Human African trypanosomiasis: Treatment and prevention

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.

The treatment and prevention of 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".)

TREATMENT OF GAMBIENSE HAT — In endemic areas, management is guided by regional or national protocols which may include specific diagnostic criteria [1]. In general, management considerations for gambiense HAT include patient age and weight, drug availability, clinical manifestations, and cerebrospinal fluid (CSF) findings; the approach is summarized below and in the algorithm (algorithm 1). (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical approach'.)

Clinical approach — The approach to treatment selection is based on assessment for signs and symptoms of severe disease (table 2). CSF examination is required for patients with signs and symptoms of severe disease as well as for patients who cannot be treated with fexinidazole.

Patients <6 years or <20 kg — Patients <6 years old or <20 kg body weight warrant routine lumbar puncture. Fexinidazole is not approved for this group (table 3):

●If CSF demonstrates white blood cell (WBC) ≤5 cells/microL and no trypanosomes, treatment consists of pentamidine (4 mg/kg/day intramuscular or intravenous [over 2 hours] for 7 days). Details regarding drug efficacy, logistics of administration, and adverse effects are discussed below. (See 'Pentamidine' below.)

●If CSF demonstrates WBC >5 cells/microL and/or presence of trypanosomes, or if lumbar puncture is not feasible, treatment consists of nifurtimox-eflornithine combination therapy (NECT; nifurtimox 15 mg/kg orally in three doses for 10 days and eflornithine 400 mg/kg per day intravenously in two 2-hour infusions for 7 days). Details regarding drug efficacy, logistics of administration, and adverse effects are discussed below. (See 'Nifurtimox-eflornithine combination therapy' below.)

Patients ≥6 years and ≥20 kg — Among individuals ≥6 years and ≥20 kg in endemic areas with no suspicion for severe second-stage disease (table 2), lumbar puncture is not required; the preferred treatment consists of fexinidazole (weight-based dosing once daily for 10 days) (table 3). Outside of resource-limited settings, CSF examination is preferred for treatment selection.

For patients with suspicion for severe second-stage disease (table 2), routine lumbar puncture is warranted:

●If CSF demonstrates WBC <100 cells/microL, treatment consists of fexinidazole (weight-based dosing once daily for 10 days) (table 3), given similar treatment success rates (relative to NECT) with less toxicity. (See 'Fexinidazole' below.)

Treatment with fexinidazole should be pursued only if there is high confidence in appropriate follow-up for early detection of relapse. Fexinidazole should be administered under direct observation of trained health personnel on an inpatient or outpatient basis [1]. Patients with history of psychiatric disorders should be hospitalized during treatment to observe for adverse neuropsychiatric reactions. Criteria for outpatient treatment include reliable food intake, anticipated adherence, absence of psychiatric disorders, and body weight ≥35 kg.

Details regarding drug efficacy, logistics of administration, and adverse effects are discussed below. (See 'Fexinidazole' below.)

●If CSF demonstrates WBC ≥100 cells/microL, or if lumbar puncture is not feasible, treatment consists of NECT: combination therapy with nifurtimox (15 mg/kg orally in 3 doses for 10 days) and eflornithine (400 mg/kg per day intravenously in 2 infusions [over 2 hours each] for 7 days) (table 3), given greater treatment success rates compared with fexinidazole. Details regarding drug efficacy, logistics of administration, and adverse effects are discussed below. (See 'Nifurtimox-eflornithine combination therapy' below.)

Alternative and rescue treatment — The preferred treatment approach is summarized above and in the algorithm (algorithm 1). (See 'Patients <6 years or <20 kg' above and 'Patients ≥6 years and ≥20 kg' above.)

For circumstances in which preferred treatment is not available, is not tolerated, or is not effective, alternative and rescue therapies are summarized in the table (table 3).

In general, if fexinidazole cannot be given, CSF examination should be used to guide subsequent management; options include pentamidine or NECT (see 'Efficacy, administration, and adverse effects' below):

●If a patient relapses after initial treatment with pentamidine, fexinidazole or NECT (depending on age/weight and CSF WBC count) should be given.

●If a patient relapses after initial treatment with fexinidazole, NECT should be given.

●If a patient relapses after treatment with NECT, alternative approaches include NECT-long (in which eflornithine is administered for 14 days rather than for 7 days) or eflornithine monotherapy.  

●Melarsoprol is a regarded as an agent of last resort due to toxicity.

Pregnant women — Data on safety of antitrypanosomal drugs in pregnancy are very limited. The World Health Organization guidelines favor management based on clinical assessment including disease severity and pregnancy stage [1]. Treatment during pregnancy may reduce the likelihood of vertical transmission; 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. The benefits and risks must be clearly explained to the patient.(See 'Efficacy, administration, and adverse effects' below.)

Newborns should be examined clinically, undergo blood concentration methods to evaluate for presence of circulating trypanosomes, and should be followed clinically [5].

Information on the use of antitrypanosomal drugs in breastfeeding women is very limited. Breastfeeding may continue during HAT treatment.

TREATMENT OF RHODESIENSE HAT

Clinical approach — Management of rhodesiense HAT is guided by lumbar puncture findings. First- (hemolymphatic) stage disease consists of ≤5 white blood cells (WBC)/microL and no trypanosomes in the cerebrospinal fluid (CSF); second- (meningoencephalitic) stage disease consists of >5 WBC/microL and/or presence of trypanosomes in CSF. In December 2023, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted a positive scientific opinion of fexinidazole as treatment of first and second stage rhodesiense HAT in adults and children ≥6 years old and weighing ≥20 kg [6]. As use of fexinidazole for management of first and second stage rhodesiense HAT supplants other drugs, lumbar puncture may no longer be needed. Updated recommendations from the WHO are in progress. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Cerebrospinal fluid'.)

Given that trypanosomes are commonly detected on blood smear in the setting of rhodesiense HAT, the first test dose of suramin (4 to 5 mg/kg intravenously [IV] on day 1) is often administered 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) [7].

First-stage disease — First-line treatment of first stage rhodesiense HAT consists of fexinidazole for patients who are ≥6 years old and weigh ≥20 kg [6]. In vitro and in vivo studies have demonstrated that fexinidazole has activity against T.b. rhodesiense [8]. The efficacy of fexinidazole in rhodesiense HAT has been assessed in a phase II/III clinical trial in Malawi and in Uganda [9].

For patients <6 years of age and/or weighing <20kg or those who cannot receive fexinidazole, suramin should be administered instead [10]. The most commonly used suramin regimen consists of 4 to 5 mg/kg IV on day 1 (test dose, administered cautiously), followed by 5 injections of 20 mg/kg (max 1 g) IV weekly (eg, on days 3, 10, 17, 24, and 31) [7]. Administration of a suramin test dose is important given the risk of immediate hypersensitivity reaction (1:20,000). Suramin should be administered by slow IV infusion. In addition, a urinalysis should be performed to check for proteinuria prior to each dose, given the potential for nephrotoxicity. (See 'Suramin' below.)

Pentamidine may have efficacy against first-stage rhodesiense HAT, based on case reports of travelers and pharmacologic data [7,11-13]. 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. (See 'Pentamidine' below.)

In the setting of treatment failure, melarsoprol (dosing as for second-stage disease) may be given as a rescue therapy. (See 'Second-stage disease' below.)

Details regarding drug efficacy, logistics of administration, and adverse effects are discussed below. (See 'Fexinidazole' below and 'Suramin' below and 'Pentamidine' below and 'Melarsoprol' below.)

Second-stage disease — Treatment for second-stage disease consists of fexinidazole or melarsoprol. New WHO recommendations are expected to be published soon.

●First-line treatment – First-line treatment of second stage rhodesiense HAT consists of fexinidazole (weight-based dosing once daily for 10 days) for individuals ≥6 years of age and weighing ≥20 kg [6]. Fexinidazole should be administered under direct observation of trained health personnel on an inpatient or outpatient basis [1]. Patients with history of psychiatric disorders should be hospitalized during treatment to observe for adverse neuropsychiatric reactions. Criteria for outpatient treatment include reliable food intake, anticipated adherence, absence of psychiatric disorders, and body weight ≥35 kg.

Details regarding drug efficacy, logistics of administration, and adverse effects are discussed below. (See 'Fexinidazole' below.)

In vitro and in vivo studies have demonstrated that fexinidazole has activity against T. b. rhodesiense [14]. A study on the efficacy and safety of fexinidazole in patients with rhodesiense HAT was completed in October 2022; data has not been published [15]. European Medicines Agency (EMA) approved fexinidazole for the treatment of rhodesiense HAT in December 2023 [6].

●Alternative treatment – For patients <6 years of age and/or weighing <20kg or those who cannot receive fexinidazole, melarsoprol, an arsenical compound associated with high frequency of severe, life-threatening adverse effects, can be administered instead [10].

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 [6]. Details regarding drug efficacy, logistics of administration, and adverse effects are discussed below. (See 'Melarsoprol' below.)

Melarsoprol should be coadministered with oral prednisolone 1 mg/kg per day (maximum dose 50 mg) for 9 days, followed by a 3-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 [16,17] (see 'Melarsoprol' below).

Onset of encephalopathy should prompt melarsoprol discontinuation.

For patients with relapse after treatment with melarsoprol, a repeat course of melarsoprol may be given.

Use of melarsoprol for treatment of rhodesiense HAT is supported by a proof-of-concept trial and utilization study using historical controls as comparator [16]. 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.

Pregnant women — Data on treatment of rhodesiense HAT in pregnant or lactating women are very limited [18]. Given the acute and rapidly progressive clinical presentation, treatment usually cannot be delayed until after delivery [1]. Newborns should be examined clinically, checked for the presence of circulating trypanosomes in the blood and CSF, and should be followed clinically [5].

FOLLOW-UP — If treatment is uncomplicated, no routine follow-up is needed in the following circumstances:

●Patients with gambiense HAT treated with pentamidine, nifurtimox-eflornithine combination therapy, or eflornithine

●Patients with rhodesiense HAT treated with suramin or melarsoprol

These regimens have high efficacy and completion of treatment can be documented given the need for intravenous or intramuscular administration. Such patients should be advised to return for evaluation if symptoms recur [1,7].

For patients treated with fexinidazole, issues related to follow-up are discussed above. (See 'Patients ≥6 years and ≥20 kg' above.)

APPROACH TO RELAPSE — For patients with signs or symptoms suggestive of relapse, blood examination and lumbar puncture should be performed. For patients with gambiense HAT, the preferred tool for blood examination is mini anion-exchange centrifugation technique (mAECT); for rhodesiense HAT, blood smear may be performed followed by mAECT if smear is negative. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnostic tools'.)

A definitive diagnosis of relapse is established if trypanosomes are observed in any body fluid or tissue.

If trypanosomes are not observed, the cerebrospinal fluid (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 [7,19]; diagnosis of relapse may be based only on observation of trypanosomes. If no trypanosomes are observed, the decision to administer rescue treatment should be based on clinical manifestations. If rescue treatment is not pursued, follow-up assessment with lumbar puncture at six months is warranted.

●At five to nine months after treatment:

•After treatment with nifurtimox-eflornithine combination therapy (NECT), eflornithine, or melarsoprol (for second-stage HAT), or after treatment with fexinidazole (for first-stage HAT or nonsevere second-stage HAT) [1,7]:

-CSF WBC ≥50 cells/microL: Presumptive diagnosis of relapse; administer rescue treatment.

-CSF WBC 6 to 49 cells/microL: The evolution of the WBC count is uncertain; follow-up assessment at 12 months is warranted. The decision to administer rescue treatment should be based on clinical features suggesting relapse.

-CSF WBC ≤5 WBC: Relapse unlikely.

•After treatment with pentamidine or suramin (for first-stage HAT) [7]:

-CSF WBC >20 cells/microL: Presumptive diagnosis of relapse; administer rescue treatment.

-CSF WBC 6 to 20 cells/microL: The evolution of the WBC count is uncertain; follow-up assessment at 12 months is warranted. The decision to administer rescue treatment should be based on clinical features suggesting relapse.

-CSF WBC ≤5 WBC: Relapse unlikely.

●At 10 to 24 months after treatment [1,7]:

•After treatment with NECT, eflornithine, or melarsoprol (for second-stage HAT), or after treatment with fexinidazole (for first-stage HAT or nonsevere second-stage HAT) [1,7]:

-CSF WBC >20 cells/microL: Presumptive diagnosis of relapse; administer rescue treatment.

-CSF WBC ≤20 WBC: Relapse unlikely.

•After treatment with pentamidine or suramin (for first-stage HAT) [7]:

-CSF WBC >20 cells/microL: Presumptive diagnosis of relapse; administer rescue treatment.

-CSF WBC 6 to 20 cells/microL: The evolution of the WBC count is uncertain; further follow-up assessment is warranted. The decision to administer rescue treatment should be based on clinical features suggesting relapse.

-CSF WBC ≤5 WBC: Relapse unlikely.

Use of the above thresholds for diagnosis of relapse is based on second-stage gambiense HAT patient follow-up data [19-21]. 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 [20]. 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 [21].

Data for follow-up evaluation of first-stage gambiense HAT and rhodesiense HAT are sparse [19,22-24].

Unreliable tools for detection of relapse include detection of trypanosomal DNA or antibodies in blood or CSF [20,25,26]. Tools under investigation include detection of trypanosomal RNA [27-29] and CSF neopterin levels [30]. Neopterin is a marker for cellular immune activation and remains largely a research tool.

ANTITRYPANOSOMAL AGENTS

Efficacy, administration, and adverse effects

Fexinidazole — Fexinidazole is recommended for the treatment of gambiense HAT in individuals ≥6 years of age and ≥20 kg in weight in whom there is no suspicion of severe second-stage disease, or in whom cerebrospinal fluid (CSF) analysis confirms white blood cell (WBC) <100 cells/microL. Use of fexinidazole for treatment of second stage gambiense HAT should be limited to individuals with CSF WBC <100 cells/microL. Further discussion of indications for fexinidazole are found above. (See 'Patients ≥6 years and ≥20 kg' above.)

In December 2023, the European Medicines Agency's Committee for Medicinal Products has adopted a positive scientific opinion of fexinidazole as treatment of first and second stage rhodesiense HAT in adults and children ≥ 6 years old and weighing ≥ 20 kg [6]. New WHO recommendations are expected soon.

Fexinidazole is available from the World Health Organization (WHO) upon request. 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) [31].

●Administration and adverse effects – Fexinidazole tablets should be swallowed whole within 30 minutes of a meal, which is important for drug absorption [32]. 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. Detailed recommendations in case of missed doses or vomiting are given in the WHO guidelines [1]. 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]. Such follow-up is important given the possibility of incomplete adherence to oral administration and limited data on the likelihood of relapse.

Adverse effects of fexinidazole include neuropsychiatric reactions (insomnia, hallucination, agitation, logorrhea, abnormal behavior, anxiety, psychosis), 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].

●Supporting data

•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) [33-35]. 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 [34].

For those with second stage gambiense HAT, fexinidazole was similar to nifurtimox-eflornithine combination therapy (NECT) for those with WBC ≤100, but inferior for those with WBC >100. In a trial including more than 390 patients with >20 CSF WBC/microL or trypanosomes in CSF were randomly assigned (2:1) to treatment with fexinidazole or NECT [33,34,36]. 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) [34,36]. 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) [33,36]. 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) [34]. Further investigation of fexinidazole for treatment of gambiense HAT and rhodesiense HAT is ongoing. [1,32]

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 [14]. 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 [15]. European Medicines Agency (EMA) approved fexinidazole for the treatment of rhodesiense HAT in December 2023 [6].

Pentamidine — Pentamidine is recommended for individuals <6 years of age or <20 kg in weight in whom CSF demonstrates WBC ≤5 cells/microL and no trypanosomes. Pentamidine clinical use is further discussed above. (See 'Patients <6 years or <20 kg' above.)

Use of pentamidine for treatment of first-stage gambiense HAT is supported by two randomized trials and nine observational studies including more than 6700 children and adults [34]. 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 [20,37-43].

Pentamidine may have efficacy against first-stage rhodesiense HAT, based on case reports of travelers and pharmacologic data [7,11-13]. In regions where pentamidine is more accessible than suramin, pentamidine may be used as initial therapy until suramin therapy can be obtained and administered. (See 'First-stage disease' above.)

Pentamidine is usually given as an intramuscular injection; this is because intravenous (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.

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 intramuscular injection 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, hepato- and nephrotoxicity with azotemia. Persistent diabetes is rare adverse effect. Pentamidine has been associated with Steven-Johnson syndrome. Seizures and hallucinations have also been described.

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.

Nifurtimox-eflornithine combination therapy — Use of NECT is recommended in individuals with confirmed severe second-stage disease (eg, in <6 years of age or <20 kg in weight with CSF WBC >5 cells/microL and/or presence of trypanosomes; in >6 years of age and >20 kg in weight with CSF WBC >100cells/microL) or if lumbar puncture is not feasible. 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. NECT clinical use is further discussed above. (See 'Patients <6 years or <20 kg' above and 'Patients ≥6 years and ≥20 kg' above.)

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 7 days) or eflornithine monotherapy (100 mg/kg IV every 6 hours for 14 days) [44]. 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 [45].

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.

Adverse effects associated with NECT include abdominal pain, nausea, vomiting, headache, seizure, psychotic reaction, and hallucination [46]. 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.

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 4). Eflornithine is approved by the FDA for the treatment of gambiense HAT [47].

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, such as in patients with epilepsy or psychosis) and when fexinidazole cannot be given. Eflornithine is not effective against rhodesiense HAT because this species has a higher turnover rate of the target enzyme.

Use of eflornithine monotherapy is supported by a retrospective study including more than 900 patients with second-stage HAT in southern Sudan treated with eflornithine or melarsoprol; those treated with eflornithine had a lower mortality rate (0.8 versus 3.5 percent; relative risk 0.2, 95% CI, 0.04-0.89) and lower rate of encephalopathy (0.4 versus 11 percent) [48]. In a subsequent cohort study including more than 1000 patients with second-stage HAT in southern Sudan treated with eflornithine monotherapy. Of 924 cases followed, 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 [49].

Eflornithine infusion catheters should be replaced at least every 48 hours to avoid local site reactions.

Eflornithine monotherapy is associated with more frequent adverse effects (grade 3 or 4) than NECT (28.7 versus 14 percent) [44]. 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].

Eflornithine is available from the WHO and can also be obtained from strategic drug stocks in nonendemic countries (table 4). Eflornithine is approved by the FDA for the treatment of gambiense HAT [47].

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]. 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].  

An immediate hypersensitivity reaction leading to nausea, vomiting, shock, and loss of consciousness can occur following suramin administration; the risk of anaphylaxis is 1:20,000 patients [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 [32]. (See "Onchocerciasis".)

Suramin is available from WHO and can be also obtained from strategic drug stocks in non-endemic countries (table 4). In the United States, suramin is available from the United States Centers for Disease Control and Prevention (CDC) on a compassionate use basis. The CDC Drug Service telephone number is (404) 639-3670 or (404) 770-7100.

Melarsoprol — Use of melarsoprol for treatment of gambiense HAT is supported by a randomized trial comparing a 10-day regimen with a longer regimen [53,54]. 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 6 deaths [53].

Data supporting use of melarsoprol for treatment of rhodesiense HAT are described above. (See 'Second-stage disease' above.)

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 [55], the Democratic Republic of Congo [56,57], Uganda [58], and South Sudan [59,60]. Between 2006 and 2010, the use of melarsoprol sharply diminished, and no further reports appeared.

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. Melarsoprol is best given IV 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 [1,7].

●Adverse effects − Melarsoprol is an arsenical compound associated with high frequency of severe, life-threatening adverse effects [61]. 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 [7,16,51]. 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 (see 'Second-stage disease' above). 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 [17,22].

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 [7]. (See "Arsenic exposure and chronic poisoning".)

Melarsoprol is available from the WHO and can be also obtained from strategic drug stocks in non-endemic countries (table 4). In the United States, melarsoprol is available from the CDC on a compassionate use protocol. The CDC Drug Service telephone number is (404) 639-3670 or (404) 770-7100.

Investigational agents — Further study of fexinidazole is ongoing. (See 'Fexinidazole' above.)

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 [62]. Further clinical trials are ongoing.

DRUG ACCESS — Antitrypanosomal drugs are donated by the manufacturers and distributed by the World Health Organization (WHO) to endemic countries. In addition, there are also strategic stocks in various non-endemic countries (table 4). Drug distribution via the WHO country offices may help avoid delay due to country-specific regulations for importation.

OUTCOMES — In general, both gambiense and rhodesiense HAT are considered fatal without treatment [7]. Rare anecdotal cases of asymptomatic T. b. gambiense infection or resolution without treatment have been described [63,64].

PREVENTION — Tools for prevention of 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 [23].

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 [7,65]. 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 [66,67]. Thus far, insecticidal resistance has not been reported among tsetse flies. Tsetse fly repellents are under development, mainly for veterinary use [68].  

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 [66].

●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 [69].

●In many African countries, the Pan African Tsetse and Trypanosomiasis Eradication Campaign has employed area-wide vector control interventions [70-72].

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 [73]. (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 [7].

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) [74-77]. The sensitivity of serology is generally >80 percent, depending on the geographic location and the test used [78]. 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 [35] (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 'Treatment of gambiense HAT' above.)

For individuals with positive serologic test but negative lymph node aspiration and/or blood examination, the optimal management is uncertain [35]. 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 [10]. Insect repellant should be used; it may have limited effect on tsetse flies but reduce the risk of other disease transmitted by bug bites. (See "Prevention of arthropod and insect 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. 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). 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. (See 'Introduction' above.)

●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): (See 'Treatment of gambiense HAT' above.)

•Patients <6 years old or <20 kg body weight warrant routine lumbar puncture. For patients with CSF white blood cell (WBC) ≤5 cells/microL and no trypanosomes, we suggest treatment with pentamidine (Grade 2C). 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 'Patients <6 years or <20 kg' above.)

•For patients ≥6 years and ≥20 kg in endemic areas, decisions regarding whether to pursue lumbar puncture should be guided by degree of suspicion for severe second-stage disease (table 2). 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 less toxicity.

-For patients with CSF WBC >100 cells/microL, or if lumbar puncture is not feasible, we suggest treatment with NECT (rather than fexinidazole) (Grade 2C), given greater treatment success rates.

•Alternative and rescue therapies for gambiense HAT are summarized above and in the table (table 3). (See 'Alternative and rescue treatment' above.)

●Management of rhodesiense HAT – Based on the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) positive scientific opinion of fexinidazole as treatment of first and second stage rhodesiense HAT in adults and children ≥6 years old and weighing ≥20 kg, we now use fexinidazole as first-line treatment for both first and second stage rhodesiense HAT. New WHO recommendations are expected soon.

For patients who cannot receive fexinidazole (<6 years of age, weigh less than 20 kg), management of first stage (hemolymphatic) disease (≤5 WBC/microL and no trypanosomes in the CSF) consists of suramin. Management of second stage (meningoencephalitic) disease (>5 WBC/microL and/or presence of trypanosomes in CSF) consists of melarsoprol, coadministered with oral prednisolone to reduce the likelihood of developing melarsoprol-induced encephalopathy. (See 'Treatment of rhodesiense HAT' 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, 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.