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.

Risk factors for treatment failure after melarsoprol for Trypanosoma brucei gambiense trypanosomiasis in Uganda.

We evaluated the treatment failure rate among late-stage human African trypanosomiasis (HAT) patients treated with melarsoprol in Arua, northern Uganda, between September 1995 and August 1996, and identified the risk factors for treatment failure. We conducted a retrospective cohort study in October 1998, and performed a survival analysis. A treatment failure was defined as a late-stage HAT patient fully treated with melarsoprol and classified as an HAT case at any follow-up visit within 2 years after treatment. Among 428 patients treated in the study period, 130 (30.4%) were identified as treatment failure within 2 years after discharge. The multivariate analysis showed that patients who experienced treatment failure after melarsoprol were more likely to have been admitted as a relapsing case (relative hazard, RH = 11.15 [6.34-19.61]), and to have been diagnosed with trypanosomes in the lymph nodes (RH = 3.19 [2.10-4.83]) or in the cerebrospinal fluid (CSF) (RH = 1.66 [1.09-2.53]). The risk of treatment failure also increased with the number of cells in the CSF. The treatment failure rate after melarsoprol observed in Arua is greatly above the expected figures of 3-9%. More research is needed to confirm whether it is related to the variation of melarsoprol pharmacokinetics between individuals, or if it is associated with a reduced susceptibility of the trypanosomes to melarsoprol. The study emphasizes the need for second-line drugs to treat patients that have already received one or several full course(s) of melarsoprol.

Hypogonadism in Rhodesian sleeping sickness: evidence for acute and chronic dysfunction of the hypothalamic-pituitary-gonadal axis.

OBJECTIVE: To investigate acute and long-term effects of Rhodesian sleeping sickness on the function of the hypothalamic-pituitary-gonadal (HPG) axis in men. DESIGN: An observational, cross-sectional study. SETTING: Primary health care centers under care of the National Sleeping Sickness Control Program in southeast Uganda. PARTICIPANTS: Fifty-two male patients with sleeping sickness at different stages of treatment and 11 clinically healthy male volunteers recruited from health care personnel. INTERVENTIONS: Patients and controls were questioned about loss of libido and impotence. All received 100 micrograms GnRH i.v. Blood was drawn before and 30 minutes after GnRH administration. MAIN OUTCOME MEASURES: Frequency of loss of libido and impotence. Baseline T and sex hormone-binding globulin baseline and GnRH- stimulated serum LH and FSH concentrations. RESULTS: Loss of libido and/or impotence were present in 39% of men with active disease before therapy, whereas 84% were biochemically hypogonadal. After cure, 45% of men still were symptomatic and 45% were biochemically hypogonadal. Compared with controls (806 +/- 59 pg/mL [conversion factor to SI unit, 0.03467]; mean +/- SEM), T concentrations were decreased substantially in patients before (249 +/- 48 ng/dL), during treatment (429 +/- 56 ng/dL), and after cure (431 +/- 58 ng/dL). Corresponding baseline LH concentrations were inappropriately low and the relative LH response to GnRH was reduced both before and during treatment (794% +/- 131% versus 322% +/- 68%). Follicle-stimulating hormone concentrations increased gradually up to 8.0 +/- 1.3 mIU/mL (conversion factor to SI unit, 1.00) at the end of treatment, returning to 4.2 +/- 0.6 mIU/mL after cure. CONCLUSIONS: Rhodesian sleeping sickness causes acute and chronic HPG axis dysfunction. The clinical and biochemical picture suggest a combined central and peripheral hypogonadism. This is only in part reversible after cure and most likely due to direct parasitic infiltration and/or secondary inflammation causing necrosis and/or fibrosis at the pituitary and gonadal levels.

Adrenocortical insufficiency in Rhodesian sleeping sickness is not attributable to suramin.

Suramin, a polysulphonated naphthylurea used in the treatment of human African trypanosomiasis (HAT), is known to cause adrenocortical insufficiency in doses exceeding the quantity used for treatment of HAT. We have previously reported that Trypanosoma brucei rhodesinese infection causes a combined central and peripheral adrenal insufficiency. To evaluate whether suramin therapy acts as an additional adrenotoxic factor, we assessed adrenocortical function in 72 patients suffering from HAT at different times during treatment with either suramin or melarsoprol by a rapid adrenocorticotropic hormone test. We found a significantly diminished peak cortisol response to stimulation in the acutely ill patients (P = 0.001), indicating impaired adrenocortical function, as well as a high incidence of partial adrenocortical insufficiency (27%). During and after trypanocidal therapy the incidence of partial adrenal insufficiency gradually declined (to 25% and 18% respectively). Stimulated peak cortisol levels did not differ significantly between patients receiving suramin and those given melarsoprol. No correlation was found between serum suramin concentration and the cortisol response to stimulation (r = 0.09, P = 0.47). Thus we conclude that suramin in trypanocidal doses neither causes nor worsens the adrenocortical dysfunction observed in Rhodesian HAT.

[Trypanosomiasis from Trypanosoma brucei gambiense in the center of north-west Uganda. Evaluation of 5 years of control (1987-1991)]. / La trypanosomiase a Trypanosoma brucei gambiense dans le foyer du nord-ouest de l'Ouganda. Bilan de 5 années de lutte (1987-1991).

In Uganda, a case-finding and treatment programme has been implemented by Médecine Sans Frontières (MSF) and the Ministry of Health in the North of West-Nile province. Data collected in the hospital of Moyo from January 1987 to June 1991 were analyzed. Forty eight hundred and twenty two cases of trypanosomiasis due to T. B. gambiense has been recorded. Cumulative incidence rate for this period was 5.6%. Passive and active case-finding strategies were used, both based on Card Agglutination Test (CATT) as screening tool, followed by parasitological examinations. The mobile teams identified 1906 of the 4,822 cases (39.5%). Case fatality rate was 2.6%. This study confirmed the association between social and political disruptions, large movements of population and extension of trypanosomiasis. Active case-finding seems to quickly reduce disease prevalence in hyper-endemic areas. An integrated programme is then necessary to control sleeping sickness transmission.

Risk factors assessment for T. b. rhodesiense sleeping sickness acquisition in S.E. Uganda. A case-control study.

The major risk factors associated with acquisition of T. b. rhodesiense sleeping sickness in the Busoga focus, S.E. Uganda were investigated using a case-control study. 122 cases and 244 matched controls were used in the study. For each case two age-, sex- and resistance controls (1 matched nearest neighbour control and 1 village control) were selected. Patients and controls answered the same questionnaire which had been developed and field tested before the field study started. A logistic regression model for a 1:2 matched case control design was fit to the data. The following factors were found significant: cases spent more time outside their village of residence than controls and visited more SS high risk areas than controls, more cases than controls collected firewood in the forests. Generally, cases had less domestic animals grazing near the places of man-fly contact, especially near water and firewood collecting and bathing points, and near farms and gardens, than controls. Cases had more antecedents of sleeping sickness in the family. Generally cases had a less well developed information network than controls, and belonged economically to a less powerful group. Based on these results we may conclude that the risk to develop T.b. rhodesiense sleeping sickness depends upon a multitude of economical, cultural and human behaviour factors. These factors should be taken into account in the planning and monitoring of sleeping sickness control programmes.

Impairment of adrenocortical function associated with increased plasma tumor necrosis factor-alpha and interleukin-6 concentrations in African trypanosomiasis.

African sleeping sickness (SS) is a severe, potentially lethal parasitic disease. The treatments of choice are the antiparasitic agents suramin, which is adrenotoxic, and/or melarsoprol. We evaluated the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis of patients with SS before, during, and after therapy with suramin and/or melarsoprol, in two sequential stages. First, we employed the standard adrenocorticotropic hormone (ACTH) 1-24 stimulation test (250 micrograms i.v.) to assess the maximal adrenocortical responsiveness of 69 patients with SS and 38 normal controls. We demonstrated paradoxically subnormal cortisol responses before suramin therapy [net cortisol response 60 min after stimulation: 10.5 +/- 2.9 (mean +/- SE) vs. 17.5 +/- 1.0 micrograms/dl for controls, p = 0.004], with 27% of the patients falling within the adrenal insufficiency range (stimulated cortisol concentration < 20 micrograms/dl). These responses subsequently and unexpectedly improved with suramin and/or melarsoprol therapy. Second, we performed a human corticotropin-releasing hormone (hCRH) test (100 micrograms i.v.) in 68 additional patients with SS and 14 control subjects to examine whether the glucocorticoid deficiency observed was primary and/or secondary. Compared to controls, the ACTH and cortisol responses to hCRH were blunted (ACTH after 60 min: 29 +/- 7 vs. 58 +/- 8 pg/ml in controls, p = 0.014; cortisol: 15.2 +/- 1.5 vs. 19.6 +/- 0.7 micrograms/dl, p = 0.018), suggesting the presence of secondary adrenal insufficiency. There was improvement of both ACTH and cortisol responsiveness to hCRH with therapy, with cortisol recovery occurring before ACTH, suggesting an additional primary component of adrenal dysfunction in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent advances in the diagnosis and treatment of African sleeping sickness.

PIP: African Sleeping Sickness is endemic in 37 countries of sub-Saharan Africa. Recent estimates suggest that 50 million people are at risk of acquiring the disease and 25,000 new cases are recorded every year. African Sleeping Sickness is caused by protozoan organisms belonging to the genus Trypanosoma which are transmitted cyclically by tsetse flies. The trypanosomes are limited in the early stage to the blood stream from which they later move to the central nervous system. The disease is very hard to diagnose and treat. Clinical manifestations are highly variable and unspecific, and parasitological diagnosis is difficult because of the frequently low and fluctuating parasitemia. Most of the available serological tests can only detect the presence of antibodies to trypanosomes and therefore only indicate exposure to trypanosomes rather than active infection. Clinical, parasitological, and serological diagnosis are discussed. Treatment of the disease remains dependent upon the use of Suramin and Pentamidine for early stage cases and Mel B for late stage cases when the central nervous system changes occur. Through compassionate clinical trials, however, eflornithine, formerly known as DFMO, was recently found to be an effective therapeutic agent against gambiense sleeping sickness. The drug acts by irreversibly blocking the action of ornithine decarboxylase, which catalyzes an essential step in polyamine synthesis, and stops the growth of trypanosomes. A multicenter conventional clinical trial is being arranged before it is made commercially available.^ieng

Thyroid dysfunction in African trypanosomiasis: a possible role for inflammatory cytokines.

OBJECTIVE: Sleeping sickness (African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. The treatments of choice are the antiparasitic agents suramin and/or melarsoprol. Experimental infection of animals with Trypanosoma brucei results in inflammatory lesions in the pituitary and/or the thyroid gland. In biochemical terms, these animals have hypothyroidism. We evaluated the functional integrity of the hypothalamic-pituitary-thyroid axis in patients with African trypanosomiasis before, during and after specific therapy. DESIGN: Prospective, controlled, cross-sectional study. PATIENTS AND MEASUREMENTS: Sixty-five patients with sleeping sickness (31 female, 34 male; aged 18-66; 32 with haemolymphatic sleeping sickness receiving suramin i.v., 33 with cerebral sleeping sickness receiving melarsoprol) and 13 control subjects (6 female, 7 male; aged 21-60) were enrolled in a cross-sectional study after giving informed consent. Fourteen patients were studied shortly after admission for sleeping sickness, 19 in the middle of the course of treatment, 18 at the end of the 5-week treatment period, and 14 patients after cure. All subjects underwent a TRH stimulation test at 1200 with bolus injection of 400 micrograms TRH i.v. Blood was drawn for determination of fT3, fT4, TSH, rT3, TNF-alpha, IL-1 and IL-6 at 0 minutes and TSH at 60 minutes. All hormones and cytokines were determined by RIA or ELISA. RESULTS: Baseline TSH concentrations (mean +/- SEM) were elevated in unmedicated patients with sleeping sickness compared to normal subjects (2.6 +/- 0.4 vs 1.4 +/- 0.2 mU/l; P = 0.01), whereas fT3 (2.7 +/- 0.5 vs 5.8 +/- 0.3 pmol/l; P = 0.0002) and fT4 concentrations (10.3 +/- 1.2 vs 15.4 + 0.8 pmol/l; P = 0.007) were low. Stimulated TSH concentrations did not significantly differ from normal controls. Reverse T3 concentration in patients with sleeping sickness were normal (2.2 +/- 0.3 vs 2.4 +/- 0.2 nmol/l; P = NS). During the course of treatment, baseline TSH, fT3 and fT4 concentrations slowly returned to normal and were indistinguishable from controls after cure. Plasma concentrations of TNF-alpha (16.0 +/- 4.1 vs 2.9 +/- 1.4 ng/l in controls; P = 0.003) and interleukin-6 (19.2 +/- 7.3 vs 1.3 +/- 0.2 ng/l; P = 0.0001), but not interleukin-1 beta (2.0 +/- 0.2 vs 0.9 +/- 0.2, ng/l P = NS), were elevated, when thyroid function impairment and disease activity were at their maximum, but gradually decreased into the normal range with therapy. We found a negative correlation between baseline cytokine concentrations and fT3 concentrations (TNF-alpha: r = -0.34, P = 0.003; IL-6: r = -0.43, P = 0.0001). CONCLUSIONS: We conclude that unmedicated sleeping sickness is associated with significant impairment of thyroid function, which is reversed with specific therapy. Elevated TSH concentrations and low fT3 and fT4 concentrations suggest primary hypothyroidism in patients with sleeping sickness. However, an additional pituitary and/or hypothalamic component cannot be excluded. This impairment may be due to the elevated plasma cytokine concentrations found in these patients or may be the result of parasitic thyroiditis.

Multicentre evaluation of an antigen-detection ELISA for the diagnosis of Trypanosoma brucei rhodesiense sleeping sickness.

The performance of an enzyme-linked immunosorbent assay (antigen ELISA) for the detection, in serum or cerebrospinal fluid, of an invariant trypanosome antigen to diagnose Trypanosoma brucei rhodesiense sleeping sickness was evaluated in four clinical treatment centres. The test, which was carried out in polystyrene test-tubes, was positive in 88 (88.9%) of 99 parasitologically confirmed cases that were tested at the National Institute for Medical Research, Tabora, United Republic of Tanzania; 99 (94.3%) of 105 cases tested at the National Sleeping Sickness Control Programme, Jinja, Uganda; 86 (87.8%) of 98 cases tested at the Uganda Trypanosomiasis Research Organisation, Tororo, Uganda; and 59 (96.7%) of 61 cases tested at the Tropical Diseases Research Centre, Ndola, Zambia. The overall detection rate was 91.5%. There was no cross-reactivity with the agents of the common bacterial, viral, or parasitic diseases prevalent in the areas where the studies were conducted. The only false-positive result involved a blood donor from a trypanosomiasis endemic focus. The test was simple to perform, was read visually, and is therefore a potential tool for diagnosing human African trypanosomiasis.

A review of human African trypanosomiasis (HAT) in Uganda.

Sleeping Sickness epidemics have been occurring in Uganda since the beginning of the present century. These epidemics have been partially controlled in the past using the conventional methods of bush clearing, mass diagnostic surveys and treatment. Political and economic upheavals have greatly influenced the recurrence of these epidemics. This paper presents a review of the past and present situation and an outline of the control activities being undertaken in the country.

Possible causes leading to an epidemic outbreak of sleeping sickness: facts and hypotheses.

Sleeping sickness epidemics have been noted to occur with some degree of periodicity and the question as to why this is so has been asked for quite a long time. These epidemics have been partially controlled in the past using the conventional methods of bush clearing, mass diagnostic surveys and treatment. Political, social and economic upheavals have been found to be very important factors in the recurrence of these epidemics. In addition, a number of facts and hypotheses have been advanced as possible causes of epidemic outbreaks of sleeping sickness. This paper presents a brief account of factual epidemic outbreaks of sleeping sickness in south eastern Uganda (Busoga) and then proceeds to discuss, in general terms, a number of hypotheses that have been incriminated to date, as possible causes that might lead to an epidemic outbreak of the disease.