What is the recommended treatment for African trypanosomiasis (sleeping sickness)?

Treatment of African Trypanosomiasis (Sleeping Sickness)

Fexinidazole is now the first-line treatment for African trypanosomiasis in patients aged 6 years and older with bodyweight ≥20 kg, eliminating the need for lumbar puncture staging and replacing the toxic older regimens of suramin and melarsoprol. 1

Treatment Algorithm by Disease Form

Rhodesiense HAT (East/Southern Africa - Acute Form)

First-Line Treatment:

• Fexinidazole (oral, 10 days) for patients ≥6 years old and ≥20 kg bodyweight
  • Effective for both first-stage (haemolymphatic) and second-stage (meningoencephalitic) disease
  • No lumbar puncture required for staging - this is a major advancement 1
  • Must be taken with food during the main meal of the day (bioavailability substantially reduced without food)
  • Requires directly observed therapy by trained health staff for all 10 days 1

Alternative/Second-Line Options:

• Children <6 years or <20 kg: Use suramin (first-stage) or melarsoprol (second-stage) 1
• If patient cannot swallow or oral absorption uncertain: Consider suramin or melarsoprol depending on disease stage 1
• Pentamidine as immediate interim treatment when first-line drugs unavailable, then switch to fexinidazole/suramin/melarsoprol as soon as available 1

Gambiense HAT (West/Central Africa - Chronic Form)

The 2019 WHO interim guidelines remain unchanged, with fexinidazole also recommended as first-line therapy for first-stage and non-severe second-stage disease 2. Nifurtimox-eflornithine combination therapy (NECT) remains an effective alternative, showing fewer relapses and better tolerability than older monotherapies 3, 4.

Critical Implementation Points

Fexinidazole Administration Requirements:

• Must be taken with food (main meal) - this is non-negotiable for therapeutic drug levels 1
• Direct observation of each dose for 10 days due to high non-compliance risk
• Common side effects: nausea (33%), vomiting (38%) 1
• Monitor for QT prolongation, neutropenia, and neuropsychiatric reactions including psychotic disorder and suicidal ideation 1

Mandatory Follow-Up Schedule: Given limited data on fexinidazole in rhodesiense HAT (only 45 patients studied), intensive monitoring is required 1:

• Clinical evaluation at end of treatment
• Follow-up at 1,3,6, and 12 months post-treatment
• Relapses can occur within weeks to months in rhodesiense HAT 1

Key Advantages of Fexinidazole Over Historical Treatments

Why This Matters for Mortality and Morbidity:

• Melarsoprol causes fatal post-treatment reactive encephalopathy in 5% of patients 5
• Fexinidazole eliminates this life-threatening complication
• Oral administration allows primary care level treatment (previously required hospitalization)
• No lumbar puncture removes a major barrier to screening and follow-up - patients feared this procedure and associated superstitions prevented care-seeking 1

Common Pitfalls to Avoid

1. Do not give fexinidazole without food - therapeutic levels will not be achieved
2. Do not skip direct observation - non-compliance is high due to GI side effects over 10 days
3. Do not use fexinidazole in children <6 years or <20 kg - no safety data; use suramin/melarsoprol instead 1
4. Do not delay treatment waiting for fexinidazole - if unavailable, start pentamidine immediately given rapid progression of rhodesiense HAT 1
5. Do not skip follow-up visits - limited safety data mandates intensive pharmacovigilance 1

Evidence Quality Context

The 2025 WHO guidelines 1 represent the most authoritative and recent guidance, based on systematic review. However, the recommendation for fexinidazole in rhodesiense HAT is conditional with very low certainty evidence - based on a single non-randomized trial of only 45 patients from Uganda and Malawi 1. Despite this limitation, the guideline development group prioritized it over melarsoprol due to melarsoprol's life-threatening toxicity profile, representing a clear mortality benefit even with limited efficacy data.