Adoption of new visceral leishmaniasis treatments in South Asia  

Policy change for control and elimination of visceral leishmaniasis brings better treatments to patients in Bangladesh, India, and Nepal

In the early 21st century, treatments for visceral leishmaniasis (also known as kala-azar) in South Asia were difficult for patients to take or growing ineffective. Resistance was increasing, including to the oral drug miltefosine. Antimonials such as sodium stibogluconate had lengthy treatment times, difficult treatment administration, and poor tolerability that caused frequent side effects.

In 2010, WHO recommended using new short-course treatments for visceral leishmaniasis in South Asia based on excellent results in Phase III studies. However, more evidence was needed on the safety and effectiveness of using these treatments for a wider population under field conditions.

DNDi convened a consortium of partners to identify the best combination therapies for South Asia. The consortium conducted a four year-long implementation study in Bangladesh and India (2012 – 2015) to assess the safety, efficacy, and patient compliance of three new treatment options including single-dose liposomal amphotericin B, paromomycin and miltefosine, and liposomal amphotericin B and miltefosine. The results showed that these treatments were safe and effective, with cure rates above 95%. They also shortened treatment length, reduced the risk of resistance, allowed reaching patients closer to home, and therefore made it simpler for patients to take the full treatment course.

The research provided key evidence for policy change by the Bangladeshi, Indian, and Nepali Ministries of Health, which made the following recommendations: single-dose liposomal amphotericin B as a first option treatment for visceral leishmaniasis patients and paromomycin & miltefosine as a second option.

Ambisome treatment
  • Indication: visceral leishmaniasis in Asia
  • Dosage: First option: single-dose liposomal amphotericin B given as an intravenous infusion; Second options: single-dose liposomal amphotericin B with miltefosine for 7 days; single-dose liposomal amphotericin B with paromomycin for 10 days; paromomycin & miltefosine, both daily for 10 days

Impact

  • Treatments recommended by WHO Expert Committee on the Control of Leishmaniases in 2010 as safe and effective treatments for visceral leishmaniasis in Asia (liposomal amphotericin B single or multiple dose, and all combinations tested in DNDi’s clinical trial)
  • Supported policy change for the control and elimination of visceral leishmaniasis in highly endemic countries: Bangladesh, India, and Nepal
  • Result of partnership in India with the Bihar State Health Society, GVK Biosciences, Indian Council of Medical Research, Kala Azar Medical Research Centre, Médecins Sans Frontières, National Vector Borne Disease Control Programme, and Rajendra Memorial Research Institute of Medical Sciences
  • Result of partnership in Bangladesh with the International Centre for Diarrhoeal Disease Research, Médecins Sans Frontières, Ministry of Health and Family Welfare, Shaheed Suhrawardy Medical College and Hospital

‘Earlier the ward used to be full of visceral leishmaniasis patients because of the long 28-day treatment. But since single-dose liposomal amphotericin B has been included in the national treatment protocol, the face of the disease has changed dramatically. Now patients come, take treatment, and go home the same day. This is an effective treatment, and now with this the number of patients have come down.’

Nutan Kumari, Sadar Hospital in Hajipur, Bihar  

Project updates

2018

In 2010, WHO recommended the use of new short-course treatment regimens for VL in South Asia. Although Phase III studies have shown excellent results, there was a lack of evidence on a wider treatment population, and on the safety and effectiveness of these regimens under field conditions. From 2012 to 2016, DNDi and partners conducted a pilot study in Bihar, India on three regimens (including new combination therapies (single dose AmBisome (SDA), a combination of miltefosine and paromomycin (AmB+PM), and a combination of AmBisome and miltefosine (AmB+Milt)) in 1761 patients. All regimens showed acceptable outcomes and safety profiles under field conditions. Cure rates were: for SDA 95.5%, AmB+Milt 95.5% and AmB+PM 99.6%. These results contributed to national treatment policy change in India, Bangladesh, and Nepal.

2017

Following a 2016 pilot study in Bihar, India on three regimens (including new combination therapies (single dose AmBisome® (SDA), a combination of miltefosine and paromomycin, and a combination of AmBisome® and miltefosine) whose results contributed to a change in the national treatment guidelines in India, a follow-up protocol was developed for a cohort observational study to estimate the incidence of post-kala-azar dermal leishmaniasis (PKDL) during or more than 24 months post-treatment in VL patients treated with any of the three regimens. Enrolment started in June 2016, and by the end of 2017, recruitment was completed with 1622 participants assessed (representing 92% of the VL patients treated in the India implementation study). Preliminary results show that PKDL was observed in 3.6% of patients at least 24 months after treatment of VL. Further analysis is ongoing.  

2016

In India, DNDi continues to support the rolling out of treatments as per the Indian National Kala-Azar Elimination Roadmap, after data from a DNDi implementation study contributed to a change in the national guidelines, which now recommend the use of single-dose AmBisome® in areas of high prevalence, and paromomycin/miltefosine combination in low-prevalence districts.

2015

In Asia, DNDi and partners, working closely with the Indian government, have provided data from an implementation study (1761 enrolled patients) to support policy change expressed in the revised National Kala-Azar Elimination Roadmap, which recommends the use of AmBisome single infusion in areas of high prevalence and paromomycin/miltefosine combination as appropriate in low prevalence districts. Follow-up visits continue to assess long-term efficacy and identify development of PKDL.

Key Scientific Articles

Field effectiveness of new visceral leishmaniasis regimens after 1 year following treatment within public health facilities in Bihar, India. PLOS Neglected Tropical Diseases, September 2019
by Goyal V, Burza S, Pandey K, Singh SN, Singh RS, Strub-Wourgaft N, Rabi Das VN, Bern C, Hightower A, Rijal S, Sunyoto T, Alves F, Lima N, Das P, Alvar J.

Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India. PLOS Neglected Tropical Diseases, October 2018
by Goyal V, Mahajan R, Pandey K, Singh SN, Singh RS, Strub-Wourgaft N, Alves F, Das VNR, Topno RK, Sharma B, Balasegaram M, Bern C, Hightower A, Rijal S,  Ellis S, Sunyoto T, Burza S, Lima N, Das P, Alvar J.

Safety and efficacy of short course combination regimens with AmBisome®, miltefosine, paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh. PLOS Neglected Tropical Diseases, June 2017
by Rahman R, Goyal V, Haque R, Jamil K, Faiz A, Samad R, Ellis S, Balasegaram M, den Boer M, Rijal S, Strub-Wourgaft N, Alves F, Alvar J, Sharma B.

Investments in research and surveillance are needed to go beyond elimination and stop transmission of Leishmania in the Indian subcontinent. PLOS Neglected Tropical Diseases, January 2017
by Olliaro P, Shamsuzzaman TAKM, Marasini B, Dhariwal AC, Be-Nazir A, Mondal D, Banjara MR, Das P, Sundar S, Rijal S, Arana B, Alvar J, Argaw D, Peeling RW, Kroeger A, Matlashewski G.

How far are we from visceral leishmaniasis elimination in Bangladesh? an assessment of epidemiological surveillance data. PLOS Neglected Tropical Diseases, August 2014
by Chowdhury R, Mondal D, Chowdhury V, Faria S, Alvar J, Nabi SG, Boelaert M, Dash AP.

Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. The Lancet, January 2011by Sundar S, Sinha P.K, Rai M, Verma D.K, Nawin K, Alam S, Chakravarty J, Vaillant M, Verma N, Pandey K, Kumari P, Lal C.S, Arora R, Sharma B, Ellis S, Strub-Wourgaft N, Balasegaram M, Olliaro P, Das P, Modabber F.

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*Project cost includes direct and indirect costs, but it does not include in-kind contributions.