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Global Health Landscape
Human African Trypanosomiasis (HAT)
Background information
• What is Human African Trypanosomiasis (HAT)?
Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by a single-celled parasitic
protozoan called a trypanosome and is transmitted by tsetse flies. The disease progresses from fever and fatigue to
severe neurological conditions. Untreated HAT results in death.
• Global burden
There are 60 million people at risk worldwide. Each year, there are an estimated 10,000 to 50,000 deaths.
• Geographic distribution
HAT is found in 36 countries in sub-Saharan Africa, but the vast majority of cases occur in just three countries: Angola,
the Democratic Republic of the Congo, and Sudan.
• Causative agent/transmission
HAT is caused by Trypanosoma brucei, a protozoan parasite transmitted to humans by the bite of an infected tsetse
fly. There are several subspecies of T. brucei; T.b. gambiense, found in Central and West Africa, causes chronic
disease, and T.b. rhodesiense, present in South and East Africa, causes acute disease. The cattle reservoir for T.b.
rhodiense has proved to be a barrier for disease control. T. brucei is related to the trypanosomes that cause Chagas
disease and leishmaniasis.
Presentation
T. brucei parasites first develop in the blood, lymph, and peripheral organs (stage 1) and then cross the blood-brain barrier and
enter the central nervous system (stage 2). Stage 2 is characterized by severe neurological disorders including extreme
fatigue, major disturbances to patients’ sleep cycle (hence “sleeping sickness”), and coma. Without treatment, the disease is
always fatal.
Trends
By the 1960s, aggressive surveillance and programs to eradicate tsetse flies resulted in the near disappearance of the
disease. Subsequently, control measures were relaxed, tsetse populations recovered, and HAT rebounded. Since the WHO
made HAT a priority in 1995, improved HAT control has caused a 68 percent reduction in cases, as of 2006.
Existing Products
Drugs
Current treatments have variable
efficacy, are prohibitive to deliver
(pentamidine is delivered by
parenteral injection; all others are
administered intravenously), and can
be highly toxic.
Vaccines
Diagnotstics
None
There are no rapid, easy-to-use,
serological point-of-care diagnostic
tests available. As a result, patients
are not typically diagnosed until the
late stage of the disease.
Case Detection
Pentamidine
• Blood smear for T.b.
rhodesiense (sensitive) or T.b.
gambiense (less sensitive)
• Card indirect agglutination test
(CATT) for T.b. gambiense
• Treats stage 1 T.b.
gambiense infection
(ineffective against stage 2
HAT)
• Side effects are rare
Staging
Suramin
• Microscopy on cerebral spinal
fluid following lumbar puncture
• Treats stage 1 T.b.
rhodesiense infection
(ineffective against stage 2
HAT)
• Side effects can be severe
Melarsoprol (Arsenic Derivative)
• Treats stage 2 HAT
• Side effects are frequent and
severe; results in reactive
encephalopathies in 5 to 10
percent of treated cases
• Showing evidence of
resistance
Eflornithine (DFMO)
• Treats stage 2 HAT; effective
only against T.b. gambiense
infection
• Side effects are numerous
and can be severe
• Requires hospital
administration
• Highly effective, but costs are
high and supply is unreliable
New Product Needs
Drugs
• Reduced toxicity
• Efficacy against T. gambiense
and T. rhodesiense
• Efficacy against stage 1 and
stage 2 disease
• Must cross blood-brain barrier
in order to eliminate central
nervous system infection in
stage 2 disease
Vaccines
• Vaccines not targeted
Diagnotstics
• Distinguishes between stage 1
and stage 2 disease (treatment
choice depends on whether or
not there is central nervous
system involvement)
• Test of cure
Pipeline
Drugs
Discovery
Pre-Clinical
Clinical
Phase I
Clinical
Phase II
Clinical
Phase III
Discovery
Pre-Clinical
Clinical
Phase I
Clinical
Phase II
Clinical
Phase III
DNDi/Accelera/STI/Axyntis/Covance/Aptuit/KARI
(fexinidazole)
DNDi/Accelera/STI/Axyntis/Covance/Aptuit/KARI
(fexinidazole)
Consortium for Parasitic Drug Development (DB
series)
DNDi/Scynexis/Pace University (HAT
consortium for lead optimization)
DNDi/STI/Fiocruz and many others
(nitroimidazoles)
DNDi/Epichem/Murdoch University (microtubule
inhibitors)
DNDi/GSK/STI (4(1H) pyridones and cysteine
protease inhibitors)
DNDi/Kitasato Institute (screening: natural
products)
DNDi/Central Drug Research Institute
(screening)
DNDi/Eskitis Institute (screening: natural
products)
University of Dundee Tropical Disease Initiative
(screening)
Sandler Center (kinase inhibitors)
Diagnostics
Nucleic acid detection
FIND/Murdoch University/Obihiro
University/Eiken Chemical Corp (loop-mediated
isothermal amplification of DNA)
Antibody or antigen detection
FIND/MicroCoat (serologic dx: T. b. gambiense)
FIND/University of Technology (Germany) (RNA
aptamers)
FIND/SBRI (optimized antibody probes)
FIND/University of Brussels (nanobodies)
Disease staging
FIND/Inst. of Tropical Medicine/Royal Tropical
Institute (IgM quantification; ‘dri-dot’ single
format test)
FIND/Aberdeen University (blood markers)
FIND/University of Geneva/Inst. of Tropical
Medicine/Makerere Univ. (biomarkers)
Market Opportunities
Primarily a disease of impoverished rural communities and will require donor support to encourage innovation.
Development Issues
Drugs
• Eradication of central nervous
system infection is difficult to
confirm (only a few residual
organisms are needed for
infection to recur)
Vaccines
• T. brucei undergo extensive
antigenic
variation, which presents
significant
obstacles to vaccine
development
Diagnotstics
• Serum biomarkers that
correlate with stage 2 disease
have only recently been
identified
Development Issues
General Disease Links
• World Health Organization (WHO)
• Centers for Disease Control and Prevention (CDC)
Key Organizations
•
•
•
•
Drugs for Neglected Diseases Initiative (DNDi)
Foundation for Innovative New Diagnostics (FIND)
Special Programme for Research and Training in Tropical Diseases (TDR)
University of Dundee, Tropical Disease Initiative
Important Papers
• Berriman, M, et al. The genome of the African trypanosome Trypanosoma brucei. Science 309:416-22 (2005)
• El-Sayed, NM, et al. Comparative genomics of trypanosomatid parasitic protozoa. Science 309:404-9 (2005)
• Legros, D, et al. Treatment of human African trypanosomiasis—present situation and needs for research and
development. Lancet Infect Dis 2:437-40 (2002)
• Njiru, ZK, et al. Loop mediated isothermal amplification (LAMP) method for rapid detection of Trypanosoma brucei
rhodesiense. PLoS NTD. 2:e147 (2008)
• Renslo, AR, and McKerrow, JH. Drug discovery and development for neglected parasitic diseases. Nature Chemical
Biology 2:701-10 (2006)
• Simarro, P, et al. Eliminating human African trypanosomiasis: Where do we stand and what comes next? PLoS Med
5:e55 (2008).
©2010 BIO Ventures for Global Health.