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
Mashamba-Thompson, Tivani P; Sartorius, Benn; Drain, Paul K (2016) Point-of-Care Diagnostics for Improving Maternal Health in South Africa. Diagnostics (Basel) 6:
Drain, Paul K; Gounder, Lilishia; Sahid, Faieza et al. (2016) Rapid Urine LAM Testing Improves Diagnosis of Expectorated Smear-Negative Pulmonary Tuberculosis in an HIV-endemic Region. Sci Rep 6:19992
Mashamba-Thompson, T P; Sartorius, B; Thabane, L et al. (2016) Impact of point-of-care diagnostics on maternal outcomes in HIV-infected women: systematic review and meta-analysis protocol. BMJ Open 6:e008002
Drain, Paul K (2015) Ebola: lessons learned from HIV and tuberculosis epidemics. Lancet Infect Dis 15:146-7
Liu, Enju; Makubi, Abel; Drain, Paul et al. (2015) Tuberculosis incidence rate and risk factors among HIV-infected adults with access to antiretroviral therapy. AIDS 29:1391-9
Drain, Paul K; Gounder, Lilishia; Grobler, Anneke et al. (2015) Urine lipoarabinomannan to monitor antituberculosis therapy response and predict mortality in an HIV-endemic region: a prospective cohort study. BMJ Open 5:e006833
Hickey, Andrew J; Gounder, Lilishia; Moosa, Mahomed-Yunus S et al. (2015) A systematic review of hepatic tuberculosis with considerations in human immunodeficiency virus co-infection. BMC Infect Dis 15:209
Drain, P K; Kleene, J M; Coleman, S M et al. (2015) Prevalence of cryptococcal antigenuria at initial HIV diagnosis in KwaZulu-Natal. HIV Med 16:640-4
Drain, Paul K; Losina, Elena; Coleman, Sharon M et al. (2015) Value of urine lipoarabinomannan grade and second test for optimizing clinic-based screening for HIV-associated pulmonary tuberculosis. J Acquir Immune Defic Syndr 68:274-80
Drain, Paul K; Losina, Elena; Coleman, Sharon M et al. (2015) Social support and mental health among adults prior to HIV counseling and testing in Durban, South Africa. AIDS Care 27:1231-40

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