An E-mail interview with Prof. Shyam Sundar

1. As one of the world’s leading researchers in the field of Kala Azar (KA), please tell us what motivated you to concentrate on leishmaniasis?

If you recall in the early 80s and 90s (around 1980–1990), there were reports, from Bihar, of large-scale pentavalent antimony treatment failure in KA. Bihar accounted for most of the KA incidence reported from India. Then, the second-line drug pentamidine was imported and used for Sb⁵ treatment failed patients. This was a highly toxic drug, and pentamidine-related insulin-dependent diabetes mellitus was reported in a significant proportion of cases. Although initially, its efficacy was good, over the years, ~30% of patients did not respond to this treatment. There was no other drug at that time. For a physician like me, it was highly frustrating to send back this Sb⁵ and pentamidine failed patients without any treatment to offer. Another thing which motivated me immensely was that I was born and brought up in Muzaffarpur (Bihar) which was the heartland of KA, reporting the highest number of KA cases. Seeing acquaintances suffering and succumbing to this disease was heartbreaking. These facts motivated me the most to find an effective and safe treatment for KA. With the help of my colleagues, I established a nongovernmental organization in Muzaffarpur offering free care including diagnosis and treatment for this disease. Use of Sb⁵ in these areas was unregulated with many patients dropping out of treatment midway. Error in dosing and duration of Sb⁵ was rampant, and I think these practices were largely responsible in promoting Sb⁵ resistance.

2. What is the current scenario of VL in India? What has been the impact of newer regimens in the control of the disease?

There is a complete change of scenario as far as VL is concerned. You can see in this graph [Figure 1] that numbers have gone down with the introduction of miltefosine treatment and there was a sharp decline when single-dose liposomal amphotericin B (AmBisome) treatment was introduced. Our group played the most important role in the development of miltefosine, and later, we developed the single-dose treatment. This turned out to a game changer and its introduction in the control program led to a sharp decline in the incidence. As I write, at this moment, out of 633 blocks of India where VL was endemic, the elimination target has been achieved in all except one block. KA cases in India fell down to 834 in 2022 from 44,533 in 2007 – A 98.7% decline

Figure 1: Decline of visceral leishmaniasis over the years with changing therapy

3. Apart from therapeutic intervention, which public health measures have been particularly useful in the control of KA in endemic areas?

Vector control has been another important aspect. The insecticide was changed from DichloroDiphenylTrichloroethane (DDT) to cypermethrin (a synthetic pyrethroid). There has been complete revamping of other aspects, spray pumps have been changed.

In the community, there has been a great increase in public awareness about KA through community education by posters, audiovisual educative videos, etc.

4. What is the current clinical efficacy of miltefosine and amphotericin B? Have you noticed any treatment failures/resistance to any of these agents in recent years?

Efficacy of miltefosine and liposomal amphotericin B (LamB) has been excellent with cure rates above 90% for both drugs. Initially, miltefosine was used in the national program with good effect, however, long treatment regimen (28 days) led to the frequent incidence of stopping prematurely. Another drawback was its teratogenic potential, which meant that women of childbearing age group had to practice contraception for the duration of treatment and for several months thereafter due to prolonged half-life (~1 week). There were indications of developing drug resistance as well. This led to a change in policy with the replacement of miltefosine after publication (by us) of the high (>95%) efficacy of single-dose liposomal amphotericin B. This was robust evidence of its efficacy. Although highly expensive, after the publication of the excellent efficacy of single-dose LamB by us, its manufacturer (Gilead Sciences) decided to donate the drug through WHO to low- and middle-income countries. Moreover, this was a boon and game changer for India with outstanding results regarding its application in the national program.

There is evidence of relapses occurring after treatment with both drugs, but it is about 5%–6% only, however, this also means that we have to handle these drugs carefully. We have generated evidence that the co-administration of multiple drugs produces excellent results with high cure rate of >98%. Moreover, I think multidrug regimen is the way forward in the treatment of this dreaded disease.

5. Which diagnostic tests have you found most useful in the confirmation of clinical diagnosis? Are the older and cheaper tests such as aldehyde test or Chopra’s antimony test still useful in field situations?

As you know, the gold standard for diagnosis of KA is the demonstration of leishmania in splenic or bone marrow smears or positive culture of parasites. Unfortunately, none of these are easily available in the field. While splenic smears provide high sensitivity, the process of splenic aspiration is a highly risky procedure and the sensitivity of bone marrow smears is not satisfactory. Now, polymerase chain reaction in various formats is being developed and used. However, you can realize that these abovementioned procedures are either not available or suitable for a field site.

I think the demonstration of specific anti-leishmanial antibodies against leishmania antigen (rK39), has changed the diagnostic paradigm of KA diagnosis. Rapid strip test is now available which is highly sensitive (>95%) and specific (>95%) in detecting the rK39 antibodies in patients’ blood or sera. We were the first in the World (in 1998) to demonstrate its applicability with excellent results, and a positive rapid strip test in a typical KA patient provides the diagnosis in 10 min without any equipment, etc., and only a positive test line gives you the diagnosis such as a pregnancy test. In a very small proportion of healthy individuals (in areas with very active KA transmission), it can be positive due to exposure to Leishmania. Thus, it is important that this test should be interpreted only in patients with typical clinical symptoms and signs of KA. Now, it is used for the diagnosis of KA in the entire world and is used almost exclusively for the diagnosis of KA in India in the KA Elimination Program with great success.

As far as tests such as aldehyde test or Chopra’s antimony test are concerned, these tests were used before modern methods of diagnosis became available. These tests are highly nonspecific and their utility has never been proved in a scientific study. These tests should never be used in the diagnosis of KA and removed from the list of diagnostics if anywhere, it is mentioned. Finally, they have no role in the diagnosis of KA.

6. What is your opinion on research approaches in parasitology in India when compared to developed nations?

I think there have been some great developments in parasitology in India compared to elsewhere. We have to work on our own problems, and the future of parasitology in India is bright. As far as comparison with developed nations, it is unfair to compare. The resources in terms of funds, equipment, and availability of accomplished research scientists cannot be compared, but still future of parasitology in India appears to be very good.

7. What you would like to suggest to the young aspirants who would like to take up parasitology as a research interest?

I will advise the young scientists carrying out research in this field that a meaningful objective of the research with aims of finding the solutions of our own neglected problems of parasitology. The target should not be just producing data which can be published in high-impact journals without any application in the local clinical issues.