Chemotherapy of second-stage Human African trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, is a painful and protracted disease transmitted through the bite of infected tsetse flies and it is found in rural parts of sub-Saharan Africa. Sleeping sickness has two clinical phases but this review focuses only on treatment of the second-stage, which is characterized by neurological changes and almost invariably fatal without treatment. There are only a few drugs currently available for second-stage sleeping sickness, all with considerable adverse events and variable efficacy.

The review includes nine trials with 2577 participants. Each trial reported different comparisons of the drugs currently available to treat second stage HAT (melarsoprol, eflornithine, nifurtimox) so no meta-analysis was possible.

Melarsoprol administration is intravenous and very painful, with many adverse reactions including a severe dysfunction of the brain, that can result in death. For this reason, trials were designed to evaluate shorter melarsoprol regimens. Giving melarsoprol for 10 days was found to be as effective as giving it for 26 days. Recently, nifurtimox and eflornithine combination therapy (NECT) was assessed. Few patients relapsed after NECT, which was generally well tolerated. It also has practical advantages: eflornithine has to be administered as a slow intravenous infusion thus requiring specialized health facilities and personnel, but nifurtimox is given orally. NECT uses less eflornithine doses and reduces the burden on health personnel and patients.

Considering that none of the current therapeutic options for HAT is optimal in terms of adverse events and ease of administration, it is essential that new anti-trypanosomal compounds are developed and tested in experimental and clinical studies. In the meantime, local availability of the drugs and the status of health facilities and personnel will dictate choice of treatment. It is envisioned that melarsoprol, with its high level of adverse events, will be phased out in favour of eflornithine and NECT. The development of parasite resistance to the drugs needs to be carefully monitored. Future research should also focus on the reduction of the adverse effects of currently used drugs and better diagnostic tests.

Authors' conclusions: 

Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.

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Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy.


To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis.

Search strategy: 

We searched the Cochrane Infectious Diseases Group Specialized Register (January 2013), CENTRAL (The Cochrane Library Issue 12 2012) , MEDLINE (1966 to January 2013), EMBASE (1974 to January 2013), LILACS (1982 to January 2013 ), BIOSIS (1926-January 2013), mRCT (January 2013) and reference lists. We contacted researchers working in the field and organizations.

Selection criteria: 

Randomized and quasi-randomized controlled trials including adults and children with second-stage HAT, treated with anti-trypanosomal drugs.

Data collection and analysis: 

Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI).

Main results: 

Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. The frequency of death and number of adverse events were similar between patients treated with fixed 10-day regimens of melarsoprol or 26-days regimens. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.

Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the frequency and number of eflornithine slow infusions to twice a day, thus easing the burden on health personnel and patients.