Post kala-azar dermal leishmaniasis treated with liposomal amphotericin B MSF OCA, OCBA Bangladesh, India *Sakib Burza1,2, Margriet den Boer5, Raman Mahajan1, Temmy Sunyoto1, Marıa Angeles Lima3, Asish Kumar Das4, Patrick Almeida4, Gaurab Mitra1, A. Be-Nazir6, Pradeep Das7, Koert Ritjmeijer5   1Médecins Sans Frontières (MSF), New Delhi, India; 2Institute of Tropical Medicine, Antwerp, Belgium: 3MSF, Barcelona, Spain; 4MSF, Dhaka, Bangaldesh; 5MSF, Amsterdam, Holland: 6Communicable Disease Control, Ministry of Health and Family Welfare, Dhaka, Bangladesh, 7Rajendra Mamorial Research Institute, Patna, India

Post Kala Azar Dermal Leishmaniasis (PKDL) Is a complication of visceral leishmaniasis Common in areas endemic for VL caused by L.donovani Characterised by a skin rash after an episode of VL In contrast to VL: Patients are typically not ill PKDL is not fatal Main issue is that of aesthetics However, is a public health problem: Based on existing evidence, PKDL is a major reservoir of L.donovani In South Asia, PKDL does not self heal Needs to be treated if transmission of disease is to be limited Estimated 5-10% of VL cases go on to develop PKDL Incidence 4.8/1000, interval 0-3 years post initial VL infection

A neglected disease within a neglected disease Very poor evidence base and understanding of PKDL as a disease process Limited evidence on pathogenesis or risk factors Accurate diagnosis is difficult, needs experience and skilled HR Serological diagnosis difficult to interpret Very little evidence on management: No evidence on ‘skin penetration’ of existing drugs No evidence on ‘end point’ of treatment Very limited evidence on treatments

Examples of PKDL morphologies:

Existing evidence for treatment of PKDL In South Asia, only one RCT to date Compared miltefosine (MF) 100mg/day 8 weeks vs 12 weeks 12 weeks recommended – 93% cure rate at 12 months (PP) Based on 15 cases No children, no macular PKDL, no safety data >4 weeks Needs contraception >7 months in women of reproductive age Adherence likely to be an issue – may lead to resistance This regimen poses high direct and indirect costs for the patient and health care system

MSF treatment for PKDL in Bangladesh and India Diagnosis: Clinical symptoms + past VL + +ve rK39 test Treatment: AmBisome 30 mg/kg total dose (6 x 5 mg/kg 2/7, ambulatory) Initially in Bangladesh, then started in India after WHO consultative meeting recommendations 2012 Subsequently AmBisome 15 mg/kg total dose (5 x 3 mg/kg 2/7, ambulatory) in Bangladesh Ambulatory treatment over 3 weeks End-points 12 months follow up, photograph assisted scoring Safety monitored closely; particularly hypokalaemia

30mg/kg AmBisome regimen for treatment of PKDL: Patient characteristics Bangladesh

30mg/kg AmBisome regimen for treatment of PKDL: Patient characteristics India

Effectiveness and safety outcomes at 12 months India: Of 50 patients completing 12 month follow up, 42 (84%) showed substantial or complete cure Bangladesh: Of 63 patients completing 12 month follow up, 59 (93%) showed substantial or complete cure Safety data (entire cohort): Concerning incidence of hypokalaemia in Bangladesh No rhabdomyolysis or other sequealae in either context Treatment switched to 15mg/kg in Bangladesh Hypokalaemia India (n=113) Bangladesh (n=110)   Number % Mild (3.0-3.5 mmol/L) 21 18.5% 53 49.1% Moderate (2.5-3.0 mmol/L) 8 7% 17 15.7% Severe (<2.5 mmol/L) 1 0.9% 7 6.5%

15mg/kg AmBisome regimen for treatment of PKDL in Bangladesh: A prospective observational study Primary objective: Evaluate effectiveness of AmBisome 15 mg/kg total dose at 12 months 3mg/kg given in 5 doses over 2-3 weeks Secondary objective: Evaluate safety of AmBisome 3mg/kg x 5 infusions (twice weekly) Evaluate the occurrence of hypokalaemia Evaluate at which point in time lesions start to respond to treatment. Sample size: 275

PKDL lesion improvement during post-treatment follow up March 2015 73% substantial or complete improvement by 6 months Excellent safety data – no SAE or severe hypokalaemia 12 month data collection has started

Limitations Difficult to standardise assessment of improvement – very subjective Irregular quality of photographs in 30mg/kg groups (improved in 15mg/kg) Inclusion was clinical assessment based – negative parasitology did not preclude inclusion

Conclusions 30mg/kg AmBisome appears effective in the treatment of PKDL Safety concerns of hypokalaemia in Bangladesh, although not seen in India 15mg/kg AmBisome appears safe, tolerable and showed good adherence in PKDL Effectiveness appears to be similar to the higher dose – pending 12 month results becoming available Urgent need for an alternative shorter course treatment exists for PKDL – AmBisome may be considered an appropriate option