Cryptococcal meningitis is a leading cause of AIDS-related mortality worldwide. Circulating cryptococcal antigens can be detected weeks before the onset of neurological symptoms, and pre-emptive anti-fungal therapy can prevent cryptococcal meningitis and death. Unfortunately, most clinics in cryptococcal endemic regions do not have access to laboratory-based testing for cryptococcal antigens. A newly-approved, rapid cryptococcal antigen test can facilitate implementing a clinic-based screening strategy in any resource-limited setting, which, when coupled with oral anti-fungal therapy, could save thousands of lives each year worldwide. However, evidence on the feasibility and impact of conducting point-of-care testing for cryptococcal antigens in a clinic-based setting is needed. My career goal is to become an independent investigator in clinical research with a focus on implementation science to improve clinical diagnosis and treatment of cryptococcal infections and prevention of cryptococcal meningitis in resource-limited settings. I will draw upon the methodological training of the K23 award and leverage the existing research infrastructure of my co-mentors and collaborators in Durban, South Africa to accomplish my scientific objective: to better understand the value of point-of-care testing, clinic-based screening, and implementation science for cryptococcal disease among HIV-infected adults in resource-limited settings. My hypothesis is that clinic-based, nurse-driven, point-of-care screening for cryptococcal antigens at the time of initial HIV diagnosis will be feasible and will improve patient outcomes. I will tes this hypothesis through the following four specific aims: (1) To estimate CD4-specific prevalence of cryptococcal antigenemia and cumulative incidence of cryptococcal meningitis and mortality for those with and without cryptococcal antigenemia within 12 months of HIV diagnosis in a standard-of-care, lab-based serum CrAg screening program, (2) To evaluate a rapid point-of-care LFA CrAg test by measuring test characteristics of whole blood and urine samples, compared with gold-standard serum-based tests, (3) To estimate cumulative incidence of cryptococcal meningitis and mortality within 12 months of HIV diagnosis when implementing an active, clinic-based screening program for CrAg in urine and/or whole blood among newly- diagnosed HIV-infected adults, and to compare cumulative incidence of cryptococcal meningitis and mortality to the standard-of-care, lab-based serum CrAg screening program (measured in Aim #1), and (4) To assess the long-term clinical outcomes, cost, and cost-effectiveness of intensified CrAg screening, compared to lab- based CrAg screening, among newly-diagnosed HIV-infected adults in South Africa. I am well positioned to accomplish these aims, based on my educational and mentorship plans, as well as my experience conducting a clinic-based, nurse-driven evaluation of a point-of-care diagnostic test for tuberculosis. I will draw upon the guidance of my renowned mentors and collaborators, who have extensive experience in HIV care, cryptococcal disease, clinical research, evaluating screening strategies, and cost-effectiveness analysis, while also developing my own distinct research trajectory. My approach is innovative by: (1) validating a point-of-care test in a clinical setting by nurses, (2) evaluatig the impact of clinic-based screening on patient outcomes, and (3) use of a novel, rapid cryptococcal antigen testing platform. The proposed research is significant because it will provide the tools to implement clinic-based screening for cryptococcus, a common and fatal disease in resource-limited settings, and provide a platform to launch my career as an independent investigator.

Public Health Relevance

Cryptococcal meningitis is a leading cause of AIDS-related mortality worldwide, due mostly to delays in diagnosing the infection and promptly initiating anti-fungal therapy in resource-limited settings. I will evaluate whether rapid, point-of-care, clinic-based screening for cryptococcal disease will prevent cryptococcal-related mortality and be cost-effective among HIV-infected adults in an urban township of Durban, South Africa. This project will produce strategies for clinicians in HIV-endemic areas to promptly diagnose life-threatening cryptococcal infections to prevent cryptococcal meningitis, and for policy makers to implement a cost-effective screening program among people living with HIV/AIDS.

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 #
1K23AI108293-01A1
Application #
8731612
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Lambros, Chris
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$188,192
Indirect Cost
$12,775
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Jaya, Ziningi; Drain, Paul K; Mashamba-Thompson, Tivani P (2017) Evaluating quality management systems for HIV rapid testing services in primary healthcare clinics in rural KwaZulu-Natal, South Africa. PLoS One 12:e0183044
Mashamba-Thompson, Tivani P; Jama, Ngcwalisa A; Sartorius, Benn et al. (2017) Implementation of Point-of-Care Diagnostics in Rural Primary Healthcare Clinics in South Africa: Perspectives of Key Stakeholders. Diagnostics (Basel) 7:
Yoon, C; Chaisson, L H; Patel, S M et al. (2017) Diagnostic accuracy of C-reactive protein for active pulmonary tuberculosis: a meta-analysis. Int J Tuberc Lung Dis 21:1013-1019
Drain, Paul K; Mock, Charles; Toole, David et al. (2017) The Emergence of Undergraduate Majors in Global Health: Systematic Review of Programs and Recommendations for Future Directions. Am J Trop Med Hyg 96:16-23
Gounder, Lilishia; Moodley, Pravikrishnen; Drain, Paul K et al. (2017) Hepatic tuberculosis in human immunodeficiency virus co-infected adults: a case series of South African adults. BMC Infect Dis 17:115
Drain, Paul K; Subbaraman, Ramnath; Heimburger, Douglas C (2017) Preserving the Fogarty International Center - Benefits for Americans and the World. N Engl J Med 377:9-11
Mugambi, Melissa L; Palamountain, Kara M; Gallarda, Jim et al. (2017) Exploring the Case for a Global Alliance for Medical Diagnostics Initiative. Diagnostics (Basel) 7:
Drain, Paul K; Losina, Elena; Coleman, Sharon M et al. (2017) Clinic-Based Urinary Lipoarabinomannan as a Biomarker of Clinical Disease Severity and Mortality Among Antiretroviral Therapy-Naive Human Immunodeficiency Virus-Infected Adults in South Africa. Open Forum Infect Dis 4:ofx167
Mashamba-Thompson, Tivani P; Morgan, Rebecca L; Sartorius, Benn et al. (2017) Effect of Point-of-Care Diagnostics on Maternal Outcomes in Human Immunodeficiency Virus-Infected Women: Systematic Review and Meta-analysis. Point Care 16:67-77
Drain, Paul K; Rousseau, Christine (2017) Point-of-care diagnostics: extending the laboratory network to reach the last mile. Curr Opin HIV AIDS 12:175-181

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