Discussion
deaths, hypersensitivity, vomiting, Vomiting
DISEASE, HYPERSENSITIVITY
This is the first randomized clinical trial to assess safety and efficacy of treatments for patients with PKDL in Sudan. The trial showed that MF combined with either PM or LAmB achieved clinically meaningful rates of definitive cure at 12 months follow-up in paediatric and adult patients with PKDL in Sudan. No new safety signals were reported and both combinations had favourable risk/ benefit profiles, with no reports of SAEs or deaths during the study. Outpatient treatment with MF was well tolerated overall, with good rates of treatment adherence.The PM/MF combination achieved a 100% cure rate at 12 months in the complete case scenario, including patients with moderate and severe disease at baseline, and was well tolerated; the large majority of ADRs were mild episodes of vomiting, and only one patient had treatment discontinued due to AE. The LAmB/MF combination was also efficacious, with a cure rate of 86% in the complete case analysis. Cases of failure were mainly patients presenting with moderate/severe PKDL at baseline, who relapsed during the 12 months of follow-up, one case of no response to therapy, and one case of hypersensitivity to LAmB. All these patients received rescue therapy. This difference in efficacy may be explained by the different skin exposures for PM and LAmB, with skin to plasma concentration ratios of 0.44 and 0.1, respectively, and the longer MF regimen in PM/MF arm.Despite the challenges of implementing this trial during the COVID-19 pandemic, only 3 patients were lost to follow-up (2.7%), and 2 withdrew consent (1.8%) during the trial. Furthermore, only 5 patients in Arm 1 and 4 in Arm 2 were not included in the PP population (due to poor compliance, exclusion criteria not met, or consent withdrawal), yielding similar efficacy rates in the mITT, PP and the complete case analyses.A Consistent with epidemiological studies of VL in Sudan [Very few studies have been conducted in patients with PKDL in East Africa. An observational study in India based on 32 mostly adult patients with predominantly nodular, papular, or macular PKDL lesions showed a 75% (12/16) cure rate with MF alone (100 mg/kg/day for 90 days) and a 100% (16/16) cure rate with LAmB/MF combination (LAmB given in 3 doses of 5 mg/kg IV over 2 weeks and MF at 100 mg/kg/day for 45 days) [The safety findings showed that these combination therapies are suitably safe for patients with PKDL. No SAEs or deaths were reported, and the vast majority of AEs were of mild or moderate intensity. Vomiting was the most frequent AE, as in previous studies with miltefosine [The current standard-of-care for treatment of PKDL in Sudan, SSG [For patients who cannot be treated with MF or women of childbearing potential who are not willing to use contraception, the SSG/PM combination can be an alternative. Pregnant women could either delay the therapy for PKDL or receive treatment with LAmB. After adoption of these therapies, effectiveness studies will be needed to confirm these results in field conditions.Patients with PKDL in Sudan present the clinical manifestations soon after being cured of VL, the majority within 6 to 12 months of VL therapy; most patients present papular or maculo-papular lesions [While the positive results of this trial represent a significant improvement on existing options and could reduce VL transmission and hence help in disease control, efficacious, safe, oral treatments need to be developed for all patients with PKDL in Eastern Africa, including mild cases and women of childbearing potential unwilling or unable to use contraception. Community engagement and educational programs are needed to raise awareness of the disease and the availability of treatments, to reduce time from PKDL onset and access to diagnosis and treatment. Finally, better treatments are needed for VL that have a reduced risk of subsequent development of PKDL, comprising anti-parasitic drugs and, potentially, host-directed immune-modulatory therapy. Only then can transmission of VL be sufficiently reduced to reach the WHO aim of eliminating the disease as a public health problem, as highlighted in the WHO NTD Roadmap [