New hope for targeting ‘Sleeping Sickness’

Image credit: qimono via pixabay

Sleeping sickness, caused by single celled species Trypanosoma brucei, is a fatal vector-borne parasitic disease. The parasite is found in 36 countries in sub-Saharan Africa, with 60 million people at risk and 30 000 deaths every year. There have been many epidemics throughout the 20th century, with 40 000 reported cases in 1998 and an additional 300 000 cases undiagnosed and untreated. But things seem to be turning around, with a significant drop in cases since the turn of the century, in which the number of reported cases between 2000 and 2012 dropped by 73% and only 2804 new cases were reported in 2015. Sleeping sickness may be on the decline but it should not be neglected along the way.

Two forms of Trypanosoma brucei cause sleeping sickness. Trypanosoma brucei gambiense (T.b. gambiense), found in West and Central Africa is responsible for 97% of reported cases and causes a chronic infection which can lie undetected for months, even years. T.b. gambiense infects both humans and animals, allowing a large infection reservoir to form outside of human treatment. The second is Trypanosoma brucei rhodesiense (T.b. rhodesiense), found in South and Eastern Africa and accounts for under 3% of cases, causing an acute infection with symptoms showing within weeks.

The parasite can be transmitted between individuals through a Tsetse fly, an aggressive blood eating fly, of the genus Glossina. Its bite is painful and memorable; however, it is often dismissed without acknowledging the dangerous parasite it carries. It inhabits rural areas, areas of vegetation by lakes and rivers, and has even been known to follow cars in its hunt for blood. The Tsetse fly is the link between humans and the animal infection reservoir, allowing the parasite to be transferred between species. The control of Tsetse flies, along with treatment, is responsible for the sharp decline in reported sleeping sickness cases. As well as the Tsetse fly, the parasite can be transferred perinatally across the placenta, and cases of sexual transmission have been documented.

There are two stages to the disease, the first (haemo-lymphatic) stage being less severe, with an individual showing signs of a red sore around the tsetse fly bite, a fever, joint pains and swollen lymph glands. During this stage the parasite is multiplying in the blood, lymph and subcutaneous tissue. The second (meningo-encephalitic) stage is the neurological stage where the parasite crosses the blood-brain barrier, causing sensory disturbances, poor coordination, and disturbances in the sleep cycle and is fatal if not treated in time. The stage the disease is at is determined by the parasite’s presence, as well as the white blood cell count in the cerebrospinal fluid (CSF), which is collected by lumbar puncture. This is an invasive procedure that is usually performed right after diagnosis, where the parasite is found in the patient’s body fluids.

When treating sleeping sickness, the stage of the infection determines the treatment an individual receives. Many different drugs have been used over the years, but most have had negative side effects. Melarsprol, developed in 1949, is a second stage intravenous drug used to treat T.b. gambiense and T.b. rhodiense infections. The drug interacts with thiol (-SH) groups of numerous proteins resulting in the inhibition of the enzyme trypanothione reductase. These thiol groups are absent in the human forms, allowing the drug to be specific in targeting the parasite. Trypanothione reductase is essential to the parasite’s survival and regulates the synthesis and metabolism of the compound trypanothione. Trypanothione is found in many protozoan parasites, such as those that cause Chagas disease, Leishmania as well as Sleeping sickness, and is used to combat oxidative stress. Melarsprol, however, causes reactive encephalopathy where 3% to 10% of patients taking the drug die. Resistance to the drug has also been seen, highlighting that new drugs are sorely needed.  Other drugs, with milder side effects and that treat T.b. gambiense infections are Eflornithine, developed in 1990, and Nifurtimox, developed in 2009. Eflornithine is administered intravenously, orally or by cream, and involves a labour intensive dosage. Nifurtimox is used to treat American Trypanosomiasis, Chagas disease in Latin America, as well as sleeping sickness. The drug is found to simplify the use of Eflornithine, by reducing its duration of treatment and the number of lumbar punctures needed to test for parasitic presence in spinal fluid. It is an orally administered drug, and is provided, along with Eflornithine, free of charge by the World Health Organisation (WHO) to endemic countries, such as the Democratic Republic of the Congo (DRC) which accounted for 84% of cases in 2015.

There is, however, a new drug on the horizon. Fexinidazole, a drug originally developed in the 1980s has been rediscovered and looks very promising in terms of administration, accessibility and effectiveness. The dosage of this rediscovered drug is a 10 day course of one orally administered pill a day. It’s effective in mild and severe cases in both forms of the disease, allowing it to be used at home in most cases, and does not require the patient’s spinal fluid to be checked for parasite presence. This reduces the number of hospitalisations caused by the disease, and the pressure on local hospitals in endemic areas. The drug is expected to be available to patients in mid-2019.

Fexinidazole is a huge achievement and great step towards the WHO’s target for Human African Trypanosomiasis’ elimination as a public health problem by 2020. This cannot, however, be the end. The disease may be on the decline, but this does not mean we have heard the last of it. Prevention, diagnosis, control and accessibility are still major concerns, with many cases left unreported. The relationship between a parasite and its host is an arms race; we may have a slight upper hand at the moment, but interest, time and research must still be invested into its understanding, diagnosis and treatment.

This post was written by Tara Wagner-Gamble and edited by Ella Mercer.

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