Version July 2025
INTRODUCTION —
Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by protozoan parasites [1-3]. There are two forms of the disease: an acute form occurring mainly in East and Southern Africa and caused by Trypanosoma brucei rhodesiense (rhodesiense HAT) and a more chronic form occurring mainly in West and Central Africa caused by Trypanosoma brucei gambiense (gambiense HAT) (table 1) [4]. These two-parasite subspecies have identical morphologic appearances and both are transmitted by tsetse flies (Glossina). However, the two forms of HAT differ with respect to epidemiology, clinical presentation, and management.
Treatment for HAT has changed dramatically over the past decade, from intravenous (IV) toxic drugs to a well-tolerated oral drug, fexinidazole. Fexinidazole is now the first-line agent for treatment of all patients with rhodesiense HAT and most patients with gambiense HAT [1].
The treatment and prevention of human African trypanosomiasis will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of these infections are discussed separately. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis".)
CLINICAL APPROACH TO TREATMENT —
In general, selection of regimen is guided by patient age and weight, drug availability, clinical manifestations (table 2), and cerebrospinal fluid (CSF) findings; the approach is summarized below and in the algorithms (algorithm 1).
In this section, we describe the approach to selecting a regimen. Discussion on dosing, logistics of administration, monitoring, adverse effects, and drug efficacy are discussed separately. (See 'Antitrypanosomal agents' below.)
In endemic areas, management is guided by regional or national protocols which may include specific diagnostic criteria [1]. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical approach'.)
Gambiense HAT
Patients <6 years or <20 kg — Patients <6 years old or <20 kg body weight warrant routine lumbar puncture since fexinidazole is not approved for this group (table 3 and algorithm 1):
●If CSF demonstrates white blood cell (WBC) ≤5 cells/microL and no trypanosomes, we suggest pentamidine.
If pentamidine is contraindicated or not tolerated, the alternative therapy is nifurtimox-eflornithine combination therapy (NECT).
●If CSF demonstrates WBC >5 cells/microL and/or presence of trypanosomes, or if lumbar puncture is not feasible, we suggest NECT.
If NECT is contraindicated or not well tolerated, the alternative therapy is eflornithine monotherapy.
Details regarding dosing, logistics of administration, adverse effects, and drug efficacy are discussed below. (See 'Pentamidine' below and 'Nifurtimox-eflornithine combination therapy' below and 'Eflornithine monotherapy' below.)
Patients ≥6 years and ≥20 kg — Among individuals ≥6 years and ≥20 kg in endemic areas, treatment choice depends on the presence or absence of neuropsychological signs and/or symptoms of severe disease, as outlined in the table (table 2 and algorithm 1). Patients presenting with those neuropsychological signs or symptoms are suspected as having severe second-stage disease and require lumbar puncture for evaluation.
No clinical suspicion of severe second-stage
●Preferred therapy – For individuals with no clinical suspicion for severe second-stage disease (table 2), lumbar puncture is not required; the preferred treatment consists of fexinidazole. Treatment with fexinidazole should be pursued only if there is high confidence in appropriate follow-up for early detection of relapse. (See 'Follow up' below.)
Outside of resource-limited settings, we still prefer to perform lumbar puncture to confirm absence of severe second-stage infection. If lumbar puncture is performed, treatment decision should follow the criteria outlined below for patients with clinical suspicion of severe second-stage.
Details regarding dosing, logistics of administration, adverse effects, and drug efficacy are discussed below. (See 'Fexinidazole' below.)
●Alternative therapy – If fexinidazole is not an option, treatment is guided by lumbar puncture results:
•If CSF demonstrates WBC ≤5 cells/microL and no trypanosomes (first-stage disease), we suggest pentamidine.
•If CSF demonstrates WBC >5 cells/microL and/or presence of trypanosomes (second-stage disease), or if lumbar puncture is not feasible, we suggest NECT.
Details regarding dosing, logistics of administration, adverse effects, and drug efficacy are discussed below. (See 'Pentamidine' below and 'Nifurtimox-eflornithine combination therapy' below.)
Clinical suspicion of severe second-stage — For patients with presence of neuropsychological symptoms suspicious for severe second-stage disease (table 2), routine lumbar puncture is warranted:
●If CSF demonstrates WBC <100 cells/microL, we suggest fexinidazole given its similar efficacy to NECT. Treatment with fexinidazole should be pursued only if there is high confidence in appropriate follow-up for early detection of relapse. (See 'Follow up' below.)
If fexinidazole is not an option, alternative therapy is guided by CSF result (diagnosing first and second stage) according to the alternative therapy outlined above for patients without clinical suspicion of severe second-stage (table 3).
Details regarding dosing, logistics of administration, adverse effects, and drug efficacy are discussed below. (See 'Fexinidazole' below.)
●If CSF demonstrates WBC ≥100 cells/microL, or if lumbar puncture is not feasible, we suggest NECT given it has greater treatment success rates compared with fexinidazole in severe second-stage disease. (See 'Nifurtimox-eflornithine combination therapy' below.)
Details regarding dosing, logistics of administration, adverse effects, and drug efficacy are discussed below. (See 'Nifurtimox-eflornithine combination therapy' below.)
Site of care — The use of fexinidazole (an oral drug) has allowed some patients with gambiense human African trypanosomiasis (HAT) to be treated in the outpatient setting rather than the hospital.
Hospitalization is warranted in patients with any of the following:
●Psychiatric disorders
●Weight <35kg
●Concern for poor adherence to treatment
●≥100 WBC in the CSF and being treated with fexinidazole (very rare situation, only as alternative therapy)
Patients who do not meet any of the following criteria and meet criteria for fexinidazole therapy may be considered for treatment in the outpatient setting under daily supervision. Decision to treat as an outpatient requires shared decision making with the patient and their family members after discussing the risks and benefits and providing detailed instructions on how to take fexinidazole correctly [1]. In general, outpatient treatment is appropriate for patients who can have close follow up, are likely to be reliably adherent to treatment, and have reliable oral daily food intake.
Rhodesiense HAT
Patients <6 years old or <20 kg — Patients who are <6 years of age or weigh <20 kg cannot receive fexinidazole and therefore require lumbar puncture to determine appropriate treatment.
Given that trypanosomes are commonly detected on blood smear in the setting of rhodesiense HAT, a clinician can administer the first dose of suramin prior to lumbar puncture, to reduce parasitemia, and minimize the theoretic risk of iatrogenic introduction of trypanosomes into the CSF (in case of a traumatic lumbar puncture) [5].
Based on lumbar puncture results (table 4):
●If CSF WBC ≤5 cells/microL and no trypanosomes are present in the CSF, we suggest suramin [6].
Pentamidine is an alternative therapy. In regions where pentamidine is more accessible than suramin, pentamidine may be used as initial therapy (especially in the setting of acute illness) until suramin therapy can be obtained and administered.
Details regarding dosing, logistics of administration, adverse effects, and drug efficacy are discussed below. (See 'Suramin' below.)
●If CSF WBC >5 cells/microL and/or trypanosomes are present in CSF, we suggest melarsoprol [6].
No alternative therapy is available for second-stage rhodesiense HAT in this patient group. If melarsoprol is contraindicated or not tolerated, we agree with the World Health Organization (WHO) to administer fexinidazole under compassionate use authorization [1].
Details regarding dosing, logistics of administration, adverse effects, and drug efficacy are discussed below. (See 'Melarsoprol' below.)
Patients ≥6 years and ≥20 kg — Fexinidazole is the preferred therapy for treatment of rhodesiense HAT in this patient population. For patients who cannot receive fexinidazole, lumbar puncture is indicated to stratify the stage of the infection to determine best alternative treatment.
●Preferred therapy – For patients who are ≥6 years of age and weigh ≥20 kg, we suggest fexinidazole (table 4) [1,7]. (See 'Follow up' below.)
Fexinidazole should be administered under direct observation of trained health personnel in an inpatient setting for the treatment of rhodesiense HAT [1].
Details regarding administration, monitoring, adverse effects, and efficacy are discussed below. (See 'Fexinidazole' below.)
●Alternative treatment – Patients who cannot receive fexinidazole require lumbar puncture to determine appropriate treatment (table 4).
•If CSF WBC ≤5 cells/microL and no trypanosomes are present in the CSF (first-stage disease), we suggest suramin.
•If CSF WBC >5 cells/microL and/or trypanosomes are present in CSF (second-stage disease), we suggest melarsoprol [6].
Details regarding administration, monitoring, adverse effects, and efficacy are discussed below. (See 'Suramin' below and 'Melarsoprol' below.)
Site of care — Hospitalization is preferred for patients receiving treatment for rhodesiense HAT, given its acute and rapidly progressive clinical presentation and the need for directly observed therapy of fexinidazole or intravenous (IV) infusion of other drugs.
Follow up — Follow up is warranted for patients who were treated with fexinidazole.
●Gambiense HAT – For patients treated with fexinidazole for gambiense HAT, follow-up clinical evaluation should be performed at 6, 12, 18, and 24 months after completion of therapy or at any time if symptoms recur [1].
●Rhodesiense HAT – For patients treated with fexinidazole for rhodesiense HAT, follow-up clinical evaluation should be performed on the last day of treatment (day 10) and at 1, 3, 6, and 12 months after completion of therapy or at any time if symptoms recur [1]. Rhodesiense HAT tends to recur in a shorter time period than gambiense HAT and thus requires a shorter and more frequent follow-up schedule.
Such follow up is important given the possibility of incomplete adherence to oral administration and limited data on the likelihood of relapse with fexinidazole. Presence of any symptoms and signs consistent with HAT warrant workup for a relapse. (See 'Approach to relapse' below.)
For patients treated with other agents, no routine follow-up is needed if treatment was uncomplicated. Agents other than fexinidazole all have high efficacy and completion of treatment can be documented given the need for IV or intramuscular (IM) administration. Such patients should be advised to return for evaluation if symptoms recur [1,5].
Pregnancy and lactation considerations — Data on the safety of antitrypanosomal drugs in pregnancy are very limited. The WHO guidelines favor management based on clinical assessment including disease severity and pregnancy stage [1].
Pentamidine and fexinidazole may be given after the first trimester. In general, nifurtimox, eflornithine alone, or NECT should be avoided during pregnancy. However, in the setting of moderate to severe disease, administration of these agents with the goal of life-saving treatment is appropriate. This is especially true with rhodesiense HAT, where treatment usually cannot be delayed until after delivery given its acute and rapidly progressive clinical presentation [8]. Treatment during pregnancy may also reduce the likelihood of vertical transmission. The benefits and risks of treatment must be clearly explained to the patient [1,8]. (See 'Antitrypanosomal agents' below.)
Newborns should be examined clinically, assessed by direct parasitological methods as early as possible (including umbilical cord blood examination where possible), and should be followed clinically [9].
Information on the use of antitrypanosomal drugs in breastfeeding women is very limited. Breastfeeding may continue during HAT treatment.
APPROACH TO RELAPSE
Evaluation of suspected relapse — For patients with signs or symptoms suggestive of relapse, blood examination and lumbar puncture should be performed to evaluate for trypanosomes in the blood and/or cerebrospinal fluid (CSF); in the majority of relapses, trypanosomes are present in the CSF and remain undetectable in the blood [10].
●Gambiense HAT – For patients with gambiense human African trypanosomiasis (HAT), the preferred tool for blood examination is mini anion-exchange centrifugation technique (mAECT).
●Rhodesiense HAT – For patients with rhodesiense HAT, blood smear can be performed first, followed by mAECT if blood smear is negative. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnostic tools'.)
Detection of trypanosomal deoxyribonucleic acid (DNA) or antibodies in blood or CSF are unreliable at adequately detecting a relapse [11-13] and should not be used when evaluating for relapse. Tools under investigation include detection of trypanosomal ribonucleic acid (RNA) [14-16].
Interpreting the results
Trypanosomes visible in specimen — A definitive diagnosis of relapse is established if trypanosomes are observed in any body fluid or tissue. Rescue (relapse) treatment options for gambiense HAT (table 3) and rhodesiense HAT (table 4) are outlined in the tables.
Trypanosomes not visible in specimen — If trypanosomes are not observed, the CSF white blood cell (WBC) count may be used to establish a presumptive diagnosis of relapse according to the following criteria [1]:
●Up to four months after treatment – Up to four months after completion of treatment, the CSF WBC count is not reliable [5,17]; diagnosis of relapse may be based only on observation of trypanosomes. If no trypanosomes are observed, the decision to administer rescue (relapse) treatment should be based on clinical manifestations. If rescue treatment is not pursued, follow-up lumbar puncture should be performed six months later.
●At five to nine months after treatment [1,5]:
•CSF WBC ≥50 cells/microL: Presumptive diagnosis of relapse; administer rescue (relapse) treatment.
•CSF WBC 6 to 49 cells/microL: The evolution of the WBC count is uncertain. The decision to administer rescue (relapse) treatment should be based on clinical features suggesting relapse.
-For gambiense HAT, follow-up assessment at 12 months is warranted.
-For rhodesiense HAT, a follow-up visit one to three months later is recommended (because of the faster evolution of disease).
•CSF WBC ≤5 WBC: Relapse unlikely.
●At 10 to 24 months after treatment [1,5]:
•CSF WBC >20 cells/microL: Presumptive diagnosis of relapse; administer rescue (relapse) treatment.
•CSF WBC ≤20 WBC: Relapse unlikely.
Use of the above thresholds for diagnosis of relapse is based on second-stage gambiense HAT patient follow-up data [13,17,18]. In a prospective study including 360 patients with gambiense HAT in the Democratic Republic of Congo, the above criteria had high sensitivity and specificity (94 and 98 percent, respectively) for prediction of treatment outcome [13]. Similarly, in a study including more than 2000 patients with second-stage gambiense HAT in six African countries, these criteria had high sensitivity and specificity (87 and 98 percent, respectively) for prediction of treatment outcome [18].
Data for follow-up evaluation of first-stage gambiense HAT and rhodesiense HAT are sparse [17,19-21].
Management of relapse — Management of relapse is determined by type of HAT and severity of disease. Rescue (relapse) treatment options for gambiense HAT (table 3) and rhodesiense HAT (table 4) are outlined in the tables.
OUTCOMES —
In general, both gambiense and rhodesiense human African trypanosomiasis (HAT) are considered fatal without treatment [5]. Rare anecdotal cases of asymptomatic T. b. gambiense infection or resolution without treatment have been described [22,23].
ANTITRYPANOSOMAL AGENTS —
The dosing recommendations, logistics of administration, monitoring, adverse effects, and drug efficacy are discussed in detail here. A clinical approach to selecting a regimen for the treatment of human African trypanosomiasis (HAT) is discussed in detail separately. (See 'Clinical approach to treatment' above.)
Fexinidazole — Fexinidazole is preferred for the treatment of gambiense and rhodesiense HAT in individuals ≥6 years of age and ≥20 kg in weight [1,7]. Details on the indications for fexinidazole are discussed above. (See 'Clinical approach to treatment' above.)
●Dosing and administration – Fexinidazole is an oral drug given once daily for 10 days. Dosing is weight-based (≥35 kg: 3 tablets [1800 mg] for four days followed by 2 tablets [1200 mg] for six days; 20 to 34 kg: 2 tablets [1200 mg] for four days followed by 1 tablet [600 mg] for six days). Fexinidazole tablets should be swallowed whole within 30 minutes of a meal, which is important for drug absorption [24]. The drug should be administered with solid food; administration with liquids only is associated with significantly diminished absorption. The tablets should not be broken or crushed, although the efficacy of crushed fexinidazole tablets is under investigation. Detailed recommendations in case of missed doses or vomiting are given in the World Health Organization (WHO) guidelines [1].
Fexinidazole should be administered under directly observed therapy for all patients (both inpatient and outpatient) [1].
●Adverse effects – Adverse effects of fexinidazole include neuropsychiatric reactions (insomnia, hallucination, agitation, logorrhea, abnormal behavior, anxiety, psychosis, and suicidal ideation), vomiting (38 percent in adults; 68 percent in children), nausea (33 percent), asthenia (20 percent), anorexia (17 percent), headache (16 percent), insomnia (15 percent), tremor (14 percent), dizziness (14 percent), neutropenia, and QTc prolongation [1].
●Availability – Fexinidazole is available from the WHO upon request and can be also obtained from strategic drug stocks in nonendemic countries (table 5). The drug is not registered for use in most nonendemic countries; it may be obtained for compassionate use within local regulatory frameworks. Fexinidazole is approved by the US Food and Drug Administration (FDA) [25] and can be obtained in the United States by contacting Sanofi Customer Service or Medical Affairs at 1-800-372-6634 or [email protected]. The Center for Disease Control and Prevention (CDC) Drug Service telephone numbers are (404) 639-3670 or (404) 770-7100.
●Efficacy
•Gambiense HAT – Use of fexinidazole for treatment of first-stage gambiense HAT is supported by two prospective, open-label, single-arm studies; one among 189 adults (DNDiFEX005) and another among 69 children ≥6 years old and ≥20 kg (DNDiFEX006) [26-28]. At 18 months follow-up, treatment failure rates were 2.1 and 1.4 percent, mortality rates were 1.6 and 1.4 percent, adverse event rates were 93.1 and 88.4 percent, and serious adverse event rates were 9.0 and 7.2 percent, respectively [27].
For those with second-stage gambiense HAT, fexinidazole was similar to nifurtimox-eflornithine combination therapy (NECT) for those with white blood cell (WBC) ≤100, but inferior for those with WBC >100. The trial included more than 390 patients with >20 cerebrospinal fluid (CSF) WBC/microL or trypanosomes in CSF who were randomly assigned (2:1) to treatment with fexinidazole or NECT [26,27,29]. At 24 months follow-up, overall treatment success rates were 89.8 versus 97.6 percent (risk ratio [RR] 0.92, 95% CI 0.87-0.96) [27,29]. Among patients with CSF WBC >100 cells/microL, the treatment success rate at 18 months was lower for fexinidazole than for NECT (86.9 versus 98.7 percent, respectively); among patients with CSF WBC ≤100 cells/microL, the treatment success rates were similar (98 and 95.9 percent, respectively) [26,29]. Rates of adverse effects were similar among fexinidazole and NECT recipients (81 versus 79 percent, respectively).
Additional data on fexinidazole for treatment of second-stage HAT include the DNDiFEX005 trial (41 adults with CSF ≤20 WBC/microL; 97.6 percent fexinidazole treatment success rate) and the DNDiFEX006 trial (56 children; 97.3 fexinidazole treatment success rate) [27].
Further study of fexinidazole for treatment of gambiense HAT will provide additional information on outpatient treatment and adherence.
•Rhodesiense HAT – In vitro and in vivo studies have demonstrated that fexinidazole has activity against T. b. rhodesiense [30,31]. A study on the efficacy and safety of fexinidazole in patients with rhodesiense HAT was completed in October 2022, although results have not yet been published [32,33]. This study cohort comprised 45 rhodesiense HAT patients from Uganda (n = 2) and Malawi (n = 43), of whom 10 were in the first stage and 35 were in the second stage [7]. All 10 patients in the first stage were successfully treated and had no recurrence of the disease at the 12-month follow-up. A total of 33 out of 35 patients (94 percent) in the second stage were successfully treated at the 12-month follow-up. One patient (3 percent) experienced a relapse at week 9 and was consequently treated successfully with melarsoprol. Another patient (3 percent) died during the treatment phase due to acute kidney failure, which was not considered to be related to fexinidazole treatment. European Medicines Agency and the World Health Organization (WHO) support fexinidazole for the treatment of rhodesiense HAT [1,7].
Pentamidine — Pentamidine is an option for the treatment of gambiense and rhodesiense HAT in certain circumstances. Pentamidine clinical use is further discussed above. (See 'Clinical approach to treatment' above.)
●Dosing, administration, and monitoring – Dosing for pentamidine is 4 mg/kg/day intramuscular (IM) or intravenous (IV; infuse over 1 to 2 hours) once daily for 7 days. Pentamidine is usually given as an IM in endemic countries; this is because IV administration is frequently associated with hypotension (up to 75 percent of cases) [1]. Patients should eat or drink a sugar source to prevent hypoglycemia and should remain supine for at least one hour after injection to reduce the likelihood of hypotension, at which time vital signs should be repeated; monitoring should continue for patients with hemodynamic instability. If pentamidine is administered intravenously, it should be infused slowly over 60 to 120 minutes and vital signs monitored during (and after) infusion. In addition, if feasible, pentamidine should be given with electrocardiogram monitoring and serum glucose monitoring.
●Adverse effects – Pentamidine is generally well tolerated; minor adverse reactions are common. Immediate adverse effects include nausea, anorexia, dizziness, pruritus, and hypotension. Sterile abscesses or necrosis may develop at the IM site. Pentamidine is also associated with hematologic effects (particularly leukopenia and thrombocytopenia) as well as electrolyte abnormalities (including hyperkalemia, hypomagnesemia, and hypocalcemia). Severe adverse effects include ventricular arrhythmias, pancreatitis, hypo- or hyperglycemia, or hepato- and nephrotoxicity with azotemia. Persistent diabetes is a rare adverse effect. Pentamidine has been associated with Steven-Johnson syndrome. Seizures and hallucinations have also been described.
●Availability – Pentamidine is available from the WHO for the treatment of HAT. Pentamidine is often available in non-HAT endemic countries since it is also used for treatment of Pneumocystis jirovecii pneumonia.
●Efficacy
•Gambiense HAT – Use of pentamidine for treatment of first-stage gambiense HAT is supported by randomized trials and observational studies including more than 6700 children and adults [27]. In seven studies including more than 5600 adults and adolescents, the relapse rate at 6 to 24 months was 7.3 percent; in one study including more than 300 children ≤15 years of age, the relapse rate was 3.6 percent [13,34-40].
•Rhodesiense HAT – Pentamidine may have efficacy against first-stage rhodesiense HAT, based on case reports of travelers and pharmacologic data [5,41-43].
Nifurtimox-eflornithine combination therapy — NECT consists of oral nifurtimox and IV eflornithine. NECT is only effective against gambiense HAT. Use of NECT (over eflornithine monotherapy) facilitates shorter duration of therapy, requires a shorter hospital stay, and may reduce the likelihood of selection for resistance. Indications for NECT use is further discussed above. (See 'Patients <6 years or <20 kg' above and 'Patients ≥6 years and ≥20 kg' above.)
●Dosing and administration – Nifurtimox is administered in tablets (15 mg/kg per day orally divided in 3 doses for 10 days) while eflornithine is an IV infusion (400 mg/kg per day IV divided every 12 hours [infuse over 2 hours] for seven days). Eflornithine infusion catheters should be replaced at least every 48 hours to avoid local site reactions. Nifurtimox tablets may be cut to achieve the correct dose; if needed, they may be crushed and mixed into food or sugar water. The tablets should be administered under careful supervision to ensure they are swallowed, preferably after a meal. If vomiting occurs within 30 minutes after intake, the same dose should be repeated. If vomiting occurs 30 to 60 minutes after intake, a half dose should be administered.
The NECT-long regimen extends the duration of eflornithine infusion from 7 days to 14 days. It is used as a rescue treatment for gambiense HAT in certain cases. (See 'Management of relapse' above.)
●Adverse effects – Adverse effects associated with NECT include abdominal pain, nausea, vomiting, headache, seizure, psychotic reaction, and hallucination [44]. Diarrhea and vomiting are frequent (>50 percent of cases) but do not warrant cessation of treatment. Other described adverse effects include tremor, headache, bone marrow suppression (anemia, leukopenia), and vertigo. NECT is better tolerated in children than in adults. Adverse effects of NECT are better tolerated than those associated with eflornithine monotherapy.
●Availability – Nifurtimox is registered for the treatment of Chagas disease in certain countries; for HAT, it is used as compassionate treatment or off-label use, under approbation by pharmaceutical authorities. Eflornithine is available from the WHO and can be also obtained from strategic drug stocks in nonendemic countries (table 5). Eflornithine is approved by the FDA for the treatment of gambiense HAT [45].
●Efficacy
•Gambiense HAT – Use of NECT for treatment of second-stage gambiense HAT is supported by a trial in the Republic of the Congo and the Democratic Republic of the Congo including more than 280 patients randomly assigned to treatment with NECT (nifurtimox 15 mg/kg orally in 3 doses for 10 days and eflornithine 400 mg/kg IV per day in 2 infusions for seven days) or eflornithine monotherapy (100 mg/kg IV every 6 hours for 14 days) [46]. After an 18-month follow-up, the patients treated with NECT had a higher cure rate (97.7 versus 91.7 percent; difference -6 percent, one-sided 95% CI -1.5), a lower relapse rate (1.4 versus 5.7 percent), and a lower rate of major adverse effects (14 versus 29 percent). Similarly, in another trial including 163 patients with second-stage gambiense HAT in Uganda randomly assigned to treatment with NECT or eflornithine monotherapy, 18-month cure rates were 90.6 and 88.5 percent, respectively [47].
•Rhodesiense HAT – NECT has no activity against rhodesiense HAT.
Eflornithine monotherapy — Eflornithine monotherapy is an alternative regimen for treatment of second-stage gambiense HAT when NECT is not feasible (because nifurtimox is unavailable or contraindicated) and when fexinidazole cannot be given.
●Dosing and administration – Eflornithine is administered via IV infusion (400 mg/kg per day [infuse over 2 hours] divided every 6 hours for 14 days). The drug should be administered within an hour of preparation and infused over at least a two-hour period. Eflornithine infusion catheters should be replaced at least every 48 hours to avoid local site reactions.
●Adverse effects – Eflornithine monotherapy is associated with more frequent adverse effects (grade 3 or 4) than NECT (28.7 versus 14 percent) [46]. The main adverse effects are fever, pruritus, hypertension, nausea, vomiting, diarrhea, abdominal pain, headaches, dizziness, hearing loss, seizure, arthralgia, rash, alopecia, and myelosuppression (anemia, leukopenia, and thrombocytopenia) [48-50].
●Availability – Eflornithine is available from the WHO and can also be obtained from strategic drug stocks in nonendemic countries (table 5). Eflornithine is approved by the FDA for the treatment of gambiense HAT [45].
●Efficacy
•Gambiense HAT – Use of eflornithine monotherapy is supported by a retrospective study including more than 900 patients with second-stage gambiense HAT in southern Sudan treated with eflornithine or melarsoprol; those treated with eflornithine had a lower mortality rate (0.8 versus 3.5 percent; RR 0.2, 95% CI, 0.04-0.89) and lower rate of encephalopathy (0.4 versus 11 percent) [49]. In a subsequent cohort study including more than 900 patients with second-stage HAT in southern Sudan treated with eflornithine monotherapy, 1.7 percent died during treatment, 7.6 percent relapsed, 1.6 percent died of disease, 43.6 percent were confirmed cured, and 45.5 percent were probably cured [50].
•Rhodesiense HAT – Eflornithine is not effective against rhodesiense HAT because this species has a higher turnover rate of the target enzyme.
Suramin — Use of suramin is restricted to treatment of first-stage rhodesiense HAT; it is not effective for second-stage disease due to poor CSF penetration [51].
●Dosing and administration – Suramin is administered by slow IV injection. Various schedules are used. The most commonly used suramin regimen consists of five injections of 20 mg/kg (max 1 g) IV weekly (eg, on days 1, 8, 15, 22, and 29) [1]. The first dose on day 1 is given initially as a test dose of 4 to 5 mg/kg IV followed by the rest of the dose a few hours later if the patient tolerated the test dose. Administration of a suramin test dose is important given the risk of immediate hypersensitivity reaction (1:20,000) [52]. The completion of the initial full dose on day 1 permits the rapid attainment of curative concentrations. In patients who are critically ill, a slower dose escalation may be considered. In addition, a urinalysis (and creatinine when feasible) should be performed to check for proteinuria prior to each dose, given the potential for nephrotoxicity.
●Adverse effects – An immediate hypersensitivity reaction leading to nausea, vomiting, shock, and loss of consciousness can occur following suramin administration [52]. Other adverse effects include nephrotoxicity, peripheral neuropathy, exfoliative dermatitis, and bone marrow toxicity.
In patients with onchocerciasis coinfection, treatment with suramin may cause a severe immunologic reaction; however, in general the prevalence of onchocerciasis overlaps with regions of gambiense HAT, not rhodesiense HAT [24]. (See "Onchocerciasis".)
●Availability – Suramin is available from WHO and can be also obtained from strategic drug stocks in nonendemic countries (table 5). In the United States, suramin is available from the CDC on a compassionate use basis. The CDC Drug Service telephone numbers are (404) 639-3670 or (404) 770-7100.
●Efficacy
•Gambiense HAT – Use of suramin for treatment of gambiense HAT is supported by data from the 1950s including cure rates of more than 90 percent; however, observed relapse rates were 25 to 35 percent [51]. Therefore, suramin is not used for treatment of gambiense HAT.
•Rhodesiense HAT – Suramin has been used in the treatment of rhodesiense HAT for over 100 years [53]. The evidence for suramin monotherapy of the first stage of rhodesiense HAT originates from seven single-arm studies comprising a total of 415 patients [54-60]. The comparability of these studies is limited due to the heterogeneity of the study populations, the outcome criteria, and the observational periods. The overall mortality ranged from 0 to 19 percent, the relapse rates from 11 to 34 percent, and the treatment success rates from 39 to 95 percent.
Melarsoprol — Given the toxicity of the drug, melarsoprol is reserved for patients with second-stage rhodesiense HAT who cannot receive other drugs.
●Dosing and administration – Melarsoprol dosing consists of 2.2 mg/kg/day (maximum 180 mg/day) IV for 10 days. Alternative dosing schedules have not been proven to have significant advantages [7]. It is best given via a butterfly as a slow bolus injection. The injection is very painful and causes a local reaction; therefore, another IV site and line must be used for the next dose. Caution must be taken to avoid IV infiltration extravasation [1,5].
Melarsoprol should be coadministered with oral prednisolone 1 mg/kg per day (maximum dose 50 mg) for nine days, followed by a three-day taper (day 10: 0.75 mg/kg; day 11: 0.5 mg/kg; day 12: 0.25 mg/kg) [1]. Use of prednisone reduces the likelihood of developing melarsoprol-induced encephalopathy [61,62]. Onset of encephalopathy should prompt melarsoprol discontinuation.
Melarsoprol should not come into contact with water, which may cause precipitation. Use of sterile, dry glass syringes is preferred if good sterilization procedures are feasible. Care must be taken with plastic syringes, since the plastic may be dissolved by propylene glycol (a solvent); therefore, melarsoprol must be administered promptly after it is drawn up into a plastic syringe.
●Adverse effects – Melarsoprol is an arsenical compound associated with high frequency of severe, life-threatening adverse effects [63]. The most feared adverse reaction is arsenic encephalopathy; this occurs in 5 to 18 percent of patients and is fatal in 10 to 70 percent of cases [5,51,61]. Onset of encephalopathy should prompt melarsoprol discontinuation.
The syndrome usually occurs 7 to 14 days after the first injection and is characterized by fever and convulsions, rapid onset of neurologic disorders, progressive coma, or abnormal behavior. Close monitoring might allow detection of early signs, such as fever or headache, prompting the cessation of melarsoprol and management with dexamethasone and diazepam.
The risk of encephalopathy increases with the trypanosomal burden and CSF WBC count and may occur as a result of inflammatory response against trypanosomes in the central nervous system. Therefore, melarsoprol should be coadministered with prednisolone. In randomized trials, this approach has been associated with reduced risk of melarsoprol-induced encephalopathy (by two-thirds) and reduced mortality (by 50 percent); no effect on treatment efficacy has been observed [19,62].
Other adverse effects include malaise, abdominal pain, nausea, vomiting, diarrhea, hepatotoxicity, peripheral neuropathy, paraplegia, cardiac arrhythmias, albuminuria, and skin reactions (pruritus); exfoliative dermatitis occurs in less than 1 percent of cases. The injection is very irritating and thrombophlebitis may occur; extravasation of the drug must be avoided, as it leads to severe local inflammation and skin necrosis [5]. (See "Arsenic exposure and chronic poisoning".)
●Availability – Melarsoprol is available from the WHO and can be also obtained from strategic drug stocks in nonendemic countries (table 5). In the United States, melarsoprol is available from the CDC on a compassionate use protocol. The CDC Drug Service telephone numbers are (404) 639-3670 or (404) 770-7100.
●Efficacy
•Gambiense HAT – Use of melarsoprol for treatment of gambiense HAT is supported by a randomized trial comparing a 10-day regimen with a longer regimen [64,65]. Among 500 patients in Angola, the parasitologic cure rate 24 hours after treatment was 100 percent in both groups; each group had 14 patients with encephalopathy with six deaths [64].
Treatment failures with melarsoprol for gambiense HAT were first observed in the 1990s; their incidence rose to 20 to 59 percent reported failure rates until the mid-2000s in regions of Angola [66], the Democratic Republic of Congo [67,68], Uganda [69], and South Sudan [70,71]. Between 2006 and 2010, the use of melarsoprol sharply diminished, and no further reports appeared.
•Rhodesiense HAT – Use of melarsoprol for treatment of rhodesiense HAT is supported by a proof-of-concept trial and utilization study using historical controls as comparator [61]. Among 107 patients in Tanzania and Uganda treated with melarsoprol (10-day regimen), the case fatality rate during treatment was 8.4 percent (versus 9.3 percent in historic controls treated with other regimens). Among discharged patients, 96 percent were clinically cured at 12-month follow-up.
Drug access — Antitrypanosomal drugs are donated by the manufacturers and distributed by the WHO to endemic countries. In addition, there are also strategic stocks in various nonendemic countries (table 5). Drug distribution via the WHO country offices may help avoid delay due to country-specific regulations for importation.
Investigational agents — Early investigational trials of acoziborole, an oral compound for treatment of all stages of gambiense HAT, showed a high efficacy and no major safety concern. In a prospective, single-arm study of 208 adults treated with a single oral dose of acoziborole (that can be taken in fasting state), the treatment success was 100 percent (41/41) in early and intermediate stages and 95.2 percent (159/167) in stage 2 gambiense HAT [72]. Further clinical trials are ongoing [73].
PREVENTION —
Tools for prevention of human African trypanosomiasis (HAT) include (1) vector control and veterinary measures and (2) community surveillance with early treatment of identified cases. There is no vaccine available; the parasite's ability to undergo antigenic switching makes vaccine development challenging. There is limited evidence that natural immunity develops following infection [20].
From a public health standpoint, gambiense HAT is responsible for a larger burden of disease than rhodesiense HAT. The regions with the highest prevalence and the largest populations at risk are those with political instability and poor infrastructure. Disease elimination can be achieved only with sustained cooperative efforts including the development and deployment of better tools for diagnosis and treatment.
Vector control and veterinary measures — Vector control is important for reduction of human contact with tsetse flies [5,74]. Such interventions should be used in combination with other approaches for disease control.
Tsetse flies are visually attracted to blue cloth and tend to land on black cloth; therefore, these colors have been used to attract them to fly traps (picture 1) and insecticide-treated screens [75,76]. Thus far, insecticidal resistance has not been reported among tsetse flies. Tsetse fly repellents are under development, mainly for veterinary use [77].
There are a number of examples of success with vector control:
●In Chad, combining vector control with treatment of human cases was effective for reducing transmission [75].
●In Guinea, under conditions where medical control of HAT could not be maintained due to the Ebola epidemics, vector control alone was effective in providing some degree of protection.
●In Uganda, a prevention campaign against rhodesiense HAT consisted of a bundled approach including mass cattle insecticide spraying (to reduce the number of tsetse flies) and mass treatment of cattle with trypanocidal drugs [78].
●In many African countries, the Pan African Tsetse and Trypanosomiasis Eradication Campaign has employed area-wide vector control interventions [79-81].
Surveillance — Surveillance may be used for early detection of gambiense HAT; this is helpful for controlling disease as well as reducing ongoing transmission during a potentially prolonged subclinical phase. Surveillance is not practical for rhodesiense HAT, since asymptomatic human infection is rare; the only prevention tools for rhodesiense HAT are vector control and veterinary measures [82]. (See 'Vector control and veterinary measures' above.)
Surveillance for gambiense HAT requires substantial resources and is especially challenging in rural areas where there is little access to health facilities. The appropriate interval between screenings in endemic areas depends on the disease prevalence and transmission intensity. Typically, screening is performed annually; if no new cases are detected for three years, the screening interval is increased to three years, and if no new cases are detected for five years, screening is discontinued [5].
Surveillance tools for gambiense HAT include clinical screening for lymphadenopathy and serologic screening (typically using the card agglutination test for T. b. gambiense trypanosomes [CATT] or a lateral flow assay) [83-86]. The sensitivity of serology is generally >80 percent, depending on the geographic location and the test used [87]. The specificity depends in part upon whether whole blood or plasma dilutions are used. In addition, cross-reactivity with antibodies against nonpathogenic animal trypanosomes can occur. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Serologic tests'.)
Individuals with positive serology require further evaluation with lymph node aspiration (if lymphadenopathy is present) and/or blood examination for presence of trypanosomes; in the setting of high clinical suspicion for HAT, lumbar puncture may be pursued [28] (algorithm 2 and algorithm 3). (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical approach'.)
Individuals with trypanosomes detected in any tissue or body fluid should be treated as described above. (See 'Gambiense HAT' above.)
For individuals with positive serologic test but negative lymph node aspiration and/or blood examination, the optimal management is uncertain [28]. In such cases, the serologic test may be falsely positive; alternatively, some cases may represent asymptomatic infection with low numbers of circulating parasites or "hidden" trypanosomes in the skin or other tissues. Follow-up should be tailored to individual circumstances; potential tools include use of more specific serologic tests, CATT titration, molecular tests, lumbar puncture, and serial follow-up examinations. The approach to subsequent clinical evaluation and management should be guided by local protocols.
Advice for travelers — Travelers should avoid areas known to harbor tsetse flies. Neutral-colored hats, long-sleeved shirts, and long pants of medium weight should be worn; tsetse flies are attracted to bright colors (especially blue) and dark colors (especially black) and can bite through thin fabric [6]. Insect repellant should be used; it may have limited effect on tsetse flies but reduces the risk of other diseases transmitted by bug bites. (See "Prevention of arthropod bites: Repellents and other measures".)
There is no role for chemoprophylaxis.
SUMMARY AND RECOMMENDATIONS
●Two forms of disease – Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by protozoan parasites known as trypanosomes and is transmitted by tsetse flies (Glossina). There are two forms of the disease (table 1):
•An acute form occurring mainly in East and Southern Africa and caused by Trypanosoma brucei rhodesiense (rhodesiense HAT)
•A more chronic form occurring mainly in West and Central Africa caused by Trypanosoma brucei gambiense (gambiense HAT)
These two-parasite subspecies have identical morphologic appearances, but differ with respect to epidemiology, clinical presentation, and management. (See 'Introduction' above and "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis".)
●Management of gambiense HAT – Management considerations for gambiense HAT include patient age and weight, clinical manifestations, and cerebrospinal fluid (CSF) findings. The approach is summarized in the algorithm (algorithm 1); drug dosing is summarized in the table (table 3):
•Patients <6 years old or <20 kg body weight – These patients warrant routine lumbar puncture since fexinidazole is not approved for this group.
-For patients with CSF white blood cell (WBC) ≤5 cells/microL and no trypanosomes, we suggest pentamidine (Grade 2C). (See 'Pentamidine' above.)
-For patients with CSF WBC >5 cells/microL and/or presence of trypanosomes, or if lumbar puncture is not feasible, we suggest treatment with nifurtimox-eflornithine combination therapy (NECT) (Grade 2C). (See 'Nifurtimox-eflornithine combination therapy' above.)
•For patients ≥6 years and ≥20 kg in body weight – In resource-limited settings, decisions regarding whether to pursue lumbar puncture should be guided by degree of suspicion for severe second-stage disease (table 2). For individuals with no clinical suspicion for severe second-stage disease, lumbar puncture is not required. Outside of resource-limited settings, CSF examination is preferred for treatment selection. (See 'Patients ≥6 years and ≥20 kg' above.)
-For patients with no suspicion for severe second-stage disease and for patients with CSF WBC ≤100 cells/microL, we suggest treatment with fexinidazole (rather than NECT) (Grade 2C), given similar treatment success rates with NECT. (See 'Fexinidazole' above.)
-For patients with CSF WBC >100 cells/microL, or if lumbar puncture is not feasible (in setting of suspected severe second-stage disease), we suggest treatment with NECT (rather than fexinidazole) (Grade 2C), given greater treatment success rates. (See 'Nifurtimox-eflornithine combination therapy' above.)
Alternative and rescue therapies for gambiense HAT are summarized above and in the table (table 3). (See 'Patients <6 years or <20 kg' above and 'Patients ≥6 years and ≥20 kg' above and 'Management of relapse' above.)
●Management of rhodesiense HAT – Management considerations for rhodesiense HAT include patient age and weight, clinical manifestations, and CSF findings. The approach is summarized in the table (table 4).
•Patients <6 years old or <20 kg body weight – These patients warrant routine lumbar puncture since fexinidazole is not approved for this group. (See 'Patients <6 years old or <20 kg' above.)
-If CSF WBC ≤5 cells/microL and no trypanosomes are present in the CSF, we suggest suramin (Grade 2C). (See 'Suramin' above.)
-If CSF WBC >5 cells/microL and/or trypanosomes are present in CSF, we suggest melarsoprol (Grade 2C). (See 'Melarsoprol' above.)
•For patients ≥6 years and ≥20 kg in body weight – In accordance with World Health Organization (WHO) guidelines, we suggest fexinidazole as first-line treatment for both first- and second-stage rhodesiense HAT (Grade 2C). (See 'Patients ≥6 years and ≥20 kg' above and 'Fexinidazole' above.)
Alternative and rescue therapies for rhodesiense HAT are discussed in the topic text. (See 'Patients <6 years old or <20 kg' above and 'Patients ≥6 years and ≥20 kg' above and 'Management of relapse' above.)
●Approach to relapse – For patients with signs or symptoms suggestive of relapse, blood examination and lumbar puncture should be performed. The approach to treatment of relapse depends on the initial treatment and time since treatment, as summarized above. (See 'Approach to relapse' above.)
●Prevention – There is no vaccine or chemoprophylaxis available for prevention of HAT; tools include (1) vector control and veterinary measures and (2) surveillance for gambiense HAT with early treatment of identified cases. Travelers should avoid areas known to harbor tsetse flies. Neutral-colored clothing should be worn and insect repellant should be used. (See 'Prevention' above.)
ACKNOWLEDGMENTS —
The UpToDate editorial staff acknowledges Dr. Karin Leder, MBBS, FRACP, PhD, MPH, DTMH, Dr. Peter Weller, MD, MACP, and Dr. August Stich, MD, MSc, DTMH, who contributed to earlier versions of this topic review.
