The phenomenon of treatment failures in Human African Trypanosomiasis

Abstract

SummaryTreatment of Human African Trypanosomiasis (HAT or sleeping sickness) relies on a few drugs which are old, toxic and expensive. The most important drug for the treatment of second stage infection is melarsoprol. During the last 50 years treatment failures with melarsoprol were not a major problem in Trypanosoma brucei gambiense patients. Commonly a relapse rate of 5±8% was reported, but in recent years it has increased dramatically in some important foci of T. b. gambiense sleeping sickness. Treatment failures for T. b. rhodesiense are much less of a problem apart from some reports between 1960 and 1985 of refractoriness in T. b. rhodesiense patients in East Africa. Analysis of those isolates revealed that their in vitro sensitivity to melarsoprol was one-tenth that of sensitive isolates, and complete failure to cure the infection in the acute mouse model with melarsoprol levels comparable with those in human patients.There was very little indication of resistance in T. b. gambiense isolates from Co à te d'Ivoire and NW Uganda. The in vitro melarsoprol sensitivities for populations from relapsing and from curable patients were in the same range. Melarsoprol concentrations in the plasma and cerebrospinal¯uid of patients 24 h after treatment did not show any difference between patients who relapsed and those who could be cured. The reason for relapses in the recent T. b. gambiense epidemics are not known. Other parasite-related factors might be involved, e.g. af®nity to extravascular sites other than the CNS which are less accessible to the drug. In conclusion, a combination of factors rather than a single one may be responsible for the phenomenon of melarsoprol treatment failures in T. b. gambiense patients.keywords Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, treatment, melarsoprol, relapse, drug resistance correspondence Dr Reto Brun,

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

“…In addition, conflicts and insecurity constrained disease control interventions (130,131). An analysis of the period showed that cases of HAT occurred significantly more often in settings with political turmoil and internationalized civil war, with a 10-year interval between onset of conflict and peak prevalence (132). By the 1990s, epidemic disease had returned to central Africa (113,130,133,134).…”

“…So far, relatively little progress has been made in the screening of rhodesiense HAT. However, suitable antigens for antibody detection and plasma biomarkers for T. b. rhodesiense infection are being searched for (24,131,132). If successful, these may allow development of rapid diagnostic tests for rhodesiense HAT as well.…”

“…Trypanosomes are more susceptible to the drug than human cells, possibly because of the slow turnover of this enzyme in T. b. gambiense (130). The rapid turnover of ornithine decarboxylase is responsible for the innate resistance of T. b. rhodesiense to eflornithine (132). For more information, see section 3.…”

Natural Products Active Against African Trypanosomes: A Step Towards New Drugs

“…Therefore, there is an urgent need for new molecules against sleeping sickness which are safe, effective, cheap and easy-to-administer and for new leads with novel mechanisms of action. [8][9][10][11] Nature with its numerous plants, microorganisms and marine organisms is a potential source of such new drugs since it contains a countless quantity of molecules with a great variety of structures and pharmacological activities. 12 Throughout the ages, mineral, plant and animal products have been the main sources of medicines for man.…”

In vitro and in vivo antitrypanosomal activities of three peptide antibiotics: leucinostatin A and B, alamethicin I and tsushimycin

“…However, drug resistance in trypanosomes is increasing and treatment failures are becoming more common. 4,5 Therefore, there is an urgent need for new antitrypanosomal drugs that are more effective and safer, especially those that have novel structures and mechanisms of action.…”