|Year : 2012 | Volume
| Issue : 4 | Page : 500-503
Efficacy of oral miltefosine in visceral leishmaniasis in rural West Bengal, India
Pradyumna Patra1, Subhasish K Guha2, Ardhendu Kumar Maji3, Pabitra Saha3, Swagata Ganguly3, Abhiram Chakraborty4, Pratip K Kundu3, Sachchidananda Sarker5, Krishnangshu Ray6
1 Canning Sub Divisional Hospital, Canning, South 24 Parganas; West Bengal, India
2 Department of Tropical Medicine, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata - 700073; West Bengal, India
3 Department of Microbiology, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata - 700073; West Bengal, India
4 Department of Radiology, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata - 700073; West Bengal, India
5 Chief Medical Officer of Health, South 24-Parganas, West Bengal, India
6 Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata - 700073; West Bengal, India
|Date of Submission||24-Dec-2010|
|Date of Decision||06-Sep-2011|
|Date of Acceptance||30-Apr-2012|
|Date of Web Publication||3-Aug-2012|
Ardhendu Kumar Maji
Department of Microbiology, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata - 700073; West Bengal
Source of Support: None, Conflict of Interest: None
Context: Visceral leishmaniasis (VL), also known as Kala-azar (KA) is a public health problem of tropical and subtropical countries, which infects about 12 million people annually, out of which about 1.5 million are new cases. India contributes a major share of the global burden of VL. For many years leishmaniasis has been treated with pentavalent antimonials. Antimony resistance is a problem in India and in other different geographic areas of the world. Amphotericin B deoxycholate and pentamidine isethionate are effective by parenteral administration and associated with toxicities. The quest for an effective, orally administered, non-toxic and less expensive alternative resulted in the identification of miltefosine (hexadecylphosphocholine). In India, therapeutic efficacy of miltefosine in VL was assessed by many groups of scientists, mainly from Bihar and Uttar Pradesh. No such data is available from West Bengal.
Aims: The present study was designed to observe the efficacy of miltefosine in VL in rural West Bengal.
Materials and Methods: A total of 71 parasitologically proven VL patients participated in the study who received miltefosine in accordance with the National Vector Born Disease Control Programme (NVBDCP) of India and were followed up for the following one year.
Results: The overall efficacy of the drug was 93% and no significant adverse side effects were observed during the study period.
Conclusions: The study concludes that miltefosine is effective, well tolerated, and easily administrable drug in the treatment of visceral leishmaniasis at the field levels.
Keywords: India, visceral leishmaniasis, miltefosine
|How to cite this article:|
Patra P, Guha SK, Maji AK, Saha P, Ganguly S, Chakraborty A, Kundu PK, Sarker S, Ray K. Efficacy of oral miltefosine in visceral leishmaniasis in rural West Bengal, India. Indian J Pharmacol 2012;44:500-3
|How to cite this URL:|
Patra P, Guha SK, Maji AK, Saha P, Ganguly S, Chakraborty A, Kundu PK, Sarker S, Ray K. Efficacy of oral miltefosine in visceral leishmaniasis in rural West Bengal, India. Indian J Pharmacol [serial online] 2012 [cited 2020 Feb 20];44:500-3. Available from: http://www.ijp-online.com/text.asp?2012/44/4/500/99326
| » Introduction|| |
Visceral Leishmaniasis (VL) or Kala-azar is caused by Leishmania donovani and transmitted by female phlebotomine sandflies. The estimated annual global burden of VL is approximately half a million new cases and more than 50,000 deaths, of which 90% occur only in five countries; India, Bangladesh, Nepal, Sudan, and Brazil.  In India, leishmaniasis is prevalent in four states; Bihar, West Bengal, Jharkhand, and Uttar Pradesh, of which Bihar contributes half of VL cases that occur globally.  In West Bengal, out of 18 districts, 12 are endemic for leishmsniasis. Early detection and prompt treatment are the important components of the control program to reduce the parasite burden of the community, thus decreasing the rate of transmission. ,, Diagnosis is based on either microscopic detection of amastigote form of the parasites in bone marrow (BM), splenic / lymph node aspirate, or detection of antibody. Demonstration of amastigotes in BM, splenic or lymph node aspirate is not possible at the field level. Detection of antibody by ELISA, IFAT, or DAT is an important tool for diagnosis of leishmaniasis. The development of rk39, an immune-chromatographic rapid diagnostic kit (RDK) has made diagnosis easier and possible even at the field level.
For many years leishmaniasis has been treated with pentavalent antimonials, which are administered parenterally over 3 to 4 weeks. Antimony resistance is being increasingly recognized in India as well as in other geographic areas. Alternatively, amphotericin B deoxycholate and pentamidine isethionate have also been used. Though effective, they have to be given parenterally and are associated with substantial toxicity. In the past decade, liposomal and lipid-associated amphotericin B have been shown to be effective for the treatment of VL and are reasonably well tolerated but are very costly. The quest for an orally effective, non-toxic, cheaper alternative drug with potential anti-leishmanial activity was fulfilled by the identification of miltefosine (hexadecylphosphocholine).
Leishmaniasis has been identified by the World Health Organization (WHO) for elimination by 2015, along with other neglected tropical diseases.  In 2005, India, Nepal, and Bangladesh agreed to initiate a VL elimination program with the target of reducing annual VL incidence to 1/10,000 population by 2015. , Visceral leishmaniasis elimination in this region is possible because it is completely anthroponotic in nature. NVBDCP of India introduced RDK (rk39) and an oral drug, miltefosine in two districts of West Bengal as a pilot project in 2005. The present study was designed to evaluate the efficacy of oral miltefosine at the field level in rural West Bengal.
| » Materials and Methods|| |
Study site and patients
The study was carried out in South 24 Parganas district of West Bengal. Three Kala-azar endemic blocks of this district named Canning 1, Canning 2, and Basanti were selected as study sites. All cases having prolonged fever for more than a fortnight and not responding to anti-malarials and antibiotics were examined for anti-leishmanial antibody by rapid diagnostic kit (RDK). All RDK positive cases were examined clinically to record hepato-splenomegaly, anemia, and lymphadenopathy and were subjected to bone marrow or splenic aspiration to demonstrate amastigote form of L. donovani (smear/culture). Patients with following were excluded from the study: platelet count < 50,000 /mm 3 ; total leukocyte count < 1000 /mm 3 ; hemoglobin concentration < 6 g/dL; bilirubin more than twice the upper limit of normal and serum creatinine or blood urea nitrogen levels of 1.5 times the upper limit of normal. No patients had been treated previously for VL. Cases with other serious concurrent medical illness, HIV seropositivity, and pregnancy were also excluded. A total of 71 patients enrolled between December 2007 and July 2009 from those attending the Canning Sub divisional Hospital and few patients were also enrolled from the field.
Persons with positive rk-39 test and or positive for amastigotes were treated with miltefosine, supplied by NVBDCP, orally for 28 days in a dose of 2.5 mg/Kg body weight/day as per NVBDCP guidelines. Patients weighing >25 kg received 100 mg daily (one 50 mg capsule in the morning and one 50 mg capsule in the evening after meals); patients weighing 25 Kg or less received one 50 mg capsule each morning after meal. Drug was administered mainly at the study sites under direct observation of the field workers. On week days, the health assistants administered the morning dose of the drug at sub centre and the evening dose as well as the doses for Sundays and holidays were handed over to the patients /family members with the instruction to take it at home (self-administered). A few cases having complications were hospitalized either at Canning Sub divisional hospital or in Carmichael Hospital for Tropical Diseases (CHTD) attached with Calcutta School of Tropical Medicine for their treatment.
Procedure and follow up
All patients were informed about the study protocol and the probable outcome and a written consent was obtained. The patients were examined on day 0 (clinical and hematological parameters) and were re-evaluated on day 7, 14, 21, and 28 during treatment and at 2, 6, and 12 months after completion of treatment. Bone marrow or splenic aspirates were examined (smear/culture) after 28 days of treatment. An initial parasitological cure was indicated by the absence of parasites on day 28. During follow-up, bone marrow or splenic aspiration was performed for all patients with palpable spleens or other conditions suggestive of VL. Relapse was defined as the presence of parasites in a bone marrow or splenic aspirate specimen after initial parasitological cure.
| » Results|| |
Demographic and clinical data of the 71 parasitologically positive study patients are listed in [Table 1]. The ratio of male to female patients was 1.45:1, and the mean age was 25.4 years (SD ± 15.33). Mean of splenic enlargement below costal margin was 5.5 cm (SD ± 3.02) and mean hemoglobin was 8.75 g/dL (SD ± 0.77). Mean values of SGOT, SGPT, billirubin, and serum creatinine are also shown in [Table 1].
|Table 1: Clinical and Laboratory characteristics of study patients suffering from visceral leishmaniasis (n = 71)|
Click here to view
The therapeutic efficacy is depicted in [Figure 1]. Out of 71 study patients, 70 cases were cured initially; one case was classified as treatment failure (fever present on day 28 and repeat splenic aspirate showed LD bodies). During two months period of follow-up, all initially cured patients remained free from the signs of VL. Among 70 initially cured cases, relapse of VL was recorded in four (two cases during first six months and remaining two cases during twelve months post treatment). The overall failure rate was 7% (5/71). In 58 (%) cases, fever subsided after 2 nd weeks of therapy and in others during 3 rd week. All treatment failure and relapsed cases were hospitalized and treated with amphotericin B deoxycholate (cumulative dose 20 mg/kg) in Carmichael Hospital for Tropical Diseases.
|Figure 1: Clinical efficacy outcome of miltefosine in visceral leishmaniasis|
Click here to view
Nausea and vomiting were recorded in 18 (25.4%) patients during first week of miltefosine therapy and were treated symptomatically. Diarrhoea and abdominal pain were observed among 8 (11.3%) cases, which subsided from second week of treatment.
| » Discussion|| |
Miltefosine (hexadecylphosphocholine) is the first orally administered drug for VL, which has been recently marketed. Three countries in South Asia (India, Nepal, and Bangladesh) have decided to use miltefosine regularly as the first line drug in their VL elimination program by the year 2015. In West Bengal, miltefosine was introduced to treat all VL cases in two districts, Murshidabad and South 24 Parganas on the basis of a pilot study conducted in 2005. Now it is in routine practice throughout the state. In the present study, 71 parasitologically proven Kala-azar patients from South 24 Parganas district were studied. The overall cure rate was 93% (66/71) following one year post-treatment period. In a pilot study and later in three Phase II studies involving 249 patients, oral miltefosine, 100-150mg/day for 28 days, was shown to cure more than 90% Kala-azar cases with reasonable safety.  The final cure rate of 94% with miltefosine was also assessed during phase-III, on the basis of which NVBDCP introduced the drug in India. Similarly, a cure rate of 94% was observed among pediatric patients also in Bihar. ,
In the present study, one patient did not respond to miltefosine after 28 days therapy. Out of 70 initially cured patients, relapse was recorded in four patients within one year post treatment period. Similar rate of relapse was also reported from Bihar. 
Vomiting and diarrhoea have been the most commonly reported side-effects among the VL cases treated with miltefosine.  In the present study, diarrhoea and abdominal pain were observed in 8 (11.3%) cases and nausea and vomiting were recorded in 18 (25.4%) patients, which could be managed symptomatically and drug discontinuation was not needed in any patient.
Miltefosine enjoys a superiority over other anti-leishmanial drugs perhaps due to better compliance as it is orally effective, hospitalization is not needed, and tolerance is good. Miltefosine has a long half-life (about 7 days) and a propensity to act upon resistant parasites. However, like tuberculosis a directly observed treatment strategy could be adopted in future.
| » References|| |
|1.||World Health Organization. Leishmaniasis: Burden of disease. Available from: http://www.who.int/leishmaniasis/ burden/en. [Last cited in 2009. Aug]. |
|2.||Sundar S, Chakravarty J, Rai VK, Agrawal N, Singh SP, Chauhan V, et al. Amphotericin B treatment for Indian visceral leishmaniasis: Response to15. daily versus alternate-day infusions. Clin Infect Dis 2007;45:556-61. |
|3.||Desjeux P. Leishmaniasis: Current situation and new perspectives. Comp Immunol Microbiol Infect Dis 2004;27:305-18. |
|4.||Boelaert M, Criel B, Leeuwenburg J, Van Damme W, Le Ray D, van der Stuyft P. Visceral leishmaniasis control: A public health perspective. Trans R Soc Trop Med Hyg 2000;94:465-71. |
|5.||Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, et al. Visceral leishmaniasis: Current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2002;2:494-501. |
|6.||World Health Organization. Global plan to combat neglected tropical diseases 2008-2015. Available from: http://whqlibdoc.who.int/hq/2007/WHO CDS NTD 2007.3 eng.pdf. [Last cited in 2009. Aug]. |
|7.||Regional strategic framework for elimination of VL from SEA Region (2005-2015). New Delhi: WHO-SEARO. SEA-VBC-8. (Rev. 15). p. 22. |
|8.||Communicable diseases: Kala-azar status in SEA region 2005. (online). Available from: http://www.searo.who.int/ en/Section10/Section2163.htm. |
|9.||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. |
|10.||Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, Berman J. Oral miltefosine treatment in children with Indian visceral leishmaniasis. Pediatr Infect Dis J 2003;22:434-8. |
|11.||Bhattacharya SK, Jha TK, Sundar S, Thakur CP, Engel J, Sindermann H, et al. Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India. Clin Infect Dis 2004;38:217-21. |
|This article has been cited by|
||4-Aminoquinoline Derivatives as Potential Antileishmanial Agents
| ||Luciana M. R. Antinarelli,Rafael M. P. Dias,Isabela O. Souza,Wallace P. Lima,Jacy Gameiro,Adilson D. da Silva,Elaine S. Coimbra |
| ||Chemical Biology & Drug Design. 2015; : n/a |
|[Pubmed] | [DOI]|