|Year : 2015 | Volume
| Issue : 2 | Page : 83-85
Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Web Publication||10-Aug-2015|
Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh
|How to cite this article:|
Sundar S. Visceral leishmaniasis. Trop Parasitol 2015;5:83-5
The disease complex, leishmaniasis, is a neglected tropical vector-borne disease caused by obligate intracellular protozoan of the genus Leishmania . Broadly, it manifests as visceral leishmaniasis (VL; also known as kala-azar), cutaneous leishmaniasis, and mucocutaneous leishmaniasis.  VL is the most severe form of leishmaniasis, caused by the Leishmania donovani complex: L. donovani, the causative organism of VL in the Indian subcontinent and Africa; Leishmania infantum (Leishmania chagasi) which causes VL in the Mediterranean basin, Central and South America. It is transmitted by sand flies (Phlebotomus species) as extracellular flagellated promastigotes and replicate as intracellular, aflagellated amastigotes in mononuclear phagocytes in mammalian host. Worldwide, around 0.2-0.4 million VL cases occur each year, 90% of which occur in just six countries including India, Bangladesh, Sudan, South Sudan, Brazil, and Ethiopia. 
HIV-VL co-infection is also emerging as a major threat and has been reported from more than 35 countries. Initially, the majority of the patients were reported from South-Western Europe, but the number of co-infected patients is increasing especially in Ethiopia, Brazil, and South Asia. , In India, two large studies from the hyperendemic region of Bihar reported HIV-VL co-infection in 1.8-4.5% patients. 
VL is fatal, if left untreated and is characterized by prolonged fever, hepatomegaly, splenomegaly, pancytopenia, progressive anemia, and weight loss. Around 50% of patients in Sudan and 5-10% in the Indian subcontinent develop dermal leishmaniasis after recovery of VL characterized by indurated nodules or depigmented macules called post kala-azar dermal leishmaniasis (PKDL). , It serves as a reservoir of infection, and its effective treatment is essential for VL elimination.
For diagnosis of VL, parasite demonstration in spleen remains the "gold standard" but the risk of life-threatening hemorrhage is a limiting factor. Other serological tests such as ELISA, IFAT, DAT, etc., with high specificity and sensitivity, are available. However, their use in field is limited by the fact that they are expensive, cumbersome besides requiring skilled personnel and electricity. It is also a technically demanding. The Rapid immunochromatographic test, using rK39 antigen (conserved in the kinesin region of the parasite) which has been evaluated extensively. It has high sensitivity (>98%) and specificity with the exception that a varying proportion (10-32%) of healthy individual from the endemic region may test positive due to exposure to Leishmania. Molecular tests such as polymerase chain reaction (PCR) and quantitative PCR are rapid and highly sensitive test for diagnosis and prognosis of leishmaniasis in the future but are technically demanding.  Thus, VL case definition includes fever for 2 weeks, splenomegaly, weight loss and with a positive K39 rapid test/parasitology. In East Africa, the sensitivity of these rapid tests is significantly lower. 
The treatment of VL is challenging as the armoury of antileishmanial drugs is sparse, consisting of pentavalent antimonials, Amphotericin B (AmB) and its lipid formulations, miltefosine, and paromomycin (PM). For several decades, pentavalent antimonials (Sb v ) have been used as the first line drug. However, widespread resistance to the drug has developed in North Bihar and neighboring areas of Nepal. , AmB deoxycholate has been used with excellent cure rates (CR ~ 100%) at doses of 0.75-1.0 mg/kg for 15-20 intravenous infusions in this region. However, infusion-related rigors and high fever are common. Nephrotoxicity is frequent, and hypokalemia, myocarditis are other uncommon adverse events. Therefore, AmB treatment warrants close monitoring and hospitalization for 4-5 weeks which escalates the treatment cost.  Various lipid formulations of AmB have been introduced to minimize the side effects; however, cost has been the limiting factor, but due to negotiation with WHO, Gilead Sciences (Foster City, US) agreed to supply its liposomal-AmB (AmBisome; L-AmB) at 10% of the market cost (20 US$) to the developing countries (now the drug is available at ~16 US$/vial for India and other developing and poor countries). In a recent development, Gilead signed a partnership agreement with WHO to donate 445,000 vials of AmBisome over 5 years. L-AmB was used in a single dose of 5 mg and 7.5 mg/kg with a CR of 91%, and 90%, respectively. , In India, a phase 3 study, in which a single dose of 10 mg/kg of body weight L-AmB, was compared to the conventional AmB deoxycholate administered in 15 infusions of 1 mg/kg and was found to be equally efficacious with a CR of >95%. The preferential pricing, along with a single day of hospitalization, makes a single infusion of the liposomal preparation an excellent option for this region.  WHO has recommended single dose (10 mg/kg) L-AmB as the most preferred regimen for the treatment of VL in the Indian subcontinent. 
Miltefosine is the first oral antileishmanial agent registered for the use in India in 2002 following a phase 3 trial in which a dose of 50-100 mg/day for 28 days resulted in a long-term CR of 94%.  It has been the backbone of the elimination program in India, Nepal, and Bangladesh for its ease of use and applicability in the control program. However, after a decade of use of the drug in the Indian subcontinent, the relapse rate doubled, and its efficacy appears to have declined. 
PM sulfate (11 mg base), in a dose of 15 mg/kg for 21 days, cured 95% patients and was approved by the Indian Government in August 2006 for the treatment of patients with VL.  However, its parenteral administration is a major hindrance for being used in a control program of a developing country, and further monotherapy with PM might increase the chance of resistance as is true for aminoglycosides.
In India, the present treatment guidelines includes a single dose of 10 mg/kg of L-AmB at the district level where cold chain requirement for L-AmB (<25°C) can be maintained or combination therapy consisting of 10 days each of miltefosine and PM are the preferred treatment options in the Indian subcontinent. ,, The combination of sodium stibogluconate (SSG) with PM for 17 days is the treatment of choice in East Africa and Yemen, whereas L-AmB up to a total dose of 18-21 mg/kg is the treatment of choice in the Mediterranean Basin, Middle East, Central Asia, and South America. , Kala-azar Elimination Program, launched in India, Nepal, and Bangladesh a decade ago, has borne fruits, with the incidence of VL coming down significantly in all the three countries.
For PKDL in India, 60-80 doses AmB at 1 mg/kg over 4 months or miltefosine for 12 weeks are the recommended regimens, but the compliance is poor. In East Africa, most of PKDL lesions heal (85%) spontaneously in a year, so treatment is not warranted. However, SSG (20 mg/kg/day) for up to 2 months or a 20-day course of L-AmB at 2.5 mg/kg/day are given to patients with severe or disfiguring disease, those with lesions that have persisted for >6 months, those with concomitant anterior uveitis and young children with oral lesions interfering with feeding. 
For HIV-VL co-infection, liposomal Amphotericin infused at a dose of 3-5 mg/kg/day or intermittently for 10 doses (on days 1-5, 10, 17, 24, 31, and 38) up to a total dose of 40 mg/kg is recommended. Along with it, patients should be started on antiretroviral therapy and secondary prophylaxis should be given until the CD4 counts are >200/μl. 
The dwindling efficacy of drugs and the emerging resistance of the parasite to antileishmanial drugs suggests that the currently used monotherapy needs to be abandoned. Further, the strategies to prevent drug resistance should be implemented as treatment options are limited.  Also, there is an urgent need to discover newer drugs with antileishmanial activity.
| References|| |
Control of the Leishmaniasis. Report of a Meeting of the WHO Expert Committee on the Control of Leishmaniases. 22-26, March, 2010. Available from: http://www.whqlibdoc.who.int/trs/WHO_Technical Report series (TRS)_949_eng.pdf. [Last assessed on 2015 Jul 22].
Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al.
Leishmaniasis worldwide and global estimates of its incidence. PLoS One 2012;7:e35671.
Desjeux P, Alvar J. Leishmania/HIV co-infections: Epidemiology in Europe. Ann Trop Med Parasitol 2003;97 Suppl 1:3-15.
Alvar J, Aparicio P, Aseffa A, Den Boer M, Cañavate C, Dedet JP, et al.
The relationship between leishmaniasis and AIDS: The second 10 years. Clin Microbiol Rev 2008;21:334-59.
Burza S, Mahajan R, Sanz MG, Sunyoto T, Kumar R, Mitra G, et al.
HIV and visceral leishmaniasis coinfection in Bihar, India: An underrecognized and underdiagnosed threat against elimination. Clin Infect Dis 2014;59:552-5.
Zijlstra EE, Musa AM, Khalil EA, el-Hassan IM, el-Hassan AM. Post-kala-azar dermal leishmaniasis. Lancet Infect Dis 2003;3:87-98.
Sundar S, Rai M. Laboratory diagnosis of visceral leishmaniasis. Clin Diagn Lab Immunol 2002;9:951-8.
Sundar S, More DK, Singh MK, Singh VP, Sharma S, Makharia A, et al.
Failure of pentavalent antimony in visceral leishmaniasis in India: Report from the center of the Indian epidemic. Clin Infect Dis 2000;31:1104-7.
Rijal S, Chappuis F, Singh R, Bovier PA, Acharya P, Karki BM, et al.
Treatment of visceral leishmaniasis in South-Eastern Nepal: Decreasing efficacy of sodium stibogluconate and need for a policy to limit further decline. Trans R Soc Trop Med Hyg 2003;97:350-4.
Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A. Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: A study of 938 cases. Trans R Soc Trop Med Hyg 1999;93:319-23.
Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 2010;362:504-12.
Sundar S, Agrawal G, Rai M, Makharia MK, Murray HW. Treatment of Indian visceral leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: Randomised trial. BMJ 2001;323:419-22.
Sundar S, Jha TK, Thakur CP, Mishra M, Singh VP, Buffels R. Single-dose liposomal amphotericin B in the treatment of visceral leishmaniasis in India: A multicenter study. Clin Infect Dis 2003;37:800-4.
Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, et al.
Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002;347:1739-46.
Sundar S, Singh A, Rai M, Prajapati VK, Singh AK, Ostyn B, et al.
Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis 2012;55:543-50.
Sundar S, Jha TK, Thakur CP, Sinha PK, Bhattacharya SK. Injectable paromomycin for visceral leishmaniasis in India. N Engl J Med 2007;356:2571-81.
Sundar S, Sinha PK, Rai M, Verma DK, Nawin K, Alam S, et al.
Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: An open-label, non-inferiority, randomised controlled trial. Lancet 2011;377:477-86.
Sundar S, Chakravarty J. Leishmaniasis: An update of current pharmacotherapy. Expert Opin Pharmacother 2013;14:53-63.
Sundar S, Singh A, Singh OP. Strategies to overcome antileishmanial drugs unresponsiveness. J Trop Med 2014;2014:646932.
|This article has been cited by|
||Assessment of quality of life using WHOQOL-BREF in patients with visceral leishmaniasis
| ||Rajendra Babu Veeri,Ashok Kumar Gupta,Biplab Pal,Niyamat Ali Siddiqui,Devi Priya,Pradeep Das,Krishna Pandey |
| ||Health and Quality of Life Outcomes. 2019; 17(1) |
|[Pubmed] | [DOI]|
||Ruthenium-Clotrimazole complex has significant efficacy in the murine model of cutaneous leishmaniasis
| ||Eva Iniguez,Armando Varela-Ramirez,Alberto Martínez,Caresse L. Torres,Roberto A. Sánchez-Delgado,Rosa A. Maldonado |
| ||Acta Tropica. 2016; 164: 402 |
|[Pubmed] | [DOI]|
||Coccinia grandis (L.) Voigt Leaf Extract Exhibits Antileishmanial Effect Through Pro-inflammatory Response: An In Vitro Study
| ||Asmita Pramanik,Dibyendu Paik,Kshudiram Naskar,Tapati Chakraborti |
| ||Current Microbiology. 2016; |
|[Pubmed] | [DOI]|