DNDi diseases focus
3 July 2003
Visceral leishmaniasis (kala-azar)
Most people in western countries have never heard of visceral leishmaniasis or kala-azar, (Hindi for "black fever") but in some parts of the world, the disease has been known to wipe out populations of entire villages. Kala-azar persists today in very poor, remote areas, where health care is extremely hard to come by and patients have little access to affordable drugs and preventive measures.
The disease is endemic in 88 countries, where 350 million people are at risk of infection. Almost all of the 500,000 new cases arising from recurrent epidemics each year occur in the rural areas of the Indian subcontinent (India, Nepal, Bangladesh), Brazil, and Sudan.
In Asia and East Africa, kala-azar spreads to people through the bite of a sand fly carrying the parasite, Leishmania donovani. The parasite then multiplies in the victim’s body, invading the immune system. Once patients develop kala-azar, almost all die within months unless they receive treatment. However, not all infected people develop the disease. A person is more likely to fall ill if his or her immune system has been weakened by malnutrition or another disease such as HIV/AIDS.
It is hard to diagnose kala-azar clinically since the early symptoms resemble those of other, more common tropical diseases such as malaria, and include an enlarged abdomen, swollen spleen and liver, irregular bouts of fever, diarrhoea, and anorexia. The most reliable current form of diagnosis in African countries is the spleen aspirate, but this procedure is invasive and poorly adapted to settings in remote areas without permanent clinics.
Pentavalent antimony (sodium stibogluconate) has been used to treat the disease for over 70 years, and is still the main treatment available today. It is administered through a drip and is painful and toxic, with occasionally dangerous side-effects. Moreover in large parts of India, the drug has become ineffective because of parasite resistance. Miltefosine, an anti-cancer drug discovered in the mid-1990s, is the first oral drug to treat the disease, but treatment takes 4 weeks and is not indicated for women in childbearing age.
It has only been registered in India.
The real miracle drug is AmbisomeÃ?® - it is simple to use (max. 10 days), revives patients within hours of getting the first shot, and has virtually no side-effects. The drawback is that there is only one producer and it is astronomically expensive – the best current price offer is US$1,500-2,400 per treatment, well beyond the reach of most patients.
There is very little investment in development of new drugs for kala-azar, since there is little possibility of financial return. Veterinary research may provide some hope, since the disease also affects dogs in wealthy countries. Safer, simpler, and cheaper drugs and diagnostic tools are urgently needed, particularly for patients in Africa. The Drugs for Neglected Diseases Initiative (DNDi) has adopted leishmaniasis as one of its focus diseases and will actively support projects that seek to research and develop new treatments for this most neglected disease.
Human African Trypanosomiasis (sleeping sickness)
I once treated a 12-year old girl called Shushu, who weighed just 14 kilos. Her father had already died of kala-azar, and this was the only child her mother had who had lived longer than 7 years. We tried so hard to save her, but she died, and that broke the mother’s heart. - Dr Jill Seaman, Sudan.
For most people, sleeping sickness (African trypanosomiasis) is an obscure, "exotic" disease that causes drowsiness. The symptoms are, in fact, much more severe, and the disease is 100% fatal if left untreated. However, as the disease affects only isolated areas of sub-Saharan Africa – where tourists rarely venture – it remains largely misunderstood.
It is estimated that between 300,000 and 500,000 people are currently infected, and the disease threatens over 60 million people in 36 countries in sub-Saharan Africa including DRC, Angola, Chad, Uganda and Sudan. Almost eradicated by the 1960s, the disease has made a massive comeback due to war, population movements, and the collapse of health systems.
Sleeping sickness is caused by Trypanosoma parasites, which are transmitted to humans by tsetse flies. When a tsetse fly bites, it injects a trypanosome (protozoan parasite) into the person’s bloodstream. In the first stage of disease, the parasite reproduces in the blood and lymphatic system, causing fever, headaches and joint pain.
In the second stage, as the parasite invades the central nervous system, patients suffer intense pain, mental confusion and convulsion. Sleep disturbances are also common – hence the name of the disease. Without treatment, patients lapse into a coma and die.
The first stage of sleeping sickness is currently treated with intramuscular injections of pentamidine, which is safe and effective. Unfortunately, most patients only seek treatment during the second stage of disease, which is notoriously difficult to treat. Melarsoprol, an arsenic derivative, is extremely toxic and very painful when injected. Patients can have complications such as encephalopathy or convulsions, and one in 20 will die from the effects of the drug.
The drug is also becoming less effective because of parasite resistance. Eflornithine, an anti-cancer drug discovered in 1990, may also have major side-effects: by depressing the bone marrow and immune system, it can lead to anaemia and infections. But on the whole, it is much safer than melarsoprol.
Although the manufacturer ceased production in 1995 because of lack of profit, an appeal led by MSF and WHO succeeded in getting Aventis to ensure production of and donate all sleeping sickness drugs for another 5 years.
A new, much-needed drug for sleeping sickness will not be available in the near future. In spite of the millions of people at risk, research into the human form of trypanosomiasis is negligible. The Drugs for Neglected Diseases Initiative has adopted sleeping sickness as one of its focus diseases and will support the research and development of new, affordable, and less toxic drugs and alternative treatments for this most neglected disease.
You do not feel good as a doctor using [melarsoprol], but sleeping sickness is always fatal if untreated. So many of my patients were faced with two choices: death from the disease, or possible death from the drug.
- Dr Nitya Udaraj, Sudan.
A widespread parasitic disease, American trypanosomiasis or Chagas disease kills an estimated 50,000 people annually on the American continent. An estimated 18 million people are living with the parasite in their blood and about 100 million people are at risk of infection in 21 Central and South American countries. This is about 25 % of the population of Latin America. In Honduras, for example, 1.8 million people live in the endemic zone, 300,000 of whom are thought to be infected with Chagas disease.
The disease is caused by Trypanosoma cruzi, a protozoan parasite transmitted to humans by blood-sucking insects that live in the walls and roofs of mud and straw housing commonly found in the poor rural areas and urban slums of Latin America. The disease can also be transmitted by blood transfusion and from mother to child during pregnancy.
In the acute phase of infection, patients may present with fever, swollen lymph glands, enlarged liver and spleen. But there are usually no apparent symptoms during the acute phase. The parasite is thus able to multiply in the body for years, or even decades, without the victim being aware of the infection. In about a third of cases, chronic forms develop 10-20 years later. And at this stage, it is usually too late for treatment: symptoms such as heart failure, or serious oesophagus and colon dysfunction can be irreversible. Patients gradually become more ill and cardiac symptoms may lead to sudden death from heart failure.
Nifurtimox and Benznidazole are the only existing drugs to treat Chagas disease. Neither is considered ideal because treatment needs to be closely monitored for toxicity. It is also long (30-60 days) and ineffective against the chronic phase of the disease. Parasite resistance is also impacting effectiveness. In poor countries, where mass detection programmes are not feasible and treatment is too expensive, children under the age of 12 are usually the only ones to receive treatment. Children have a greater chance of benefiting from the treatment, as it is unlikely they will have developed chronic lesions.
There is little ongoing research to find less toxic and more effective drugs that would enable Chagas patients of all ages to be treated. It is therefore vital to develop new methods to detect the disease at an early stage. One promising avenue is a couple of anti-fungal drugs being developed that might have an application for Chagas disease. The Drugs for Neglected Diseases Initiative aspires to discover and develop critically needed new drugs or new formulations of existing drugs for patients suffering from this most neglected disease.
"Es triste vivir con Chagas" (life with Chagas is sad) sighs Juana Francisca, who has endured life with the disease for 20 years. Every day she has palpitations, headaches, dizzy spells and breathlessness. Her husband, a farm labourer, uses half his wages to pay for the drugs she needs