Current situation of African trypanosomiasis.

African trypanosomiasis (sleeping sickness) is fatal, if untreated, and occurs in 36 African countries, south of the Sahara, where some 50 million people are at risk of acquiring infection. In the absence of adequate control measures epidemics occur, which are costly and difficult to control. The history of sleeping sickness has been characterized by waves of epidemics, resurgences and outbreaks. Nevertheless, sleeping sickness has been brought practically under control in the early 1950s, in West and Central Africa, through systematic surveillance of the population at risk and in East Africa, mainly by vector control. Following the attainment of independence from colonial rule in subsequent years, failure by national health authorities to give due attention to sleeping sickness control, due to civil and political unrest, lack of adequate resources and competing national health priorities, has resulted in epidemics and the recrudescence of many old foci and the appearance of new ones. Thus, sleeping sickness is currently a major concern among many countries, particularly in East and Central Africa. During the past decade, progress has been achieved through research in the development of new tools for diagnosis, which are simple to use by national health personnel and for vector control, which can be used at the community level. Eflornithine, a new drug, has been registered for the treatment of gambiense sleeping sickness, and although it is expensive, it is relatively safe and provides an alternative therapy to the existing treatment, which may cause severe adverse effects. These tools have raised hopes for improved control, but their integration into health care systems, which could improve surveillance of the population at risk, has been slow. In view of the worsening economic situation of endemic countries, and the focus of attention and resources on the AIDS pandemic, prospects of any significant improvement in the sleeping sickness situation would largely depend on the successful mobilization of external resources.

[Breeding sites of Glossina palpalis s.1. pupae in a transitional woodland area in Ivory Coast]. / Gîtes à pupes de Glossina palpalis s.1. dans une zone préforestière de Côte d'Ivoire.

Search for pupae of G. palpalis s.1. was conducted from February to December 1981 in the Bouaflé area, Ivory Coast. 1909 pupae were collected from 70 breeding sites after 518 hours of search. Pupae were found both in the dry and the rainy seasons. The vegetation and the nature of the soil seem to be two inseparable factors for the creation and the maintenance of Glossina breeding sites in the study area. In localities with high pig population density, a greater number of pupae were found either at the edge of the village or at a distance not exceeding 500 m from the houses. This observation confirms peridomestic behaviour of G. palpalis s.1. in these localities. On the contrary, in localities with low pig population density or without pigs, peridomestic breeding was not observed; all the pupae were found at a distance 500 m to 3 km away from the houses, in coffee and cocoa plantations and in woodlands. The epidemiological significance of the distribution of G. palpalis s.1. breeding sites in the study area is discussed.

Perspectives in research on and control of African trypanosomiasis.

African trypanosomiasis affects both man and his domestic animals, and is fatal if untreated. The risk of epidemics makes the disease a major public health problem in 36 sub-Saharan African countries, where some 50 million people are at risk of contracting the disease. Continued suppression of the disease through medical surveillance is indispensable to prevent epidemics which are difficult and costly to control. Recent epidemics and flare-ups have occurred in certain countries due to breakdown in medical surveillance occasioned by political, social and economic factors. The development of new tools through research over the last decade has improved the diagnosis of patients and vector control. The development of eflornithine (DFMO) for the treatment of gambiense sleeping sickness is a major breakthrough in view of its safety compared with current treatment alternatives, and it has been nicknamed the 'resurrection drug'. In spite of these achievements, however, there is no radical solution to the problem of sleeping sickness. The use by the endemic countries of improved tools for disease control depends upon the availability of resources from national, bilateral and multilateral sources, and commitment of the countries concerned.

Current knowledge on epidemiology and control of sleeping sickness.

African trypanosomiasis (sleeping sickness) occurs in some 200 known foci within tsetse inhabited areas in sub-saharan Africa, where an estimated 50 million people are at risk of acquiring infection. Only 25,000 new patients are reported each year but this is an underestimate. Where medical surveillance was inadequate or lacking, serious epidemics could occur and this potential risk makes the disease one of the serious health problems in sub-saharan Africa. The chronic gambiense form of sleeping sickness occurs in West and Central Africa, while the acute rhodesiense form occurs in East and Southern Africa. Recent advances in science have improved knowledge on the epidemiology of the disease and provided tools for improved diagnosis, treatment and vector control. The current strategy for control of the disease is based upon continuous suppression through diagnosis and treatment and limited vector control with community participation. Nevertheless, long-term solution to the problem of African trypanosomiasis lies in effective land-use management and rural development.

Differences in rate of wing fray between Glossina species.

Differences exist in the rate of wing fray, as shown by correlation with ovarian age as a time scale, and thus presumably flight activity, for Glossina pallidipes, G. f. fuscipes, G. morsitans, G. tachinoides, G. palpalis s.l. and G. palpalis gambiensis. The wings of females fray more slowly than males for all the above species. Female G. palpalis s.l. in the forest habitat of Ivory Coast seem on this basis to be considerably less active than other flies considered. G. p. gambiensis females are more active in the dry season, than the wet season in Upper Volta, as judged by wing fray and this is the first time a seasonal viration in rate of wing fray has been observed as far as we are aware.

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 pharmacokinetics of eflornithine (alpha-difluoromethylornithine) in patients with late-stage T.b. gambiense sleeping sickness.

OBJECTIVE: To investigate the plasma, cerebrospinal fluid (CSF) levels and pharmacokinetics of eflornithine (DFMO) in patients with late-stage T.b. gambiense sleeping sickness who were treated with an oral DFMO at 100 mg/kg or 125 mg/kg body weight every 6 h for 14 days. METHODS: Plasma and CSF concentrations of DFMO were measured during day 10 and day 15 in patients following oral DFMO at 100 mg/kg (group I: n=12) and 125 mg/kg (group II: n=13) body weight every 6 h for 14 days. Clinical and parasitological assessments were performed at 24 h after the last dose of DFMO and at 12 months. RESULTS: Patients in each group had a good initial response, but relapse was observed in six patients (three patients for each group) during 12 months follow-up. Plasma DFMO concentrations did not increase proportionally to doses when the dose increased from 100 mg/kg to 125 mg/kg body weight given every 6 h (60-70% of the expected increase). In most cases, concentration-time profiles of DFMO in each group were best fit using a two-compartment open model with first-order input, with absorption lag-time and first-order elimination. Average trough (C(ss-min)) and average (C(ss-ave)) plasma DFMO concentrations during steady state varied between 189-448 nmol/ml and 234-528 nmol/ml, following 100 mg/kg and 125 mg/kg dose group, respectively. C(max), t(max) and AUC(0- infinity ) values following the last dose were 296-691 nmol/l, 2-3 h, and 2911-6286 nmol h/ml, respectively. V(z)/F, CL/F and t(1/2z) values were 0.47-2.66 l/kg, 0.064-0.156 l/h/kg, and 3.0-16.3 h, respectively. CSF concentrations at steady state varied between 22.3 nmol/ml and 64.7 nmol/ml. Patients who had treatment failure tended to have lower plasma and CSF DFMO concentrations than those who had successful treatment. CONCLUSION: Oral DFMO at the dose of 125 mg/kg body weight given every 6 h for 14 days may not produce adequate therapeutic plasma and CSF levels for patients with late-stage T.b. gambiense sleeping sickness.

Trypanosome infection rates of Glossina spp. (Diptera: Glossinidae) in transitional forest-savanna near Bouaflé, Ivory Coast.

Tsetse, caught in biconical traps near Bouaflé, Ivory Coast in 1980-81, were examined for trypanosome infections. In a sample of 1138 non teneral Glossina palpalis s.l. there were infection rates of 12.2% (all infections) and 5.3% (mature infections). Female flies had a significantly higher infection rate than males. In G. palpalis only 3 (0.26%) salivary gland infections were detected, 62.3% of the mature infections were T. vivax-like and 71.4% of all infections were restricted to the midgut. The infection rate in forest/plantation caught G. palpalis was twice that of village caught flies. The infection rate increased with fly age and is correlated in female flies. In smaller samples of G.p. pallicera and G. fusca group flies the trypanosome infection rates were 37% and 46% respectively. In both these groups of flies 64.7% of infections were mature and were predominantly T. vivax-like and in females.

Traps to control and estimate populations of Glossina species.

Biconical traps were used to capture continuously Glossina palpalis s.l. in Ivory Coast and G. morsitans centralis in Zambia for 19 and 20 days respectively. Both fly populations declined markedly during the continuous trapping period though populations subjected to intermittent trapping or where the traps were very widely spaced did not do so to the same extent. Fly density was estimated by applying the principles of removal trapping and were compared with other trapping studies. The results demonstrated that biconical traps removed 7% of the female component of the population each day and that this 7% removal value was itself a measure of absolute trapping efficiency; providing a novel means of population estimation. The potential of traps to control tsetse and thus break trypanosome transmission cycles or reduce 'challenge' on a self-help basis at the village level is discussed.

A multi-centre evaluation of the card indirect agglutination test for trypanosomiasis (TrypTect CIATT).

A version of the card indirect agglutination test for trypanosomiasis, the TrypTect CIATT, was evaluated for the diagnosis of Trypanosoma brucei gambiense and T. b. rhodesiense sleeping sickness. The results of this antigen-detection test indicated high relative sensitivity (99.3%) and specificity (99.4%), and also much higher prevalences of infection in the general population of endemic foci (27.9% for T. b. gambiense and 21.8% for T. b. rhodesiense) than detected by parasitological diagnosis (1.6% and 1.1%, respectively). TrypTect CIATT detected (and could therefore be used for the diagnosis of) non-patent infections. Among the suspected cases (i.e. those initially found to be parasite-negative but to be antigen-positive), trypanosomes were detected in 29 (4.2%) of those checked at a 3-month follow-up, and 17 more such suspects when they were followed up at 6-18 months. Moreover, a high proportion of blood samples from a random sample of the rest of the suspects tested positive for trypanosome-specific DNA by PCR (79.9% for T. b. gambiense and 13.9% for T. b. rhodesiense). ELISA also demonstrated the presence of anti-trypanosome antibodies in many of the suspects tested (63%, 38%, 24% and 66.9% of those in Cameroon, Côte d'Ivoire, Tanzania, and Malawi, respectively). A follow-up of 164 patients treated with melarsoprol revealed that, by 9 months post-treatment, 113 (69.0%) had no detectable trypanosome antigens in their peripheral blood. The test could therefore be used for evaluating chemotherapeutic cure, as well as for diagnosis.

Short-course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial.

OBJECTIVE: A randomized controlled trial was conducted to determine whether 7 days of intravenous eflornithine (100 mg/kg every 6 h) was as effective as the standard 14-day regimen in the treatment of late-stage Trypanosoma brucei gambiense trypanosomiasis. METHODS: A total of 321 patients (274 new cases, 47 relapsing cases) were randomized at four participating centres in Congo, Côte d'Ivoire, the Democratic Republic of the Congo, and Uganda to one of these treatment regimens and followed up for 2 years. RESULTS: Six patients died during treatment, one of whom was on the 7-day regimen, whereas the other five had been on the 14-day regimen (P = 0.2). The response to eflornithine differed markedly between Uganda and other countries. Among new cases in Uganda, the 2-year probability of cure was 73% on the 14-day course compared with 62% on the 7-day regimen (hazard ratio (HR) for treatment failure, 7-day versus 14-day regimen: 1.45, 95% CI: 0.7, 3.1, P = 0.3). Among new cases in Côte d'Ivoire, Congo, and the Democratic Republic of the Congo combined, the 2-year probability of cure was 97% on the 14-day course compared with 86.5% on the 7-day regimen (HR for treatment failure, 7-day vs 14-day: 6.72, 95% confidence interval (CI): 1.5, 31.0, P = 0.003). Among relapsing cases in all four countries, the 2-year probability of cure was 94% with 7 days and 100% with 14 days of treatment. Factors associated with a higher risk of treatment failure were: a positive lymph node aspirate (HR 4.1; 95% CI: 1.8-9.4), a cerebrospinal fluid (CSF) white cell count > or = 100/mm3 (HR 3.5; 95% CI: 1.1-10.9), being treated in Uganda (HR 2.9; 95% CI: 1.4-5.9), and CSF trypanosomes (HR 1.9; 95% CI: 0.9-4.1). Being stuporous on admission was associated with a lower risk of treatment failure (HR 0.18; 95% CI: 0.02-1.4) as was increasing age (HR 0.977; 95% CI: 0.95-1.0, for each additional year of age). DISCUSSION: The 7-day course of eflornithine is an effective treatment of relapsing cases of Gambian trypanosomiasis. For new cases, a 7-day course is inferior to the standard 14-day regimen and cannot be recommended.

Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries.

Reported are the results of a study to determine the efficacy and safety of liposomal amphotericin B (AmBisome) for treating visceral leishmaniasis (kala-azar) in several developing countries where the disease is endemic (Brazil, India, and Kenya). At each study site, sequential cohorts of 10 patients each were treated with AmBisome at a dose of 2 mg.kg-1.day-1 (2 MKD). The first cohort received regimen 1:2 MKD on days 1-6 and day 10 (total dose: 14 mg/kg). If the efficacy with this regimen was satisfactory, a second cohort received regimen 2:2 MKD on days 1-4 and 10 (total dose: 10 mg/kg); and a third cohort received regimen 3:2 MKD on days 1, 5, and 10 (total dose: 6 mg/kg). In India, regimens 1, 2, and 3 (which were studied concurrently) each cured 100% of 10 patients. In Kenya, regimen 1 cured all 10 patients, regimen 2 cured 90% of 10 patients, but regimen 3 cured only 20% of 5 patients. In Brazil, regimen 1 was only partially curative: 5 of 13 patients (62%). Therefore, 15 patients were administered regimen 4 (2 MKD for 10 consecutive days; total dose, 20 mg/kg) and 13 patients were cured (83%). These results suggest that for the treatment of kala-azar the following doses of AmBisome should be administered: in India and Kenya, 2 mg/kg on days 1-4 and day 10; and in Brazil, 2 mg/kg on days 1-10.

PIP: The efficacy and safety of liposomal amphotericin B (AmBisome) for the treatment of visceral leishmaniasis (kala-azar) were evaluated in a phase II clinical trial conducted in Brazil, India, and Kenya--countries where kala-azar is endemic. At each study site, sequential cohorts of 10 patients each received three different dosage regimens of AmBisome. The first cohort received 2 mg/kg/day (MKD) on days 1-6 and day 10 (total dose, 14 mg/kg). If the efficacy of this regimen was satisfactory, the second cohort received 2 MKD on days 1-4 and day 10 (total dose, 10 mg/kg) and a third cohort was administered 2 MKD on days 1, 5, and 10 (total dose, 6 mg/kg). In India, all three regimens (studied concurrently) cured 100% of the total of 30 patients. In Kenya, the first regimen cured all 10 patients (100%), the second cured 9 of 10 patients (90%), and the third cured only 1 of 5 patients (20%). In Brazil, since the first regimen cured only 5 of 13 patients (62%), the next 15 patients were given 2 MKD for 10 consecutive days (total dose, 20 mg/kg); this intensified regimen cured 13 of the 15 patients (83%). Adverse effects were minor, primarily fever and chills associated with infusion and irregular pulse. These findings suggest that leishmaniasis patients in India and Kenya should receive 2 mg/kg of AmBisome on days 1-4 and day 10, while those in Brazil should be given 2 mg/kg on days 1-10. AmBisome treatment is especially recommended for those for whom standard agents are likely to be ineffective, toxic, or difficult to administer.