F. Milord

Efficacy and toxicity of eflornithine for treatment of Trypanosoma brucei gambiense sleeping sickness.

The usual first-line treatment for Trypanosoma brucei gambiense sleeping sickness is melarsoprol, but when that fails the outlook has hitherto been grim. The polyamine synthesis inhibitor eflornithine (difluoromethylornithine, DFMO) has emerged as an alternative therapy. 207 patients with late-stage T b gambiense sleeping sickness were treated in rural Zaire with three different regimens of DFMO in an open-trial design. During treatment, trypanosomes disappeared from the CSF of all 87 patients in whom parasites had been seen before DFMO administration, and there was a sharp fall in CSF white cell count from a mean of 186/microliters to 21/microliters. 152 patients have been followed for at least a year after DFMO treatment, and only 13 (9%) have relapsed. Treatment failures were more common in children less than 12 years, among patients treated with oral DFMO only, and among patients who received DFMO as the initial treatment of their recently diagnosed trypanosomiasis. Toxicity was acceptable. Only 4 patients died during or shortly after treatment. Bone marrow suppression resulting in anaemia (43%) or leucopenia (53%) was common but bore little consequence. This open trial shows that DFMO is as active as and possibly less toxic than melarsoprol. For economic and logistic reasons DFMO may not be the first-choice therapy in rural Africa but for the vast majority of patients who relapse after melarsoprol DFMO will be curative.

Risk factors for encephalopathy and mortality during melarsoprol treatment of Trypanosoma brucei gambiense sleeping sickness.

This paper reviews the incidence of, and risk factors for, drug-induced encephalopathy and mortality (from all causes) during treatment with melarsoprol of 1083 patients with Trypanosoma brucei gambiense sleeping sickness in Nioki hospital (Zaire) between 1983 and 1990. Sixty-four patients (5.9%) developed encephalopathy and 62 (5.7%) died: 43 from reactive encephalopathy and 19 from other causes. Univariate and multivariate analyses showed that the administration of prednisolone reduced significantly the incidence of encephalopathy and mortality during treatment, especially in patients with trypanosomes observed in the cerebrospinal fluid (CSF) and/or with a CSF white blood cell (WBC) count of 100 or more per mm3. The risk of encephalopathy was associated more strongly with the CSF WBC count than with the presence of CSF trypanosomes. In the subgroup of patients with a CSF WBC count of 100 or more mm3, changing the melarsoprol regimen to 3 series of 3 injections instead of 3 series of 4 injections halved the mortality rate during treatment. Treatment of patients who do develop reactive encephalopathy with the heavy metal chelator dimercaprol, in addition to intravenous steroids and anticonvulsants, may be harmful. The data suggest that a further reduction of the total dose of melarsoprol may decrease toxicity without jeopardizing efficacy.

TRIAL OF PREDNISOLONE FOR PREVENTION OF MELARSOPROL-INDUCED ENCEPHALOPATHY IN GAMBIENSE SLEEPING SICKNESS

In a prospective randomised trial, 620 patients who had Trypanosoma brucei gambiense trypanosomiasis with central nervous system involvement were treated either with prednisolone plus melarsoprol or with melarsoprol only. 598 patients were evaluable: morbidity and death associated with melarsoprol-induced encephalopathy was reduced in patients who were given prednisolone. The two groups did not differ either in the incidence of other complications of melarsoprol therapy or in relapse rate after melarsoprol therapy. The cost of prednisolone would be outweighed by savings on the treatment of encephalopathies in such patients.

African trypanosomiasis and drug-induced encephalopathy: risk factors and pathogenesis

Data on 598 patients with Trypanosoma brucei gambiense sleeping sickness, with abnormal cerebrospinal fluid (CSF) and treated with melarsoprol, were reviewed to determine risk factors for drug-induced encephalopathy. The incidence of melarsoprol-induced encephalopathy was increased in patients with trypanosomes present in the CSF, in patients with a high CSF lymphocyte count, and among patients in whom no trypanosomes were found in either the blood or the lymph node aspirate. Among patients with trypanosomes in the CSF, the risk of encephalopathy was similar whether or not they also had trypanosomes seen in the haemolymphatic system. Dimercaprol, a heavy metal chelator, did not reduce the case-fatality rate of patients with encephalopathy. These observations and others are compatible with the hypothesis that an immune phenomenon is involved in the pathogenesis of melarsoprol-induced encephalopathy. Whether the basic mechanism relates to deposits of immune complexes in the central nervous system or to the release of trypanosomal antigens which subsequently bind to brain cells and attract antibodies or T lymphocytes, the rapidity with which trypanosomal antigens are released may be critical, and very aggressive therapeutic schemes may result in higher toxicity, especially in patients with an impaired blood-brain barrier.

DIFLUOROMETHYLORNITHINE FOR ARSENO-RESISTANT TRYPANOSOMA BRUCEI GAMBIENSE SLEEPING SICKNESS

26 patients with arseno-resistant Trypanosoma brucei gambiense trypanosomiasis were treated with difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, given intravenously, then orally. There was rapid disappearance of trypanosomes in the cerebrospinal fluid (CSF), gradual decrease of CSF lymphocytosis, and parallel improvement in central nervous system status. Side-effects, including diarrhoea, anaemia, and hair loss, were common but tolerable and reversible. 5 patients died during or shortly after treatment. None of the 21 patients who completed therapy has had a relapse during the 6-30 month follow-up.

Gambiense trypanosomiasis: Frequency of, and risk factors for, failure of melarsoprol therapy

1083 patients with late-stage Trypanosoma brucei gambiense sleeping sickness were treated with melarsoprol in Nioki hospital, Zaire, between 1983 and 1990. Sixty-two (5.7%) died during treatment. Of the 1021 patients who survived the treatment, 63 (6.2%) subsequently relapsed, 58 (92%) of whom were diagnosed within 2 years of melarsoprol treatment. There was no evidence of an increase in the frequency of treatment failures during the study period, and the rate of relapses that we documented is comparable to that reported from Zaire more than 30 years ago. Relapses were more frequent among patients who had trypanosomes seen in the cerebrospinal fluid (CSF) at the time of the initial diagnosis (odds ratio [OR] = 2.76, 95% confidence interval [CI] = 1.65-4.63, P = 0.0001). Male patients had twice as many relapses as females (OR = 2.00, 95% CI = 1.19-3.36, P = 0.009), which was partly explained by males having trypanosomes in the CSF more often than females. There were important geographical variations in the frequency of relapses within the territory of the Nioki rural health zone, suggesting that the circulation of trypanosomes was geographically limited. Prednisolone treatment did not increase the risk of treatment failure, nor did decreasing the total dose of melarsoprol from 12 to 9 injections for patients with > or = 100 white blood cells/mm3 of CSF. Since patients with trypanosomes in the CSF are also those who are at the highest risk of melarsoprol-induced encephalopathy, more aggressive treatment regimens cannot be recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire

Thirty patients with arseno-resistant Trypanosoma brucei gambiense sleeping sickness were treated with high-dose nifurtimox (30 mg/kg/d for 30 d). During treatment, the cerebrospinal fluid (CSF) white blood cell (WBC) count decreased in all patients except one (mean CSF WBC count before nifurtimox: 117/mm3; after nifurtimox: 25/mm3), and trypanosomes disappeared from the CSF of all 9 patients in whom parasites had been demonstrated before nifurtimox. Among 25 patients seen at least once after treatment, 9 (36%) have relapsed so far. High-dose nifurtimox was significantly toxic: one patient died during treatment and 8 others developed adverse neurological effects. High-dose nifurtimox seems more effective than the previously used regimen (15 mg/kg/d for 60 d), but at the expense of significant toxicity.

Eflornithine concentrations in serum and cerebrospinal fluid of 63 patients treated for Trypanosoma brucei gambiense sleeping sickness

Eflornithine (difluoromethylornithine, DFMO) has recently been approved for the treatment of Trypanosoma brucei gambiense trypanosomiasis. Treatment failures have been infrequent but have occurred among patients treated with oral DFMO only, and among children. To investigate the higher frequency of failures observed in young patients, DFMO trough concentrations in serum and cerebrospinal fluid (CSF) were measured at the end of treatment in 13 children and 50 adults who had received 200 mg/kg intravenously every 12 h for 14 d. Mean DFMO concentration in CSF was significantly lower among children aged less than 12 years when compared to older patients (25.1 vs 68.9 nmol/mL, P < 0.001). Mean serum concentration was also lower in children (49.2 vs 87.5 nmol/mL, P = 0.03). Among patients who received DFMO as initial therapy for sleeping sickness, the mean CSF/serum ratio was lower in children (0.41 vs 0.91, P < 0.005). The 3 patients who failed DFMO treatment had CSF trough concentrations around or below 50 nmol/mL. Convulsions and anaemia were associated with higher drug levels and previous therapy with melarsoprol. The lower CSF drug concentrations observed in children could result from higher renal clearance and different CSF pharmacokinetics of DFMO in that age group. To avoid treatment failures, a 6-hourly regimen as well as higher DFMO dosage based on body surface area rather than on weight are recommended for children.

An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire

Twenty-five patients with arseno-resistant Trypanosoma brucei gambiense sleeping sickness were treated with oral nifurtimox, 12-17 mg/kg/d for 60 d. During treatment, trypanosomes disappeared from the cerebrospinal fluid (CSF) of 7/7 patients; the CSF infections; leucocyte was significantly lower at the end of treatment than before it was begun (pre-nifurtimox: 124.2 (+/- 149.3) per microliter; post-nifurtimox: 11.9 (+/- 12.1) per microliter; P less than 0.001). Nifurtimox was well tolerated, with gastro-intestinal disturbances in 6 patients and a reversible cerebellar syndrome in 2 patients. Among the 19 patients seen at least once at follow-up, 12 (63%) relapsed. The other 7 patients have been followed for 3-18 months, and the CSF remained completely normal in 4 of them. This study confirms that nifurtimox has some activity against T.b. gambiense, but a daily dosage higher than 15 mg/kg/d will be necessary to achieve cure of most patients.

Epidemiological evidence for immunity following Trypanosoma brucei gambiense sleeping sickness

In order to investigate whether protective immunity appears after Trypanosoma brucei gambiense sleeping sickness, we undertook a retrospective cohort study of 3 remote villages in central Zaire (total population 1431), in which 38% of all adults had a past history of human African trypanosomiasis. Among adults previously diagnosed with trypanosomiasis and treated, the risk of a second episode of trypanosomiasis during the 10 years period of observation was only 15% (with a 24 months refractory period) and 30% (without a refractory period) of the risk of a first episode in adults never previously diagnosed. We could not demonstrate a similar difference among children, to some extent because only a few of them were diagnosed for a first time with trypanosomiasis. Our findings suggest that very significant immunity appears after Gambian sleeping sickness, and that developing a vaccine against this subspecies of trypanosomes is biologically plausible.