Approach
Human African trypanosomiasis (HAT) is a serious and life-threatening disease that is usually fatal without treatment.
Once the diagnosis has been confirmed, a detailed clinical assessment must be carried out to establish the presence or absence of signs and symptoms that raise the suspicion of meningoencephalitic disease. A lumbar puncture may be required in order to determine disease severity and guide treatment decisions.[32]
Antitrypanosomal drugs are the mainstay of treatment. The aim of treatment is to cure the disease; however, efficacy is variable. Supportive treatments may be required to treat other conditions related to the disease or other concomitant diseases.
General principles of antitrypanosomal treatment
Antitrypanosomal treatment is recommended for all patients diagnosed with HAT. These drugs should be used under specialist guidance. Immediate treatment is recommended in patients with confirmed rhodesiense HAT as it can be rapidly progressive.[32]
Antitrypanosomal drugs for the treatment of HAT include:
Fexinidazole
Pentamidine
Nifurtimox plus eflornithine (also known as NECT)
Eflornithine monotherapy
Suramin
Melarsoprol
The choice of drug depends on numerous factors, including:[32][125]
Subspecies of causative trypanosome (i.e., Trypanosoma brucei gambiense or T b rhodesiense)
Patient's age and body weight
Disease severity
Availability of drugs
Antitrypanosomal drugs are available worldwide and free of charge from the World Health Organization (WHO).[32] In the US, some of the drugs (e.g., suramin, melarsoprol) may not be commercially available and must be obtained via the Centers for Disease Control and Prevention (CDC).[125]
The approval of fexinidazole, a nitroimidazole derivative, has changed the management of HAT in recent years. Unlike previously available drug regimens, fexinidazole can be administered orally, and it is less toxic.[32]
Fexinidazole may be used to treat first- and second-stage disease in all patients, except for those with severe disease (≥100 white blood cells [WBC]/microliter in the cerebrospinal fluid [CSF]), and children <6 years of age or body weight <20 kg.
Availability of fexinidazole has removed the need for lumbar puncture for disease staging in certain patients. Lumbar puncture and CSF examination are only required in patients who are not eligible to receive fexinidazole.
Patients ≥6 years of age and body weight ≥20 kg who have a low index of suspicion of severe disease based on clinical judgment, and a high confidence that the patient will have appropriate follow-up to detect a relapse early, do not require lumbar puncture and may be treated preferentially with fexinidazole.
Patients <6 years of age or body weight <20 kg must still undergo a lumbar puncture and CSF examination to determine the treatment of choice.
Gambiense HAT: first-stage disease
First-stage disease (also known as early stage or hemolymphatic stage) is defined as ≤5 WBC/microliter and no trypanosomes in the CSF without clinical features consistent with severe disease.[32][125]
Treatment options depend on the patient's age and body weight.[32][125]
<6 years of age or body weight <20 kg:
Pentamidine is the recommended first-line treatment.
≥6 years of age and body weight ≥20 kg:
Fexinidazole is the recommended first-line treatment.
Pentamidine is an alternative option if the patient cannot receive fexinidazole (e.g., it is contraindicated or not available), provided there is no suspicion for severe disease.
Gambiense HAT: second-stage disease
Second-stage disease (also known as late stage or meningoencephalitic stage) is defined as >5 WBC/microliter or trypanosomes in the CSF and with clinical features consistent with severe disease.[32][125]
Treatment options depend on the patient's age and body weight, as well as disease severity.[32][125]
Nonsevere disease (<100 WBC/microliter in the CSF)
<6 years of age or body weight <20 kg:
Nifurtimox plus eflornithine is the recommended first-line treatment.
≥6 years of age and body weight ≥20 kg:
Fexinidazole is the recommended first-line treatment.
Nifurtimox plus eflornithine is an alternative option.
Severe disease (≥100 WBC/microliter in the CSF with or without trypanosomes)
Nifurtimox plus eflornithine is the recommended first-line treatment, regardless of the patient's age and body weight.
Fexinidazole is an alternative option in patients ≥6 years of age and body weight ≥20 kg. However, the efficacy of fexinidazole is inferior to nifurtimox plus eflornithine in patients with ≥100 WBC/microliter in the CSF, and it is therefore only an option for patients who cannot tolerate nifurtimox plus eflornithine, or if nifurtimox or eflornithine are unavailable.
Nifurtimox plus eflornithine is the recommended treatment for patients where a lumbar puncture is not done or results are unreliable.[32]
Eflornithine monotherapy is an alternative option to nifurtimox plus eflornithine in areas where nifurtimox is contraindicated or unavailable, or fexinidazole cannot be given. However, the treatment course is longer and requires maintenance of venous access for 14 days. Parasite elimination may not be complete with eflornithine monotherapy in immunocompromised patients.[32]
Gambiense HAT: relapse
Patients must be monitored closely for 24 months after treatment for signs of relapse as there is no test of cure. Relapse may occur more than 1 year after treatment.[32][125]
A relapse is defined as the presence of trypanosomes in any body fluid or tissue, or a high WBC in the CSF if trypanosomes are not seen.[32]
The choice of rescue treatment depends on the patient's age and body weight, WBC count in the CSF, and the previous treatments used. The following general principles apply:[32]
If a patient relapses after being treated with fexinidazole initially, nifurtimox plus eflornithine is recommended.
If a patient relapses after being treated with pentamidine initially, fexinidazole or nifurtimox plus eflornithine is recommended (depending on the patient's age, body weight, and WBC count in the CSF).
If a patient relapses after a standard course of nifurtimox plus eflornithine, a longer course of nifurtimox plus eflornithine (14 days rather than 7 days of eflornithine) is recommended. Eflornithine monotherapy or fexinidazole are other options (depending on the patient's age, body weight, and WBC count in the CSF).
If a patient relapses after these rescue treatments, melarsoprol is a last-line option owing to its toxicity.
Specific recommendations depend on the patient's age and body weight.[32]
<6 years of age or <20 kg body weight:
Nifurtimox plus eflornithine is the recommended first-line rescue treatment. The standard course is recommended if ≤5 WBC/microliter and there are no trypanosomes in the CSF. The longer course is recommended if >5 WBC/microliter or there are trypanosomes in the CSF.
Melarsoprol is an alternative option if >5 WBC/microliter or there are trypanosomes in the CSF.
≥6 years of age and ≥20 kg body weight:
Nifurtimox plus eflornithine (standard or long course) is the recommended rescue treatment if <100 WBC/microliter in the CSF.
Nifurtimox plus eflornithine (long course) or melarsoprol are the recommended rescue treatments if ≥100 WBC/microliter in the CSF (severe second-stage disease) or a failed lumbar puncture.
Consult a specialist for further guidance on treating patients with relapse.
Rhodesiense HAT: first-stage disease
Rhodesiense HAT is the more rapidly progressive form of disease and requires immediate treatment.
First-stage disease (also known as early stage or hemolymphatic stage) is defined as ≤5 WBC/microliter and no trypanosomes in the CSF.[32]
There are currently differences in recommended treatments between international guidelines.
The WHO recommends fexinidazole, suramin, or pentamidine for first-stage disease, depending on the patient's age and body weight.[32]
The CDC recommends suramin only for first-stage disease, regardless of the patient's age and body weight. However, the CDC guidelines were published prior to the WHO guidelines, which may account for this discrepancy.[125]
The treatment options recommended here are based on WHO guidance.
Treatment options depend on the patient's age and body weight.[32]
<6 years of age or body weight <20 kg:
Suramin is the recommended first-line treatment.
Pentamidine is an alternative option.
≥6 years of age and body weight ≥20 kg:
Fexinidazole is the recommended first-line treatment.
Suramin or pentamidine may be used in patients who cannot receive fexinidazole. However, a lumbar puncture is required for staging.
Immediate interim treatment with pentamidine may be used if the recommended treatments are not available. However, the patient should be switched to the recommended treatment as soon as it becomes available.[32]
Rhodesiense HAT: second-stage disease
Second-stage disease (also known as late stage or meningoencephalitic stage) is defined as >5 WBC/microliter or trypanosomes in the CSF.[32]
There are currently differences in recommended treatments between international guidelines.
The WHO recommends either fexinidazole or melarsoprol for second-stage disease, depending on the patient's age and body weight.[32]
The CDC recommends melarsoprol only for second-stage disease, regardless of the patient's age and body weight. However, the CDC guidelines were published prior to the WHO guidelines, which may account for this discrepancy.[125]
The treatment options recommended here are based on WHO guidance.
Treatment options depend on the patient's age and body weight.[32]
<6 years of age or body weight <20 kg:
Melarsoprol is the recommended first-line treatment.
Pentamidine is an alternative option.
≥6 years of age and body weight ≥20 kg:
Fexinidazole is the recommended first-line treatment.
Melarsoprol may be used in patients who cannot receive fexinidazole. However, a lumbar puncture is required for staging.
Immediate interim treatment with pentamidine may be used if the recommended treatments are not available. However, the patient should be switched to the recommended treatment as soon as it becomes available.[32]
Rhodesiense HAT: relapse
Patients must be monitored closely for 24 months after treatment for signs of relapse as there is no test of cure. Relapse may occur more than 1 year after treatment.[32][125] Relapses may occur earlier (e.g., weeks or months) compared with gambiense HAT as disease progression is usually more rapid.[32]
A relapse is defined as the presence of trypanosomes in any body fluid or tissue, or a high WBC in the CSF if trypanosomes are not seen.[32]
The choice of rescue treatment depends on the patient's age and body weight, WBC count in the CSF, and the previous treatments used. The following general principles apply:[32]
If a patient relapses after being treated with fexinidazole initially, a lumbar puncture is required for staging and suramin or melarsoprol are recommended (depending on stage).
If a patient relapses after being treated with suramin initially, pentamidine or melarsoprol are recommended (depending on stage).
If a patient relapses after being treated with melarsoprol, fexinidazole may be considered (on a compassionate use basis).
Specific recommendations depend on the patient's age and body weight.[32]
<6 years of age or <20 kg body weight:
Fexinidazole is the recommended first-line rescue treatment (on a compassionate use basis), regardless of disease stage.
≥6 years of age and ≥20 kg body weight:
A lumbar puncture is required for staging.
Suramin is recommended for first-stage disease.
Melarsoprol is recommended for second-stage disease.
Consult a specialist for further guidance on treating patients with relapse.
Treatment of pregnant and breast-feeding women
The safety of antitrypanosomal drugs during pregnancy and breast-feeding has not been clearly established. Recommendations are based on clinical practice rather than evidence.[32] Consult a specialist for guidance on the management of pregnant women.
The decision to treat the patient during pregnancy should be determined considering the potential benefits and risks for the mother and fetus.[126] The benefits and risks of treatment must be clearly explained to the patient.
Safety data for the use of antitrypanosomal drugs during pregnancy are limited.
Fexinidazole: there is some minimal evidence of fetotoxicity and fetal loss in animals with fexinidazole, and clinical trials in pregnant women are ongoing.[127]
Pentamidine: has been described as non-mutagenic and non-genotoxic.[128]
Nifurtimox: there are limited data on the use of nifurtimox in pregnancy.
Eflornithine: has been described as a cause of abortions, smaller fetuses, and retarded development in rats.[129]
Suramin: has been shown to be teratogenic and a cause of fetal growth retardation in animals.[126][130]
Melarsoprol: has been reported as a cause of low birth weight, spontaneous abortion, and malformations.[131]
Fexinidazole and pentamidine may be given after the first trimester. Melarsoprol, suramin, nifurtimox, and eflornithine are contraindicated in pregnancy, but they may be used in certain circumstances depending on the maternal condition. Nifurtimox plus eflornithine should be administered only after delivery.[32]
If the mother's condition allows for watchful waiting, clinical assessment is recommended (at least monthly). Fexinidazole or pentamidine can be given to reduce the risk of perinatal transmission.
If the mother's condition is moderately or severely altered, treatment - with fexinidazole, nifurtimox plus eflornithine, or eflornithine monotherapy (depending on the subspecies of causative trypanosome) - must be given to save the mother's life.
Suramin and melarsoprol may need to be given as rescue treatment for rhodesiense HAT.
Close follow-up during pregnancy and delivery is recommended. Newborns from mothers with confirmed HAT need to be checked for the presence of the disease and followed up. Breast-feeding should continue during treatment.[32]
Fexinidazole administration
Recommendations regarding the administration of fexinidazole are a key element of management as efficacy depends on swallowing the medication after an appropriate intake of food, and making sure the full 10-day treatment regimen is completed.
A substantial meal must be consumed prior to dose administration to ensure sufficient absorption to reach therapeutic levels. Direct supervision by trained healthcare staff is necessary to ensure the patient is in a fed condition and for daily compliance.
Outpatient administration may be appropriate in select patients (under daily supervision). However, hospitalization may be mandatory in certain circumstances (e.g., children with body weight <35 kg, patients with psychiatric disorders, risk of poor compliance, severe disease).
Alcohol should not be consumed during treatment or for 48 hours after the last dose due to a disulfiram-like reaction.
Fexinidazole should only be prescribed when patients can meet these conditions and there is appropriate long-term follow-up to ensure that relapse is detected early.
Efficacy of antitrypanosomal treatment
Antitrypanosomal drugs are highly effective.
Fexinidazole
Fexinidazole has shown equivalent efficacy to pentamidine in first-stage gambiense HAT, equivalent efficacy to nifurtimox plus eflornithine in nonsevere second-stage gambiense HAT, but inferior efficacy to nifurtimox plus eflornithine in severe second-stage gambiense HAT.[32][132][133][134]
Efficacy for first-stage gambiense HAT in clinical trials was 97.9% to 98.6%, 98% for nonsevere second-stage gambiense HAT, and 86.9% for severe second-stage gambiense HAT.[32]
Efficacy for first-stage rhodesiense HAT in clinical trials was 100%, and 94.3% for second-stage rhodesiense HAT, but data are limited.[32]
Pentamidine
Pentamidine has a cure rate of 93% to 98% in first-stage gambiense HAT, and the rate has not decreased in decades.[32][135][136]
Nifurtimox plus eflornithine (or eflornithine monotherapy)
Nifurtimox plus eflornithine has a cure rate of 95% to 98% in second-stage gambiense HAT, with a fatality rate <1%. Eflornithine monotherapy has a cure rate of 90% to 95%, with a fatality rate <2%.[32][114][137]
Melarsoprol
Adverse effects of antitrypanosomal treatment
Antitrypanosomal drugs have the potential for significant toxicities. Strict monitoring is required during treatment.[32][114][125][137][140][141][142][143][144][145]
Fexinidazole
Fexinidazole has been associated with neuropsychiatric adverse effects, QT prolongation, neutropenia, and gastrointestinal adverse effects.
Contraindications include jaundice, bleeding or other clinical signs of hepatic insufficiency, generalized edema, risk of QT interval prolongation, or Cockayne syndrome.
Pentamidine
Pentamidine is generally well tolerated, but the injection is painful.
Pentamidine has been associated with hypotension, cardiac disorders, nephrotoxicity, leukopenia, thrombocytopenia, anemia, acute pancreatitis, hypoglycemia, hyperglycemia, and diabetes.
Treatment should be preceded by the ingestion of sugar to combat the risk of hypoglycemia.
Patients should remain in a supine position for 1-2 hours after administration, while blood pressure and cardiac rhythm are monitored.[60]
Monitoring of glucose, blood calcium, renal and pancreatic function, potassium, and serum creatinine during treatment is recommended. Periodic electrocardiogram monitoring is desirable.
Nifurtimox
Gastrointestinal adverse effects are common.
Eflornithine
Eflornithine is a toxic drug with an iatrogenic mortality of 0.7% to 2%.[137]
It may cause bone marrow suppression, gastrointestinal adverse effects, vertigo, tremor and, more rarely, seizures, and psychotic reactions or hallucinations.
Considering the bone marrow suppressor effect of the drug, monitoring of blood cell counts is needed together with identifying and treating early possible infections (phlebitis, cellulitis, infectious dermatitis, polymyositis). Monitoring should be continued for up to 2-4 weeks after finishing treatment.[114][137]
Nifurtimox plus eflornithine is generally better tolerated than eflornithine monotherapy.
Suramin
Suramin is associated with hypersensitivity reactions; a test dose is recommended prior to the first full dose.
Adverse effects are common, but are usually mild and reversible. Adverse effects include gastrointestinal adverse effects, drug rash, peripheral neuropathy, agranulocytosis, hemolytic anemia, thrombocytopenia, and nephrotoxicity.
Contraindications include severe renal disease.
Monitoring of blood parameters and renal function is recommended.
Melarsoprol
Melarsoprol is a highly toxic drug.
It must be administered with prednisone to help prevent melarsoprol encephalopathy, which occurs in 5% to 18% of cases and is fatal in 10% to 70% of cases.
Other adverse effects include skin reactions, exfoliative dermatitis, gastrointestinal adverse effects, myocardial damage, hypertension, cardiac failure, and albuminuria.
Close monitoring is required, and treatment stopped immediately in case of significant adverse effects (e.g., encephalopathy, phlebitis, local necrosis).[139]
Monitoring of blood parameters and renal and liver function is recommended.
Consult your local drug information source for full details on contraindications, cautions, and adverse effects associated with these highly toxic drugs.
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