This proposal describes a career development plan and research proposal for Dr. Max O'Donnell, a pulmonologist at Albert Einstein College of Medicine. Working with collaborators and mentors at Einstein and in South Africa, Dr. O'Donnell is establishing himself as a translational investigator in drug-resistant tuberculosis (TB) and HIV research. Nowhere has drug-resistant TB generated more alarm than in South Africa, where synergies between endemic TB and HIV have caused 'explosive'increases in TB incidence and case-fatality rates. The most resistant form of TB, extensively drug resistant tuberculosis (XDR-TB), is increasingly prevalent in South Africa. An important obstacle to improving survival for XDR-TB is lack of a rapid, biomarker to serve as a surrogate outcome in clinical trials and guide clinician's by measuring treatment response. Fluoromycobacteriophage (FMP) assays use genetically modified mycobacteria-specific viruses to quantify viable M tuberculosis (Mtb) using a fluorescence reporter system. Utilizing a novel FMP assay with superior test characteristics, Dr. O'Donnell proposes to measure decrease in Mtb in XDR-TB patients'sputum as a biomarker for treatment response (Aim 1). Among XDR-TB patients who fail to respond to treatment Dr. O'Donnell proposes to use the same assay to rapidly diagnose emergent second-line drug resistance (Aim 2). This research component of this proposal is a result of an ongoing funded collaboration between researchers at Albert Einstein College of Medicine with researchers at the KwaZulu-Natal Research Institute for Research in Tuberculosis and HIV/AIDS (K-RITH), and the Centre for AIDS Programme of Research in South Africa (CAPRISA). The training component of this proposal involves developing the applicant as a TB molecular epidemiologist including training in the mentor's laboratory, coursework, seminars, lectures, and specific training in drug-resistant TB microbiology. Unique features include co-mentoring from a renowned TB basic scientist, TB epidemiologist, and translational researcher with additional support from career development committee with extensive TB and career development experience. This is an innovative approach with the potential to make substantial impact in our ability to rationally manage drug-resistant tuberculosis, rapidly evaluate the comparative efficacy of different drug regimens, and rapidly diagnose emergent drug-resistance among TB patients on treatment. This research will form the basis for a prospective study of the application of clinical biomarkers for treatment outcome in drug-resistant tuberculosis that will be proposed in an R01 grant application before the end of the K award.

Public Health Relevance

In order to accelerate the development of new antimycobacterial agents and improve treatment outcomes for patients with drug-resistant tuberculosis (TB), we are developing a TB biomarker to rapidly predict treatment response and diagnose new drug-resistance. By improving treatment outcomes we may improve survival, decrease patients'infectivity and reduce community spread of drug-resistant tuberculosis strains, particularly in HIV endemic settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
7K23AI098479-03
Application #
8687579
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Srinivasan, Sudha
Project Start
2012-07-11
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$134,163
Indirect Cost
$9,938
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
O'Donnell, Max (2018) Isoniazid Monoresistance: A Precursor to Multidrug-Resistant Tuberculosis? Ann Am Thorac Soc 15:306-307
Yang, Wan; Cummings, Matthew J; Bakamutumaho, Barnabas et al. (2018) Dynamics of influenza in tropical Africa: Temperature, humidity, and co-circulating (sub)types. Influenza Other Respir Viruses 12:446-456
Law, Stephanie; Daftary, Amrita; O'Donnell, Max et al. (2018) Interventions to improve retention-in-care and treatment adherence among patients with drug-resistant tuberculosis: a systematic review. Eur Respir J :
Yuengling, Katharine A; Padayatchi, Nesri; Wolf, Allison et al. (2018) Effect of Antiretroviral Therapy on Treatment Outcomes in a Prospective Study of Extensively Drug-Resistant Tuberculosis (XDR-TB) HIV Coinfection Treatment in KwaZulu-Natal, South Africa. J Acquir Immune Defic Syndr 79:474-480
Zelnick, J R; Seepamore, B; Daftary, A et al. (2018) Training social workers to enhance patient-centered care for drug-resistant TB-HIV in South Africa. Public Health Action 8:25-27
Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017; Ahmad, Nafees; Ahuja, Shama D et al. (2018) Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet 392:821-834
Cummings, Matthew J; Bakamutumaho, Barnabas; Yang, Wan et al. (2018) Emergence, Epidemiology, and Transmission Dynamics of 2009 Pandemic A/H1N1 Influenza in Kampala, Uganda, 2009-2015. Am J Trop Med Hyg 98:203-206
Yang, Wan; Cummings, Matthew J; Bakamutumaho, Barnabas et al. (2018) Transmission dynamics of influenza in two major cities of Uganda. Epidemics 24:43-48
Cummings, Matthew J; Tokarz, Rafal; Bakamutumaho, Barnabas et al. (2018) Precision surveillance for viral respiratory pathogens: virome capture sequencing for the detection and genomic characterization of severe acute respiratory infection in Uganda. Clin Infect Dis :
Bionghi, N; Daftary, A; Maharaj, B et al. (2018) Pilot evaluation of a second-generation electronic pill box for adherence to Bedaquiline and antiretroviral therapy in drug-resistant TB/HIV co-infected patients in KwaZulu-Natal, South Africa. BMC Infect Dis 18:171

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