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. 2021 Dec 9;12(12):CD015374.
doi: 10.1002/14651858.CD015374.

Chemotherapy for second-stage human African trypanosomiasis: drugs in use

Vittoria Lutje  1 , Katrin Probyn  2 , Jorge Seixas  3 , Hanna Bergman  2 , Gemma Villanueva  2
Affiliations

Chemotherapy for second-stage human African trypanosomiasis: drugs in use

Vittoria Lutje et al. Cochrane Database Syst Rev. .

Abstract

Background: Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions. OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT).

Search methods: On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations.

Selection criteria: Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use.

Data collection and analysis: Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI). MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up. We judged the study to be at low risk of bias in all domains except blinding; as the route of administration and dosing regimens differed between treatment groups, participants and personnel were not blinded, resulting in a high risk of performance bias. Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence). We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence.

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Conflict of interest statement

VL has no known conflicts of interest. VL works as an independent consultant conducting literature searches for various research groups. None of them has any potential relevance to the submitted work.

KP received payment for work on this review from Cochrane Response, an evidence services unit operated by the Cochrane Collaboration. Cochrane Response was contracted by the WHO to produce a systematic review upon which a part of this review update is based (see ‘Sources of support').

JS has participated as an expert in the WHO guideline development group for the use of fexinidazole; collaborates in the WHO network for Human African Trypanosomiasis Elimination Group; is designated chairman of the subgroup 'Integration of new tools into national and global policies' of the aforementioned WHO Group; is designated member of the WHO Human African Trypanosomiasis Elimination Technical Advisory Group (HAT‐e‐TAG); and participated in 2018 as an expert in the Scientific Advisory Group meeting on Fexinidazole Winthrop, promoted by the Committee for Medicinal Products for Human Use of the European Medicines Agency.

HB received payment for work on this review from Cochrane Response, an evidence services unit operated by the Cochrane Collaboration. Cochrane Response was contracted by the WHO to produce a systematic review upon which a part of this review update is based (see ‘Sources of support').

GV received payment for work on this review from Cochrane Response, an evidence services unit operated by the Cochrane Collaboration. Cochrane Response was contracted by the WHO to produce a systematic review upon which a part of this review update is based (see ‘Sources of support').

Figures

1
1
Study flow diagram.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
1.1
1.1. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 1: Death during treatment, up to the last drug administration
1.2
1.2. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 2: Overall mortality (up to 24 months)
1.3
1.3. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 3: Relapse (up to 24 months)
1.4
1.4. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 4: Treatment failure (up to 24 months)
1.5
1.5. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 5: Adverse events that lead to treatment discontinuation
1.6
1.6. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 6: Serious adverse events (up to 24 months)
1.7
1.7. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 7: Adverse events (up to 24 months)
1.8
1.8. Analysis
Comparison 1: Fexinidazole versus NECT, Outcome 8: Adverse events (up to 24 months) (specific)
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References

References to studies included in this review

Mesu 2018 {published and unpublished data}
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References to studies excluded from this review

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Pelfrene 2019 {published data only}
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Pollastri 2018 {published data only}
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Schmid 2012 {published data only}
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Tarral 2014 {published data only}
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References to ongoing studies

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