2017 was a busy year for advancing visceral leishmaniasis (VL or kala-azar) elimination efforts globally and on the Indian sub-continent.
The year saw: the completion of a cohort study to estimate the prevalence of post-kala-azar dermal leishmaniasis (PKDL) in VL patients in Bihar; the launch of a multicentre Phase II study to assess safety and efficacy of two PKDL treatment regimens; and involvement in a new study in Bihar to evaluate safe and effective treatments in patients co-infected with HIV and VL.
On the knowledge transfer and capacity building side, DNDi in India trained health workers from five district hospitals in Bihar to diagnose relapsed cases of kala-azar and post-kala-azar dermal leishmaniasis. In addition, master’s and undergraduate students at three Indian universities are now involved in the Open Synthesis Network, in which students are supporting DNDi drug discovery projects by working on compounds that kill kala-azar parasites as part of their lab training.
During the year, Director, DNDi in India, Dr Suman Rijal was recognized for his expertise with his appointment to the National Advisory Committee on Kala-azar Elimination, formed by Ministry of Health and Family Welfare, Government of India.
DNDi in India also participated in several major scientific conferences to share research findings, including WorldLeish 6, the premier global leishmaniasis conference that is hosted every four years by an endemic country and was co-organized by DNDi in 2017.
Capacity building for diagnosis of kala-azar and post-kala-azar dermal leishmaniasis
In 2017, DNDi supported the Indian National Kala-azar Elimination Programme by strengthening the capacity of five health care facilities in Bihar (Purnia, Saharsa, Saran, Vaishali and Mauzzafarpur District Hospitals) to conduct parasitological diagnosis of visceral leishmaniasis, also known as kala-azar, for confirmation of relapse, and diagnosis of post-kala-azar dermal leishmaniasis (PKDL) by microscopy.
Early diagnosis and appropriate treatment for kala-azar are the two main strategies being used in the kala-azar elimination initiative in the Indian sub-continent. While some of the available rapid diagnostic tests have excellent sensitivity and specificity for the diagnosis of new cases, they are not useful in relapse cases, where parasitology of tissue aspirates is recommended for diagnosis. However, a lack of infrastructure and expertise in district-level treatment centres to perform this type of diagnosis results in missed cases and loss to follow-up of patients, who are then not appropriately treated. DNDi in India’s Capacity Building for Parasitological Diagnosis in VL and PKDL Diagnosis Project is filling this diagnostic gap. With increased diagnostic capacity, the catchment areas for the five district hospitals can now appropriately treat patients and help prevent new outbreaks.
In 2018, DNDi plans to train staff in four additional district hospitals in Jharkand: Godda, Dumka, Pakur and Sahibgunj. In a second phase of training, the staff of public health centres will be trained in diagnosis of suspected PKDL cases to refer patients to the district hospital.
Study to determine cases of PKDL in previously treated leishmaniasis patients
Following a request for evidence from the Indian National Kala-azar Elimination Programme on the occurrence of post-kala-azar dermal leishmaniasis (PKDL), DNDi in India is analysing patient data to determine the proportion and timing of patients who go on to develop PKDL following treatment for kala-azar with any of three new treatment regimens.
Between 2012 and 2015, DNDi conducted a study to assess the feasibility of using the three-new kala-azar treatment regimens at public health facilities in Bihar, which led the national programme to revise its treatment recommendations. All 1761 kala-azar patients treated in the initial study in two districts of Bihar (Patna and Saran/Vaishali) were invited to participate in the new study of PKDL occurrence and timing. At a follow-up visit at least 24 months after kala-azar treatment, participants were assessed. Suspected PKDL cases were screened with a rapid diagnostic test and probable PKDL patients referred to the Rajendra Memorial Research Institute for parasitological confirmation and appropriate treatment.
The study results, which will be available in early 2018, will enable a better determination of the potential PKDL burden in the endemic areas of Bihar, as this study enrolled and followed up more than 1600 patients. Current estimates are based on limited data. The results will also indicate if there is any difference of the occurrence of PKDL following treatment with the three regimens.
Treating a neglected condition: Kala-azar-HIV co-infection in Bihar
DNDi is technical partner in a study launched in Bihar in 2017 to evaluate safe and effective treatments for kala-azar in HIV co-infected patients. The results of the study, which is sponsored by MSF in collaboration with DNDi and Rajendra Memorial Research Institute (RMRI), will provide evidence to national and regional decision makers regarding the best treatment for co-infected patients. Findings will also inform the national road map for kala-azar elimination in India.
Kala-azar-HIV co-infection is an emerging global problem; in India, a growing number of kala-azar-HIV coinfected patients have been observed in Bihar in the last few years. Kala-azar patients who are co-infected with HIV are at a greater risk of death because the pathogens reinforce each other in suppressing the immune system. Treatment requirements are different in co-infected patients, and relapses tends to be the rule rather than the exception.
Existing treatments for kala-azar in HIV co-infected patients are not based on evidence from the region, and more effective treatment regimens are needed. Diagnosis of kala-azar is also a challenge in low-income settings where there is a lack of awareness about the disease, poor referrals, and stigma around HIV.
This is an open label, parallel arm, non-comparative, randomized controlled trial at one site in Bihar. In this study, AmBisome® monotherapy (at a higher dose than current practice) and a combination of AmBisome® and miltefosine are being tested. The first patient was recruited in January 2017 and a total of 112 of 150 patients were enrolled in the study as of January 2018. Results are expected by 2019.
Clinical trial begins for PKDL treatment
A Phase II study testing both AmBisome® monotherapy and a combination of AmBisome® and miltefosine has just been kicked off in India to assess safety and efficacy for treating patients with PKDL. The first patient in India was enrolled in November, and this study will be launched in Bangladesh in February 2018.
The partners in this project in India are Kala Azar Medical Research Centre, Institute of Medical Sciences, Banaras Hindu University and Rajendra Memorial Research Institute of Medical Sciences. In Bangladesh, the study will be conducted in collaboration with International Centre for Diarrhoeal Disease Research, Dhaka and SK Hospital, Mymensingh.
DNDi is prioritizing the management of post-kala-azar dermal leishmaniasis (PKDL) patients, who are believed to constitute a reservoir of infection for kala-azar in the Indian sub-continent and East Africa. Early treatment of PKDL patients is likely to be a critical element of any kala-azar public health and elimination strategy.
Launched in 2016, the Open Synthesis Network (OSN) is a collaborative project that engages master’s and undergraduate students in research for neglected diseases as part of their lab training. Out of ten participating universities around the world, three are from India: NMIMS School of Pharmacy (Mumbai), Indian Institute of Technology (Gandhinagar), and the Indian Institute of Chemical Technology (Hyderabad). Students of these universities are working on compounds that kill leishmania donovani and leishmania infantum, the parasites that cause kala-azar.
DNDi’s current objective for kala-azar is to discover compounds that could be developed into new medicines that are suited for oral administration, easier to use in the field, and with fewer side effects than existing treatments. Any successful compounds that come from the OSN project will be evaluated further as part of DNDi’s drug discovery pipeline.
Sharing what we learn
Participation in scientific conferences is an important way for DNDi to share research findings and to build awareness and support for the important work of developing new drugs for neglected patients.
In 2017, Director, DNDi in India, Dr Suman Rijal participated in several key conferences, presenting on:
- “The Role of Research in the Elimination of Kala-azar in the Indian Sub-Continent” at the 13th Conference on Vectors and Vector-borne Diseases in Chennai
- “Diversity of Visceral Leishmaniasis Treatments in Different Regions and Disease Niches” in a session sponsored by DNDi at the 12th Annual Conference of India Society for Malaria and other Communicable Diseases in Pune
- “Opportunities & Challenges in Antimicrobial Drug Discovery” at IMTechCon 2017 in Chandigarh.
DNDi in India participated in the WorldLeish 6 Congress, the premier global leishmaniasis conference held every four years, where more than 1500 scientists, researchers, and policymakers met in Toledo, Spain to discuss how to bring the best science to the 350 million people at risk of leishmaniasis. The WorldLeish 6 Congress was co-organised by the WHO Collaborating Centre for Leishmaniasis at the Instituto de Salud Carlos III, Madrid and DNDi.
DNDi in India also collaborated with Health Analytics India and DataLEADS to conduct a data boot camp for more than 150 doctors, data researchers, and health journalists in Delhi as part of an initiative to strengthen health data collection and data-driven reporting on healthcare in Asia. DNDi was a key sponsor of the event, with the Australian High Commission, which was held in May at India International Centre.
Looking ahead to 2018
DNDi in India’s substantial work to support kala-azar drug development and trialling will continue in 2018, including training in the Phase II PKDL treatment study in India and Bangladesh, the Bihar study of treatment for kala-azar-HIV co-infected patients, and a Phase I study of a new chemical entity for kala-azar.
In 2018, DNDi in India will launch a new area of work in fighting antimicrobial resistance with its support for a new project of the Global Antibiotic Research & Development Partnership (GARDP), a joint initiative of DNDi and WHO to develop novel treatments for drug-resistant neonatal sepsis. The office will support the study of a four-in-one formulation for paediatric HIV followed by product registration in India. The office will also explore opportunities in pharmaceutical development in India to respond to DNDi global needs.
In terms of drug discovery work, DNDi in India plans to build a Lead Optimisation Consortium in India (LOCI) with multidisciplinary drug discovery partners in India with a focus on early stage discovery of new treatments for neglected diseases. The initial focus of the consortium will be discovery and optimization of novel pre-clinical candidates against visceral leishmaniasis (VL, or kala-azar). With many world-class research institutions and global pharmaceutical organizations, India is rich in both scientific expertise and drug discovery capabilities. DNDi in India is working to identify as many potential partners across India as possible, with capabilities and expertise in the various disciplines required by the consortium, including but not limited to: medicinal and synthetic chemistry; parasitology screening; microbiology; structural biology; absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetics; and toxicology.
Photo credit: Manis Gupta-DNDi, Kishore Pandit-DNDi, Anita Khemka-DNDi