What is African sleeping sickness and its treatment?

African Sleeping Sickness (Human African Trypanosomiasis)

African sleeping sickness, or Human African Trypanosomiasis (HAT), is a neglected tropical disease caused by flagellated protozoan parasites of the Trypanosoma brucei species, transmitted by the tsetse fly in sub-Saharan Africa, with treatment now centered on fexinidazole as first-line therapy for most patients.

Epidemiology and Causative Agents

• HAT commonly affects low-income populations in rural environments in sub-Saharan Africa 1
• The disease is caused by two subspecies of Trypanosoma brucei:
  • T.b. gambiense (West and Central Africa) - chronic form, primarily anthroponotic 1
  • T.b. rhodesiense (East and Southern Africa) - acute form, zoonotic 1
• Uganda is the only country where both forms are endemic, though in distinct regions 1

Disease Progression and Clinical Features

• The disease progresses through two distinct stages:

  • First stage (hemolymphatic): parasites multiply in blood and lymph 2
  • Second stage (meningoencephalitic): parasites cross the blood-brain barrier and invade the CNS 2

• Gambiense HAT (West/Central Africa):

  • Chronic course progressing over months to years 1
  • Characterized by non-specific symptoms initially, making diagnosis difficult 3

• Rhodesiense HAT (East/Southern Africa):

  • Acute disease with rapid progression over weeks or months 1
  • More aggressive clinical course 4

• Common neurological symptoms in late-stage disease include:

  • Sleep disturbances (disruption of sleep-wake cycle) 1
  • Personality changes and irritability 1
  • Headaches, ataxia, and extrapyramidal signs 1
  • Progressive neurologic impairment leading to coma and death if untreated 1

Diagnosis

• Diagnosis is challenging, particularly for T.b. gambiense due to low parasite numbers in blood 3

• Key diagnostic approaches include:

  • Microscopic examination of Giemsa-stained thick and thin blood films or buffy coat preparations 1
  • Examination of chancres (if present) and lymph nodes 1
  • Serological testing (card agglutination test has 96% sensitivity for gambiense HAT) 1
  • CSF analysis to determine disease stage and guide treatment 1

• Staging of disease is crucial for treatment decisions:

  • First stage: ≤5 white blood cells/μL in CSF, no trypanosomes 1
  • Second stage: >5 white blood cells/μL in CSF or presence of trypanosomes 1

Treatment

Current First-Line Treatment Recommendations

• For rhodesiense HAT in individuals aged ≥6 years with bodyweight ≥20 kg, fexinidazole is now the first-line therapy for both disease stages, replacing suramin and melarsoprol 1

• Fexinidazole advantages:

  • Effective for both stages, eliminating the need for lumbar puncture for staging 1
  • Oral administration with fewer side effects than previous treatments 1
  • Can be administered at primary care level with trained staff 1

• For children <6 years or with bodyweight <20 kg:

  • First stage: suramin remains the treatment of choice 1
  • Second stage: melarsoprol remains necessary 1

• In settings where first-line drugs are not readily available:

  • Pentamidine can be initiated immediately given the rapid progression of rhodesiense HAT 1
  • Treatment should be switched to first-line drugs when available 1

Administration and Monitoring

• Fexinidazole must be administered with food to ensure adequate bioavailability 1
• Each dose must be directly observed by trained health staff for the full 10-day treatment course 1
• All patients treated with fexinidazole must be closely monitored for relapse at treatment end and at 1,3,6, and 12 months post-treatment 1

Special Considerations

• For patients unable to swallow or with uncertain oral absorption, suramin or melarsoprol might be preferred depending on disease stage 1
• Compassionate use of fexinidazole may be considered for children <6 years when other treatments fail, with specialist consultation 1

Potential Complications and Side Effects

• Fexinidazole side effects include:

  • Common: nausea (33%) and vomiting (38%) 1
  • Serious: QT prolongation, neutropenia, and neuropsychiatric reactions including psychosis and suicidal ideation 1

• Melarsoprol (still used for some patients) has significant toxicity:

  • Post-treatment reactive encephalopathy occurs in approximately 5% of patients and can be lethal 2, 4

Prevention and Control

• No vaccine is currently available 5
• Control strategies include:
  • Active and passive case-finding for early detection 5
  • Treatment of identified cases 5
  • Vector control (tsetse fly) 5
  • Management of animal reservoirs, particularly for rhodesiense HAT 5

Future Directions

• Acoziborole, a single-dose oral treatment for gambiense HAT, has shown promise in clinical trials 1
• Pre-clinical data suggests acoziborole may also be active against T.b. rhodesiense 1
• Ongoing research aims to develop safer, more effective treatments, particularly for pediatric populations 1