CNTRP POSITIVE Study
Condition: Transplant; Adaptive Immunity; EBV; Medication Adherence; PTLD
Study type: Observational

Summary: 
      Adequate control of immunosuppression is critical in preventing graft failure after solid
      organ transplantation (SOT) and in avoiding life-threatening viral and malignant
      complications. Prolonging patient and graft survival and delaying re-transplantation as
      children reach adulthood is critical to optimal use of a scarce resource. This requires
      tailoring post-transplant management to the unique needs of the child. Immunosuppression
      management is challenging in infants, children and youth. The interval from birth to young
      adulthood sees profound changes in physiological processes, body size and immune maturation;
      infancy and adolescence are the periods of most rapid and dramatic change. Three pivotal
      factors affect immunosuppression control in the child: 1) age-dependent variation in drug
      metabolism; 2) developmental changes in immune function with increased childhood
      susceptibility to infections, including those caused by viruses; and 3) behavioural changes
      in adolescence and young adulthood linked with poor treatment adherence.

      This project will identify the most important factors influencing immunosuppression control
      across the pediatric age range, from infancy to young adulthood, including age-related
      changes in drug metabolism, immune function, and susceptibility to viral infections, as well
      as health care system factors affecting treatment adherence. This is the first comprehensive,
      multi-organ transplant study to identify age-related biologic and health care systems
      determinants of variability in immunosuppression control in children and youth. Results will
      inform personalized age-appropriate strategies to improve immunosuppression control and
      reduce the unacceptably high graft failure and viral complication rates in this vulnerable
      population.

      The POSITIVE Study brings together researchers across Canada and is one of 6 projects and 3
      cores that constitute the Canadian Institute of Health Research (CIHR) funded
      interdisciplinary research program called the Canadian National Transplant Research Program
      (CNTRP). The CNTRP is a national program designed to increase organ and tissue donation in
      Canada and enhance the survival and quality of life of Canadians who receive transplants. As
      a national program, CNTRP provides robust power for pediatric studies that would not
      otherwise be possible. While primarily focused on issues unique to a pediatric and young
      adult population, this study will interact closely with all other CNTRP projects. These
      reciprocal interactions will accelerate new discovery that can be cross-applied in different
      populations outside of pre-specified age groups. Interactions will ensure rapid knowledge
      transfer, uptake and dissemination into practice. This is the largest national cohort study
      of pediatric transplant patients to date in Canada, and it will create a longitudinal dataset
      with clinical and biological specimens linkable to transplant registries and provincial
      administrative datasets.
    

Detailed description: 
      The overall objective of this project is to analyze physiological factors that impact immune
      response and effect of immunosuppression across different pediatric age groups, to develop
      age-appropriate medical and health care strategies that can improve graft survival and reduce
      complications in a pediatric and young adult population. There are 3 primary aims of this
      study:

      Aim 1: Develop age-appropriate calcineurin inhibitor (CNI) dosing for pediatric SOT patients:
      We hypothesize that physiologically-based (PB) modeling will enable personalized CNI dosing
      for infants, children and youth based on age, pharmacogenotype and immune maturity. Aim 1
      deliverables include 1) a personalized physiologically-based CNI dosing algorithm in SOT; 2)
      validation of pediatric sensitive immunosuppression monitoring tools and their therapeutic
      targets; and 3) validation of immunologic assays for assessing age-specific immune responses.
      We anticipate that personalized CNI dosing will result in early attainment and maintenance of
      therapeutic drug concentrations, reduce the frequency of out-of-range concentrations
      post-transplant, improve safety and efficacy of immunosuppression, and reduce dependence on
      therapeutic drug monitoring to guide drug dosing. Standardized assessment of immune function
      may also monitor immunosuppression more reliably and eventually reduce the need for invasive
      monitoring like biopsies.

      Aim 2: Develop risk prediction tools based on viral-host interactions that predispose young
      SOT and hematopoietic stem cell transplant patients to Epstein-Barr virus
      disorders/post-transplant lymphoproliferative disorder (EBV disorders/PTLD): We hypothesize
      that susceptibility to EBV disorders/PTLD is influenced by the interaction of high-risk EBV
      subtypes with host factors like age, immune maturation and intensity of immunosuppression. In
      the above context, "EBV disorders" refers to non-malignant EBV disease as well as sustained
      elevation of viral loads in the absence of PTLD. We will identify high-risk viral subtypes
      and age-related differences in host immunity that interact to increase susceptibility to EBV
      disorders/PTLD in young patients. Important clinical applications are: 1) knowledge of host
      susceptibility factors (age and immune maturation) at the time of transplant may assist
      choice of less intensive immunosuppression to reduce risk of developing EBV (e.g., avoidance
      of T cell depletion therapies, primary prevention) and promote use of EBV prophylaxis in at
      risk patients (secondary prevention); 2) an EBV genotype panel will be developed as a
      clinical tool for detecting high risk subtypes in patients with EBV. This will help identify
      patients exposed to EBV who should receive aggressive therapy for EBV and/or PTLD
      (personalized therapy). This innovative risk stratification will enable personalized
      immunosuppression strategies and strategies to prevent and treat EBV/PTLD.

      Aim 3: Develop health care systems strategies to enhance medication adherence in adolescents
      and young adults: Medication adherence is determined by factors at a variety of different
      "levels": patient-level (patient-, condition-, and therapy-related factors), "micro"-level
      (social factors and interactions with the care team), "meso"-level (organization and
      expertise of the healthcare team and care processes), and "macro"-level (high-level
      healthcare systems factors, including care and medication cost coverage, and overall care
      environment). We hypothesize that there are significant differences in modifiable meso- and
      macro-level systems factors between pediatric programs, between adult programs, and between
      pediatric and adult programs. Furthermore, we hypothesize that modifiable meso- and
      macro-level systems factors are independently associated with medication adherence. This aim
      has two primary objectives:

      Objective 1: To characterize differences between Canadian solid organ transplant programs in
      potentially modifiable meso- and macro-level systems factors.

      Objective 2: To identify potentially modifiable meso- and macro-level factors that are
      determinants of adherence, adjusting for potential confounders.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        End stage organ failure, Solid organ transplant
      
Biospecimen description: 
      Immune function testing: blood Pharmacokinetic testing: blood EBV/PTLD viral sequencing:
      blood EBV/PTLD immunoassays: blood
    
Keywords: Transplant; Adaptive Immunity; EBV; Medication Adherence; Tacrolimus; PTLD