Sundar, Shyam, Pandey, Krishna, Mondal, Dinesh, Madhukar, Major, Kamal Topno, Roshan, Kumar, Ashish, Kumar, Vinod, Kumar Verma, Deepak, Chakravarty, Jaya, Chaubey, Rahul, Kumari, Poonam, Rashid, Md. Utba, Maruf, Shomik, Ghosh, Prakash, Raja, Sheeraz, Rode, Joelle, den Boer, Margriet, Das, Pradeep, Alvar, Jorge, and Rijal, Suman
Background: In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF. Methodology/Principal findings: An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred. Conclusions/Significance: Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia. Trial registration: CTRI/2017/04/008421. Author summary: Post-kala-azar dermal leishmaniasis (PKDL) is a skin rash which can appear after successful treatment of visceral leishmaniasis caused by the parasite Leishmania donovani. Although not life-threatening for the patient, this condition can be associated with social stigma, and the sandfly that transmits the disease can become infected after feeding on patients with PKDL lesions. Therefore, all patients are treated to control visceral leishmaniasis within the Southeast Asia kala-azar elimination initiative. It is difficult to justify the use of existing treatments in patients who are otherwise generally well, since they are prolonged, potentially toxic, and expensive. We designed a trial at two sites in India and one in Bangladesh to assess the efficacy and safety of two treatment options for patients with PKDL: 20 mg/kg liposomal amphotericin B in monotherapy and 20 mg/kg liposomal amphotericin B in combination with three weeks of miltefosine. These two regimens were found to have a similar efficacy to the current first line treatment, but with a much shorter treatment duration, which also reduces the risk of side-effects and makes them particularly useful in the current context of elimination in the region. [ABSTRACT FROM AUTHOR]