.

Analysis 9.1

Comparison 9 IMMA (30 mg/kg/d for 3 weeks) + 40 mg omeprazole versus IMMA (60 mg/kg/d for 3 weeks) + placebo, Outcome 1 Participants complete cure.

Analysis 10.1

Comparison 10 ILMA + non‐silver polyester dressing versus ILMA (weekly injections for 6 weeks), Outcome 1 Lesions cured.

Analysis 10.2

Comparison 10 ILMA + non‐silver polyester dressing versus ILMA (weekly injections for 6 weeks), Outcome 2 Adverse effects (itching and burning).

Analysis 10.3

Comparison 10 ILMA + non‐silver polyester dressing versus ILMA (weekly injections for 6 weeks), Outcome 3 Adverse effects (oedema).

Analysis 11.1

Comparison 11 ILMA (weekly injections for 6 weeks) + silver polyester dressing versus ILMA (weekly injections for 6 weeks), Outcome 1 Lesions cured.

Analysis 11.2

Comparison 11 ILMA (weekly injections for 6 weeks) + silver polyester dressing versus ILMA (weekly injections for 6 weeks), Outcome 2 Adverse effects (itching and burning).

Analysis 11.3

Comparison 11 ILMA (weekly injections for 6 weeks) + silver polyester dressing versus ILMA (weekly injections for 6 weeks), Outcome 3 Adverse effects (oedema).

Analysis 12.1

Comparison 12 ILMA (weekly injections for 6 weeks) + silver polyester dressing versus ILMA (weekly injections for 6 weeks) + non‐silver polyester dressing, Outcome 1 Lesions cured.

Analysis 12.2

Comparison 12 ILMA (weekly injections for 6 weeks) + silver polyester dressing versus ILMA (weekly injections for 6 weeks) + non‐silver polyester dressing, Outcome 2 Adverse effects (itching and burning).

Analysis 12.3

Comparison 12 ILMA (weekly injections for 6 weeks) + silver polyester dressing versus ILMA (weekly injections for 6 weeks) + non‐silver polyester dressing, Outcome 3 Adverse effects (oedema).

Analysis 13.1

Comparison 13 ILMA (weekly injections for 6 weeks) + gel mask twice a day versus ILMA (weekly injections for 6 weeks) + vehicle, Outcome 1 Participants complete cure.

Analysis 14.1

Comparison 14 ILSSG (20 mg/kg/d) + IMSSG (remaining total dose days 1, 3, 5) versus ILSSG (1000 mg/mL days 1, 3, 5), Outcome 1 Lesions cured.

Analysis 15.1

Comparison 15 ILSSG (5 injections of 2 mL to 5 mL every 5 to 7 d for 29 days) versus IMSSG (20 mg/kg/d for 3 weeks), Outcome 1 Participants complete cure.

Analysis 15.2

Comparison 15 ILSSG (5 injections of 2 mL to 5 mL every 5 to 7 d for 29 days) versus IMSSG (20 mg/kg/d for 3 weeks), Outcome 2 Adverse effects (mild heart symptoms).

Analysis 16.1

Comparison 16 Ketoconazole 600 mg/d for 6 weeks versus ketoconazole 800 mg/d for 6 weeks, Outcome 1 Participants complete cure.

Analysis 16.2

Comparison 16 Ketoconazole 600 mg/d for 6 weeks versus ketoconazole 800 mg/d for 6 weeks, Outcome 2 Adverse effects (nausea and vomiting).

Analysis 17.1

Comparison 17 Ketoconazole 600 mg/d for 30 d versus ILMA (6 to 8 biweekly injections), Outcome 1 Participants cured.

Analysis 17.2

Comparison 17 Ketoconazole 600 mg/d for 30 d versus ILMA (6 to 8 biweekly injections), Outcome 2 Adverse effect (liver enzymes increase).

Analysis 18.1

Comparison 18 ILSSG (100 mg/mL days 1, 3, 5) + oral ketoconazole (600 mg/d for 4 weeks) versus ILSSG (100 mg/mL days 1, 3, 5), Outcome 1 Lesions cured.

Analysis 19.1

Comparison 19 ILSSG (100 mg/mL days 1, 3, 5) + ketoconazole (600 mg/d for 4 weeks) versus ILSSG (20 mg/kg/d) + IMSSG (remaining total dose days 1, 3, 5), Outcome 1 Lesions cured.

Analysis 20.1

Comparison 20 Itraconazole (200 mg for 6 weeks) versus placebo, Outcome 1 Participants complete cure.

Analysis 21.1

Comparison 21 Itraconazole (200 mg for 3 weeks) versus placebo, Outcome 1 Participants complete cure.

Analysis 22.1

Comparison 22 Itraconazole (200 mg for 6 to 8 weeks) versus placebo, Outcome 1 Participants complete cure.

Analysis 22.2

Comparison 22 Itraconazole (200 mg for 6 to 8 weeks) versus placebo, Outcome 2 Adverse effects.

Analysis 22.3

Comparison 22 Itraconazole (200 mg for 6 to 8 weeks) versus placebo, Outcome 3 Microbiological cure of skin lesions.

Analysis 23.1

Comparison 23 Itraconazole (200 mg for 6 to 8 weeks) versus no treatment, Outcome 1 Participants complete cure.

Analysis 23.2

Comparison 23 Itraconazole (200 mg for 6 to 8 weeks) versus no treatment, Outcome 2 Adverse effects (headache and dizziness).

Analysis 23.3

Comparison 23 Itraconazole (200 mg for 6 to 8 weeks) versus no treatment, Outcome 3 Microbiological cure of skin lesions.

Analysis 24.1

Comparison 24 Fluconazole (200 mg for 6 weeks) versus placebo, Outcome 1 Lesions cured.

Analysis 24.2

Comparison 24 Fluconazole (200 mg for 6 weeks) versus placebo, Outcome 2 Participants complete cure.

Analysis 25.1

Comparison 25 Fluconazole (400 mg/d for 6 weeks) versus fluconazole (200 mg/d for 6 weeks), Outcome 1 Participants complete cure.

Analysis 25.2

Comparison 25 Fluconazole (400 mg/d for 6 weeks) versus fluconazole (200 mg/d for 6 weeks), Outcome 2 Adverse effects.

Analysis 26.1

Comparison 26 Oral dapsone (200 mg/d for 6 weeks) versus placebo, Outcome 1 Participants complete Cure.

Analysis 26.2

Comparison 26 Oral dapsone (200 mg/d for 6 weeks) versus placebo, Outcome 2 Adverse effects.

Analysis 27.1

Comparison 27 Allopurinol (15 mg/kg/d for 3 weeks) + IMMA (20 mg/kg/d for 2 weeks) versus allopurinol (15 mg/kg/d for 3 weeks), Outcome 1 Lesions cured.

Analysis 28.1

Comparison 28 Allopurinol (15mg/kg/d for 3 weeks)+ IMMA (20 mg/kg/d for 2 weeks) versus IMMA (20 mg/kg/d for 2 weeks), Outcome 1 Lesions cured.

Analysis 29.1

Comparison 29 Allopurinol (15 mg/kg/d for 3 weeks) versus IMMA (20 mg/kg/d for 2 weeks), Outcome 1 Lesions Cured.

Analysis 30.1

Comparison 30 Allopurinol (20 mg/kg/d for 3 weeks) + IMMA (30 mg/kg/d for 20 days) versus IMMA (60 mg/kg/d for 20 d), Outcome 1 Lesions cured.

Analysis 30.2

Comparison 30 Allopurinol (20 mg/kg/d for 3 weeks) + IMMA (30 mg/kg/d for 20 days) versus IMMA (60 mg/kg/d for 20 d), Outcome 2 Adverse effects.

Analysis 30.3

Comparison 30 Allopurinol (20 mg/kg/d for 3 weeks) + IMMA (30 mg/kg/d for 20 days) versus IMMA (60 mg/kg/d for 20 d), Outcome 3 Microbiological cure of skin lesions.

Analysis 31.1

Comparison 31 Allopurinol (20 mg/kg/d for 3 weeks)+ IMMA (10 mg/kg/d for 20 d) versus IMMA (20 mg/kg/d for 28 d), Outcome 1 Adverse effects.

Analysis 32.1

Comparison 32 Allopurinol (20 mg/kg/d for 3 weeks) versus IVSSG (20 mg/kg/d for 15 d), Outcome 1 Participants complete cured.

Analysis 32.2

Comparison 32 Allopurinol (20 mg/kg/d for 3 weeks) versus IVSSG (20 mg/kg/d for 15 d), Outcome 2 Adverse effects.

Analysis 33.1

Comparison 33 Oral rifampicin (10 mg/kg/d for 4 to 6 weeks) versus placebo, Outcome 1 Participants complete cure.

Analysis 33.2

Comparison 33 Oral rifampicin (10 mg/kg/d for 4 to 6 weeks) versus placebo, Outcome 2 Microbiological cure of skin lesions.

Analysis 34.1

Comparison 34 Oral rifampicin (10 mg/kg/d) + omeprazole (20 mg/d) for 6 weeks versus placebo, Outcome 1 Participants complete cure.

Analysis 35.1

Comparison 35 Azythromicin (500 mg/d for 5 d/month up to 4 months) versus IMMA (60 mg/kg/d for 20 d), Outcome 1 Lesions cured.

Analysis 35.2

Comparison 35 Azythromicin (500 mg/d for 5 d/month up to 4 months) versus IMMA (60 mg/kg/d for 20 d), Outcome 2 Adverse effects.

Analysis 36.1

Comparison 36 Azythromicin (10 mg/kg/d) + allopurinol (10 mg/kg/d) for 1 month versus IMMA (20 mg/kg/d for 20 d), Outcome 1 Participants complete cure.

Analysis 36.2

Comparison 36 Azythromicin (10 mg/kg/d) + allopurinol (10 mg/kg/d) for 1 month versus IMMA (20 mg/kg/d for 20 d), Outcome 2 Adverse effects.

Analysis 37.1

Comparison 37 Oral pentoxifylline (400 mg 3 times daily) + IMMA (20 mg/kg/d) for 20 d versus placebo + IMMA (20 mg/kg/d) for 20 d, Outcome 1 Participants complete cure.

Analysis 37.2

Comparison 37 Oral pentoxifylline (400 mg 3 times daily) + IMMA (20 mg/kg/d) for 20 d versus placebo + IMMA (20 mg/kg/d) for 20 d, Outcome 2 Adverse effects.

Analysis 38.1

Comparison 38 Oral miltefosine (2.5 mg/kg/d for 4 weeks) versus IMMA (60 mg/kg/d for 2 weeks), Outcome 1 Participants complete cure.

Analysis 39.1

Comparison 39 Oral miltefosine (2.5 mg/kg/d for 4 weeks) versus IMMA (60 mg/kg/d for 2 weeks), Outcome 1 Participants complete cure.

Analysis 40.1

Comparison 40 Oral zinc sulphate 2.5 mg/kg/d for 45 days versus oral zinc sulphate 5 mg/kg/d for 45 d, Outcome 1 Participants complete cure.

Analysis 40.2

Comparison 40 Oral zinc sulphate 2.5 mg/kg/d for 45 days versus oral zinc sulphate 5 mg/kg/d for 45 d, Outcome 2 Adverse effects.

Analysis 41.1

Comparison 41 Oral zinc sulphate 2.5 mg/kg/d for 45 d versus oral zinc sulphate 10 mg/kg/d for 45 d, Outcome 1 Participants complete cure.

Analysis 41.2

Comparison 41 Oral zinc sulphate 2.5 mg/kg/d for 45 d versus oral zinc sulphate 10 mg/kg/d for 45 d, Outcome 2 Adverse effects.

Analysis 42.1

Comparison 42 Oral zinc sulphate 5 mg/kg/d for 45 d versus oral zinc sulphate 10 mg/kg/d for 45 d, Outcome 1 Participants complete cure.

Analysis 42.2

Comparison 42 Oral zinc sulphate 5 mg/kg/d for 45 d versus oral zinc sulphate 10 mg/kg/d for 45 d, Outcome 2 Adverse effects.

Analysis 43.1

Comparison 43 Oral zinc sulphate (10 mg/kg/d for 45 d) versus IMMA (20 mg/kg/d for 20 d), Outcome 1 Participants complete cure.

Analysis 44.1

Comparison 44 Artesunate 400 mg + sulphamethoxypyrazine/pyrimethamine 1000 mg/50 mg 4 times daily for 4 d versus placebo, Outcome 1 Participants complete cure.

Analysis 45.1

Comparison 45 Topical 2% miconazole (twice a day) versus topical 1% clotrimazole (twice a day) for 30 d, Outcome 1 Lesions cured.

Analysis 46.1

Comparison 46 Topical ketoconazole (twice a day) versus vehicle (twice a day) for 30 d, Outcome 1 Participants complete cure.

Analysis 47.1

Comparison 47 Topical amphotericin B (3 to 7 drops twice daily for 8 weeks) versus ILMA (max 2 mL) once a week for 8 weeks, Outcome 1 Participants complete cure (ITT).

Analysis 47.2

Comparison 47 Topical amphotericin B (3 to 7 drops twice daily for 8 weeks) versus ILMA (max 2 mL) once a week for 8 weeks, Outcome 2 Adverse effects.

Analysis 48.1

Comparison 48 Paromomycin 15% + 12% MBCL (twice daily for 28 d) versus vehicle (twice daily for 28 d), Outcome 1 Lesions cured.

Analysis 48.2

Comparison 48 Paromomycin 15% + 12% MBCL (twice daily for 28 d) versus vehicle (twice daily for 28 d), Outcome 2 Scarring.

Analysis 48.3

Comparison 48 Paromomycin 15% + 12% MBCL (twice daily for 28 d) versus vehicle (twice daily for 28 d), Outcome 3 Microbiological cure of skin lesions.

Analysis 49.1

Comparison 49 Paromomycin (twice daily for 30 d) versus vehicle (twice daily for 30 d), Outcome 1 Lesions cured.

Analysis 50.1

Comparison 50 Paromomycin 15% + 10% urea (twice daily for 14 d) versus vehicle (twice daily for 14 d), Outcome 1 Participants complete cure.

Analysis 50.2

Comparison 50 Paromomycin 15% + 10% urea (twice daily for 14 d) versus vehicle (twice daily for 14 d), Outcome 2 Adverse effects.

Analysis 50.3

Comparison 50 Paromomycin 15% + 10% urea (twice daily for 14 d) versus vehicle (twice daily for 14 d), Outcome 3 Microbiological cure of skin lesions.

Analysis 51.1

Comparison 51 Paromomycin 15% (daily for 20 d) versus vehicle, Outcome 1 Participants complete cure.

Analysis 52.1

Comparison 52 Paromomycin 15% + gentamicin 0.5% (daily for 20 d) versus vehicle, Outcome 1 Participants complete cure.

Analysis 53.1

Comparison 53 Paromomycin 15% + gentamicin 0.5% (daily for 20 d) versus paromomycin 15% alone (daily for 20 d), Outcome 1 Participants complete cure.

Analysis 54.1

Comparison 54 Paromomycin 15% + 10% urea (twice daily for 45 d) versus ILMA (weekly for up to 3 months), Outcome 1 Participants complete cure.

Analysis 54.2

Comparison 54 Paromomycin 15% + 10% urea (twice daily for 45 d) versus ILMA (weekly for up to 3 months), Outcome 2 Recurrence.

Analysis 54.3

Comparison 54 Paromomycin 15% + 10% urea (twice daily for 45 d) versus ILMA (weekly for up to 3 months), Outcome 3 Scarring.

Analysis 55.1

Comparison 55 Paromomycin 15% + 10% urea (twice daily for 20 d) versus ILMA (weekly for up to 20 d), Outcome 1 Participants complete cure.

Analysis 55.2

Comparison 55 Paromomycin 15% + 10% urea (twice daily for 20 d) versus ILMA (weekly for up to 20 d), Outcome 2 Adverse effects.

Analysis 56.1

Comparison 56 Paromomycin + MBCL (twice daily for 15 d) versus ketoconazole (weekly for up to 30 d), Outcome 1 Participants complete cure.

Analysis 56.2

Comparison 56 Paromomycin + MBCL (twice daily for 15 d) versus ketoconazole (weekly for up to 30 d), Outcome 2 Microbiological cure of skin lesions.

Analysis 57.1

Comparison 57 Paromomycin (15% + 12% MBCL twice daily for 28 days) versus PDT (weekly for 4 weeks), Outcome 1 Lesions cured.

Analysis 57.2

Comparison 57 Paromomycin (15% + 12% MBCL twice daily for 28 days) versus PDT (weekly for 4 weeks), Outcome 2 Scarring.

Analysis 57.3

Comparison 57 Paromomycin (15% + 12% MBCL twice daily for 28 days) versus PDT (weekly for 4 weeks), Outcome 3 Microbiological cure of skin lesions.

Analysis 58.1

Comparison 58 Paromomycin (4 weeks) versus paromomycin (2 weeks) + vehicle (2 weeks), Outcome 1 Participants complete cure.

Analysis 58.2

Comparison 58 Paromomycin (4 weeks) versus paromomycin (2 weeks) + vehicle (2 weeks), Outcome 2 Microbiological cure of skin lesions.

Analysis 59.1

Comparison 59 IL zinc 2% (twice a week for 2 weeks) versus ILSSG (100 mg/mL) for 2 weeks), Outcome 1 Lesions cured.

Analysis 60.1

Comparison 60 IL zinc 2% (twice a week for 2 weeks) versus IL 7% HSCS for 2 weeks, Outcome 1 Lesions cured.

Analysis 61.1

Comparison 61 ILSSG (100 mg/mL) for 2 weeks versus IL 7% HSCS for 2 weeks, Outcome 1 Lesions cured.

Analysis 62.1

Comparison 62 IL zinc 2% (weekly for up to 6 weeks) versus ILMA (max 2 mL weekly for up to 6 weeks), Outcome 1 Lesions cured.

Analysis 62.2

Comparison 62 IL zinc 2% (weekly for up to 6 weeks) versus ILMA (max 2 mL weekly for up to 6 weeks), Outcome 2 Participants complete cured.

Analysis 62.3

Comparison 62 IL zinc 2% (weekly for up to 6 weeks) versus ILMA (max 2 mL weekly for up to 6 weeks), Outcome 3 Adverse effects.

Analysis 63.1

Comparison 63 IL zinc 2% (twice a week for 2 weeks) versus ILMA (60 mg/kg/d for 2 weeks), Outcome 1 Lesions cured.

Analysis 63.2

Comparison 63 IL zinc 2% (twice a week for 2 weeks) versus ILMA (60 mg/kg/d for 2 weeks), Outcome 2 Adverse effects.

Analysis 64.1

Comparison 64 Imiquimod (5% 3 times/week for 28 d) + IMMA (20 mg/kg/d for 14 d) versus vehicle + IMMA, Outcome 1 Participants complete cure.

Analysis 64.2

Comparison 64 Imiquimod (5% 3 times/week for 28 d) + IMMA (20 mg/kg/d for 14 d) versus vehicle + IMMA, Outcome 2 Participants with treated lesions that recur.

Analysis 64.3

Comparison 64 Imiquimod (5% 3 times/week for 28 d) + IMMA (20 mg/kg/d for 14 d) versus vehicle + IMMA, Outcome 3 Adverse effects.

Analysis 65.1

Comparison 65 IL 7% HSCS (0.2 mL to 7 mL per lesion) versus ILSSG (max 2 mL) max 5 injections, Outcome 1 Lesions cured.

Analysis 66.1

Comparison 66 IL 5% HSCS (0.5 mL to 1 mL per lesion) versus ILMA (0.5 mL to 1 mL per lesion) weekly for 6 to 10 weeks, Outcome 1 Lesions cured.

Analysis 66.2

Comparison 66 IL 5% HSCS (0.5 mL to 1 mL per lesion) versus ILMA (0.5 mL to 1 mL per lesion) weekly for 6 to 10 weeks, Outcome 2 Adverse effects.

Analysis 67.1

Comparison 67 IL 7% HSCS (0.1 mL to 0.5 mL per lesion) versus IL 2% ciprofloxacin solution (0.1 mL to 0.5 mL per lesion), Outcome 1 Lesions cured.

Analysis 68.1

Comparison 68 IL 15% HSCS (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 1 Lesions cured.

Analysis 68.2

Comparison 68 IL 15% HSCS (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 2 Recurrence.

Analysis 68.3

Comparison 68 IL 15% HSCS (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 3 Speed of healing (weeks).

Analysis 68.4

Comparison 68 IL 15% HSCS (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 4 Adverse effects.

Analysis 69.1

Comparison 69 ILSSG (0.2 mL to 4 mL per lesion) max 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 1 Lesions cured.

Analysis 69.2

Comparison 69 ILSSG (0.2 mL to 4 mL per lesion) max 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 2 Recurrence.

Analysis 69.3

Comparison 69 ILSSG (0.2 mL to 4 mL per lesion) max 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 3 Speed of healing (weeks).

Analysis 69.4

Comparison 69 ILSSG (0.2 mL to 4 mL per lesion) max 5 injections versus IL 10% HSCS (0.2 mL to 4 mL per lesion), Outcome 4 Adverse effects.

Analysis 70.1

Comparison 70 ILSSG (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 15% HSCS (0.2 mL to 4 mL per lesion), Outcome 1 Lesions cured.

Analysis 70.2

Comparison 70 ILSSG (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 15% HSCS (0.2 mL to 4 mL per lesion), Outcome 2 Recurrence.

Analysis 70.3

Comparison 70 ILSSG (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 15% HSCS (0.2 mL to 4 mL per lesion), Outcome 3 Speed of healing (weeks).

Analysis 70.4

Comparison 70 ILSSG (0.2 mL to 4 mL per lesion) maximum 5 injections versus IL 15% HSCS (0.2 mL to 4 mL per lesion), Outcome 4 Adverse effects.

Analysis 71.1

Comparison 71 IL IFN‐γ (weekly for 5 weeks) versus ILMA (0.5 mL to 1 mL per lesion) weekly for 5 weeks, Outcome 1 Lesions cured.

Analysis 71.2

Comparison 71 IL IFN‐γ (weekly for 5 weeks) versus ILMA (0.5 mL to 1 mL per lesion) weekly for 5 weeks, Outcome 2 Microbiological cure of skin lesions.

Analysis 72.1

Comparison 72 WR279,396 (twice a day for 20 d) versus vehicle (twice a day for 20 d), Outcome 1 Participants complete cure.

Analysis 72.2

Comparison 72 WR279,396 (twice a day for 20 d) versus vehicle (twice a day for 20 d), Outcome 2 Adverse effects.

Analysis 73.1

Comparison 73 IL metronidazole (2.5 mg to 10 mg each lesion) versus ILMA (150 mg to 600 mg each lesion) for up to 8 weeks, Outcome 1 Participants complete cure.

Analysis 73.2

Comparison 73 IL metronidazole (2.5 mg to 10 mg each lesion) versus ILMA (150 mg to 600 mg each lesion) for up to 8 weeks, Outcome 2 Adverse effects.

Analysis 74.1

Comparison 74 Topical miltefosine 6% (once daily) versus ILMA (twice a week) for up to 28 d, Outcome 1 Participants complete cure.

Analysis 75.1

Comparison 75 Dapsone gel 5% (twice a day) + ILMA (weekly) versus cryotherapy (every 2 weeks) + IMMA (weekly) for up to 16 weeks, Outcome 1 Lesions cured.

Analysis 76.1

Comparison 76 DAC‐055 + MWT (for 15 min) versus DAC‐055 alone for up to 75 d, Outcome 1 Participants complete cure.

Analysis 76.2

Comparison 76 DAC‐055 + MWT (for 15 min) versus DAC‐055 alone for up to 75 d, Outcome 2 Adverse effects.

Analysis 77.1

Comparison 77 DAC‐055 + heat (for 15 min) versus ILSSG (0.6 mL) for up to 75 d, Outcome 1 Participants complete cure.

Analysis 77.2

Comparison 77 DAC‐055 + heat (for 15 min) versus ILSSG (0.6 mL) for up to 75 d, Outcome 2 Adverse effects.

Analysis 78.1

Comparison 78 DAC‐055 alone (for 15 min) versus ILSSG (0.6 mL) for up to 75 d, Outcome 1 Participants complete cure.

Analysis 78.2

Comparison 78 DAC‐055 alone (for 15 min) versus ILSSG (0.6 mL) for up to 75 d, Outcome 2 Adverse effects.

Analysis 79.1

Comparison 79 Thio‐Ben (1 mL to 2 mL daily) + cryotherapy (fortnightly) versus ILMA (0.5 mL to 2 mL per lesions) weekly + cryotherapy (fortnightly) for up to 12 weeks, Outcome 1 Lesions cured.

Analysis 79.2

Comparison 79 Thio‐Ben (1 mL to 2 mL daily) + cryotherapy (fortnightly) versus ILMA (0.5 mL to 2 mL per lesions) weekly + cryotherapy (fortnightly) for up to 12 weeks, Outcome 2 Recurrence.

Analysis 79.3

Comparison 79 Thio‐Ben (1 mL to 2 mL daily) + cryotherapy (fortnightly) versus ILMA (0.5 mL to 2 mL per lesions) weekly + cryotherapy (fortnightly) for up to 12 weeks, Outcome 3 Adverse effects.

Analysis 80.1

Comparison 80 CO₂ laser (30 W continuous) versus IMMA (50 mg/kg/d) for up to 15 d, Outcome 1 Lesions cured.

Analysis 80.2

Comparison 80 CO₂ laser (30 W continuous) versus IMMA (50 mg/kg/d) for up to 15 d, Outcome 2 Adverse effects.

Analysis 81.1

Comparison 81 CO₂ laser (30 W continuous) versus cryotherapy (fortnightly) + ILMA (weekly) for up to 12 weeks, Outcome 1 Lesions cured.

Analysis 81.2

Comparison 81 CO₂ laser (30 W continuous) versus cryotherapy (fortnightly) + ILMA (weekly) for up to 12 weeks, Outcome 2 Adverse effects.

Analysis 82.1

Comparison 82 Ablative CO₂ laser (25 kW for 1 session) versus 3 weeks fractional CO₂ laser, Outcome 1 Partcipants complete cure.

Analysis 82.2

Comparison 82 Ablative CO₂ laser (25 kW for 1 session) versus 3 weeks fractional CO₂ laser, Outcome 2 Adverse effects.

Analysis 83.1

Comparison 83 TCA (50% wt/vol) fortnightly up to 3 times versus ILMA alone (weekly for up to 6 weeks), Outcome 1 Participants complete cure.

Analysis 83.2

Comparison 83 TCA (50% wt/vol) fortnightly up to 3 times versus ILMA alone (weekly for up to 6 weeks), Outcome 2 Recurrence.

Analysis 83.3

Comparison 83 TCA (50% wt/vol) fortnightly up to 3 times versus ILMA alone (weekly for up to 6 weeks), Outcome 3 Adverse effects.

Analysis 83.4

Comparison 83 TCA (50% wt/vol) fortnightly up to 3 times versus ILMA alone (weekly for up to 6 weeks), Outcome 4 Microbiological cure of skin lesions.

Analysis 84.1

Comparison 84 Topical TCA 50% + local heat versus ILMA twice a week for up to 8 weeks, Outcome 1 Participants complete cure.

Analysis 84.2

Comparison 84 Topical TCA 50% + local heat versus ILMA twice a week for up to 8 weeks, Outcome 2 Lesions cured.

Analysis 85.1

Comparison 85 TCA + ILMA (weekly for up to 8 weeks) versus ILMA alone (twice a week for up to 8 weeks), Outcome 1 Participants complete cure.

Analysis 85.2

Comparison 85 TCA + ILMA (weekly for up to 8 weeks) versus ILMA alone (twice a week for up to 8 weeks), Outcome 2 Speed of healing (weeks).

Analysis 86.1

Comparison 86 Fractional laser + ILMA (fortnightly 2 sessions) versus ILMA alone (twice a week for up to 8 weeks), Outcome 1 Participants complete cure.

Analysis 87.1

Comparison 87 TCA + ILMA (weekly for up to 8 weeks) versus fractional laser + ILMA (fortnightly 2 sessions), Outcome 1 Participants complete cure.

Analysis 87.2

Comparison 87 TCA + ILMA (weekly for up to 8 weeks) versus fractional laser + ILMA (fortnightly 2 sessions), Outcome 2 Speed of healing (weeks).

Analysis 88.1

Comparison 88 TCA fortnightly up to 8 weeks + ILMA (twice a week) versus ILMA alone (weekly for up to 8 weeks), Outcome 1 Participants complete cure.

Analysis 89.1

Comparison 89 Cryotherapy + ILMA (weekly) versus cryotherapy (weekly) for up to 6 weeks, Outcome 1 Participants complete cure.

Analysis 89.2

Comparison 89 Cryotherapy + ILMA (weekly) versus cryotherapy (weekly) for up to 6 weeks, Outcome 2 Adverse effects.

Analysis 90.1

Comparison 90 Cryotherapy + ILMA (weekly) versus ILMA (weekly) for up to 6 weeks, Outcome 1 Participants complete cure.

Analysis 90.2

Comparison 90 Cryotherapy + ILMA (weekly) versus ILMA (weekly) for up to 6 weeks, Outcome 2 Adverse effects.

Analysis 91.1

Comparison 91 Cryotherapy + ILMA (weekly) versus ILMA alone (weekly) for up to 6 weeks, Outcome 1 Participants complete cure.

Analysis 91.2

Comparison 91 Cryotherapy + ILMA (weekly) versus ILMA alone (weekly) for up to 6 weeks, Outcome 2 Adverse effects.

Analysis 92.1

Comparison 92 Cryotherapy (weekly) versus ILMA (weekly) for up to 6 weeks, Outcome 1 Participants complete cure.

Analysis 93.1

Comparison 93 Cryotherapy + ILMA (weekly) versus cryotherapy alone (weekly) for up to 6 weeks, Outcome 1 Lesions cured.

Analysis 93.2

Comparison 93 Cryotherapy + ILMA (weekly) versus cryotherapy alone (weekly) for up to 6 weeks, Outcome 2 Adverse effects.

Analysis 94.1

Comparison 94 Cryotherapy + ILMA (weekly) versus ILMA (fortnightly) for up to 6 weeks, Outcome 1 Lesions cured.

Analysis 94.2

Comparison 94 Cryotherapy + ILMA (weekly) versus ILMA (fortnightly) for up to 6 weeks, Outcome 2 Adverse effects.

Analysis 95.1

Comparison 95 Cryotherapy alone (weekly) versus ILMA (fortnightly) for up to 6 weeks, Outcome 1 Lesions cured.

Analysis 95.2

Comparison 95 Cryotherapy alone (weekly) versus ILMA (fortnightly) for up to 6 weeks, Outcome 2 Adverse effects.

Analysis 96.1

Comparison 96 Cryotherapy (fortnightly) + 15% paromomycin + 10% urea cream (twice a day) + ILMA (twice a day for 4 weeks) versus ILMA (twice a week) for up to 6 weeks, Outcome 1 Participants complete cure.

Analysis 97.1

Comparison 97 Cryotherapy (weekly) + 3% salicylic + 3% sodium nitrite cream (twice a day) for up to 12 weeks versus cryotherapy (weekly) + 3% salicylic cream (twice a day), Outcome 1 Lesions cured.

Analysis 97.2

Comparison 97 Cryotherapy (weekly) + 3% salicylic + 3% sodium nitrite cream (twice a day) for up to 12 weeks versus cryotherapy (weekly) + 3% salicylic cream (twice a day), Outcome 2 Adverse effects.

Analysis 98.1

Comparison 98 Radiofrequency waves versus ILMA (1 mL to 7 mL per lesion) weekly for 4 weeks, Outcome 1 Lesions cured.

Analysis 98.2

Comparison 98 Radiofrequency waves versus ILMA (1 mL to 7 mL per lesion) weekly for 4 weeks, Outcome 2 Participants complete cure.

Analysis 98.3

Comparison 98 Radiofrequency waves versus ILMA (1 mL to 7 mL per lesion) weekly for 4 weeks, Outcome 3 Adverse effects.

Analysis 99.1

Comparison 99 Radiofrequency waves (50 uCTM applied for 30 s) versus ILSSG (10 days of 20 mg/kg/d), Outcome 1 Lesions cured.

Analysis 99.2

Comparison 99 Radiofrequency waves (50 uCTM applied for 30 s) versus ILSSG (10 days of 20 mg/kg/d), Outcome 2 Adverse effects (serious).

Analysis 100.1

Comparison 100 Radiofrequency waves (1 treatment of > 1 consecutive application at 50ºC for 30 s) versus IMSSG (20 mg/kg/d for 3 weeks), Outcome 1 Participants complete cure.

Analysis 100.2

Comparison 100 Radiofrequency waves (1 treatment of > 1 consecutive application at 50ºC for 30 s) versus IMSSG (20 mg/kg/d for 3 weeks), Outcome 2 Adverse event (secondary infection).

Analysis 101.1

Comparison 101 Radiofrequency waves (1 treatment of > 1 consecutive application at 50ºC for 30 s) versus ILSSG (5 injections of 2 mL to 5 mL every 5 to 7 days), Outcome 1 Participants complete cure.

Analysis 101.2

Comparison 101 Radiofrequency waves (1 treatment of > 1 consecutive application at 50ºC for 30 s) versus ILSSG (5 injections of 2 mL to 5 mL every 5 to 7 days), Outcome 2 Adverse event (secondary infection).

Analysis 102.1

Comparison 102 Radiofrequency waves versus ILSSG, Outcome 1 Participants complete cure.

Analysis 103.1

Comparison 103 Electrocauterisation + DAC n‐055 (daily) versus electrocauterisation, Outcome 1 Adverse effects.

Analysis 104.1

Comparison 104 PDT (weekly for 4 weeks) versus placebo (twice a day for 4 weeks), Outcome 1 Lesions cured.

Analysis 104.2

Comparison 104 PDT (weekly for 4 weeks) versus placebo (twice a day for 4 weeks), Outcome 2 Scarring.

Analysis 104.3

Comparison 104 PDT (weekly for 4 weeks) versus placebo (twice a day for 4 weeks), Outcome 3 Microbiological cure of skin lesions.

Analysis 105.1

Comparison 105 Mesotherapy gun (0.5 mL of MA weekly) versus ILMA (0.1 mL weekly) for up to 6 weeks, Outcome 1 Participants complete cure.

Analysis 105.2

Comparison 105 Mesotherapy gun (0.5 mL of MA weekly) versus ILMA (0.1 mL weekly) for up to 6 weeks, Outcome 2 Adverse effects.

Analysis 105.3

Comparison 105 Mesotherapy gun (0.5 mL of MA weekly) versus ILMA (0.1 mL weekly) for up to 6 weeks, Outcome 3 Development of cell‐mediated immunity.

Analysis 106.1

Comparison 106 Diminazene aceturate solution (weekly) versus cetrimide + chlorhexidine solution for 50 d, Outcome 1 Participants complete cure.

Analysis 107.1

Comparison 107 Topical garlic (twice a day) versus vehicle for 3 weeks, Outcome 1 Participants complete cure.

Analysis 108.1

Comparison 108 Topical herbal extract + placebo (5 d) versus IMMA (15‐20/mg/kg/d) + vehicle for 20 d, Outcome 1 Participants complete cure.

Analysis 109.1

Comparison 109 Topical honey (twice a day) + ILMA (weekly) versus ILMA (weekly) for 4 weeks, Outcome 1 Participants complete cure.

Analysis 110.1

Comparison 110 Cassia fistula (topical gel) + ILMA (0.5 mL to 2 mL), twice a week versus ILMA (0.5 mL to 2 mL), twice a week + vehicle, Outcome 1 Participants complete cure.

Analysis 110.2

Comparison 110 Cassia fistula (topical gel) + ILMA (0.5 mL to 2 mL), twice a week versus ILMA (0.5 mL to 2 mL), twice a week + vehicle, Outcome 2 Adverse effects.

Analysis 111.1

Comparison 111 Cassia fistula boiled (topical) versus ILMA (0.5 mL to 2 mL), twice a week for 4 weeks, Outcome 1 Participants complete cure.

Analysis 111.2

Comparison 111 Cassia fistula boiled (topical) versus ILMA (0.5 mL to 2 mL), twice a week for 4 weeks, Outcome 2 Speed of healing (weeks).

Analysis 111.3

Comparison 111 Cassia fistula boiled (topical) versus ILMA (0.5 mL to 2 mL), twice a week for 4 weeks, Outcome 3 Adverse effects.

Analysis 112.1

Comparison 112 Cassia fistula hydroalcoholic (topical) versus ILMA (0.5 mL to 2 mL), twice a week for 4 weeks, Outcome 1 Participants complete cure.

Analysis 112.2

Comparison 112 Cassia fistula hydroalcoholic (topical) versus ILMA (0.5 mL to 2 mL), twice a week for 4 weeks, Outcome 2 Speed of healing (weeks).

Analysis 112.3

Comparison 112 Cassia fistula hydroalcoholic (topical) versus ILMA (0.5 mL to 2 mL), twice a week for 4 weeks, Outcome 3 Adverse reaction.

Analysis 113.1

Comparison 113 Cassia fistula boiled (topical) versusC fistula hydroalcoholic (topical) for 4 weeks, Outcome 1 Participants complete cure.

Analysis 113.2

Comparison 113 Cassia fistula boiled (topical) versusC fistula hydroalcoholic (topical) for 4 weeks, Outcome 2 Speed of healing (days).

Analysis 113.3

Comparison 113 Cassia fistula boiled (topical) versusC fistula hydroalcoholic (topical) for 4 weeks, Outcome 3 Adverse effects.

Analysis 114.1

Comparison 114 Topical gel Achilles millefollium (twice daily) + ILMA (weekly 20 mg/kg/d) versus ILMA (weekly 20 mg/kg/d) + vehicle (twice daily) for 4 weeks, Outcome 1 Participants complete cure.

Analysis 114.2

Comparison 114 Topical gel Achilles millefollium (twice daily) + ILMA (weekly 20 mg/kg/d) versus ILMA (weekly 20 mg/kg/d) + vehicle (twice daily) for 4 weeks, Outcome 2 Adverse effects.

Analysis 114.3

Comparison 114 Topical gel Achilles millefollium (twice daily) + ILMA (weekly 20 mg/kg/d) versus ILMA (weekly 20 mg/kg/d) + vehicle (twice daily) for 4 weeks, Outcome 3 Microbiological cure of skin lesions.