Single-dose liposomal amphotericin B: an effective treatment for visceral leishmaniasis
Authors: Prabhat Kumar Sinha, Sujit Bhattacharya
Journal: The Lancet Global Health (2013)

Visceral leishmaniasis (also known as kala-azar) is a vector-borne disease transmitted through the bite of female phlebotomine sandflies. It is carried by people in the Indian subcontinent (India, Nepal, and Bangladesh) and human beings are the only disease reservoir. Clinical features are characterised by fever, weight loss, hepatosplenomegaly, and pancytopenia; the disease is typically fatal if untreated. Early diagnosis and effective treatment are thus key to the management of patients with visceral leishmaniasis. Since the 1920s, the mainstay of treatment for visceral leishmaniasis has been antimonials. Upendranath Brahmachari first treated patients with visceral leishmaniasis in Bengal and Assam with the antimonial urea stibamine. After the 1940s, pentavalent antimony compounds such as sodium antimony gluconate (sodium stibogluconate) began to be used to treat patients. However, because of their ineffectiveness in endemic districts in north Bihar and adjoining districts of Nepal from the 1980s, improved treatment options were needed.1Thakur CP Kumar A Mitra G et al.Impact of amphotericin-B in the treatment of kala-azar on the incidence of post-kala-azar dermal leishmaniasis in Bihar, India.Indian J Med Res. 2008; 128: 38-44PubMed Google Scholar When responsiveness to sodium antimony gluconate became less than 50%, it was replaced by amphotericin B deoxycholate, which had cure rates of more than 95%. However, infusion of this drug is associated with adverse effects such as rigor, fever, and occasional nephrotoxicity. In the past two decades, three important drugs for the treatment of visceral leishmaniasis have been registered in India, Nepal, and Bangladesh after positive clinical trials: liposomal amphotericin B, miltefosine, and paromomycin. Liposomal amphotericin B has shown much the same activity as amphotericin B deoxycholate, but with lesser infusion-related adverse effects owing to liposomal encapsulation of the active ingredient. Relatively uncommon side-effects related to infusion of liposomal amphotericin B include chest tightness, low blood pressure, and back or bone pain; these side-effects are reversible soon after the infusion is stopped. To date, however, multidose liposomal amphotericin B has mainly been used as rescue therapy because of its high cost. Nevertheless, this regimen has key advantages compared with other drugs such as miltefosine (which requires 28 days of oral therapy) and paromomycin (which requires 21 intramuscular injections). In Dinesh Mondal and colleagues' new study2Mondal D Alvar J Hasnain MG et al.Efficacy and safety of single-dose liposomal amphotericin B for visceral leishmaniasis in a rural public hospital in Bangladesh: a feasibility study.Lancet Glob Health. 2013; (published online Dec 5.)http://dx.doi.org/10.1016/S2214-109X(13)70118-9Google Scholar in The Lancet Global Health, the final cure rate at 6 months after treatment with 10 mg/kg liposomal amphotericin B at the primary health-care level in Bangladesh was 97%, with few side-effects that were easily manageable at the primary-health care level. No patients needed referral to the tertiary hospital for management of adverse events. However, one patient had hypersensitivity to liposomal amhpotericin and another had interruption of treatment during intravenous infusion because of development of bradycardia. Six treated patients had a decrease in haemoglobin by 2 g/L. A notable proportion of patients with visceral leishmaniasis (27%) were hypotonic, meaning that medical staff should therefore be trained for its management before start of treatment at peripheral level. These findings add to those from another study in Bihar, India, in which a single dose (10 mg/kg) of liposomal amphotericin B was effective in 96% of participants at 6 months.3Sundar S Chakravarty J Agarwal D Rai M Murray HW Single-dose liposomal amphotericin B for visceral leishmaniasis in India.N Engl J Med. 2010; 362: 504-512Crossref PubMed Scopus (311) Google Scholar Thus, liposomal amphotericin B can be said to have high cure rates, low relapse rates, few side-effects related to infusion, and good rates of treatment compliance. The ideal drug to reduce disease burden and prevent relapse and post-kala-azar dermal leishmaniasis will need to be effective, cheap, usable at the peripheral level, and have a strong safety profile. Mondal and colleagues2Mondal D Alvar J Hasnain MG et al.Efficacy and safety of single-dose liposomal amphotericin B for visceral leishmaniasis in a rural public hospital in Bangladesh: a feasibility study.Lancet Glob Health. 2013; (published online Dec 5.)http://dx.doi.org/10.1016/S2214-109X(13)70118-9Google Scholar show for the first time that single-dose liposomal amphotericin B could meet all such expectations. A particular advantage is that it can be used in children and women of childbearing age without any contraceptive precautions. Conversely, miltefosine, an oral drug brought into the visceral leishmaniasis elimination programme as the first-line therapy in many of the endemic districts of India, is contraindicated in pregnancy and breastfeeding and, because of its long half-life, a high potential for development of resistance exists. Notably, a decrease in efficacy of miltefosine from 97% in the phase 3 trial3Sundar S Chakravarty J Agarwal D Rai M Murray HW Single-dose liposomal amphotericin B for visceral leishmaniasis in India.N Engl J Med. 2010; 362: 504-512Crossref PubMed Scopus (311) Google Scholar to 82% in the phase 4 trial4Bhattacharya SK Sinha PK Sundar S et al.Phase IV trial of miltefosine in the treatment of Indian visceral leishmaniasis.J Infect Dis. 2007; 196: 591-598Crossref PubMed Scopus (209) Google Scholar at 6 months was shown in India. Additionally, single-dose liposomal amphotericin B has advantages such as near 100% compliance (one-off administration) compared with other regimens such as sodium antimony gluconate, miltefosine, or amphotericin B deoxycholate. The major concern is that monotherapy can foster emergence of drug resistance. Other important factors are the cost of treatment and the fact that a proper cold chain must be maintained and standard operating procedure followed. However, the cost of liposomal amphotericin B has recently been dropped, and single-dose treatment could reduce costs associated with non-medical transportation and hospital stays. Mondal and colleagues' study shows the feasibility of the drug's use under "real-life" conditions. The Drugs for Neglected Diseases Initiative and WHO's Special Programme for Research and Training in Tropical Diseases are presently undertaking studies to assess the feasibility, safety, and efficacy of treatment with single-dose liposomal amphotericin B 10 mg/kg for the management of visceral leishmaniasis in endemic regions at district hospitals and primary health-care services in Bihar, India. The Drugs for Neglected Diseases Initiative is also assessing the safety and efficacy of different combination regimens, including miltefosine and paromomycin for 10 days, and single-dose liposomal amphotericin B 5 mg/kg and miltefosine for 7 days at a district hospital and the primary health-care level in Bihar, India. WHO's expert committee on the control of leishmaniasis (WHO Technical Report Series no 949)5WHOControl of the leishmaniases.http://whqlibdoc.who.int/trs/WHO_TRS_949_eng.pdfGoogle Scholar in its 2010 meeting recommended the use of liposomal amphotericin B, 10 mg/kg, as single infusion as a first choice for the treatment of anthroponotic visceral leishmaniasis in the Indian subcontinent. In our opinion, single-dose treatment with liposomal amphotericin B will indeed be the most effective and best drug to treat poor patients with visceral leishmaniasis at primary health-care level in the visceral leishmaniasis elimination programme undertaken by India, Bangladesh, and Nepal, and will thus help to reduce the burden of the disease in this region. We declare that we have no conflicts of interest. Efficacy and safety of single-dose liposomal amphotericin B for visceral leishmaniasis in a rural public hospital in Bangladesh: a feasibility studyTreatment of visceral leishmaniasis in a primary health-care facility with single-dose liposomal amphotericin B could safely and effectively be adopted by the national visceral leishmaniasis elimination programme in Bangladesh. Full-Text PDF Open Access