Treatment and control of human African trypanosomiasis.

PURPOSE OF REVIEW: Access to treatment is a multi-step process and little progress has been made to improve treatments for sleeping sickness over the past 50 years. The current strategy is based on diagnostic tools developed in the 1960s while available drugs are still the same as those developed in the middle of the last century. Strategic opportunities can only be based on two achievements: improved diagnosis and safer drugs. This paper reviews the development of new diagnostic tools and drugs and the opportunity offered by new technologies for their further improvement. RECENT FINDINGS: The prodrug DB289 shows excellent oral activity with low toxicity for the treatment of early-stage sleeping sickness; it has recently entered phase II(b) clinical trials. The recent ability to identify and test specific host and parasite biomarkers has allowed the development of new, more-specific and sensitive, diagnostic and stage-determination tools. The accurate diagnosis of an infection by use of proteomic signature analysis has been achieved. Urinary nitrites and nitrates follow closely the increase of brain nitric oxide associated with the penetration of trypanosomes in the brain. Sleep-onset rapid eye movement-like episodes have been shown to occur at onset of late-stage trypanosomiasis. This unique disturbance of the wake/sleep cycle seems to be the first pathognomonic sign in the occurrence of late-stage trypanosomiasis. SUMMARY: Following the description of the disease, and diagnostic tools and drugs that have been used, and are still in use today, the authors show how it has influenced over time the evolution of strategies for surveillance and control. Recent developments and prospects for new, more-specific and sensitive diagnostic tools and a safer drug will undoubtedly improve the accuracy of patient recruitment and facilitate treatment, and provide ways towards new strategic opportunities.

Sleeping sickness surveillance: an essential step towards elimination.

In the last decades, with little or no surveillance sleeping sickness has returned to alarming levels comparable to the early twentieth century. Sixty million people are considered at risk but only 3-4 million are under surveillance, yielding some 45 000 new cases annually. It is estimated that at least 300 000-500 000 people are presently infected. Despite the almost universal presence of the vector in sub-Saharan Africa and the existence of an animal parasite reservoir, it is technically feasible to control and eliminate the disease as a public health problem. The authors describe, step-by-step, a surveillance method based on the epidemiological status of the village and using several approaches ranging from passive to active surveillance. Co-ordinated by the WHO, such surveillance has been incepted in several countries. Epidemiological data is spatially linked to the village, whose geographical co-ordinates are collected using a Global Positioning Systems (GPS). Information is transmitted to WHO through internet. Data analysis and mapping is carried out using Geographical Information System (GIS) software and thematic maps are generated to illustrate epidemiological status. Examples from Central African Republic (CAR), Cameroon and Gabon illustrate the process and mapping.

[The epidemiology of human African trypanosomiasis: a complex multifactorial history]. / L'épidémiologie de la trypanosomiase humaine africaine: une histoire mulifactorielle complexe.

Sleeping sickness has long been known from descriptions by Arab merchants and slave traders. However it was not until 1901 that Forbes discovered the offending agent and 1903 that Bruce described the role of the tsetse fly. The basic epidemiological transmission cycle was described less than 10 years later. Although the main outline of the original model can still be considered as sound, subsequent research has greatly expanded our knowledge. Molecular biology has identified different parasites causing clinical forms of varying severity. Understanding of the antigenic variability to the parasite has also improved. While available data is still insufficient on the relationship between the vector and human being and the vector and the animal reservoir, the behavior of glossinae is well-documented. Current geographical information systems have promoted understanding of the distribution of the disease to enhance targeting of screening, treatment, and vector-control activities. To repeat the success achieved in controlling the disease in endemic countries in the 1960s, it will be necessary to develop new strategies based on this new knowledge.

Analytical tools for planning cost-effective surveillance in Gambiense sleeping sickness.

The re-emergence of sleeping sickness as a major health problem in parts of Africa, combined with the new sources of financial support and provision of drugs means that an investigation of the cost-effectiveness of the different approaches is timely. There has been very little work done on the economics of controlling either form of sleeping sickness. This paper builds on work done for WHO by the authors on developing a framework for analysing the cost-effectiveness of different methods for surveillance in gambiense sleeping sickness. The framework has been used to build a spreadsheet which makes it possible to simulate the effects of controlling the disease at different prevalences, for example using mobile teams or various forms of fixed post surveillance and screening different proportions of the population in a year. Prices, control strategies, prevalence, sensitivity and specificity of tests are all variables which can be altered to suit different situations or investigate how different approaches perform. As new research is beginning to produce calculations of the burden of sleeping sickness, in terms of disability-adjusted life years (DALY) potentially averted by controlling the disease, it is possible to combine these DALY estimates with the analyses of cost-effectiveness undertaken in these exercises to look at the cost-utility of the work, both to compare different approaches and demonstrate that controlling sleeping sickness represents good value for money as an investment in health.

Cost-effectiveness analysis of alternative treatments of African gambiense trypanosomiasis in Uganda.

African trypanosomiasis, or sleeping sickness, is a tropical disease caused by trypanosome parasites transmitted by tsetse flies. The focus of this paper is on the cost-effectiveness of alternative drug treatments for patients in the late stage of the disease. Melarsoprol has been used for many decades. More recently, eflornithine has been developed. It has fewer side effects and improves the overall cure rate. It is much more expensive than melarsoprol, however. The objective of the present cost-effectiveness is to identify the costs and benefits that would be involved in switching from melarsoprol to eflornithine in the treatment of late stage sleeping sickness. Benefits are expressed in lives saved as well as in disability adjusted life years (DALYs). The analysis is applied to the case of Uganda. The implications for affordability are also considered, by taking account of how the treatment costs would be shared between the national government, donors and patients. The baseline results indicate that melarsoprol treatment is associated with an incremental cost per life and DALY saved of $209 and $8, respectively. Each additional life saved by switching from melarsoprol alone to a combination of melarsoprol and eflornithine would cost an extra $1,033 per life saved, and an extra $40.9 per DALY gained. Shifting from this second alternative to treatment of all patients with eflornithine leads to an incremental cost per life saved of $4,444 and an incremental cost of $166.8 per DALY gained.

The scourge of human African trypanosomiasis.

PIP: Human African trypanosomiasis (sleeping sickness) is a parasitic disease caused by two different trypanosome subspecies, Trypanosoma brucei rhodesiense and T.b. gambiense. Each causes a different form of the disease. Untreated, the outcome of both infections is death. Sleeping sickness occurs exclusively on the African continent, south of the Sahara. It is restricted to the distribution area of its vector, Glassina or tsetse fly. 36 out of the 52 African countries are considered endemic for sleeping sickness. It is estimated that some 55 million people are exposed to the risk of infection, of whom only 3.5 million are under surveillance throughout the endemic zone. Available data indicate an average observed prevalence of 0.6% (approximately 20,000 annually reported cases among the people surveyed), which represents only 7% of the total population at risk. However, recent surveys in Zaire and Angola have found village prevalence rates as high as 57-70%. Extrapolation from these figures suggests that over 300,000 individuals are probably infected with the trypanosome. Only 20,000 cases are reported and treated. Zaire alone has over 50 foci and Angola at least 30. Thus, the 20,000 cases reported each year probably represent 40,000-60,000 patients and, should the total population at risk (55 million) be under exhaustive surveillance, the annual number of new cases could be estimated to be over half a million. Trypanosomiasis causes death through various systemic infections, respiratory diseases, and heart failure. It is an important cause of morbidity and mortality in at least 23 of the 36 countries endemic for the disease. Preventive and control measures constitute medical surveillance, treatment of infected individuals, and vector control. The World Health Organization has adopted a three-fold control strategy with active medical surveillance of populations at risk; passive medical surveillance through health centers or hospitals; and vector control. However, the most cost-effective strategy is undoubtedly a measured combination of the three actions.^ieng

New geographical approaches to control of some parasitic zoonoses.

The advent of new technology for geographical representation and spatial analysis of databases from different sectors offers a new approach to planning and managing the control of tropical diseases. This article reviews the geographical and intersectoral aspects of the epidemiology and control of African trypanosomiasis, cutaneous and visceral leishmaniasis, Chagas disease, schistosomiasis, and foodborne trematode infections. The focal nature of their transmission, increasing recognition of the importance of animal reservoirs, and the need to understand environmental factors influencing their distribution are common to all these diseases. Geographical information systems (GIS) open a completely new perspective for intersectoral collaboration in adapting new technology to promote control of these diseases.

Situation de la trypanosomiase humaine en Afrique centrale en 1994 : interpretation programmatique des donnees

L'Afrique Centrale; en tant qu'espace geographique ou sevit la trypanosomiase humaine africaine (THA) a Trypanosoma brucei gambiense represente dix etats : quatre ou la THA est un probleme majeur (Zaire; Soudan; Angola et Ouganda) et les six etats de l'OCEAC (Cameroun; Congo; Gabon; Guinee-Equatoriale; Republique Centrafricaine et Tchad). Dans ces dix etats; on arrive a ce paradoxe d'une situation de plus en plus preoccupante dans de nombreux foyers alors que les capacites a decrire l'importance epidemiologique de la maladie sont de plus en plus limitees. Les raisons sont multiples parmi lesquelles l'absence de moyens ou de volonte politique; les desordres socio-economiques; la guerre civile parfois. Les auteurs presentent ici les donnees declarees depuis quinze ans en utilisant une methodologie essayant de tenir compte de leur caractere imparfait

Trypanosomiase humaine africaine : L'analyse decisionnelle comme outil de coordination et de gestion des programmes de lutte

La prise en charge de la maladie sommeil souffre de quelques difficultes. En effet; cette maladie est speficiquement africaine; et plus specifiquement subsaharienne et rurale. Cette prise en charge necessite donc un niveau de competence et un niveau technique eleve. La trypanosomiase entre en competition avec les grandes pandemies; telles que le SIDA; le paludisme; la bilharziose et bien d'autres. Ces constatations montrent que le depart du controle de la maladie du sommeil se fait avec un handicap considerable. La reussite d'un tel combat exige alors de travailler en reseau; afin de creer un veritable circuit de l'information et de savoir-faire

Propositions pour une stratégie alternative de lutte contre la trypanosomiase humaine africaine en Afrique Centrale

Autour de l'execution du Programme National de Lutte contre la Trypanosomiase en Republique Centrafricaine au cours de la periode 1990-1992 s'est instauree une reflexion valant proposition pour une approche strategique differente. La chaine de prospection alors utilisee reposait sur des methodes classiques de depistage immunologique; de recherche parasitologique et de traitement des trypanosomes averes. Un piegeage etait par ailleurs entrepris. En depit des contraintes habituelles; politiques et techniques; qui pesent sur les programmes de lutte; le Programme National a connu un deroulement satisfaisant pendant deux ans. Pourtant; du fait de la strategie utilisee dans le foyer hyper-endemique de Nola; de nombreux suspects immunologiques ne rentraient pas en traitement; en meme temps que restait stable l'incidence. La nouvelle strategie proposee consiste a instaurer un traitement pour tous les suspects immunologiques meme si la recherche parasitaire reste negative. L'inconvenient principal de cette approche se situe au niveau du traitement a la Pentamidine de sujets consideres a tort en phase I (faux positifs immunologiques). Le risque iatrogene discute est celui d'un diabete potentiellement induit. D'autres contraintes; logistiques; d'acceptabilite et de faisabilite doivent etre apprecies. Pourtant; face a un foyer hyper-endemique; il semble judicieux de proposer aux autorites nationales ce changement strategique

Long-term exposure of Trypanosoma brucei gambiense to pentamidine in vitro.

In order to study the sensitivity in vitro of Trypanosoma brucei gambiense to pentamidine, 5 x 10(4) parasites were exposed to 0, 0.1, 1.0, 2.0, 10, 100, 1000 and 10,000 micrograms/L of pentamidine isethionate for up to 10 d. The viability of parasites was determined each day by microscopy. Multiplication was retarded during continuous exposure to 2 micrograms/L. After 4 d no further multiplication took place, although the trypanosomes remained alive for another 3 d. The parasiticidal effect was more pronounced when higher concentrations were used; when exposed to 10 and 100 micrograms/L, all parasites were dead after 4 and 3 d, respectively. Despite exposure to 1000 micrograms/L, 74% of the parasites were still alive the next day. 10,000 micrograms/L killed all parasites within 24 h of exposure. Our results show that the time period of exposure to pentamidine plays a major role in determining the sensitivity in vitro of T. b. gambiense, and we suggest that prolonged exposure in vivo may be more important than attaining high but brief peak concentrations.

[Evaluation of the parasitologic technics used in the diagnosis of human Trypanosoma gambiense trypanosomiasis in the Ivory Coast]. / Evaluation des techniques parasitologiques utilisées dans le diagnostic de la trypanosomose humaine a Trypanosoma gambiense en Côte-d'Ivoire.

The investigators carried out a comparative evaluation of twelve or parasitological techniques used nowadays in the diagnosis of human trypanosomiasis and parasite isolation in the lymph fluid, blood and cerebro-spinal fluid (CSF). The tests were performed on 64 seropositive suspects selected with TESTRYP-CATT among 661 attendants examined at the Projet de Recherches Cliniques sur la Trypanosomiase (PRCT), Daloa, Côte-d'Ivoire. The study showed that the sensitivity of the different techniques varies between 17.2% (for CSF inoculation to Mastomys) and 84.5% (for the anion exchange centrifugation technique-mAECT). The classical techniques, says lymph fluid examination, direct blood examination and thick blood have a sensitivity of 58.6, 22.4 and 34.5% respectively. The most sensitive methods are lymph fluid examination, mAECT and double centrifugation of CSF (69%). The sensitivity increases up to 98.3% with the combination of two or three techniques. The combination of lymph fluid examination/mAECT/double centrifugation of CSF is either the most sensitive and the most suitable one for use in the field. The combination of lymph fluid examination and mAECT which detects 91.4% of the infected subjects is the most efficient. The authors discussed the results and recommended that similar study be done in field conditions to assess methods which either demonstrated better sensitivity and are more suitable for field use.

[African human trypanosomiasis: study of a scoring system of presumptive diagnosis in the Congo]. / Trypanosomiase humaine africaine: étude d'un score de présomption de diagnostic au Congo.

A case-control study was carried out in the Congo to define a scoring system based on a number of clinical and epidemiological criteria of African trypanosomiasis due to Trypanosoma brucei gambiense which could be used by peripheral health services to establish a diagnosis. The survey comprised 163 cases and 326 controls. Clinical signs and symptoms were fever, headache, pruritus and skin lesions due to scratching, diarrhoea, oedema, cervical adenopathies, sleep rhythm disturbances, changes in appetite, amenorrhoea or impotence, mental confusion, neurological signs, and other minor clinical disturbances. Other criteria were a history of previous trypanosomiasis and the presence of domestic animals in the home environment. Analysis of the results showed that neither a single criterion nor a group of criteria is pathognomonic for the disease. The selected criteria do not allow discrimination of sleeping sickness patients among suspected individuals who present themselves. A scoring system is therefore of little use at the peripheral level of health services, particularly when considering the additional workload involved. The low diagnostic value of these clinical signs and symptoms and other indicators in African trypanosomiasis stresses the difficulty in developing an early warning tool for an integrated control strategy in primary health care.