Safety and efficacy of a combination of paromomycin and miltefosine for two vs. three courses in patients with post-kala-azar dermal leishmaniasis: an observational pilot study

Dear Editor, Post‐kala‐azar dermal leishmaniasis (PKDL) is a dermal form of leishmaniasis caused by the protozoal parasite Leishmania donovani. It is characterized by macular, papular and nodular lesions or a mixture of these.1 It is seen mainly in Sudan and India, where it follows treatment of visceral leishmaniasis in 50% and 5–10% of cases, respectively.2 A phase III study on miltefosine–paromomycin combination for 10 days for treatment of Indian visceral leishmaniasis (n = 157) revealed a high cure rate (98·7%), with minimal toxicity, good compliance, shorter treatment and noninferiority to standard amphotericin B.3 Therefore we aimed to assess the efficacy and safety of miltefosine–paromomycin combination in 30 patients with PKDL. This study was conducted at Rajendra Memorial Research Institute of Medical Sciences, Patna, India between June 2013 and January 2016, inclusive of a 1‐year follow‐up period. The study was approved by the institutional ethics committee and registered in the Clinical Trial Registry India (CTRI/2016/04/006898). Written informed consent was obtained from all the participants, and from the legal guardians in case of minors. Patients of both sexes, aged 5–65 years and diagnosed clinically with skin lesions consistent with PKDL, underwent parasitological confirmation for PKDL. PKDL was confirmed by microscopic visualization of Leishmania amastigote in a slit‐skin smear stained with Giemsa stain.4 Baseline evaluations included complete haemogram and renal and liver function tests. Patients seropositive for HIV, hepatitis B or hepatitis C, patients with hearing impairment and pregnant or lactating women were excluded. Thirty eligible patients were randomized into two groups, 15 patients in group A and 15 in group B. Group A received intramuscular injection of paromomycin (11 mg kg−1) plus a miltefosine capsule orally (2·5 mg kg−1 per day) daily for 10 days for two courses with a gap of 15 days, whereas group B received three courses of the same combination. Assessment of adverse events was done on the 15th day of each course and then at 3, 6, 9 and 12 months of follow‐up. Auditory function was assessed by an otorhinolaryngologist. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria (CTC) for Adverse Events, version three.5 Efficacy was assessed as initial cure and final cure. Initial cure was defined as clearance of the parasite from the dermal lesions at the end of treatment, and final cure as disappearance of lesions (Fig. 1) and grade 0 parasite score at the 1‐year follow‐up. Papulonodular lesions (a) before and (b) after treatment. The demographic and clinical characteristics of all 30 patients with PKDL are shown in Table 1. After receiving two courses of therapy, patients in group A did not improve greatly, as most of the macular lesions persisted and most of the patients did not achieve grade 0 parasitic score; however, the papular and nodular lesions disappeared. The decision to give three courses was based on clinically persistent macular lesions and parasitic score. All 15 patients in group A underwent a third course of combination therapy and completed three courses of treatment. Demographic and clinical characteristics of all 30 patients with post‐kala‐azar dermal leishmaniasis treated with miltefosine–paromomycin VL, visceral leishmaniasis. Demographic and clinical characteristics of all 30 patients with post‐kala‐azar dermal leishmaniasis treated with miltefosine–paromomycin VL, visceral leishmaniasis. At the end of treatment, the lesions disappeared completely in 25 participants, whereas a few macular lesions persisted in five patients. All of them had a grade 0 parasite score, which gave an initial cure rate of 100%. Out of 30 initially cured patients, five (17%) relapsed. Thus the final cure rate was 83% (95% confidence interval 69·5–96·5%). Relapsed cases were treated with amphotericin B (1 mg kg−1), with 15 injections on alternate days for three courses in 5% intravenous dextrose. In total 24 patients experienced adverse events of CTC grade I. The most commonly occurring adverse events were pain at the injection site, increased hepatic enzymes, eosinophilia and vomiting. Hypokalaemia, gastritis and swelling of the legs were among the others. The currently available treatment regimen for PKDL is lengthy and associated with numerous side‐effects. Hence we need a monotherapy or combination treatment that is highly effective and of shorter duration, and has good tolerability and safety. A study on the combination of sodium stibogluconate (SSG) with allopurinol, rifampicin and an immunomodulator showed no major advantage of this regimen over SSG alone in treatment of PKDL.6 Miltefosine is recommended in a dose of 2·5 mg kg−1 for 12 weeks (84 days), but in combination with paromomycin it is required to be administered for a period of 60 days, including the intervals between each course. Thus, the advantages of this combination therapy include shorter treatment duration, lower period of hospitalization, and being highly affordable. A recent study by Ramesh et al. showed that the efficacy of miltefosine is 85% in the treatment of PKDL (with18 months of follow‐up), which is similar to the results in our study.7 Apart from one patient with mild elevation of serum creatinine, none of the patients showed nephrotoxicity. Pain at the site of injection was found to be the most commonly occurring drug‐related adverse event. A similar observation was also reported with paromomycin monotherapy in PKDL.8 None of the patients experienced auditory dysfunction or any serious adverse events. The compliance was excellent as none of the patients discontinued or was lost to follow‐up; this could have been due to the short duration of therapy and excellent safety profile. The main limitation of this study is the lack of confirmation of parasite clearance through quantitative polymerase chain reaction; this method is more sensitive than conventional microscopy. However, the outcome of this novel combination therapy appears to be optimal, with excellent safety and tolerability. The authors would like to thank Dr Kanhaiya Agarwal, Mr Dhirendra Kumar and Mr Naresh Kumar Sinha for coordinating the study and Dr Anima for writing assistance. The authors are also thankful to all of the participants for their involvement in the study. Conflicts of interest: none declared.