Chagas Disease in the Americas: Impacts and Opportunities for Control

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1 Chagas Disease in the Americas: Impacts and Opportunities for Control Rick Tarleton Center for Tropical and Emerging Global Diseases University of Georgia The Chagas Disease Foundation

2 Trypanosoma cruzi and Chagas Disease the most neglected of the neglected diseases?

3 General Background 10 to 20 million infected worldwide - mostly (but not exclusively) in Latin America -poor surveillance limits the accuracy of estimates Transmission occurs by insect vector, food contamination, transplantation/transfusion and congenitally -none of these mechanism is especially efficient Diagnosis is usually decades after the initial infection and most do not receive treatment -Success of treatment is variable and/or difficult to assess -Adverse events Limited support for detection, prevention, treatment -diagnostics are poor -treatments are limited -vaccines are non-existent This is a zoonotic infection: it will not be eradicated

4 Situation outside of Latin America U.S. Southern U.S. is endemic although transmission to humans is low ~300,000 infected residents, most undiagnosed and untreated 70-80% (?) of donated blood screened; sensitivity of test is unknown other donated tissues are largely unscreened no licensed diagnostic test Physician awareness is very low Elsewhere Spain: ~50,000 infected immigrants rest of Europe, Canada, Australia, Japan (1,000 s each) limited screening and treatment capabilities in most countries Congenital and transfusion/transplantation associated transmission are largest concerns; poor monitoring and prevention

5 Immunity and Disease The vast majority of individuals infected with T. cruzi develop highly effective control of the infection but never clear the infection An effective treatment or preventative is going to have to do better than the normal immune response e.g. clear 100% of parasites Detection of infected individuals is difficult and detection of cure is even more difficult 5

6 Priority Issues for Chagas Disease: Development of better diagnostics Discovery, development and testing of better treatment regimens, including new drugs Better methods for assessing treatment efficacy Development of integrated, sustainable vector control protocols

7 Diagnosis of T. cruzi infection serological tests ELISA, IFA, IHA, CF Mostly with crude lysates or whole epimastigotes; a few with recombinant proteins Best 2 out of 3 detection (PCR) culture (xenodiagnosis or hemaculture)

8 Current serodiagnostics are inadequate Positive serology depends on the test. Results of random blood bank screening in Santa Cruz, Bolivia 8 Pirard, et al., 2005 Transfusion 45:

9 Seronegative subjects in endemic areas have T cell responses to T. cruzi 9 Olivera, et al Microbes and Inf.

11 10 insects per box; 40,640 total insects Cerisola, J.A PAHO Pub #347

12 PCR/Hemoculture results for confirmed seropostive U.S. blood donors + - % PCR (EDTA) Hemoculture (Heparin) Conclusion: PCR (or other parasite detection techniques) is not likely to be an effective method for diagnosis or for monitoring of treatment efficacy. Source: David Leiby, American Red Cross

13 Chemotherapeutics for Chagas disease Nifurtimox nitrofuran, appears to act by reduction of nitro groups to nitroanion radicals and consequently, reduced oxygen metabolites such as superoxide and peroxide Benznidazole a nitroimidazole that appears to induce reductive stress through the covalent modification of macromolecules by nitroreduction intermediates J. Urbina, Current Pharmaceutical Design, 2002

14 Chemotherapeutics for Chagas disease Dogma is that treatment is not effective unless given in the acute phase of infection Two drugs, nifurtimox and benznidazole, are capable of curing at least 50% of recent infections. These products are active in the acute and short-term (up to a few years) chronic phase. However, they have little or no activity in long-term chronic forms of the disease. WHO Problems -the definition of cure -what is accepted as proof of cure Absence of proof is not proof of absence

15 Efficacy of Benznidazole Treatment in Chronic Chagas disease Accessible tests of cure are needed in order to evaluate new therapies Viotti, et al Ann. Intern. Med. 144:

16 Chagas Disease: Vector Control Source: WHO/TDR

20 Short-comings of a vector control only approach: time-consuming, labor-intensive, never-ending insecticidal resistance is extensive distinct behavioral characteristics of various vector species

21 Opportunities: Diagnosis Almost certainly will have to depend on detection of immune responses rather than direct detection of parasites/products Tests do not need to be rapid point-of-care tests (testing can be centralized) Tests need to be rigorously certified and uniform (the format, e.g. ELISA, IFA, etc., is not the issue) single test without discordant or false negative outcomes preferably quantitative (for monitoring changes over time/post-treatment)

22 Assessing treatment efficacy this is the single biggest factor that prevents the utilization of existing drugs and the development of new drugs drug treatment in all acute and chronic cases is the only effective means of preventing the development of clinical disease direct parasite detection or detection of parasite products (proteins, DNA, etc.) is unlikely to satisfy this need development of a test that absolutely certifies parasitological cure is going to be difficult (but this is not unique to Chagas disease)

23 Pre-treatment Successful treatment Post-treatment Need: Cheaper platform

24 Can other biomarkers of cure be identified? Gene expression profiles Minning, et al., unpublished

25 Opportunities: Drug Development Much improved high and medium throughput screening assays have been developed - facilitates large (>1 million compounds) library screens -fast in vivo screens as follow-up Involvement of industry, PPP, non-profits in drug discovery (GSK, Novartis, Pfizer, Sanofi Aventis, DNDi, etc.) Needs: -Coordination and prioritization -post-screening financial support -follow-through -development/agreement on tools for assessment Chagas Drug Discovery Consortium 2 nd meeting Nov. 3, 2010, Atlanta, GA

26 Opportunities: Vector Control Vector control has been and can be highly effective in preventing transmission But vector control has to be more than simply spraying; insecticidal resistance is a big challenge One size does not fit all different characteristics of different environments Decisions/recommendations can not be based upon dogma, anecdotal evidence, or insufficient data Needs: Better use of simple tools and development of new tools Integration of methods for specific local situation Improved infrastructure for and commitment to supporting vector and transmission control

27 Example: Eliminate dogs as reservoirs of infectivity for reduviids Elimination of infected dogs from a household with infected people is nearly sufficient to extinguish transmission of T. cruzi, barring reintroduction of infected dogs, children, or bugs Cohen, et al., Science (2001) Strategy: Generate attentuated parasite lines by gene knockout Produce infective metacyclic trypomastigotes Deliver/vaccinate by oral administration Key Benefits: Vaccine does not have to provide 100% protection from infection just the prevention of development of a parasitemic infection cleared Neither the vaccine nor the challenge infection have to be completely Vaccine can be delivered rapidly to multiple animals

28 Summary: Drug therapy is the only option for the 20 million individuals already infected and for those who will become infected in the future. current treatments should be more widely used new therapies should be aggressively pursued Diagnostic assays to better protect against new infections and to assess the efficacy of treatment require development Integrating control efforts will require money, political will and local buy-in Policy Better articulation of the realistic opportunities Establishment of research and development priorities based upon rigorous and educated evaluations Development of mechanisms (funding) for improved and focused efforts in Chagas disease

Chagas Initiative. Chagas disease is one of the main public health problems in Latin America, where it is more common than malaria

Chagas Initiative. Chagas disease is one of the main public health problems in Latin America, where it is more common than malaria Chagas Initiative Chagas Initiative The Chagas Initiative aims to increase access to effective diagnosis and treatment for patients with Chagas disease, both in endemic and non-endemic countries, and to