Fighting disease

India has been talking about defeating kala azar since 1947 – and now has a good chance of doing so

In Bihar, the work done by researchers and non-profits over the decades has put the government's 2017 elimination goal within reach.

In the 1940s, when former Union Health Minister Dr CP Thakur was about 15 years old, he was diagnosed with kala azar.

“I was a well-fed boy and, therefore, I survived the illness,” he said. “Imagine what would happen to a poor man at the time.”

Kala azar belongs to the Neglected Tropical Diseases family and affects the poorest populations.

Thakur received the first known treatment for kala azar – urea stibamine, which was produced by the scientist Upendra Nath Brahmachari in 1928. Brahmachari was nominated for the Nobel Prize in Medicine the following year.

Thakur, from Muzaffarpur district in Bihar, went on to head the medicine department at Patna Medical College and conducted some of the most important research work in the country on kala azar, along with Dr Shyam Sundar from Benaras Hindu University.

Kala azar, whose scientific name is visceral leishmaniasis, is caused by a leishmania parasite. It is transmitted by the female sandfly or balu makhi, which cannot be seen by the naked eye. It is characterised by irregular bouts of fever, weight loss, enlargement of the spleen and liver that give the patient a pot belly, and anaemia.

Kala azar literally means black fever, signifying the greyish discolouration it causes to the hands, skin and face.

If left untreated for over two years, it can prove fatal. A person suffering from kala azar dies after catching another infection such as tuberculosis or of severe anaemia.

The government is committed to eliminating kala azar by 2017, while similar efforts are on in Nepal and Bangladesh too. Elimination is defined as reducing the annual incidence of a disease to less than one case per 10,000 people at the sub-district level.

And while talk of kala azar elimination has been going on since Independence, this is the first time the goal seems reachable.

History of the disease

Distribution of kala azar in 1903. The endemic areas remain the same today.
Distribution of kala azar in 1903. The endemic areas remain the same today.

In the late 1800s, kala azar spread across the tea gardens of Assam, killing scores of plantation workers, before making its way into Bihar, West Bengal and Bangladesh. At the time, the disease was considered a severe form of malaria and often referred to as coolie’s anemia disease, after the symptom it caused.

It was only in 1903, when Scottish pathologist and British Army medical officer William Leishman isolated the parasite causing the mysterious fever deaths in these regions, that the disease got the name visceral leishmaniasis.

To find the vector or organism that was transmitting the disease, British doctor Leonard Rogers conducted an experiment where sandflies fed on cultured leishmania were allowed to bite subjects. This unethical experiment proved the sandfly was indeed the vector spreading the disease from person to person.

Failed attempts

There were several unsuccessful attempts to eliminate kala azar in the past. Between 1953 and 1964, the National Malaria Eradication Programme used DDT – an insecticide now banned for being carcinogenic and harmful to the environment – for vector control, and kala azar was thought to have been eliminated. As a result, many new cases after 1964 were ignored.

"Kala azar is the disease of the poorest of poor," said Dr Suman Rijal, the country director, Drugs for Neglected Disease initiative, a nonprofit drug research and development organisation. "Even in Bihar, it was the lower socio-economic class who were affected, especially the Musahar caste people. There was very little voice and political push."

From the 1970s onwards, every 10-15 years, the Central government launched a programme to control kala azar and suspended these abruptly after mortality came down. The Centre would launch the programme whenever there was an epidemic, such as in 1977 and 1992, and run it for three years.

“During the programme, some money would come from the Centre and DDT would be sprayed,” said Thakur. “Then it would stop after three years.”

Search for effective cure

For about 70 years-80 years, the only drug available for curing kala azar was sodium stibogluconate. This compound was a synthesis of urea stibamine, the first known cure for kala azar.

“By 2000, only about 10% of patients were accepting sodium stibogluconate,” said Sundar.

Thakur and Sundar were among the few doctors at that time leading trials to check the effectiveness of various drug protocols to check kala azar.

Progressively better drugs and their protocols

  • Sodium stibogluconate: 28 injections administered daily, but it is toxic and painful. 
  • Amphotericin-B deoxycholate: given in slow intravenous infusions every alternate day for 14 doses.
  • Paromomycin: administered intramuscularly for 21 days.
  • Miltefosine: oral drug for 28 days but it is toxic for pregnant women.
  • Liposomal Amphotericin-B: given for three hours intravenously.

These included sodium stibogluconate, amphotericin B, miltefosine and a single-dose liposomal amphotericin B.

All the drugs tested on patients were not specifically developed or marketed for kala azar. Most of them, including liposomal amphoceterin B, targeted cancer patients.

Wonder drug

The game changer that promises to make kala azar elimination a reality is a modification of an older drug, amphotericin B. Liposomal amphotericin B is a lipid-based drug that sits in a layer of fat or cholesterol, which enables slow release of the medicine in the body and helps it overcome toxicity.

Before 2012, the approved treatment protocol was administering liposomal amphotericin B intravenously every alternate day for 14 days and miltefosine orally for 28 days. This essentially meant a month-long stay at the hospital. Besides, miltefosine could not be given to pregnant and lactating women or any woman of reproductive age, unless she was using contraception.

“This disease affects the marginalised community who depend on daily wages,” said Dr Nupur Roy, additional director at the National Vector Borne Disease Control Programme. “After a week, when the patient was capable of getting out of bed, he would just go to work. But the parasite would still be in his body.”

In 2012, Medecins Sans Frontieres and the Drugs for Neglected Diseases Initiative started working on various protocols of liposomal amphotericin B at the Sadar Hospital in Hajipur in Vaishali district of Bihar. The drug is also used to treat fungal infections among cancer patients. After years of work, they proved the efficacy of a single-dose liposomal amphotericin B with fewer side effects, which could be taken by pregnant or lactating women too. The drug, though expensive at approximately Rs 9,000 per injection, is being supplied free of cost by the World Health Organisation.

Earlier, in around 2002, the technology of the rk39 dipstick was made available. This could detect kala azar with just a few drops of blood from a prick of the finger, and made diagnosis simpler.

In 2014, after the effectiveness of the single-dose liposomal amphotericin B had been proved, Dr Harsh Vardhan, who was then the Union health minister, launched the Kala Azar Elimination Programme with a deadline of 2015. This has now been extended to 2017.

Challenges remain

However, there are still some challenges to the government’s ambitious elimination drive. The diagnosis of post-kala azar leishmaniasis – a skin presentation of the disease characterised by visible lesions or discolouration of the skin – is tough to diagnose. The compliance rate of the treatment, which is longer and toxic, is also low.

Apart from this, the diagnosis and treatment of patients with a Human Immunodeficiency Virus and kala azar co-infection has proved difficult. No effective treatment protocol has been developed yet. There is also very little research on disease transmission from asymptomatic patients.

Despite these factors, optimism for the elimination programme is high. “Yes, we have some challenges to overcome,” said Sundar. “But with these tools for early diagnosis and an assured 100% compliance of treatment, I feel we could possibly achieve elimination.”

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