African Trypanosomiasis

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic disease caused by subspecies of the protozoan Trypanosoma brucei and transmitted by the bite of an infected tsetse fly (genus Glossina).

Also Called / Synonyms

• Sleeping sickness
• African sleeping sickness
• Trypanosoma brucei gambiense HAT (gHAT)
• Trypanosoma brucei rhodesiense HAT (r-HAT)

Causative Organisms and Classification

Two distinct subspecies cause human disease, each producing a different clinical phenotype and geographic distribution:

T. b. gambiense accounts for >95% of reported cases and is the target of elimination efforts ^[6]D5. T. b. rhodesiense causes a more rapidly progressive illness. The traditional (sub)species classification has been challenged by genomic evidence suggesting polyphyly; an "ecotype" designation may be more accurate ^[7]D5.

Disease Stages

HAT evolves through two obligate stages that dictate treatment choice:

• Stage 1 (early, hemolymphatic stage): Parasites proliferate in blood and lymph. Symptoms are nonspecific (fever, headache, lymphadenopathy).
• Stage 2 (late, meningoencephalitic stage): Parasites cross the blood-brain barrier, causing neuroinflammation. Cerebrospinal fluid (CSF) shows >5 leukocytes/μL or detectable trypanosomes ^[3]B3b. Without treatment, stage 2 disease is uniformly fatal ^[3]B3b.

Accurate staging by lumbar puncture is essential because drugs used for stage 2 (e.g., melarsoprol, eflornithine) are toxic and unnecessary for stage 1, while stage 1 drugs (e.g., pentamidine, suramin) do not cross the blood-brain barrier.

Clinical Significance

HAT is a neglected tropical disease that caused major epidemics in the 1990s. Thanks to new rapid diagnostic tests, a single-dose oral treatment (fexinidazole, acoziborole in trials), and vector control, interruption of gHAT transmission by 2030 is considered achievable ^[6]D5. However, r-HAT remains a persistent threat in foci such as Malawi, where focus-dependent clinical phenotypes and high incidence continue ^[3]B3b.

Controversies and Guideline Disagreement

The next section examines the microbiology and pathogenesis of T. brucei, including the molecular mechanisms of antigenic variation and host-parasite interaction.

Pearl: The single most critical decision in HAT management is distinguishing stage 1 from stage 2 disease - this determines whether a drug that penetrates the CNS is required, and a lumbar puncture with CSF cell count is the only reliable method to make that distinction ^[3]B3b.

Two subspecies of the extracellular protozoan Trypanosoma brucei - T. b. gambiense (West and Central Africa) and T. b. rhodesiense (East Africa) - cause distinct clinical syndromes that reflect their differing virulence and transmission dynamics. The parasite's remarkable ability to evade host immunity while maintaining a chronic infection is the central pathogenic driver, leading to the hallmark clinical features of anemia, cardiac dysfunction, and progressive neuroinflammation that define the disease course.

Virulence Factors and Immune Evasion

The trypanosome surface is densely packed with variant surface glycoprotein (VSG) molecules, which form a physical barrier against antibody and complement attack ^[23]D5. Through an intricate system of antigenic variation, the parasite sequentially expresses different VSG genes, allowing it to continuously evade the host's adaptive immune response ^{[11]D5[22]D5[26]D5}. This mechanism is so effective that no field-applicable vaccine exists for HAT ^[23]D5. Beyond antigenic switching, trypanosomes actively ablate vaccine-induced memory B cells, providing long-term protection against host immunity ^[23]D5. The parasite also employs a quorum-sensing system mediated by di- and tri-peptides that trigger differentiation from proliferative long-slender forms to non-dividing stumpy forms, limiting peak parasitemia and favoring transmission ^[23]D5.

In humans, serum apolipoprotein L1 (APOL1) is a trypanolytic factor that forms membrane pores in the parasite ^[24]D5. T. b. gambiense and T. b. rhodesiense have evolved specific resistance factors: the serum resistance-associated (SRA) protein in T. b. rhodesiense and the T. b. gambiense-specific glycoprotein (TgsGP) in T. b. gambiense inhibit APOL1 activity, making them resistant to lysis ^{[24]D5[26]D5[31]D5}. Paradoxically, APOL1 variants G1 and G2, which confer resistance to T. b. rhodesiense (G2 shows a five-fold dominant protective association ^[34]B3b), are also associated with increased risk of chronic kidney disease, particularly in the context of virus-induced inflammation ^[24]D5[33]D5. G2 also associates with faster progression of T. b. gambiense infection, while G1 associates with asymptomatic carriage ^[34]B3b.

Host-Pathogen Interaction

Infection begins when the tsetse fly deposits trypanosomes into the dermal layer during a blood meal ^[28]D5. The parasites migrate via skin-draining lymph nodes to the systemic circulation, establishing chronic infection ^[28]D5. The skin has recently been identified as an important anatomical reservoir, with implications for transmission and residual infection after treatment ^[28]D5[36]D5.

During early infection, a profound pro-inflammatory type 1 activation of the mononuclear phagocyte system (MPS) - involving classically activated (M1) macrophages - is required for initial parasite control ^[32]D5. However, persistent M1 activation in susceptible hosts causes immunopathology, with anemia as the most prominent feature. M1 macrophages produce galectin-3 (Gal-3) and macrophage migration inhibitory factor (MIF), which enhance erythrophagocytosis and suppress erythropoiesis, respectively ^[32]D5. In trypanotolerant animals, IL-10 drives alternatively activated (M2) macrophages, dampening tissue damage ^[32]D5.

Pathogenesis and Clinical Syndromes

The transition from the early hemolymphatic stage to the late meningoencephalitic stage occurs when parasites cross the blood-brain barrier. This triggers a neuroinflammatory response characterized by astrocyte activation and inflammatory cell infiltration ^[31]D5. Diverse neurological manifestations develop, including sleep disorder, movement abnormalities, and cognitive decline ^[25]D5[31]D5. The characteristic sleep disturbance is thought to involve disruption of the circadian pacemaker by parasite-derived factors and inflammatory cytokines.

Cardiac involvement is also a significant feature. Animal models of T. b. brucei TREU 927 infection demonstrate increased frequency of ventricular arrhythmias and heart rate at endpoint, with the myocardium showing increased susceptibility to β-adrenergic stimulation ^[38]D5. This suggests that chronic infection modifies the myocardial substrate, predisposing to arrhythmias and contributing to the heart failure seen in some patients ^[35]D5.

Genetic Susceptibility

APOL1 variants G1 and G2, while protecting against trypanosomiasis (G2 confers a five-fold dominant protective association against T. b. rhodesiense ^[34]B3b), are also strongly associated with chronic kidney disease, especially in the context of HIV or COVID-19 ^[24]D5[33]D5. These variants occur at high frequency in populations of African ancestry, illustrating a classic evolutionary trade-off between resistance to infection and risk of autoimmune-like nephropathy.

Pearl: The trypanosome's VSG coat is not just a shield - it is the central virulence factor that simultaneously drives antigenic variation, prevents vaccination, and, through its release by phospholipase-C, contributes to the inflammatory storm that causes anemia and neuropathology. Newer oral therapies like fexinidazole are effective for both stages, but the parasite's ability to hide in the skin and lymphoid tissues means that even treated patients require careful follow-up to ensure elimination.

Transmission of T. b. gambiense and T. b. rhodesiense occurs through the bite of an infected tsetse fly, and the epidemiology of human African trypanosomiasis (HAT) reflects the distribution of the vector and the parasite subspecies. The disease is confined to sub-Saharan Africa, where tsetse flies inhabit rural areas ^[55]D5.

Incidence and Prevalence

HAT incidence has declined dramatically over the past two decades. In Angola, one of the most historically affected countries, new cases fell from an average of 3,496 per year (1990-2006) to an average of 56 per year (2016-2023) ^[56]C4. Between 2016 and 2023, 450 cases were identified from 493,796 people screened, yielding a positivity rate of 0.09% ^[56]C4. In Guinea, the total number of new cases dropped below 1 per 10,000 inhabitants in endemic areas over 2019-2023, allowing validation of elimination as a public health problem ^[52]D5. A meta-analysis of Nigerian studies (1962-2016) reported a seroprevalence of 5.01% (95% CI 1.72-9.93), but actual parasitological or PCR-confirmed prevalence was only 0.1% (95% CI 0.000-0.002) ^[47]A1a.

Demographic and Geographic Distribution

• Geography: gHAT is endemic in foci across West and Central Africa; rHAT occurs in East and Southern Africa ^[55]D5. In Angola, 7 of 18 provinces are endemic, with most recent cases in Bengo, Cuanza Norte, and Uíge ^[56]C4. In Nigeria, seroprevalence is higher in southern than northern regions ^[47]A1a.
• Age and sex: Specific age- and sex-stratified incidence rates are not reported in the available evidence.

Temporal Trends

HAT has resurged and declined in waves. Angola experienced major epidemics in the 1920s-1940s (peaking at ~9,000 cases in 1940) and again in the 1990s-mid-2000s ^[56]C4. Control efforts reduced cases to near zero by 1974 (3 cases), but a 27-year civil war (1975-2002) disrupted surveillance and led to resurgence ^[56]C4. After peace, aggressive screening and vector control drove cases down again. The COVID-19 pandemic temporarily disrupted activities, causing a spike from 33 cases in 2020 to 174 in 2021 in Angola ^[56]C4. The Ebola epidemic (2013-2016) similarly disrupted control in Guinea ^[52]D5.

Risk Factors

Note: The only quantified odds ratios come from a historical study of iatrogenic transmission of blood-borne viruses during HAT treatment campaigns ^[41]B3b; contemporary risk factors for HAT acquisition itself lack reported ORs in the available evidence.

Seasonal Variation

Seasonal patterns are not reported in the available evidence.

Special Considerations

• Skin as a reservoir: Extravascular dermal trypanosomes have been detected in a substantial proportion of seropositive individuals without detectable parasitemia (up to 41% in Guinea ^[44]B2b and 31% in Côte d'Ivoire ^[50]B3b), suggesting a cryptic human reservoir that may sustain low-level transmission ^{[39]B2b[44]B2b[50]B3b}.
• Animal reservoirs: Domestic animals may harbor T. b. gambiense, but modelling indicates they are unlikely to maintain transmission alone ^[57]D5.
• Impact of conflict and health system disruption: Civil war, Ebola, and COVID-19 have repeatedly interrupted control activities, leading to case resurgences ^[52]D5[56]C4.

Pearl: The dramatic decline in HAT incidence, from thousands to tens of cases annually in Angola, demonstrates that sustained active screening, treatment, and vector control can achieve elimination as a public health problem, but gains are fragile and can be reversed by conflict or pandemic disruption ^[56]C4.

From the epidemiological patterns described above, the clinical expression of African trypanosomiasis follows two distinct trajectories depending on the infecting subspecies. The features at presentation, their progression, and the neurological examination findings are the clinician's primary guide to staging and treatment decisions.

Presenting Symptoms

Infection begins with a painful, erythematous chancre at the tsetse fly bite site 5-15 days after inoculation, though this is often missed in endemic settings. The initial hemolymphatic stage (stage 1) is marked by intermittent fevers, headache, arthralgias, and prominent lymphadenopathy, especially in the posterior cervical triangle (Winterbottom's sign). In a prospective diagnostic accuracy study in Guinea, the odds of HAT were dramatically increased by the presence of:

• Swollen lymph nodes (OR 96.7, 95% CI 20.7-452.0) ^[66]B2b
• Severe itching (pruritus) (OR 45.9, 95% CI 7.3-288.7) ^[66]B2b
• Important weight loss (OR 20.4, 95% CI 7.05-58.9) ^[66]B2b
• Motor disorders (OR 4.5, 95% CI 0.89-22.5) ^[66]B2b

The presence of at least one of these four features was 97.9% sensitive (95% CI 88.9-99.9%) for HAT, though only 75.6% specific ^[66]B2b. Weight loss and pruritus are particularly discriminating in chronic T. b. gambiense infection. Without treatment, symptoms progress over weeks to months, with the patient experiencing increasing fatigue, personality changes, and sleep cycle disruption, the "sleeping" inversion that gives the disease its name.

Neurological Examination Findings

Once the parasite invades the central nervous system (stage 2, or meningoencephalitic stage), the examination becomes critical. The hallmark is a progressive sleep-wake cycle reversal: daytime somnolence alternating with nocturnal insomnia. Motor examination may reveal:

• Tremor, choreiform movements, or ataxia
• Hyperreflexia and Babinski sign (upper motor neuron signs)
• Parkinsonian rigidity in advanced cases
• Sensory disturbances: deep hyperesthesia (Kerandel's sign) and paresthesias

Cranial nerve findings include optic neuritis , facial palsy, and hearing loss. Autonomic instability, including cardiac arrhythmias, can occur, though the heart is less affected than in Chagas disease , Trypanosoma brucei primarily causes CNS disease ^[58]D5. The extrapyramidal and cerebellar signs distinguish African trypanosomiasis from other meningoencephalitides.

Phenotypic Variants

The two subspecies produce strikingly different clinical courses.

The gambiense form is the target of elimination efforts, while rhodesiense is a zoonosis requiring urgent treatment due to its rapid progression ^[63]D5.

Red Flags

Several findings demand immediate action:

• Seizures or status epilepticus (reported in 6% of patients on treatment, but also as a presenting feature) ^[61]A1b
• Coma or rapidly declining consciousness
• Respiratory compromise or aspiration from dysphagia
• Autonomic instability with hypotension or bradycardia
• Severe confusion or psychosis

These signs indicate advanced meningoencephalitis or, in the case of rhodesiense, overwhelming parasitemia. Urgent staging and treatment are required.

Atypical Presentations

Clinicians must be aware of several less common presentations:

• Dermal trypanosomes: In a prospective cohort, T. brucei parasites were detected in the extravascular dermis of all unconfirmed seropositive individuals and all confirmed cases, often presenting with pruritus ^[39]B2b. Another study found parasites in the skin of up to 71% of confirmed cases ^[44]B2b. This dermal reservoir may cause pruritus and can be a diagnostic target.
• Cardiac involvement: While less prominent than in Chagas disease, myocarditis and pericarditis can occur, especially in rhodesiense infection ^[58]D5.
• Asymptomatic seropositive individuals: Some individuals with positive serology but no detectable parasites remain well, yet may harbour dermal trypanosomes ^{[39]B2b[44]B2b}.
• Persistent fever of unknown origin: In travellers or expatriates, HAT should be considered among the causes of persistent fever (≥7 days) if there is travel to endemic areas ^[68]B2b.

The recognition of these clinical patterns, especially the cardinal features of swollen lymph nodes, weight loss, pruritus, and motor disorders, guides the selection of diagnostic tests discussed in the next section.

Pearl: In a patient from an endemic area with any combination of swollen lymph nodes, severe itching, unexplained weight loss, or motor disorder, the probability of HAT is substantial (OR 97 for lymphadenopathy alone); these four features should trigger immediate serological screening ^[66]B2b.

The clinical suspicion raised by lymphadenopathy, weight loss, itching, or neurological signs must be confirmed through a sequential diagnostic algorithm that begins with serological screening and ends with parasitological confirmation and disease staging.

Gold-Standard Test

Microscopic examination of thick and thin blood smears, lymph node aspirate, or cerebrospinal fluid remains the cornerstone of diagnosis ^[59]D5. Visualization of motile trypanosomes confirms the infection. In practice, however, screening with serological tests is the first step because microscopy is labour-intensive and has imperfect sensitivity, especially when parasitaemia is low ^[59]D5.

Laboratory Studies

Serological screening is performed using the Card Agglutination Test for Trypanosomiasis (CATT) or one of several rapid diagnostic tests (RDTs). In a prospective diagnostic accuracy study in Guinea, the HAT Sero-K-Set and SD Bioline HAT RDTs had sensitivities of 100% (95% CI 92.5-100%) and 93.8% (82.8-98.7%), respectively, with specificities above 97% ^[66]B2b. However, a more recent evaluation in the Democratic Republic of the Congo found that none of the 2nd-generation RDTs met the WHO-recommended 95% specificity threshold; CATT remained the most specific screening test at 98.3% (95% CI 97.6-99.0%) ^[48]B2b. The T. b. gambiense inhibition ELISA (g-iELISA) offers a promising alternative with a sensitivity of 98.0% (96.7-98.9%) and specificity of 99.5% (98.6-99.9%) on plasma ^[42]C4.

Parasitological confirmation follows a positive serology. Direct microscopy of blood (wet mount, Giemsa-stained thick and thin films), lymph node aspirate, and CSF is performed. If initial microscopy is negative but suspicion remains, molecular tests such as PCR, LAMP, or quantitative PCR (qPCR) can be used, though they are currently confined to research and reference laboratories ^[64]D5.

Disease staging requires a lumbar puncture. Stage 1 (early disease) is defined by a CSF white blood cell count ≤5 cells/µL; stage 2 (late disease) by >5 cells/µL. Within stage 2, a count >100 cells/µL indicates severe disease and guides treatment choice toward nifurtimox-eflornithine combination therapy (NECT) or melarsoprol ^[72]D5. Lejon et al. found that pretreatment CSF WBC ≥102 cells/µL and IL-10 ≥37 pg/mL were associated with treatment failure ^[71]B2b. Six months after treatment, a CSF WBC count ≤5 cells/µL indicated cure (negative predictive value >0.93) ^[71]B2b.

Diagnostic Test Performance

PPV and NPV are prevalence-dependent; the values from ^[66]B2b derive from a population with 2.0% HAT prevalence.

Diagnostic Algorithm

Step 1: Serological screening in any person with suggestive symptoms or residence in an endemic area. Step 2: Parasitological confirmation of seropositive individuals. Step 3: Lumbar puncture for CSF WBC count to determine stage and guide treatment. The algorithm is designed to avoid over-treatment with toxic drugs, particularly in low-prevalence settings where false-positive serology is common.

Differential Diagnosis

The differential diagnosis of human African trypanosomiasis includes malaria, tuberculosis, HIV, lymphoma, and other causes of persistent fever and lymphadenopathy. In a prospective four-country study, HAT was diagnosed in only 0.2% of patients with fever lasting ≥7 days ^[68]B2b. The presence of swollen lymph nodes (OR 96.7, 95% CI 20.7-452.0) and severe itching (OR 45.9, 95% CI 7.3-288.7) are highly specific for HAT and can help prioritise testing ^[66]B2b.

Pearl: The diagnostic algorithm, serological screening followed by parasitological confirmation and CSF staging, is essential to avoid over-treatment with toxic drugs, especially in low-prevalence settings where false-positive serology is common.

Once the diagnosis of human African trypanosomiasis is confirmed, the next critical step is staging the disease to determine severity and guide therapy. Staging is the central severity assessment, as it decides whether the patient requires a drug that crosses the blood-brain barrier or can be treated with a less toxic peripheral-stage agent.

Staging as the Central Severity Assessment

The cornerstone of severity assessment is the cerebrospinal fluid (CSF) white-blood-cell count. The World Health Organization classifies stage 1 (haemo-lymphatic) as CSF ≤5 white cells/μL and no trypanosomes; stage 2 (meningo-encephalitic) as >5 cells/μL or any trypanosomes in CSF ^[63]D5. A retrospective cohort study in the Republic of the Congo found that increasing the threshold from 5 to 10 cells/μL resulted in a relapse rate of 5% overall, with a significantly higher risk among patients who had a CSF count of 6-10 cells/μL at diagnosis (adjusted hazard ratio 3.27, 95% CI 1.52-7.01; P = 0.002), leading the authors to conclude that the lower threshold of 5 cells/μL is safer for determining stage 2 and reducing relapse risk ^[81]B2b.

This staging dichotomy directly determines the intensity of therapy: stage 1 patients can be treated with pentamidine (for gambiense) or suramin (for rhodesiense), while stage 2 patients require drugs that cross the blood-brain barrier to avoid relapse ^[63]D5[83]D5.

Subspecies and Focus-Specific Severity

Infection with Trypanosoma brucei gambiense accounts for over 95% of cases and typically follows a chronic course lasting months to years ^[31]D5. In contrast, T. b. rhodesiense causes an acute illness that can progress to the meningo-encephalitic stage within weeks ^[63]D5. Even within the rhodesiense subspecies, severity varies dramatically by focus. A retrospective cohort study of 275 patients in East Africa found that HAT presented as a chronic haemo-lymphatic infection in Malawi, but as an acute disease with marked neurological impairment in Uganda; within Uganda, one focus (Soroti) showed more rapid progression to the meningo-encephalitic stage, while another (Tororo) had more severe neuropathology ^[80]C4. These focus-specific phenotypes likely reflect differences in both parasite virulence and host genetics ^[80]C4.

Biomarkers of Disease Severity

CSF chemokine levels have been linked to disease severity. Courtioux et al. found that IL-1β, CXCL-8, CCL-2, and CCL-3 in CSF were significantly associated with the presence of neurological signs and with trypanosome presence in the CSF, suggesting they are potential markers of CNS invasion ^[87]C4. Maclean et al. identified that a higher plasma interferon-γ response was associated with more rapid progression to the meningo-encephalitic stage and with the Tororo genotype, which carries increased virulence ^[91]C4. These findings point to the host immune response as a driver of severity, though such biomarkers are not yet used in routine clinical staging.

Risk Stratification for Treatment Selection

For oral fexinidazole therapy, a prospective cohort study of 238 patients with stage 1 or early stage 2 gambiense HAT used additional severity criteria: patients had to be able to ingest at least one complete meal per day, have a Karnofsky score >50, and have no severe malnutrition ^[79]B2b. Treatment success was 99% overall (95% CI 96.2-99.7), with no new safety issues, indicating that careful patient selection allows safe use of oral therapy even in early stage 2 disease ^[79]B2b.

Pearl: The CSF white-cell count threshold of 5 cells/μL is the most critical severity cutoff; exceeding it mandates CNS-penetrating therapy to prevent relapse, and the lower threshold of 5 cells/μL is safer than 10 cells/μL for distinguishing stage 2 from stage 1.

The choice of empiric therapy now hinges on the infecting subspecies, patient age and weight, and, for gambiense disease, the cerebrospinal fluid (CSF) leucocyte count, with fexinidazole replacing older parenteral regimens as the first-line option for most patients.

Step 1: Confirm subspecies and determine disease stage

Subspecies identification is essential because drug options differ between T. b. gambiense and T. b. rhodesiense. The geographic origin of exposure (West/Central Africa vs East/Southern Africa) and the clinical presentation (chronic vs acute) guide the initial subspecies assignment, confirmed by species-specific PCR or isoenzyme analysis where available.

Staging is no longer required for rhodesiense disease. The 2024 WHO guidelines state that fexinidazole is effective in both stages of rhodesiense human African trypanosomiasis, so a lumbar puncture for staging is no longer necessary ^[96]A1c. For gambiense disease, the 2019 WHO guidelines recommend CSF examination to determine the leucocyte count: fexinidazole is recommended for patients with <100 leucocytes/μL, while nifurtimox-eflornithine combination therapy (NECT) remains recommended for patients with ≥100 leucocytes/μL ^[99]A1c.

Figure 1: Diagnostic staging algorithm for gambiense vs rhodesiense disease (adapted from ^{[96]A1c[99]A1c}).

Step 2: Select empiric trypanocidal therapy

The empiric drug of choice for most patients is fexinidazole . For rhodesiense, the 2024 WHO guidelines recommend fexinidazole as first-line therapy in individuals aged 6 years and older with a bodyweight of 20 kg or more ^[96]A1c. For gambiense, fexinidazole is recommended for first-stage and second-stage disease with a CSF leucocyte count less than 100 per μL according to the 2019 WHO guidelines ^[99]A1c.

Step 3: Immediate management and supportive care

Hospitalization is recommended for the duration of treatment with fexinidazole to supervise intake and monitor for adverse events, though a phase 3b study showed that carefully selected outpatients with caregiver support achieved 100% adherence ^[100]B2b. NECT requires intravenous eflornithine and therefore in-hospital care.

Adverse event monitoring:

• Fexinidazole: vomiting (24%), headache (18%), nausea (16%), asthenia (13%), insomnia (11%), pyrexia (11%). Most are mild or moderate ^[100]B2b. Mean QTcF increase of ~10 ms at day 4 ^[100]B2b.
• NECT: vomiting, dizziness, headache, convulsions. Severe AEs occurred in 9.6% of patients in the trial ^[95]A1b; in a large cohort of 684 patients, severe AEs included vomiting (n=32), dizziness (n=16), headache (n=11), convulsions (n=11); in-hospital case fatality 0.15% ^[40]C4.

Supportive care: Ensure adequate nutrition and hydration. Antiemetics may be used for vomiting. Manage seizures with benzodiazepines. Monitor hepatic and hematologic parameters during fexinidazole therapy (transient neutropenia and thrombocytopenia may occur, but clinically significant hepatotoxicity is not seen in gambiense patients ^[102]C4).

Step 4: Transition to definitive therapy and source control

The selected empiric agent is continued for the full course (fexinidazole: 10 days; NECT: 7 days of eflornithine + 10 days of nifurtimox). Definitive dosing details are covered in the next section. Source control, reducing the human reservoir of infection, is achieved by treating all confirmed cases. In the context of elimination efforts, the availability of a single-dose oral agent like acoziborole may enable a “screen-and-treat” strategy where seropositive individuals are treated presumptively without parasitological confirmation ^{[45]D5[97]B2b}.

What NOT to do:

• Do not use lumbar puncture for staging in rhodesiense disease when fexinidazole is available ^[96]A1c.
• Do not use melarsoprol for rhodesiense disease if fexinidazole is accessible, given its 5-10% treatment-related mortality ^[45]D5.
• Do not use pentamidine for stage 2 disease; it does not cross the blood-brain barrier adequately.

Pearl: Initiate fexinidazole as first-line empiric therapy for all patients with African trypanosomiasis aged ≥6 years and weighing ≥20 kg, except gambiense patients with CSF WBC ≥100/μL who require NECT; this single oral regimen eliminates the need for lumbar puncture in rhodesiense disease and simplifies care ^{[96]A1c[99]A1c[100]B2b[105]C4}.

Once the infecting subspecies and disease stage are confirmed, pathogen-directed therapy can be selected from a greatly simplified armamentarium. The introduction of oral fexinidazole has transformed the treatment landscape, replacing most prior regimens and reducing the need for lumbar puncture in many cases.

Step 1: Confirm subspecies and assess severity

Before selecting therapy, confirm the subspecies (T. b. gambiense or T. b. rhodesiense) and, for gambiense disease, determine whether severe meningoencephalitic features are present. For gambiense, fexinidazole is first-line for patients with stage 1 or non-severe stage 2 disease (CSF white blood cell count ≤100 cells/μL and absence of severe neurological signs). For severe stage 2 gambiense (CSF WBC >100 cells/μL or marked neurological impairment), nifurtimox-eflornithine combination therapy (NECT) remains the preferred regimen, as fexinidazole trial data excluded this population ^[62]A1b. For rhodesiense disease, the 2024 WHO guidelines (conditional recommendation, very low certainty) recommend fexinidazole as first-line for all patients aged ≥6 years and weighing ≥20 kg, irrespective of stage; a lumbar puncture for staging is no longer required ^[96]A1c.

Step 2: First-line therapy - fexinidazole

Fexinidazole is the drug of choice for most patients with both gambiense and rhodesiense human African trypanosomiasis. The oral regimen is 10 days: for patients weighing ≥35 kg, 1800 mg once daily for 4 days, then 1200 mg once daily for 6 days. For patients weighing 20-34 kg, dose is 1200 mg once daily for 4 days, then 600 mg once daily for 6 days ^{[100]B2b[105]C4}. The dose must be taken immediately after a solid meal, as food increases absorption ^[100]B2b. In the pivotal phase 2/3 trial, success at 18 months was 91% in the fexinidazole group versus 98% in the NECT group (difference -, 97.06% CI -11.2 to -1.6; p=0.0029) ^[62]A1b. A subsequent phase 3b study in a wider population (including pregnant/ breastfeeding women and outpatients) reported an 18-month success rate of 93% (95% CI 88.3-96.4) ^[100]B2b.

Step 3: Alternative therapy - NECT (for severe stage 2 gambiense or when fexinidazole is not available)

NECT consists of eflornithine 400 mg/kg/day IV divided every 12 hours for 7 days plus nifurtimox 15 mg/kg/day orally divided every 8 hours for 10 days ^{[61]A1b[95]A1b}. In the multicentre phase III trial, NECT achieved cure rates of 96.5% (ITT) versus 91.6% for eflornithine monotherapy (difference -4.9%, one-sided 95% CI -0.3; p<0.0001) ^[61]A1b. NECT is associated with fewer severe adverse events (grade 3-4: 14.0% vs 28.7% for eflornithine alone) and a simpler administration schedule (IV every 12 hours vs every 6 hours) ^[61]A1b. In field settings, the in-hospital case fatality rate was 0.15% and relapses were rare (n=14/684) ^[40]C4.

Step 4: Dosing and monitoring

Step 5: De-escalation and IV-to-oral switch

The major de-escalation in African trypanosomiasis is the replacement of intravenous regimens (NECT, eflornithine monotherapy, melarsoprol) with oral fexinidazole. For patients already started on NECT or eflornithine, there is no established crossover to oral therapy mid-course; the decision to use fexinidazole should be made at treatment initiation. For rhodesiense, fexinidazole eliminates the need for lumbar puncture staging and the toxic alternative melarsoprol ^[96]A1c. In settings where first-choice drugs are not readily available, immediate interim treatment with pentamidine is suggested before definitive therapy ^[96]A1c.

Step 6: Treatment failure and rescue

Relapse after fexinidazole is rare (7% in the phase 3b study) ^[100]B2b. Rescue therapy for fexinidazole failures in gambiense disease is NECT for stage 2 disease and pentamidine for stage 1 disease ^[100]B2b. For rhodesiense, relapses after fexinidazole have been reported (one of 45 patients in the phase 2-3 study) ^[105]C4; management should follow expert consultation. Markers of treatment failure include a CSF WBC count ≥8 cells/μL combined with a LATEX/IgM end titer ≥1:4 at 12 months (97% specificity, 79% sensitivity), and any single marker at 18 months ^[71]B2b.

What NOT to Do

• Do not use melarsoprol when fexinidazole is available for rhodesiense, given melarsoprol’s 5-10% treatment-related mortality ^[96]A1c.
• Do not use fexinidazole in patients with severe meningoencephalitic gambiense disease (CSF WBC >100 cells/μL or severe neurological signs); NECT is required ^[62]A1b.
• Do not omit food when administering fexinidazole - absorption is significantly reduced if taken on an empty stomach ^[100]B2b.
• Do not rely on gambiense NECT or fexinidazole for rhodesiense disease without expert guidance; efficacy data for rhodesiense are specific to the fexinidazole phase 2-3 study ^[105]C4.

Pearl: Fexinidazole, an oral 10-day regimen, is now first-line for both gambiense (non-severe stage 2 and stage 1) and rhodesiense (all stages) human African trypanosomiasis, replacing toxic and logistically complex IV alternatives; NECT retains a role only for severe stage 2 gambiense disease ^{[62]A1b[96]A1c[100]B2b[105]C4}.

No articles were found for this section.

Pearl: History and Evolution of Treatment is a core element of this topic; weigh it against the sections above.

The transition from multi-drug injection regimens to oral fexinidazole and the upcoming acoziborole has reduced toxicity and simplified care, but antimicrobial resistance (AMR) in Trypanosoma brucei remains a major threat to the WHO 2030 elimination target ^[111]B2a. Resistance to every approved HAT drug has been documented either in the field or generated in the laboratory, and treatment failure rates are highest with melarsoprol: 41.49% (95% CI 24.94-59.09), compared to 6.56% (95% CI 3.06-11.25) for eflornithine ^[111]B2a.

Resistance Mechanisms

Pentamidine, melarsoprol, and nifurtimox share a common entry pathway through the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2) and the aquaglyceroporins TbAQP2 and TbAQP3 ^[111]B2a. Loss of the high-affinity pentamidine melarsoprol transporter (HAPT 1) further amplifies cross-resistance ^[111]B2a. Deletion of the TbAQP2 locus increases the effective concentration (EC₅₀) of pentamidine and melarsoprol by 2- to 15-fold ^[72]D5. Cryo-EM structures of TbAQP2 show that both drugs bind within the channel at the same site as glycerol; drug-resistant mutations line the channel and weaken central binding, impairing transport at pharmacologically relevant concentrations ^[125]D5.

Eflornithine resistance is linked to loss of the amino acid transporter 6 (AAT6) ^[111]B2a. Nifurtimox-eflornithine combination therapy (NECT) resistance involves both AAT6 and nitroreductase loss, with high resistance and parasite regrowth driving treatment relapse ^[111]B2a.

Fexinidazole, the first oral drug for HAT, is activated by a type 1 nitroreductase (NTR); resistance can be generated in vitro through NTR mutation, and prior use of nifurtimox may already have selected for such mutants ^[72]D5. Acoziborole, a single-dose benzoxaborole nearing approval, inhibits the cleavage and polyadenylation specificity factor 3 (CPSF3); a single A → C nucleotide change in CPSF3 (N232H) confers resistance in vitro ^{[72]D5[113]D5}.

Molecular Diagnostics for Resistance Surveillance

A Cas13a-based SHERLOCK assay has been developed to detect the AQP2/3(814) chimera, the most prevalent melarsoprol‑resistant genotype, found in 31.7% of known melarsoprol‑resistant HAT infections ^[72]D5. This assay discriminated RNA from field strains of patients who relapsed after melarsoprol or pentamidine treatment, with no cross-reactivity to wild-type strains ^[72]D5. A second SHERLOCK assay targeting the CPSF3(SNV) mutation distinguished wild-type from acoziborole-resistant T. brucei ^[72]D5. These assays are amenable to high‑throughput screening and can be rapidly adapted as new resistance markers emerge ^[72]D5.

Stewardship Principles

Stewardship must address both human and animal African trypanosomiasis (AAT) to avoid inter-species cross-resistance, as recommended by the One Health approach ^[121]D5. Fexinidazole’s 10-day oral regimen must be taken with food; vomiting and nausea increase the risk of non‑compliance and sub‑therapeutic dosing, which could select for resistance ^[72]D5. Prior use of nifurtimox may prime fexinidazole resistance ^[72]D5. In animal health, poor farmer knowledge, use of untrained personnel, incorrect dosing, and limited drug options drive AAT resistance ^[112]D5. Active surveillance with SHERLOCK, rational monotherapy avoidance, and enforced compliance are essential to preserve the efficacy of the shrinking HAT drug arsenal ^{[72]D5[111]B2a}.

Pearl: The AQP2/3(814) chimera accounts for nearly one‑third of known melarsoprol‑resistant HAT infections; a SHERLOCK assay now enables rapid field detection of this and other resistance markers ^[72]D5.

The evolution of treatment from melarsoprol to NECT and fexinidazole has substantially reduced the frequency of life-threatening drug reactions, but complications of both the disease and its therapy remain clinically important. The table below summarises the principal adverse events and their management, drawn from clinical trials and field studies.

Cardiac Complications

Cardiac involvement in HAT is generally benign. ECG alterations, repolarisation changes and low voltage, are frequent but do not cause relevant congestive heart failure and subside with anti-trypanosomal treatment ^[98]D5. No specific respiratory monitoring thresholds (e.g., FVC) are reported in the evidence; clinical evaluation for dyspnea and signs of heart failure should guide intervention.

Neurological and Autonomic Complications

Neurological adverse events are common, particularly with NECT and eflornithine monotherapy. Severe convulsions occurred in 11 of 684 patients (1.6%) in one NECT cohort ^[40]C4, and loss of consciousness or coma was managed in approximately 5% of patients in the NECT-FIELD study ^[132]C4. Autonomic complications such as blood pressure instability, ileus, or urinary retention are not specifically reported in the available literature, but clinicians should remain vigilant for these in patients with severe neurological involvement.

Gastrointestinal and Metabolic Adverse Events

Gastrointestinal toxicity dominates the safety profile of all current regimens. Vomiting affects 61-69% of patients ^{[130]C4[133]C4} and is more frequent with fexinidazole than with NECT (63% vs 19% in one South Sudan cohort) ^[49]C4. Antiemetics and antipyretics are the most commonly prescribed concomitant medications ^[132]C4. Metabolic disorders (e.g., electrolyte disturbances) occur in 26% of NECT-treated patients ^[133]C4 and should be monitored.

Drug-Specific Toxicities

Melarsoprol, now largely replaced, carried life-threatening adverse reactions including encephalopathy ^[96]A1c. Pafuramidine, discontinued due to delayed nephrotoxicity, caused glomerulonephritis or nephropathy approximately 8 weeks post-treatment in 2 of 3 affected patients ^[127]A1b. No such delayed toxicity has been reported for fexinidazole or NECT in the studied populations.

Hospital-Acquired Complications

Prolonged hospitalization (10-14 days for NECT, 10 days for fexinidazole) creates risk for nosocomial infections. In the NECT-FIELD study, antibiotics were prescribed for cellulitis and respiratory tract infections ^[132]C4. Antimalarials and anthelmintics were also used, reflecting endemic co-infections. Standard prevention measures, pressure injury care, catheter-associated UTI prevention, and early mobilization, should be applied, though specific protocols are not reported in the evidence.

Pain Management and Rehabilitation

Headache is the most common pain complaint, occurring in 11-33% of patients ^{[40]C4[79]B2b[130]C4}. Simple analgesics (e.g., paracetamol) are routinely used ^[132]C4. Rehabilitation needs are not addressed in the available studies; patients with disabling neurological deficits may benefit from physiotherapy, but no evidence-based protocols exist.

Pearl: The most frequent complication of HAT treatment is gastrointestinal (vomiting in >60% of patients), and antiemetic availability should be considered essential in any treatment ward; cardiac involvement is common but benign and resolves with anti-trypanosomal therapy.

Given the fatal progression of untreated disease, treatment outcomes depend critically on disease stage at diagnosis, drug regimen, and host factors.

Untreated Natural History

Untreated human African trypanosomiasis is uniformly fatal, with irreversible neurological deterioration leading to death ^[100]B2b. The course differs by subspecies: T. b. gambiense follows a chronic trajectory over months to years, whereas T. b. rhodesiense progresses acutely over weeks to months ^[76]C4.

Treatment Outcomes

With appropriate therapy, outcomes are excellent. In the pivotal fexinidazole trial, 18-month success was 91% (239/264) for fexinidazole versus 98% (124/130) for nifurtimox-eflornithine combination therapy (NECT) in late-stage T. b. gambiense ^[62]A1b. A subsequent phase 3b study confirmed 93% (162/174) success at 18 months with fexinidazole, including in a cohort treated at home ^[100]B2b. NECT in a field setting achieved a 94.1% cure rate at 24 months ^[131]C4. For early-stage disease, fexinidazole and pentamidine showed comparable outcomes at discharge ^[49]C4.

Predictors of Treatment Outcome

Not all patients are cured. Pretreatment cerebrospinal fluid markers identify those at risk of failure:

• CSF WBC count ≥102 cells/μL
• IL-10 ≥37 pg/mL
• LATEX/IgM end titer ≥1:32
• LATEX/T. b. gambiense end titer ≥1:2
• Protein ≥674 mg/L

All are associated with treatment failure ^[71]B2b.

Six months after treatment, a CSF WBC count ≤5 cells/μL predicts cure with a negative predictive value >0.93 ^[71]B2b. At 12 months, the combination of CSF WBC ≥8 cells/μL and LATEX/IgM end titer ≥1:4 predicts treatment failure with 97% specificity and 79% sensitivity ^[71]B2b. By 18 months, each individual marker accurately predicts outcome ^[71]B2b.

More recently, detection of spliced leader RNA in blood or CSF showed ≥98.9% specificity for treatment failure, potentially detecting relapses without lumbar puncture ^[67]B2b.

Mortality During and After Treatment

Treatment-related mortality is low. In the fexinidazole trial, 3% (9/264) of fexinidazole-treated patients died versus 2% (2/130) in the NECT group ^[62]A1b. In the field NECT study, 4.3% (28/629) died over 24 months, most from causes unrelated to treatment ^[131]C4.

Improving access to early diagnosis, as demonstrated in Malawi, shifts detection to earlier stages and reduces mortality ^[138]C4. These findings underscore the importance of the prevention and infection control measures discussed in the next section.

Pearl: A CSF WBC count ≤5 cells/μL at 6 months post-treatment is a reliable marker of cure; a count ≥8 cells/μL combined with IgM titer ≥1:4 at 12 months should prompt concern for relapse ^[71]B2b.

Outcomes depend on early treatment, but the greatest public health impact lies in preventing infection. However, no randomized controlled trials have evaluated any preventive intervention for human African trypanosomiasis (HAT) ^[142]A1a. The evidence base for prevention is drawn from ecological studies, case series, and the biology of the parasite, not from clinical trials.

Vector Control and Personal Protection

Tsetse fly avoidance is the cornerstone of primary prevention. Personal protective measures include:

• Wearing long-sleeved, neutral-coloured clothing (tsetse are attracted to bright or dark colours)
• Using insect repellent (permethrin-treated clothing, DEET on exposed skin)
• Sleeping under insecticide-treated nets
• Avoiding bush and waterhole areas where tsetse rest

No chemoprophylaxis exists for HAT. Iatrogenic transmission, historically via shared needles during treatment campaigns, has been implicated in the early spread of HIV-1 in Central Africa, underscoring the importance of sterile injection practices ^[143]D5.

Surveillance and Early Detection

Surveillance serves as secondary prevention by detecting infections early, before they progress to stage 2. Modelling from north-western Uganda shows that a 70% reduction in passive surveillance sites (from 170 to 51) could still maintain >95% of the population at risk within 1 hour of a diagnostic centre, indicating that surveillance can be scaled back without losing coverage as elimination approaches ^[149]D5. Projections to 2030 suggest that the age-standardized DALY rate for HAT may increase, reinforcing the need for sustained surveillance capacity ^[144]B2c.

Vaccine Development: Current Status

Vaccination remains the best theoretical option, but two major biological obstacles have thwarted progress. First, the variant surface glycoprotein (VSG) coat undergoes antigenic variation, allowing the parasite to evade antibody responses ^[146]D5. Second, infection actively destroys host B-cell memory, undermining vaccine-induced immunity ^[150]D5. A vaccine candidate (VIVβ8) from the vivaxin family elicits a strong immune response in mice but does not prevent disease, largely because the antigen is inaccessible to antibody in vivo ^[147]B3b. No vaccine is currently available for human use ^[142]A1a.

Travel Medicine and Patient Education

Among 42 173 ill returned travellers in the GeoSentinel network, only 40.5% reported a pretravel medical visit, and travellers visiting friends and relatives had the lowest rate (18.3%) ^[148]C4. African trypanosomiasis, though rare, was reported as a life-threatening diagnosis. Clinicians should counsel travellers to endemic areas of sub-Saharan Africa on tsetse fly avoidance and the need for prompt evaluation of fever, headache, or sleep disturbance after return.

Pearl: No vaccine exists; the single most effective prevention strategy is tsetse fly avoidance, and the best evidence for surveillance design comes from elimination modelling rather than controlled trials ^{[142]A1a[149]D5}.

Before fexinidazole, special populations relied on parenteral therapies with significant toxicity; today, host-specific data from field studies and clinical trials guide safer, simpler regimens across age, pregnancy, and immune status.

Children

Fexinidazole is the first-line oral therapy for children aged 6 years and older with a bodyweight of ≥20 kg for both gambiense and rhodesiense human African trypanosomiasis (HAT) ^{[96]A1c[99]A1c}. Dosing is weight-based: children 20 kg to <35 kg receive 1200 mg once daily for 4 days, then 600 mg once daily for 6 days; those ≥35 kg receive the full adult dose of 1800 mg then 1200 mg ^{[100]B2b[130]C4}. In a phase 2-3 trial of 125 children (all stages), treatment success at 12 months was 97.6% (95% CI 93.1-99.5), exceeding the 92% target ^[130]C4. The most common adverse event was vomiting (69%), but no new safety issues emerged ^[130]C4. Children below the age or weight cutoffs remain ineligible for fexinidazole and must be treated with nifurtimox-eflornithine combination therapy (NECT) or alternative regimens ^{[96]A1c[99]A1c}. NECT has also been evaluated in 100 children under 12 years, with 98.4% discharged alive and no major safety concerns ^[133]C4; children experienced fewer adverse events than adults ^[40]C4.

Pregnancy and Breastfeeding

NECT was studied in 14 pregnant and 33 breastfeeding women in a field study in the Democratic Republic of the Congo, with 98.4% of all patients discharged alive and no major safety signals ^[133]C4. A 24-month follow-up confirmed that NECT is effective and sufficiently well tolerated in these groups ^[131]C4. Fexinidazole has been evaluated in 24 women who took the drug before or during pregnancy, or during breastfeeding, with no specific safety issues detected ^[100]B2b. In the phase 3b study, women in the second or third trimester and breastfeeding women could be included only as inpatients, as a precaution ^[100]B2b. For rhodesiense HAT, fexinidazole is permitted after the first trimester ^[105]C4. The risk of untreated HAT, which can progress to congenital infection, outweighs the theoretical embryotoxicity risk, though post-marketing surveillance is warranted ^[100]B2b.

Immunocompromised Hosts

Immunosuppression, particularly from HIV infection, increases susceptibility to central nervous system (CNS) infections ^[60]D5. In a rural hospital setting, HIV infection was independently associated with cerebrospinal fluid pleocytosis (white blood cell count >5/μL) in patients with neurological disorders, and positive HAT serology was also a predictor ^[154]C4. Lumbar puncture is safe even without neuroimaging, with self-limiting adverse events in 7.5% of patients and no deaths or long-term sequelae ^[154]C4. No dedicated trials have examined treatment outcomes in HIV-HAT coinfection, but standard staging and treatment algorithms should be applied, with attention to drug interactions (e.g., efavirenz with fexinidazole, though not specifically studied).

Organ Dysfunction

Patients with severe renal or hepatic impairment were excluded from fexinidazole trials ^[100]B2b; caution is advised if these are present. Eflornithine, a component of NECT, is primarily renally excreted, and dose adjustment may be needed in renal insufficiency. Suramin and melarsoprol are no longer first-line, but both carry risks of nephrotoxicity and encephalopathy, respectively, which are magnified in patients with pre-existing organ dysfunction. The shift to oral fexinidazole and NECT has substantially reduced these risks.

Pearl: For children weighing 20-34 kg, the fexinidazole dose is 1200 mg daily for 4 days then 600 mg daily for 6 days; for ≥35 kg, use 1800 mg then 1200 mg, this weight-based schedule applies to both gambiense and rhodesiense HAT.