Human African trypanosomiasis (HAT), also known as ‘sleeping sickness’ is a parasitic disease caused by protozoan parasites of the Genus Trypanosoma. The disease is transmitted by tsetse flies, and is found in low-income, rural regions in sub-Saharan Africa.
The disease presents in two forms depending on the sub-species of the infecting parasite:
- Chronic infection, which accounts for 98% of reported cases and has a long latency period—people can be infected for years without becoming symptomatic.
- Acute infection, which is more virulent than the chronic form and manifests within weeks or months of infection.
In the early or first stage of illness, the disease causes non-specific symptoms and generally goes undiagnosed. The late stage is associated with invasion of the brain by parasites, which ultimately causes death if left untreated. Early diagnosis is critical: after the disease has advanced to the second stage, treatment procedures are complicated and risky.
In recent years, concerted efforts in surveillance and control of HAT have achieved impressive success. The WHO goal of eliminating the disease by 2020 is now more realistic than ever.
The diagnostic landscape
Since 2006, FIND has collaborated with WHO and partners in research, industry and government to develop user-friendly tests that enable early detection of cases and are appropriate for remote resource-limited settings.
At present, diagnosis of HAT requires: 1) screening to identify suspects, 2) lab work to confirm presence of the disease in suspects, and 3) ‘staging’ to verify whether the disease has advanced to the brain and what treatment is appropriate.
Current screening strategies require heavy logistics and their sensitivity is unsatisfactory. Only a small fraction of at-risk populations are screened and a significant number of cases go undetected. A first-generation rapid diagnostic test (RDT) is helping to address these challenges, but a better-quality, second-generation RDT that is easier to manufacture is needed.
Improved case confirmation and staging methods are also imperative. Currently, patients who are found positive for HAT with RDTs have to be confirmed because available treatments can cause serious side effects. Current methods for staging and confirmation of cure require an invasive and uncomfortable lumbar puncture and are either insufficiently accurate, labour intensive, or not widely used.
FIND's strategic approach
FIND has prioritized development of diagnostic solutions to improve screening and case confirmation of HAT, and to sustain elimination. These interventions include developing and introducing: i) highly accurate RDTs for screening HAT, ii) an RDT that detects both HAT and malaria, iii) improved microscopy tools, and iv) highly sensitive molecular methods for case confirmation.
To improve the impact of new diagnostic solutions, FIND simultaneously supports related policy, access and advocacy activities.
Current screening strategies have an unsatisfactory sensitivity and require heavy logistics. This means that a significant number of HAT cases remain undetected, and that only a small fraction of the at-risk population is tested.
FIND has prioritized:
1. development and introduction of a second generation RDT
2. development and introduction of an RDT for simultaneous detection of HAT and malaria.
1. 2nd generation RDT
Although a first generation RDT for brucei gambiense HAT has recently been introduced, a second generation RDT based on recombinant antigens, which are easier to produce than the native antigens used in the current test, is needed. This will enable sustainable and affordable large-scale production.
A prototype 2nd generation RDT has been developed and its performance is being evaluated in a prospective study in the DRC. If the results or this study are satisfactory, the new test is expected to be commercialized during the first half of 2016.
2. HAT-malaria combo RDT
To ensure continued surveillance and detection of cases and prevent re-emergence as the prevalence of HAT decreases, and since all settings where HAT is found are also endemic for malaria, development and introduction of an RDT to simultaneously detect HAT and malaria would be an attractive approach.
A prototype HAT-malaria combo RDT has been developed and its evaluation on stored clinical samples is in progress.
- 1. 2nd generation RDT
Confirmation of HAT cases is a necessity because the treatments that are currently available are relatively complicated to administer and can sometimes cause significant side-effects. Current confirmatory methods are either insensitive, labour-intensive or not widely available because of production and logistical constraints. Extra efforts are needed to develop and introduce new tools that are more sensitive and easier to implement, so that cases can be detected more efficiently and more widely.
FIND has prioritized:
1. development and introduction of improved microscopy tools (e.g. by combining capillary tube centrifugation with fluorescence microscopy)
2. evaluation and introduction of a highly sensitive molecular method based on LAMP.
The possibility of combining the capillary tube centrifugation (CTC) method with acridine orange (AO) staining and examination by LED fluorescence microscopy is being explored. This approach is expected to result in markedly improved sensitivity compared to classical CTC, while remaining simple to implement, without any need for a cold chain, and with minimal training.
Loop-mediated isothermal amplification (LAMP) is a promising molecular technique that can be used to amplify target trypanosomal DNA at a constant temperature, meaning that it can be carried out with minimal equipment at low-level laboratories. Development of the LAMP kit for HAT was completed by Eiken in 2011. Further optimization of sample preparation and clinical evaluation of the kit at multiple sites in the DRC and Uganda is at an advanced stage.
- 1. AO-CTC
Staging/Test of cure
Staging and confirmation of cure involve performing an invasive and uncomfortable lumbar puncture and examination of the spinal fluid by microscopy, which has limited accuracy. While there is likelihood that a safe and effective drug for both stages of the disease will become available quite soon, it is necessary to develop new staging tools for use until this drug is widely available. These staging tools would also be needed in the event that the new drug does not meet expectations, in order to avoid exposing stage 1 patients to potentially toxic stage 2 drugs. These tools could also be used to confirm cure after treatment, with the advantage of requiring fewer lumbar punctures.
FIND has been working with a number of partners to identify biomarkers and developing new staging tests. Special attention has been given to speed, simplicity, cost and reliability of the new tests, as well as reduced invasiveness. To date, neopterin and CXCL13 have been identified as the best biomarkers that can be used to identify patients with brain disease, and for confirming cure and detecting relapses. Based on this, FIND and concile GmbH are working to optimize an RDT that was originally developed to detect neopterin in blood samples, to be used for staging and for follow-up using CSF samples.
Implementation of diagnostics
A number of implementation projects to introduce new diagnostic tools and strategies that have been recently made available have been initiated by national control programmes of HAT endemic countries, FIND and other partners. These capacity building projects include strengthening of health facilities, installation of solar energy, procurement of laboratory equipment and consumables, training of personnel, quality assurance, advocacy and sensitization of communities. In addition, they are expected to significantly contribute to accelerating elimination of HAT by facilitating early detection of cases and preventing transmission of the disease.
Implementation projects are currently ongoing in Uganda, Malawi, Guinea, Chad, South Sudan, Nigeria, DRC, Angola and the Republic of the Congo. For detailed information and updates, visit the project page linked in the button below.