The journey towards elimination of gambiense human African trypanosomiasis: not far, nor easy.

Considering the epidemic situation of gambiense human African trypanosomiasis (HAT) at the end of the twentieth century, the World Health Organization (WHO) and partners strengthened disease control and surveillance. Over the last 15 years, the activities implemented through the National Control Programmes have brought gambiense HAT under control and now its elimination is deemed as an achievable goal. In 2012, WHO targeted gambiense HAT for elimination as a public health problem by 2020. The final goal will be the sustainable disease elimination by 2030, defined as the interruption of the transmission of gambiense HAT. The elimination is considered feasible, because of the epidemiological vulnerability of the disease, the current state of control, the availability of strategies and tools and international commitment and political will. Integration of activities in the health system is needed to ensure the sustainability of the elimination. The development of user-friendly diagnostic and treatment tools will facilitate the integration process. Adequate funding is needed to implement activities, but also to support research that will make the elimination sustainable. A long-term commitment by donors is needed and ownership of the process by endemic countries is critical.

Diversity of human African trypanosomiasis epidemiological settings requires fine-tuning control strategies to facilitate disease elimination.

In 2001, the World Health Organization (WHO) established a public-private partnership to fight human African trypanosomiasis (HAT). As a result of this continuous collaboration, and in addition to the coordination with nongovernmental organizations and bilateral cooperation agencies, the number of new cases of HAT annually reported by the WHO has strikingly decreased. In 2012, HAT was included in WHO's roadmap on neglected tropical diseases with a 2020 target date for elimination. Although the prevalence of HAT is decreasing and its elimination is targeted, control approaches must be adapted to the different epidemiological patterns in order to adopt the most adequate strategies to maintain their cost-effectiveness. These strategies must be flexible and dynamic in order to be adapted to the disease progression, as well as to the changes affecting the existing health facilities in transmission areas, including their accessibility, their capabilities, and their involvement in the elimination process. Considering the different patterns of transmission (Trypanosoma brucei (T.b.) rhodesiense HAT) and transmission intensity (T.b. gambiense HAT), different settings have been defined. In the case of T.b. rhodesiense, this form exists primarily where wild animals are the main parasite reservoir, and where the main parasite reservoir is cattle. In T.b. gambiense, this form exists in areas with high intensity transmission, areas with moderate intensity transmission, and areas with low intensity transmission. Criteria and indicators must be established to monitor and evaluate the actions implemented toward the elimination of HAT.

Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis.

Despite the fact that eflornithine was considered as the safer drug to treat human African trypanosomiasis (HAT) and has been freely available since 2001, the difficulties in logistics and cost burden associated with this drug meant that the toxic melarsoprol remained the drug of choice. The World Health Organization responded to the situation by designing a medical kit containing all the materials needed to use eflornithine, and by implementing a training and drugs distribution programme which has allowed a transition to this much safer treatment. The introduction of the combination of nifurtimox and eflornithine (NECT) has accelerated the shift from melarsoprol to the best treatment available, due to reduced dosage and treatment time for eflornithine that has significantly lessened the cost and improved the burden of logistics encountered during treatment and distribution. The decrease in the use of more dangerous but cheaper melarsoprol has meant a rise in the per patient cost of treating HAT. Although NECT is cheaper than eflornithine monotherapy, an unexpected consequence has been a continuing rise in the per patient cost of treating HAT. The ethical decision of shifting to the best available treatment imposes a financial burden on HAT control programmes that might render long-term application unsustainable. These factors call for continuing research to provide new safer and more effective drugs that are simple to administer and cheaper when compared to current drugs.

Controlling sleeping sickness - a review.

Following a period characterized by severe epidemics of sleeping sickness, restoration of effective control and surveillance systems has raised the question of eliminating the disease from sub-Saharan Africa. Given sufficient political and financial support, elimination is now considered a reasonable aim in countries reporting zero or less than 100 cases per year. This success may lead health authorities across the affected region to downgrade the disease from 'neglected' to simply being ignored. In view of the significant levels of under-reporting of sleeping sickness mortality in rural communities, this could be a short-sighted policy. Loss of capacity to deal with new epidemics, which can arise as a consequence of loss of commitment or civil upheaval, would have serious consequences. The present period should be seen as a clear opportunity for public-private partnerships to develop simpler and more cost-effective tools and strategies for sustainable sleeping sickness control and surveillance, including diagnostics, treatment and vector control.

Mapping sleeping sickness in Western Africa in a context of demographic transition and climate change.

Human population growth, climate change and economic development are causing major environmental modifications in Western Africa, which will have important repercussions on the epidemiology of sleeping sickness. A new initiative, the Atlas of human African trypanosomiasis (HAT), aims at assembling and geo-referencing all epidemiological data derived from both active screening activities and passive surveillance. A geographic database enables to generate up-to-date disease maps at a range of scales and of unprecedented spatial accuracy. We present preliminary results for seven West African countries (Benin, Burkina Faso, Côte d'Ivoire, Ghana, Guinea, Mali and Togo) and briefly discuss the relevance of the Atlas for future monitoring, control and research activities.

[The Mandoul human African trypanosomiasis focus in Chad: from evaluation to control]. / Le foyer de trypanosomiase humaine africaine du Mandoul au Tchad : de l'evaluation au contrôle.

The Mandoul focus of human African trypanosomiasis in southern Chad was first described by Gaston Muraz in the 1920s. After 40 years of control measures, case reports became rare and the focus was forgotten. However the number of cases began to increase in 1993 and coordinated control measures were implemented in 2002. The first phase of control consisted of mapping out the focus that was shown to involve 45 villages and camps on both sides of the Mandoul River. The estimated number of inhabitants in the area is 20.000 and the endemic prevalence was 3.78%. Dynamic passive screening and regular active screening undertaken in the framework of the Chadian human African trypanosomiasis control program with the assistance of expert technicians from the subregion reduced the prevalence to 0.77% in 2006. Although this reduction is encouraging, control measures must be maintained and greater involvement of the health care system will be needed to achieve sustainable control of the disease and ultimately to eliminate human African trypanosomiasis as a public health problem.

[Organizing an active screening campaign for human African trypanosomiasis due to Trypanosoma brucei gambiense]. / Organisation d'une campagne de dépistage actif de la trypanosomiase humaine africaine à Trypanosoma brucei gambiense.

Organization of an active screening program for human African trypanosomiasis in an outbreak area is subject to strict guidelines that must take into account the size of the population, the specificity and sensitivity of the diagnostic techniques used, and the cost of screening. Numerous parameters can affect the outcome including accessibility of the outbreak area (road conditions, rainy season); awareness of village populations and of local administrative, traditional, and religious personalities; quality of local health-care facilities and personnel; possibility of referring patients to a health care institution able to provide treatment, etc. For these reasons the cost of screening programs can be high in terms of human, physical, and financial resources. Careful planning and preparation is necessary to ensure worthwhile results. The model described in this article allows screening of 300 to 600 persons a day in areas in which the endemic disease prevalence is higher than 1%. A variant for areas with lower endemicity allows screening of up to 1500 persons a day.

The elimination of Trypanosoma brucei gambiense sleeping sickness in the focus of Luba, Bioko Island, Equatorial Guinea.

After the resurgence of sleeping sickness in Luba, Equatorial Guinea, a major campaign to control the disease was established in 1985. The campaign comprised no vector control, but intensive active and passive surveillance using serology for screening, and treatment of all parasitological and suspected serological cases. Total prevalence was used to classify villages as endemic, at risk, anecdotal and non-endemic which also allowed defining the geographic extent of the focus. Active case-finding was implemented from 1985 to 2004. The frequency of surveys was based on parasitological prevalence: twice a year during intensified control, once a year during ordinary control and once every 2 years during the control consolidation phase, when the parasitological prevalence in the whole focus fell to 0.1%. From 1985 to 1999, the indirect immunofluorescent antibody test (IFAT) was used as an initial screening tool, followed by parasitological confirmation of IFAT positive cases, and the Card Agglutination Trypanosomiasis Test (CATT) if necessary. In 2000, the IFAT was replaced by the CATT. Serum-positive individuals without parasitological confirmation were subsequently tested on serial dilution. All cases underwent lumbar puncture to determine the stage of the disease. First-stage cases were treated with pentamidine and second-stage cases with melarsoprol. A few relapses and very advanced cases were treated with eflornithine. The last sleeping sickness case was identified and treated in 1995.

Molecular epidemiology of tuberculosis in the Bata and Malabo districts of Equatorial Guinea.

SETTING: Bata and Malabo districts, Equatorial Guinea, 1 March 1999 to 28 February 2001. OBJECTIVE: To study the molecular epidemiology of tuberculosis (TB). RESULTS: During the study period, 429 patients were diagnosed with TB in the Bata and Malabo districts. A positive culture was obtained in 206 (48%) TB patients, with RFLP analysis being performed in 185 (89.8%). Ninety-two different patterns were identified. Single patterns were found in 71 strains (38.3%) and the remaining 114 strains (61.6%) were classified into 21 clusters (of 2 to 25 patients). In addition, 37 of the typing strains were resistant to one or more anti-tuberculosis drugs, and 30 were included in clusters (81%), with 21 low level isoniazid (MIC < or = 1 microg/ml) resistance strains in the same cluster. Statistical analysis showed that resistance to anti-tuberculosis drugs (OR 3.1; 95% CI 1.2-7.6; P = 0.014), and positive smear results (4+ grade smear) (OR 4.3; 95% CI 1.5-12; P = 0.005), were significantly more frequent among patients with clustered strains. No epidemiological links were related to clustering. CONCLUSIONS: The level of clustering (61.6%) observed suggests a high degree of recent transmission and a predominance of determined patterns of Mycobacterium tuberculosis strains among the population of Equatorial Guinea.

[The concept of neglected disease]. / Le concept de maladie négligée.

"Neglected disease", "neglected population" and more generally "public health negligence" are emerging concepts being put forward by numerous humanitarian groups. Sleeping sickness provides a typical example to illustrate these concepts. After causing a major epidemic in the 1930s, sleeping sickness had been practically eradicated by the end of decolonization. Because of more urgent priorities, independent national governments relinquished control activities thus allowing the disease to return insidiously. By the beginning of the 1990s the situation was comparable to that prevailing in 1930 without inciting a response commensurate with the extent of the problem. Sleeping sickness is currently not a priority and, more simply, is not given proper attention because it affects only a few people living in regions presenting little economic interest. This point underlines the especially devastating combination of neglected disease and neglected population. As early as 1999 the World Health Organization with the determined support of Medecins Sans Frontieres launched a campaign not only to promote control measures for sleeping sickness at the international level but also to use initiatives in the domain to illustrate the enormous potential for progress against neglected disease. The effects of this campaign are now beginning to be felt.

[Status of sleeping sickness in 2003]. / Situation de la maladie du sommeil en 2003.

On May 3, 2001, the World Health Organization signed a major agreement with the pharmaceutical industry for the supply of drugs necessary for treatment of sleeping sickness. At that time Dr. Gro Harlem Brutland, director of the WHO, announced, "We can now look forward to halting the spread of sleeping sickness...". The purpose of this article is to take a look at the situation two years later. A first assessment showed that most national programs for the control of human African trypanosomiasis (NPCHAT) had practically become inoperative. One of the first steps in the new eradication campaign consisted of reviving these NPCHAT teams. However this goal could be achieved only insofar as awareness of the severity of the disease and of the need to act was felt at every level of decision-making. In 2001 the Pan-African Tse-Tse Trypanosomiasis Eradication Campaign (PATTEC) initiative was launched by African State leaders to promote special attention at the ministerial level, high-level training, and international cooperation sometimes involving several NPCHAT teams. Actions in the field include trials using new strategies, expert assistance for personnel throughout the duration of prospection, and screening and immediate treatment of numerous patients in outbreak areas where the disease was thought to be extinct. Although progress has not always been measurable in concrete terms, the dynamics have shifted almost everywhere.

[Sleeping sickness, forgotten illness: what are the consequences in the field?]. / Maladie du sommeil, maladie oubliée: quelles conséquences sur le terrain?

For nearly 25 years, sleeping sickness was forgotten and increasingly neglected. Research programs and control activities against human African trypanosomiasis were discontinued. Statistical studies show a constant decrease in the number of people screened and cases detected and little change in the ratios of actively versus passively diagnosed cases and of the early (blood and lymph involvement) versus late (cerebral involvement) stage cases. In the field neglect of the disease led to deterioration not only physical facilities but also human resources. As teams aged, senior members were often replaced by less than fully qualified people resulting in a decline in efficiency and organization. Many basic notions were lost and the albeit scarce innovations in diagnosis and therapy were often overlooked. When the fight against sleeping sickness was finally resumed, these factors had to be taken into account. Efforts in the field have been focused on four areas: renovation of equipment, didactic and practical training for health care personnel, development of a decision-making algorithm based on diagnostic findings, and implementation of new therapeutic protocols.

[Human African trypanosomiasis in an urban area: an emerging problem?]. / Trypanosomose humaine africaine en milieu urbain: une problématique émergente?

The human African trypanosomiasis is essentially a rural disease. The notification of cases in urban area has always been incidental; either a diagnosis made in town revealed a disease contracted in rural environment or it meant the preservation of a complete epidemiological cycle in a remaining urban micro-focus. In Kinshasa, in Democratic Republic of Congo, about forty cases have been notified each year. All of them came from the nearby foci of Bandundu, Lower Congo and Kasaï. In 1996 the number of cases reached suddenly 254 and today the average annual number comes up to 500 in spite of all the efforts undertaken to fight the disease. A study of cases in 1998 and 1999 shows that patients are essentially distributed in suburbs and that the most affected by the disease are the 15-49 year old ones whose job is related with agricultural or fishing activities. Two phenomena seem to explain this sudden increase: the massive inflow of refugees in outskirts of town coming from provinces where trypanosomiasis is endemic and a major economic crisis throwing out urban population in suburbs living on a subsistence micro-agriculture. These concomitant factors have contributed to the setting up of a trypanosomiasis belt around the capital. Today a strategy has to be reconsidered in order to fight against the disease in the capital itself and to make the medical staff aware of the diagnosis of a disease still unknown in their sanitary district.

[Sleeping sickness: one hundred years of control strategy evolution]. / Maladie du sommeil: cent ans d'évolution des stratégies de lutte.

Sleeping sickness has been known since the fifteenth century but the real progress in the knowledge of the disease occurred in the nineteenth century with the development of microscopy. From 1841 to 1901 the parasites and their vectors have been identified, the symptomatology and the epidemiology have been described. However, due to absence of any effective cure, the campaign against the disease was still based on the isolation of the patients and the transfer of exposed populations. The discovery of atoxyl in 1905 provided doctors with their first therapeutic weapon and, in 1910, the first action of vector control was undertaken with success in the Island of Principe. Between the two world conflicts, Jamot published the rules to fight against major outbreaks. Their application in Oubangui-Chari, in Cameroon and in French Occidental Africa brought tremendous results and signed the triumph of the mobile unit concept. Success which will not be denied until the sixties when the disease was believed to be eradicated. From the sixties to the nineties, the concept of the integration of prevention and care added to the exclusion of any vertical system will result in a progressive reniewed outbreak of the sleeping sickness in the known foci. As a paradox, it is a time rich in discovery as regards diagnosis, treatment and entomology. In 1994, the World Health Organisation got concerned with the situation of the disease in Central Africa where the outbreak of the disease reinforced. A second paradox appeared; it is the next to total disinterest from the politics and fund raisers which will save the disease. Today, sleeping sickness is the typical example of the orphan disease, a show case brandished by all the good souls. In 2001, an agreement between the WHO and the pharmaceutical industry brings back the financial funds required to fight the disease. Basically, it is a matter of resuming the action by using what is still existing and by creating new strategies considering the extreme lack of human and logistical resources. The objective is to eradicate the sleeping sickness as a public health problem. The challenge is huge, but is on the way to success.

Increased trypanolytic activity in sera of sleeping sickness patients after chemotherapy.

We tested sera from patients previously treated for human African trypanosomiasis, from patients infected with trypanosomes, and from individuals never diagnosed with African trypanosomiasis living in the Trypanosoma brucei gambiense sleeping sickness focus of Mbini in Equatorial Guinea for their trypanolytic activity against bloodstream forms of T. b. rhodesiense expressing a metacyclic and bloodstream variant surface glycoprotein (VSG). Nearly 80% of the sera from treated patients showed high trypanolytic activity against trypanosomes expressing a metacyclic VSG. The trypanolytic activity of part of these sera was mediated by IgM while that of the other part was antibody-independent. On the other hand, only 40% of the sera exhibited high trypanolytic activity against trypanosomes expressing a bloodstream VSG which also was almost completely abolished by heat-inactivation. In contrast, most sera from infected and negative individuals displayed only low to moderate trypanolytic activity against either trypanosomes expressing a metacyclic or a bloodstream VSG. These results suggest that trypanolytic activity of sera increases after African sleeping sickness and is directed against trypanosomes expressing metacyclic VSG.

[Cost of a national program to control human African trypanosomiasis in the high Mbomou region, Central African Republic]. / Cout d'un projet d'appui au programme national de lutte contre la trypanosomiase humaine africaine dans le foyer du Haut Mbomou, Republique Centrafricaine.

An outbreak of human African trypanosiaisis is ongoing in the High Mbomou area of the Central African Republic. This area is located on the Sudanese border approximately 1,100 kilometers from the capital city of Bangui. According to current estimates, the cost of implementing the National Human African Trypanosomiasis Program is 754,000 United States Dollars, i.e., 4.1 dollars per protected inhabitant. However actual conditions in the field suggest that this estimate should be revised. Special field conditions include constant refugee movement across the border, lack of accurate epidemiological data concerning neighboring Haut Zaire, and low participation of village residents in mass screening operations (less than 50%). In response to these problems, the authors recommend the organization of more exploratory missions to allow better targeting of screening and therapy. In the initial plan, exploratory missions were to account for 1% of the total cost. This proportion will probably require upward adjustment.

[Control of human African trypanosomiasis: back to square one]. / Lutte contre la trypanosomiase humaine africaine: la boucle bouclée?

The natural history of sleeping sickness is cyclic. The first epidemic outbreak in the 19th century devastated the population and resolved spontaneously for lack of victims. Intensive development during the colonial period and the movement of population that it spawned led to another epidemic in the early 1920s that reached such severe proportions that drastic steps had to be taken. At that time, Jamot was given complete political, administrative, and financial freedom to combat the disease. This program led to the development of the mobile team concept and so-called vertically structured vector control strategy and was so successful that sleeping sickness ceased to be considered as a major public health problem at the beginning of the 1960s. In the ensuing years sleeping sickness was largely neglected. Monitoring the disease required specialized teams that were no longer considered as cost-effective. One by one the measures that had been implemented to control the disease disappeared, thus setting the scene for a new outbreak grew. In 1995, the incidence of sleeping sickness reached the same levels as in the 1920s. The current situation is a classic example of a neglected disease with a paucity of competent specialists, diagnostic tests, effective drugs, and operational facilities. It was not until 2001 that new hope appeared thanks to a combined public- and private-sector initiative allowing restructuring of treatment teams, renovation of facilities, free distribution of drugs, and research to develop new therapeutic agents. Also thanks to the PATTEC initiative, the governments of the African affected nations are showing new in interest in sleeping sickness. However the battle is far from won and much effort will be required. Time is running out and the stakes are high.