Economic value of a therapeutic Chagas vaccine for indeterminate and Chagasic cardiomyopathy patients
Introduction
Therapeutic vaccines to prevent Chagas disease progression to cardiomyopathy are under development because the only available medications (antitrypanosomal treatment such as benznidazole and nifurtimox) are limited by their efficacy, long treatment course, and side effects. With at least 12 therapeutic candidates in pre-clinical trials [1], decision makers (e.g., policy makers, vaccine developers, manufacturers, third-party payers, and potential funders) need to understand the potential clinical and economic value of such a vaccine. Those infected with Trypanosoma cruzi may progress to severe heart disease and while the medications available to prevent this progression are effective in the early stages of Chagas infection [2], they have limited efficacy in later stages. A recent randomized clinical trial (RCT) of patients with Chagasic cardiomyopathy failed to show any improvement in cardiac clinical outcomes and 17–18% of patients died within five years, regardless of benznidazole treatment [3]. Additionally, these medications have a treatment course up to two months and are highly toxic, with adverse reactions in up to 40% of patients, and 20% of patients unable to tolerate a full treatment course [4].
Currently, therapeutic vaccines, either used alone or with benznidazole in a vaccine-linked chemotherapy approach, are the most desired and feasible development strategy to overcoming current treatment deficiencies [1], [4]. Pre-clinical trials in mice have demonstrated reductions in parasite heart burdens and cardiac fibrosis and pathology [5], [6], [7], [8], [9], [10]. Besides delaying the onset of clinical cardiac outcomes, vaccination could also reduce chemotherapy duration and dosage, leading to higher treatment completion rates [4]. While our previous work evaluated a Chagas therapeutic vaccine for intermediate patients, it explored only vaccination and its impact on delaying cardiac outcomes [11]. Here, we evaluate administering the vaccine in conjunction with benznidazole (accounting for reductions in drug regimen and progression of disease) and in patients with indeterminant and chronic disease. With therapeutic vaccines in the pipeline, evaluating the economic value prior to licensure can help guide development and implementation, determine appropriate target populations, desired efficacy profiles, and vaccine price points [12], [13], [14]. Therefore, we developed a computational simulation Markov model to determine the economic value of a therapeutic vaccine (given in combination with benznidazole) for Chagas patients in Mexico at different stages of disease to improve treatment completion and to prevent and delay the onset of Chagasic cardiomyopathy. We used Mexico as our test case as it has one of the largest number of persons living with Chagas disease and cardiomyopathy [15], [16].
Section snippets
Model
Using TreeAge Pro 2017 (Williamstown, MA), we developed a computational Markov model of Chagas disease to evaluate the use of vaccine-linked chemotherapy from the third-party payer and societal perspectives. Our model consisted of six mutually exclusive states (four clinical classes, successfully treated/seroreverted, and death; Fig. 1). The four clinical classes followed the Kuschnir Classification system [17]: class 0 [i.e., reactive serology, normal echocardiogram (ECG), and no cardiac
Vaccination of patients with indeterminate Chagas disease (Kuschnir class 0)
Table 2 shows the impact of vaccine-linked chemotherapy and disease progression per 1000 indeterminate Chagas patients for a lower, moderate, and higher impact lifelong vaccine, as well as the Chagas outcomes for non-vaccinated patients. With benznidazole-only treatment, 219 [95% uncertainty interval (UI): 191–248] Chagas patients progressed to chronic disease, resulting in 119 Chagas-related deaths (4 in class 1, 10 in class 2, and 105 in class 3) over their lifetime. Compared to
Discussion
Our results show that therapeutic vaccination used in conjunction with benznidazole treatment for indeterminate and chronic Chagas disease not only provides health benefits but results in cost-savings (up to $89,759 or $190,049 per patient treated, depending on the conversion method used) under a wide range of scenarios for several vaccine characteristics. Thus, vaccine-linked chemotherapy may pay for itself. Even a vaccine costing $200 and 10-year duration of action, vaccination provided
Funding
This work was supported by the Carlos Slim Foundation, Mexico Agency for Healthcare Research and Quality (AHRQ) via grant R01HS023317, the National Institute of General Medical Sciences (NIGMS) via MIDAS grant U24GM110707, and the United States Agency for International Development (USAID) under agreement number AID-OAA-A-15-00064. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval
Declaration of Competing Interest
SMB, LA, US, SM, SR, and BYL have no significant conflicts of interest.
JAFL works for the Carlos Slim Foundation but has no competing financial interests.
MEB and PJH are patentholders and lead investigators of a program for the development of a therapeutic Chagas disease vaccine.
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