This is an application for a K23 award for Dr. Christina Yoon, a pulmonologist at the University of California, San Francisco. Dr. Yoon is establishing herself as a young investigator in patient-oriented clinical research of HIV/TB. This K23 award will provide Dr. Yoon with the support necessary to accomplish the following goals: 1) to become expert at patient-oriented clinical research in HIV-associated tuberculosis (TB); 2) to conduct clinical investigations of TB screening and diagnostic tests in an international setting 3) to implement advanced biostatistical methods in clinical studies; 4) to conduct economic evaluations of healthcare interventions. To achieve these goals, Dr. Yoon has assembled a mentoring team comprised of a primary mentor Dr. Laurence Huang, an international expert in HIV-associated respiratory infection research, and two co-mentors: Dr. Adithya Cattamanchi, an expert in TB diagnostics and implementation science research; Dr. Saunak Sen, a biostatistician with expertise in statistical genetics. Effective control of TB among people living with HIV (PLHIV) cannot be achieved without implementation of TB preventive therapies such as isoniazid preventive therapy (IPT). The current symptom-based TB screen recommended by the WHO to determine IPT eligibility fails to identify more than two-thirds of PLHIV eligible for this life-saving and cost-effective intervention. The objective of Dr. Yoon's application is to evaluate novel biomarkers that have strong potential to improve scale-up of IPT. The first two Aims focus on an immediately deployable, inexpensive (<2 USD), rapid (3 minutes), and simple-to-use point-of-care (POC) assay for C- reactive protein (CRP).
In Aim 1, Dr. Yoon will use the existing research infrastructure of Dr. Huang's NIH- funded International HIV-associated Opportunistic Pneumonia Study to expand her current pilot study to enroll 500 additional HIV-infected Ugandans initiating antiretroviral therapy to compare the diagnostic accuracy and predictive values of POC CRP vs. the WHO symptom screen for active TB.
In Aim 2, Dr. Yoon will use decision analysis with Markov modeling to project the incremental cost-effectiveness of POC CRP-based TB screening.
In Aim 3, Dr. Yoon proposes to further advance the field by evaluating whether a host blood transcriptional signature can further improve selection of patients for IPT. Using clinical data and banked specimens from Aim 1, Dr. Yoon will conduct a nested case-control study to evaluate the high sensitivity, specificity, and predictive values of this signature in the context of TB screening, laying the necessary groundwork for the potential development of this marker into a future POC assay. These studies are significant because they represent the first step in a continuum of research that may lead to improved approaches to TB screening, increased uptake of IPT, and decreased TB incidence among PLHIV worldwide. This research will form the basis for future work investigating the impact of TB screening strategies on IPT initiation and clinically important outcomes, which will be proposed in an R01 grant application before the end of the K23 award period.
The proposed research may lead to new and improved approaches to the systematic screening of people living with HIV for active tuberculosis (TB). More accurate, practical, and cost-effective TB screening tools will ultimately enable the full potential of isoniazid preventive therapy - to prevent hundreds of thousands of TB cases each year in communities affected by HIV - to be realized.
