African trypanosomiasis, often known as sleeping sickness, is a parasitic disease caused by protozoan parasites of the genus Trypanosoma brucei. This illness is primarily transmitted to humans through the bite of an infected tsetse fly, a vector prevalent in sub-Saharan Africa. If left untreated, African trypanosomiasis is invariably fatal, underscoring the importance of prompt and appropriate medication.
Disease Stages and Treatment Approach
African trypanosomiasis progresses through distinct stages, which directly influence the choice of medication. The initial or hemolymphatic stage, known as Stage 1, involves the presence of parasites in the bloodstream and lymphatic system. During this phase, symptoms may include fever, headache, and joint pain.
As the disease advances, it enters the meningoencephalitic stage, known as Stage 2, where the parasites cross the blood-brain barrier and infect the central nervous system. This progression leads to neurological symptoms such as confusion, seizures, and difficulties with walking. The distinction between these stages is paramount because drugs effective in Stage 1 often cannot penetrate the blood-brain barrier to reach parasites in the central nervous system, requiring different therapeutic agents for Stage 2.
Medications for Early Stage Disease
Pentamidine is a recognized treatment for Trypanosoma brucei gambiense infection, a subspecies found in West and Central Africa. Administered via intramuscular or intravenous injection, pentamidine interferes with DNA, RNA, phospholipid, and protein synthesis in the parasite, disrupting its nuclear metabolism. Common side effects include hypotension, hypoglycemia, and gastrointestinal disturbances.
Suramin is another medication for the early hemolymphatic stage, particularly effective against Trypanosoma brucei rhodesiense, prevalent in East Africa. This drug is given intravenously and inhibits enzymes involved in the oxidation of reduced nicotinamide-adenine dinucleotide (NADH), which is crucial for the parasite’s energy production. Side effects include nausea, vomiting, diarrhea, headache, and skin tingling. More severe reactions include kidney dysfunction and allergic reactions.
Medications for Late Stage Disease
Melarsoprol, an arsenic-containing compound, has historically been used for both T. b. rhodesiense and T. b. gambiense infections. Its mechanism involves binding to sulfhydryl groups on parasite enzymes, disrupting energy production and causing oxidative stress within the parasite. Melarsoprol is administered intravenously and is known for its significant toxicity, with potential side effects including encephalopathic reactions, peripheral neuropathy, and cardiovascular toxicity. Approximately 1-5% of patients may die during treatment with melarsoprol, although this is considered in the context of the disease’s nearly 100% mortality rate if untreated.
Eflornithine is another medication used for late-stage T. b. gambiense infections. This drug irreversibly inhibits ornithine decarboxylase (ODC), an enzyme that catalyzes the synthesis of polyamines, which are necessary for cell division and growth in trypanosomes. Eflornithine is administered through multiple intravenous infusions. While generally better tolerated than melarsoprol, side effects can include bone marrow suppression (leading to anemia, leucopenia, and thrombocytopenia), gastrointestinal issues like nausea, vomiting, and diarrhea, and seizures.
Nifurtimox, while primarily used for Chagas disease, has also been incorporated into combination therapy for late-stage African trypanosomiasis. Its mechanism involves the generation of reactive oxygen species that damage the parasite’s DNA and cellular structures, leading to cell death. Nifurtimox is typically given orally as part of a combination regimen. Common side effects include gastrointestinal discomfort, such as nausea and vomiting, as well as neurological effects like headache and insomnia.
Emerging Treatments and Combination Therapies
Recent advancements in treating African trypanosomiasis aim to improve patient outcomes by simplifying administration and reducing drug toxicity. Nifurtimox-eflornithine combination therapy (NECT) represents a significant step forward for late-stage T. b. gambiense infection. This regimen combines oral nifurtimox with intravenous eflornithine, significantly reducing the number of eflornithine infusions from 56 to 14 and shortening the treatment duration from 14 to 10 days, making it more convenient for patients and healthcare providers. NECT has shown comparable efficacy and a favorable safety profile compared to eflornithine monotherapy, and it is considered suitable for first-line use in disease control programs.
Fexinidazole is another notable advancement, being the first all-oral drug approved for both early and non-severe late-stage T. b. gambiense in patients aged 6 years and older weighing at least 20 kg. This nitroimidazole derivative is a prodrug that is activated within the parasite, forming reactive intermediates that damage DNA and proteins. Fexinidazole offers the advantage of simplified oral administration over a 10-day period, reducing the need for hospitalization and complex intravenous infusions. While highly effective for early and early-late stage disease, a higher treatment failure rate has been observed for severe late-stage patients with a cerebrospinal fluid white blood cell count exceeding 100 cells/µL, where NECT is still recommended. Research continues to explore even safer and more accessible treatments, including other new chemical entities and single-dose options, to further improve the management of this disease.