Cryptococcal meningitis is a leading cause of death among persons with AIDS in the resource-limited settings, responsible for approximately 20% of deaths in HIV treatment programs in Africa. Many of these deaths are preventable. Despite the aggressive roll out of ART in South Africa, the incidence of cryptococcal meningitis has only slightly decreased by 10- 15% per the National Institute of Communicable Diseases (NICD) national surveillance. Cryptococcus remains the most common cause of meningitis among adults in South Africa. Recent research has shown that routine screening for sub-clinical early infection among asymptomatic patients presenting to ART programs using a simple blood test (cryptococcal antigen or CRAG) can identify which patients are at high risk of developing meningitis or death. The prevalence of this detectable sub-clinical cryptococcal infection is 4.1% among South Africans with CD4<100. If identified, these asymptomatic persons can be given preemptive anti-fungal fluconazole therapy to prevent meningitis and/or death. Our research collaboration has demonstrated that such a screening strategy would be highly cost-effective, at an estimated <$10 per quality-adjusted life year (QALY) saved. In South Africa, such a CRAG screening would be cost-saving overall to the healthcare system and result in better survival. Based on our team's previous cost-effectiveness research, South Africa has included CRAG screening of HIV-infected persons with CD4<100 cells/mcL as part of their 2015 National HIV Treatment Guidelines, yet broad implementation has not yet occurred. We propose to implement CRAG screening using lab-based reflex testing of leftover plasma specimens in persons with CD4<100 cells/mcL. We will implement at CD4 testing labs across South Africa using a stepped wedge design phased implementation in order to assess the public health impact. First, we will determine if implementation of CRAG screening using lab- based reflex testing provides better uptake as compared with provider initiated testing in HIV- infected persons with CD4<100 cells/mcL(Aim 1). Second, we will implement an enhanced metrics and evaluation surveillance cohort to determine the barriers for care of CrAg+ preemptive therapy and determine those at high risk of treatment failure for 6 month cryptococcal-free survival (Aim 2). Lastly, we will determine if customization of care with target lumbar punctures based of CrAg titer >1:160 will improve 6-month survival and decrease the current 25% failure rate (i.e. meningitis or death) with current WHO recommended CrAg+ preemptive therapy (Aim 3).

Public Health Relevance

Cryptococcal meningitis, a fungal infection around the brain, is the most common cause of meningitis in adults in Sub-Saharan Africa and a leading cause of death due to AIDS. Cryptococcal infection is potentially detectable during an asymptomatic subclinical phase and preventable with preemptive anti-fungal therapy. In Africa, approximately 7% of persons with AIDS and CD4<100 presenting to HIV care have evidence of subclinical, early infection with a detectable cryptococcal antigen (CRAG+) in peripheral blood and will die with HIV therapy alone. This operational research will assess the impact, challenges, and cost-effectiveness of cryptococcal antigen screening to improve retention-in-care in South Africa.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
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Huebner, Robin E
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University of Minnesota Twin Cities
Internal Medicine/Medicine
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United States
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