Christian Burri

Human African trypanosomiasis

Human African trypanosomiasis (sleeping sickness) occurs in sub-Saharan Africa. It is caused by the protozoan parasite Trypanosoma brucei, transmitted by tsetse flies. Almost all cases are due to Trypanosoma brucei gambiense, which is indigenous to west and central Africa. Prevalence is strongly dependent on control measures, which are often neglected during periods of political instability, thus leading to resurgence. With fewer than 12 000 cases of this disabling and fatal disease reported per year, trypanosomiasis belongs to the most neglected tropical diseases. The clinical presentation is complex, and diagnosis and treatment difficult. The available drugs are old, complicated to administer, and can cause severe adverse reactions. New diagnostic methods and safe and effective drugs are urgently needed. Vector control, to reduce the number of flies in existing foci, needs to be organised on a pan-African basis. WHO has stated that if national control programmes, international organisations, research institutes, and philanthropic partners engage in concerted action, elimination of this disease might even be possible.

The phenomenon of treatment failures in Human African Trypanosomiasis.

Treatment of Human African Trypanosomiasis (HAT or sleeping sickness) relies on a few drugs which are old, toxic and expensive. The most important drug for the treatment of second stage infection is melarsoprol. During the last 50 years treatment failures with melarsoprol were not a major problem in Trypanosoma brucei gambiense patients. Commonly a relapse rate of 5–8% was reported, but in recent years it has increased dramatically in some important foci of T. b. gambiense sleeping sickness. Treatment failures for T. b. rhodesiense are much less of a problem apart from some reports between 1960 and 1985 of refractoriness in T. b. rhodesiense patients in East Africa. Analysis of those isolates revealed that their in vitro sensitivity to melarsoprol was one‐tenth that of sensitive isolates, and complete failure to cure the infection in the acute mouse model with melarsoprol levels comparable with those in human patients. There was very little indication of resistance in T. b. gambiense isolates from Côte d’Ivoire and NW Uganda. The in vitro melarsoprol sensitivities for populations from relapsing and from curable patients were in the same range. Melarsoprol concentrations in the plasma and cerebrospinal fluid of patients 24 h after treatment did not show any difference between patients who relapsed and those who could be cured. The reason for relapses in the recent T. b. gambiense epidemics are not known. Other parasite‐related factors might be involved, e.g. affinity to extravascular sites other than the CNS which are less accessible to the drug. In conclusion, a combination of factors rather than a single one may be responsible for the phenomenon of melarsoprol treatment failures in T. b. gambiense patients.

Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial

BACKGROUND African trypanosomiasis is a fatal disease caused by protozoan parasites of the species Trypanosoma brucei. The disease has reached epidemic dimensions in various countries of central Africa. Treatment of the second stage is long and complicated, and is hampered by severe adverse reactions to the first-line drug, melarsoprol. Despite these problems, melarsoprol is likely to remain the drug of choice for the next decade. We therefore did a randomised trial comparing the standard treatment schedule with a new, concise regimen. METHODS The safety and efficacy of the new schedule were assessed in patients presenting to a hospital in Kwanza Norte, Angola with sleeping sickness. The control group followed the 26-day standard Angolan schedule of three series of four daily injections of melarsoprol at doses increasing from 1.2 to 3.6 mg/kg within each series, with a 7-day interval between series. The new treatment schedule comprised 10 daily injections of 2.2 mg/kg. Primary outcomes assessed were elimination of parasites, deaths attributed to treatment, and rate of encephalopathy. Analysis was by intention to treat. FINDINGS Of 767 patients with second-stage disease, 500 were enrolled: 250 were assigned the standard schedule, and 250 the new schedule. 40 patients on the standard schedule and 47 on the new schedule had adverse events which resulted in treatment disruption or withdrawal. 50 patients on the standard regimen deviated or withdrew from treatment, compared with two on the new regimen. Parasitological cure 24 h after treatment was 100% in both groups; there were six deaths (all due to encephalopathy) 30 days after treatment in each group. The number of patients with encephalopathic syndromes was also the same in each group (14). Skin reactions were more common with the new treatment, but all could be resolved by additional medication or withdrawal of treatment. INTERPRETATION Considering the economic and practical advantages of the new 10-day schedule over the standard 26-day treatment schedule, and the similarity of treatment outcome, the new schedule is a useful alternative to the present standard, especially in epidemic situations and in locations with limited resources.

Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis

Encephalopathies are the most feared complications of sleeping sickness treatment with melarsoprol. To investigate the existence of risk factors, the incidence of encephalopathic syndromes and the relationship between the development of different types of encephalopathies and the clinical outcome was studied in a clinical trial with 588 patients under treatment with melarsoprol. The 38 encephalopathy cases were classified into three types according to the leading clinical picture: coma type, convulsion type and psychotic reactions. Nine patients were attributed to the convulsion type, defined as a transient event of short duration with convulsions followed by a post‐ictal phase, without signs of a generalized disease. None of these patients died from the reaction. Febrile reactions in the 48 h preceding the reaction were generally not observed in this group. Twenty‐five patients were attributed to the coma type, which is a progredient coma lasting several days. Those patients often had signs of a generalized disease such as fever (84%), headache (72%) or bullous skin (8%) reactions. The risk of mortality was high in this group (52%). About 14/16 patients with encephalopathic syndrome of the coma type were infected with malaria. Patients with psychotic reactions or abnormal psychiatric behaviour (3/38) and one patient who died after alcohol intake were excluded from the analysis. The overall rate of encephalopathic syndromes in the cases analysed (n=34) was 5.8%, of which 38.2% died. We did not find any parameters of predictive value for the risk of developing an encephalopathic syndrome based on the symptoms and signs before treatment initiation. The appearance during treatment of febrile reactions (RR 11.5), headache (RR 2.5), bullous eruptions (RR 4.5) and systolic hypotension (RR 2.6) were associated with an increased risk for the occurrence of encephalopathic syndromes especially of the coma type.

New drugs for the treatment of human African trypanosomiasis: research and development.

Chemotherapy of human African trypanosomiasis is problematic because of the high frequency of severe adverse events, the long duration and high cost of treatment, and an increasing number of treatment-refractory cases. New cost-efficient, easy-to-use drugs are urgently needed. Whereas basic research on potential drug targets is anchored in academia, the complex, highly regulated and very expensive process of preclinical and clinical drug development is almost exclusively in the hands of pharmaceutical companies. Jennifer Keiser, August Stich and Christian Burri here review, from the angle of industrial drug research and development, the past ten years of research activities at different stages of the development of trypanocidal drugs, and assess future prospects. The absence of compounds in clinical development Phases I-III indicates no new drugs will become available in the next few years.

Effectiveness of a 10-Day Melarsoprol Schedule for the Treatment of Late-Stage Human African Trypanosomiasis: Confirmation from a Multinational Study (Impamel II)

BACKGROUND Treatment of late-stage human African trypanosomiasis (HAT) with melarsoprol can be improved by shortening the regimen. A previous trial demonstrated the safety and efficacy of a 10-day treatment schedule. We demonstrate the effectiveness of this schedule in a noncontrolled, multinational drug-utilization study. METHODS A total of 2020 patients with late-stage HAT were treated with the 10-day melarsoprol schedule in 16 centers in 7 African countries. We assessed outcome on the basis of major adverse events and the cure rate after treatment and during 2 years of follow-up. RESULTS The cure rate 24 h after treatment was 93.9%; 2 years later, it was 86.2%. However, 49.3% of patients were lost to follow-up. The overall fatality rate was 5.9%. Of treated patients, 8.7% had an encephalopathic syndrome that was fatal 45.5% of the time. The rate of severe bullous and maculopapular eruptions was 0.8% and 6.8%, respectively. CONCLUSIONS The 10-day treatment schedule was well implemented in the field and was effective. It reduces treatment duration, drug amount, and hospitalization costs per patient, and it increases treatment-center capacity. The shorter protocol has been recommended by the International Scientific Council for Trypanosomiasis Research and Control for the treatment of late-stage HAT caused by Trypanosoma brucei gambiense.

Efficacy of 10-day melarsoprol schedule 2 years after treatment for late-stage gambiense sleeping sickness

In 2000, we reported that a new short treatment schedule of melarsoprol was not worse than the longer and demanding standard treatment for late-stage human African trypanosomiasis. This alternative schedule was assessed in an open, randomised clinical equivalence trial of 500 patients in Angola. 24 h after treatment, all patients were parasite free. Of 442 patients, 12 (3%) had relapsed after 1 year, of whom seven (3%) had had standard treatment and five (2%) the alternative treatment. After 2 years, 23 (5%) relapsing patients were reported, 11 (5%) in the standard treatment group and 12 (6%) in the new group. The results at the 2-year follow-up support and strengthen our previous findings.

Cardiac involvement in African and American trypanosomiasis

American trypanosomiasis (Chagas disease) and human African trypanosomiasis (HAT; sleeping sickness) are both caused by single-celled flagellates that are transmitted by arthropods. Cardiac problems are the main cause of morbidity in chronic Chagas disease, but neurological problems dominate in HAT. Physicians need to be aware of Chagas disease and HAT in patients living in or returning from endemic regions, even if they left those regions long ago. Chagas heart disease has to be taken into account in the differential diagnosis of cardiomyopathy, primarily in patients with pathological electrocardiographic (ECG) findings, such as right bundle branch block or left anterior hemiblock, with segmental wall motion abnormalities or aneurysms on echocardiography, and in young patients with stroke in the absence of arterial hypertension. In HAT patients, cardiac involvement as seen by ECG alterations, such as repolarisation changes and low voltage, is frequent. HAT cardiopathy in general is benign and does not cause relevant congestive heart failure and subsides with treatment. We review the differences between the American and African trypanosomiasis with the main focus on the heart.

Assessment of global reporting of adverse drug reactions for anti-malarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

BackgroundIn spite of enhanced control efforts, malaria remains a major public health problem causing close to a million deaths annually. With support from several donors, large amounts of artemisinin-based combination therapy (ACT) are being deployed in endemic countries raising safety concerns as little is known about the use of ACT in several of the settings where they are deployed. This project was undertaken to profile the provenance of the pharmacovigilance reporting of all anti-malarials, including ACT to the WHO adverse drug reaction (ADR) database (Vigibase™) over the past 40 years.MethodsThe WHO Programme for International Drug Monitoring, the Uppsala Monitoring Centre (UMC) provided anonymized extracts of Vigibase™ covering the period 1968-2008. All countries in the programme were clustered according to their malaria control phase and income status. The number of individual case safety reports (ICSRs) of anti-malarials was analyzed according to those clusters.ResultsFrom 1968 to 2008, 21,312 ICSRs suspecting anti-malarials were received from 64 countries. Low-income countries, that are also malaria-endemic (categorized as priority 1 countries) submitted only 1.2% of the ICSRs. Only 60 out of 21,312 ICSRs were related to ACT, 51 of which were coming from four sub-Saharan African countries. Although very few ICSRs involved artemisinin-based compounds, many of the adverse events reported were potentially serious.ConclusionsThis paper illustrates the low reporting of ADRs to anti-malarials in general and ACT in particular. Most reports were submitted by non-endemic and/or high-income countries. Given the current mix of large donor funding, the insufficient information on safety of these drugs, increasing availability of ACT and artemisinin-based monotherapies in public and private sector channels, associated potential for inappropriate use and finally a pipeline of more than 10 new novel anti-malarials in various stages of development, the presence of well functioning national pharmacovigilance systems is vital to ensure safe and responsible scale up of ACT deployment. Bringing together the competencies of national pharmacovigilance centres and various types of organizations in the NGO, academic and private sectors with global coordination to create short- and long-term solutions may help address the lag between rapidly growing ACT use and poor ADR reporting.

Comparative Detection of Trypanosomal DNA by Loop-Mediated Isothermal Amplification and PCR from Flinders Technology Associates Cards Spotted with Patient Blood

ABSTRACT We analyzed DNA eluted from FTA (Flinders Technology Associates) cards spotted with blood from human African trypanosomiasis (HAT) patients admitted at Lwala Hospital in eastern Uganda and Kaliua Health Centre in northwestern Tanzania. The aims were to evaluate loop-mediated isothermal amplification (LAMP) for detection of trypanosomal DNA in clinical samples and to characterize the infecting trypanosomes to the subspecies level. LAMP targeting the Trypanozoon conserved random inserted mobile element (RIME-LAMP) and that for the serum resistance-associated (SRA) gene (SRA-LAMP) were performed. For comparison, PCRs for the SRA gene specific for Trypanosoma brucei rhodesiense (SRA-PCR) and that to amplify the Trypanosoma brucei gambiense-specific surface glycoprotein (TgSGP-PCR) were done. Out of 128 samples analyzed, SRA-PCR was positive in 101 samples (78.9% sensitivity; 95% confidence interval [CI], 71.1 to 85.1%), SRA-LAMP was positive in 120 (93.8%; 95% CI, 88.2 to 96.8%), while RIME-LAMP revealed signals in 122 (95.3%; 95% CI, 90.2 to 97.8%). RIME-LAMP and SRA-LAMP were each significantly more sensitive than SRA-PCR (P values of 0.000 and 0.001, respectively; Fishers exact test). There was poor agreement between RIME-LAMP and SRA-LAMP and the SRA-PCR, yielding kappa values of 0.31 and 0.40, respectively. Agreement between SRA-LAMP and RIME-LAMP was almost perfect (kappa value, 0.85; 95% CI, 0.64 to 1). All the 128 field samples were negative by TgSGP-PCR. Blood spots from three T. b. gambiense HAT cases from northwestern Uganda were positive by TgSGP-PCR and RIME-LAMP. PCR took five times longer to execute than LAMP. LAMP may be useful to monitor emerging HAT foci or to test travelers returning from countries where HAT is endemic. It should be evaluated in a case-control study to determine its utility as a HAT diagnostic.