This is an application for a K23 award for Dr. John Metcalfe, a pulmonary and critical care physician at the University of California, San Francisco. Dr. Metcalfe is establishing himself as an investigator in patient-oriented clinical research on the epidemiology and transmission of multidrug resistant tuberculosis in high-HIV burden, resource-limited settings. This K23 award will provide Dr. Metcalfe with the support necessary to accomplish the following goals: (1) to improve scientific understanding of the burden and impact of the multidrug resistant tuberculosis (MDR TB) epidemic within HIV prevalent settings in order to craft effective public health responses; (2) to apply laboratory research techniques for molecular drug susceptibility testing of clinical specimens; (3) to apply novel biostatistical methods to improve prediction of at-risk patients and to evaluate the incremental value of new diagnostic tests; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Metcalfe has assembled a mentoring team comprised of a primary mentor, Dr. Philip Hopewell, UCSF Professor of Medicine and world-renowned authority on global TB control; and two co-mentors: Dr. Arthur Reingold, UC Berkeley Professor of Epidemiology, Associate Dean for Research, and internationally recognized infectious disease epidemiologist, and Dr. Laurence Huang, UCSF Professor of Medicine, an expert researcher in HIV-associated pulmonary diseases. The convergence of the drug-resistant TB and HIV epidemics represents a major threat to global TB control. The lack of rapid drug susceptibility testing has been a major impediment to effective prevention, treatment and epidemiologic research of drug resistant TB. While recently introduced molecular assays dramatically reduce detection times, these techniques are not routinely available in most settings. Patients with MDR TB in low-income settings are typically only identified after multiple failed treatment attempts. Dr. Metcalfe's research will capitalize on an extensive pre-existing research infrastructure in Zimbabwe centered on an NIH Division of AIDS-funded Clinical Trials Unit (5U01AI069436-04) to improve early identification of patients with MDR TB through novel prediction rules applicable to low-income, high-HIV burden settings (Aim 1), determine which patients are most likely to benefit from molecular drug susceptibility testing (Aim 2), and provide pilot data towards the first prospective study of the contribution of microbial factors to drug resistant TB transmission in a high HIV prevalence setting (Aim 3). This research will form the basis for a future R01-level proposal utilizing longitudinal patient- and pathogen-specific data to characterize development of drug resistant TB in real-time.

Public Health Relevance

MDR TB now accounts for 3.6% of global TB cases, and it is estimated that only 7% of the 440,000 annual cases of MDR TB are currently detected. In most settings, MDR TB patients are routinely identified only after multiple failed treatment attempts. Improved clinical prediction models, long used in the cardiovascular and cancer literature to augment precision of diagnoses and inform decisions about treatment, would allow cost-effective application of molecular assays in areas where available, and improve early detection of high risk MDR TB suspects where they are not.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Huebner, Robin E
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Metcalfe, J Z; Makumbirofa, S; Makamure, B et al. (2016) Xpert(®) MTB/RIF detection of rifampin resistance and time to treatment initiation in Harare, Zimbabwe. Int J Tuberc Lung Dis 20:882-9
Coscolla, Mireia; Barry, Pennan M; Oeltmann, John E et al. (2015) Genomic epidemiology of multidrug-resistant Mycobacterium tuberculosis during transcontinental spread. J Infect Dis 212:302-10
Metcalfe, John Z; Vittinghoff, Eric; Hopewell, Philip C (2015) Analysis of Green Light Committee implementation and acquisition of second-line drug resistance. Clin Infect Dis 60:970
Metcalfe, John Z; Makumbirofa, Salome; Makamure, Beauty et al. (2015) Suboptimal specificity of Xpert MTB/RIF among treatment-experienced patients. Eur Respir J 45:1504-6
Metcalfe, John Z; Mason, Peter; Mungofa, Stanley et al. (2014) Empiric tuberculosis treatment in retreatment patients in high HIV/tuberculosis-burden settings. Lancet Infect Dis 14:794-5
Tagmouti, Saloua; Slater, Madeline; Benedetti, Andrea et al. (2014) Reproducibility of interferon gamma (IFN-?) release Assays. A systematic review. Ann Am Thorac Soc 11:1267-76
Pai, Madhukar; Denkinger, Claudia M; Kik, Sandra V et al. (2014) Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev 27:3-20
Metcalfe, John Z; Makumbirofa, Salome; Makamure, Beauty et al. (2014) Drug-resistant tuberculosis in high-risk groups, Zimbabwe. Emerg Infect Dis 20:135-7
Davis, J Lucian; Kawamura, L Masae; Chaisson, Lelia H et al. (2014) Impact of GeneXpert MTB/RIF on patients and tuberculosis programs in a low-burden setting. a hypothetical trial. Am J Respir Crit Care Med 189:1551-9
Mupfumi, L; Makamure, B; Chirehwa, M et al. (2014) Impact of Xpert MTB/RIF on Antiretroviral Therapy-Associated Tuberculosis and Mortality: A Pragmatic Randomized Controlled Trial. Open Forum Infect Dis 1:ofu038

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