Treatment options for second-stage gambiense human African trypanosomiasis

Figures & data

Table 1. Summary of published data on effectiveness and safety of drugs for second-stage gambiense human African trypanosomiasis before the nifurtimox-eflornithine combination therapy era.

Compound	Population size	Cure rate (%)^†	In-hospital case fatality rate (%)^‡	Most frequent adverse events		Ref.
Melarsoprol (before 1999)	880–2221	89.7–97.2	2.2–6.5	≥1 Adverse events Encephalopathic syndrome^§ Melarsoprol reaction^¶ Headache Tremor Peripheral neuropathy Diarrhea Skin rash	30–75% 2.2–8.2% 4.4–32% 3.4–41.8% 17.7–20.4% 2.5–10.8% 2.2–11.7% 6.5–7.5%	[13,14]
Melarsoprol^# (after 1999)	62–2270	62.9–92				[18,20–25]
Eflornithine^††	144–1055	84–95.6	0.4–3.1	Headache Seizures Anemia Leucopenia Infection Diarrhea Reaction at the injection site	31.2–45.8% 3.2–9% 41.7% 52.4% 15–17.4% 11.8–35.6% 3.5–24.6%	[22,31–35]
Nifurtimox	4–70	44–80	0–6.3	Headache Seizures Dizziness Tremor Anorexia Nausea Diarrhea Skin rash	15.7–27.3% 2.9–13.3% 10–18.2% 8–16.7% 10–40% 4–4.3% 14.3% 1.4–25%	[23,38–42]
Nifurtimoxeflornithine combination therapy	17–1735	93.5–98.4	0–1.6	≥1 Adverse events Headache Seizures Dizziness Tremor Psychiatric disorders^‡‡ Anorexia Nausea/vomiting Diarrhea	60.1–95.1% 0–38.5% 1.4–23.5% 1.7–32.3% 0–41.9% 2.5–23.1% 4.1–25.2% 5.9–58% 1.1–23.5%	[34,44,45,48–50]

^†To allow for comparison between studies, patients lost to follow-up were considered as cured, and patients with non-response, relapse and death (in-hospital or after discharge) were considered as treatment failures. All patients included in the studies for treatment were used as denominator.

^‡Deaths occurring ≤30 days after treatment initiation.

^§Defined as repeated or prolonged seizures and/or rapid deterioration of level of consciousness or coma. Deaths presumably due to encephalopathic syndromes were included, except in Bisser et al. [23].

^¶The definition used to define ‘melarsoprol reaction’ varied among studies; it refers to several symptoms and signs (e.g., headaches, tremor, hypertension) that are considered as warning signs preceding the encephalopathic syndrome.

^#Both the conventional and abridged schedules were included.

^††Only studies reporting the use of eflornithine administered intravenous for 14 days were included.

^‡‡The most frequently reported psychiatric disorders were anxiety, insomnia, confusion and hallucinations.

Table 2. Target product profile of a new treatment against both stage 1 and 2 gambiense human African trypanosomiasis.

Ideal	Acceptable	NECT (current first-line treatment)
Effective against stage 1 and 2	Effective against stage 1 and 2 (used against stage 2 only)	Stage 1 and 2 (used against stage 2 only)
Broad spectrum (gambiense and rhodesiense)	Efficacy against gambiense only	Gambiense
Clinical efficacy >95% at 18 months follow-up	To be determined in an expert consultation	Clinical efficacy 96.5% [34]
Effective in melarsoprol refractory patients		Effective
<0.1% drug-related mortality	<1% drug possibly related mortality	1.2% possibly related mortality [49]
Safe also during pregnancy, for breast-feeding women and children		No specific adverse event found in babies born or being breast-fed after treatment [49]
Adult and pediatric formulations (rectal?)		Eflornithine pediatric dosing available + nifurtimox 120 mg tablets to be cut
No monitoring for adverse events	Weekly simple laboratory testing	Hospitalization required
<7 days p.o. once daily	10 days p.o. (up to t.i.d.)	7 days iv. infusion (b.i.d.) + 10 days p.o. (t.i.d.)
<7 days im. once daily	<10 days im. once daily
Stability in zone 4 for >3 years	Stability in zone 4 for >12 months	Stability in zone 4 for >24 months
Trypanocidal	Trypanostatic	Trypanostatic (eflornithine) and trypanocidal (nifurtimox)
Multi-target	Unique target (but not uptake via P2-transporter only)
<€30/course^† (only drug cost)	<€100^†/course	€288^†/course (in 4 treatments kits; WHO) [53]
	<€200^†/course if very good on other criteria

Definition: zone 4: hot and humid climate; temperature: 30°C, relative humidity: 60%.

^†Includes transport to the clinical site.

b.i.d.: Twice daily; im.: Intramuscular; NECT: Nifurtimox-eflornithine combination therapy; p.o.: Per os; t.i.d.: Three-times daily.

Adapted from [70].

Figure 1. Metabolism of fexinidazole into fexinidazole sulfoxide and sulfone by cytochrome P450 and flavin-containing monooxygenase.

Figure 2. Preclinical profiles of SCYX-7158 and two potential back-up compounds.

Figure 3. Fexinidazole and DNDi-2035811.

Figure 4. DDD85646.

Figure 5. Diamidines.

Figure 6. Present and potential future diagnosis treatment algorithms for second-stage gambiense human African trypanosomiasis.

Bisser S, N’Siesi FX, Lejon V, et al. Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis 2007;195(3):322-9

 PubMed Web of Science ®Google Scholar

Priotto G, Kasparian S, Mutombo W, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet 2009;374(9683):56-64

 PubMed Web of Science ®Google Scholar

Schmid C, Kuemmerle A, Blum J, et al. In-hospital safety in field conditions of nifurtimox eflornithine combination therapy (NECT) for T. b. gambiense sleeping sickness. PLoS Negl Trop Dis 2012;6(11):e1920

 Google Scholar

Simarro PP, Franco J, Diarra A, et al. Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology 2012;139(7):842-6

 PubMedGoogle Scholar

Target product profile of new treatments for human African trypanosomiasis. Available from: www.dndi.org/diseases-projects/diseases/hat/target-product-profile.html

 Google Scholar