Sleeping sickness is a devastating disease where tsetse fly stings inject parasites that infect the brain. Since the 1920s, pharmaceutical research has introduced many medicines to treat it. The industry continues its investigations and is collaborating with the World Health Organisation to try and eradicate this scourge.
Sleeping sickness is a harmless-sounding name for an illness that, if left untreated, leads inevitably to a terrible death caused by parasites called trypanosomes. They appear only south of the Sahara, where they unleash two forms of Human African Trypanosomiasis or HAT, one acute and the other chronic. The condition has been present in Africa from at least the 14th century. The pathogens that cause it are Trypanosoma brucei gambiense in West and Central Africa, and Trypanosoma bruceirhodesiense in East Africa. T. b. gambiense has a chronic and protracted course, and may last several years, whereas T. b. rhodesiense is acute and can cause death in a matter of weeks or months. Both types of sleeping sickness are fatal if left untreated.
The parasites are transferred to humans by the sting of the tsetse fly (glossina species). In the ﬁrst phase of HAT, the trypanosomes multiply in the blood and the lymph glands. In HAT caused by T.b. gambiense, this phase can last for years without the infected person noticing anything more than occasional fever with headaches and rheumatic pains. Yet it is also during this phase that severely swollen lymph glands in the neck can act as a sure sign of the disease’s presence. Sleeping sickness becomes dangerous in its second phase, when the parasites cross the blood-brain barrier and infect the central nervous system.
This leads to a confused mental state, severe sensory disturbances, and abrupt changes in the sleep cycle that causes victims to fall asleep instantly no matter what they are doing – even walking, eating, or talking. Then, increasingly severe convulsions and neurological changes set in, followed by eventual death. If HAT is diagnosed and treated in time, it can always be cured. Yet if treatment begins too late, neurological damage can remain even after the patient is cured of the illness itself.
Sleeping sickness is a daily threat to more than 60 million people in 36 sub-Saharan African countries, 22 of which are among the least developed countries in the world. Today, major flare-ups occur in Angola, Central African Republic, Congo, Democratic Republic of Congo, Guinea and Sudan. Disease surveillance covers only 3 to 4 million of these people and the 50,000 cases reported annually do not reflect the reality of the situation, but simply show the absence of case detection. The estimated number of people thought to have the disease is between 300,000 and 500,000.
In the 1960s, the disease had been brought under control, thanks to pervasive screening programs, a good supply of medicines and determined attempts to attack tsetse fly habitats. But since then, national and international interest has faded and civil conflicts have made reaching many affected areas very difﬁcult. Today, sleeping sickness ranks seventh in sub-Saharan Africa in terms of causing disability adjusted life years.
Sleeping sickness has a major economic and social impact on the development of rural areas by decreasing the labour force and hampering production and work capacity. It remains a major obstacle to the development of entire regions. In countries such as Angola, Democratic Republic of Congo or Sudan, the operational capacity to respond to the epidemic situation has been largely exceeded and in certain endemic areas the prevalence is greater than 20 per cent.
The key medicines to treat both forms of HAT are suramin, pentamidine, melarsoprol and eflornithin. They have to be administered either by the intravenous route or as intramuscular injection. Suramin was ﬁrst introduced in the 1920s, pentamidine in the late 1930s, melarsoprol in the 1940s, and eflornithin in the early 1980s. All these medicines, especially melarsoprol, may cause severe side-effects, and the treatment regime is often difﬁcult to enforce.
The primary condition of HAT caused by T. b. rhodesiense is treated with suramin, which is still given, as no signiﬁcant resistance to the compound has emerged despite 80 years of use. The compound pentamidine is active in the ﬁrst stage of the T. b. gambiense disease. It is given as intramuscular injections over a period of seven days. Melarsoprol is used as treatment in the protracted stages of both T. b. gambiense and T. b. rhodesiense. The dosage is three intravenous injections per day over a period of ten days. Eflornithin is used in patients infected with T.b. gambiense who, due to resistance of the causing agent, do not respond to melarsoprol or have experienced severe side-effects. The compound is further used as ﬁrst-line therapy in patients with protracted disease. When given as a ﬁrst line therapy, eflornithin is administered in four daily infusions of two hours every six hours over a period of two weeks; when used as treatment for a relapse, the medication is given as four infusions daily during seven days only.
Sleeping sickness is one of the few communicable diseases where systematic population screening is necessary, particularly for T. b. gambiense, which has a long and almost asymptomatic period. There are several reasons for this, including the difﬁculty of diagnosis, which cannot normally be made in remote primary health care facilities, the difﬁculty and higher risk for medical treatment of the late stage, for which special skills are required, and the near impossibility of vector control. Therefore, the control measure most often used is systematic screening of the population using mobile teams to detect all clusters and cases of the disease, including those in both the ﬁrst and second stages, and then curing them.
In May 2001, the World Health Organisation (WHO) announced the enlargement of its Programme to Eliminate Sleeping Sickness, a public-private partnership in collaboration with several large pharmaceutical companies to merge all the organisation’s efforts to combat the disease. Other partners include Médecins Sans Frontières, the governments of Belgium and France, and the Bill and Melinda Gates Foundation. The consortium also engages in vector control activities conducted by the Pan African Trypanosomiasis and Tsetse Eradication Campaign (PATTEC), which was set up during a summit of the Organisation of the African Union (OAU) in June 2000.
In the framework of the WHO programme, new medications are under investigation, for example a further use of a compound that is registered for the treatment of Chagas’ disease, which is caused by another trypanosome species. One of the biggest questions about the development of new compounds is whether they can cross the blood-brain barrier, the body’s natural ﬁlter between the bloodstream and the nervous system.
In the ﬁrst half of 2004, a pentamidine derivative for oral administration completed Phase 3 clinical trials. The compound functions by altering the DNA of the trypanosomes, preventing the frequent metamorphosis process of the parasite which makes it impossible for the immune system to cope with the pathogen. The US FDA has granted fast track status to this new product to treat HAT. The molecule would be the ﬁrst oral therapy for this disease to be marketed. Apparently, it has shown efﬁcacy in treating HAT without the side-effects associated with alternative therapies.
Concerted efforts are vitally needed in sub-Saharan Africa to combat this devastating disease. Without systematic screening of exposed populations and without treatment, everyone infected will die. Detection of people infected with sleeping sickness and subsequent patient care will require well-trained staff, sophisticated technical resources, medicines and well-equipped health centres.
To address the scientiﬁc challenges of the future, i.e. the support of new research and development activities on sleeping sickness, efforts are especially needed in the ﬁeld of: (i) adapting present treatments: oral rather than injectable formulations, and shorter courses of treatment are pursued; (ii) identifying ways to address resistance to current treatments; (iii) testing new combinations of existing products; and (iv) identifying new molecules for future therapies.