CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: One hundred participants who died of cryptococcal meningitis within the first two-weeks (non-survivors) and a random selection of 200 participants who survived (survivors) were selected using the R software for statistical computing. Levels of UCHL1, NSE, and GFAP in day 1 cerebrospinal fluid (CSF) were measured using Luminex analysis, and associations between these biomarkers and clinical and laboratory variables determined. Data was analyzed using Graphpad Prism software. Results: Non-survivors were more likely to have Glasgow Coma Score <15 and had significantly higher median CSF cryptococcal quantitative culture, and lower median CD4-cell counts and CSF white blood cell counts. The mean concentration of NSE in the survivors was 23463 pg/mL, and 30984 pg/mL in the non-survivors (p<0.001). Mean concentration of UCHL1 was also significantly higher in the non-survivors at 548.9 pg/mL compared to 243 pg/mL in the survivors (p<0.0001). Mean concentration of GFAP did not differ significantly, at 561.8 pg/mL in the non-survivors, and 369.9 pg/mL in the survivors (p=0.2635). Conclusion: The neurological markers UCHL1 and NSE were significantly elevated on day 1 CSF in cryptococcal meningitis patients who died by 2 weeks compared to those who survived. Further study of these markers may be used to identify patients who require more intensive management, monitoring and follow-up and generate novel insights into cryptococcal disease pathology.

mortality. Higher fungal loads are strongly associated with mortality; but obtaining fungal loads requires serial CrAg LFA dilutions or quantitative fungal cultures (QFC), both are time and resource consuming, need expertise, and are difficult to implement in resource limited settings (RLS). The IMMY CrAgSQ is an improvement on the widely used IMMY CrAg LFA with comparable diagnostic performance, yielding a semi-quantitative (SQ) score. Previous studies involved fewer HIV-CM patients and did not definitively evaluate the utility of CrAgSQ in predicting mortality. We conducted a study on stored plasma and CSF samples from the AMBITION trial to evaluate whether CrAgSQ can predict outcomes. Methods: 810 patients with HIV-CM were enrolled onto the Ambition Phase 3 randomised clinical trial evaluating CM therapy in Botswana, Zimbabwe, Malawi, Uganda and South Africa. Stored plasma and CSF samples collected at disease diagnosis before treatment were tested using CrAgSQ, yielding a score of 1-5. Clinical outcomes and laboratory data were documented during 10 weeks of follow-up. Associations between CrAg SQ scores in plasma and CSF and 2- and 10-week mortality were examined. Results: 756 CSF and 745 plasma collected from 796 Ambition Trial patients were assessed; 61% of the patients were male, median age was 37 (IQR 32-43 years), and median CD4 count was 27 (IQR 10-58 cells/uL). Overall mortality was 13% and 23% by 2 and 10 weeks. In plasma, 0.13% (1/745) were negative, 4.03% (30/745) had an SQ score of 1, 3.49% (26/745) 2, 83.62% (623/745) 3, and 8.72% (65/745) 4. In CSF, 1.32% (10/756) were negative, 7.01% (53/756) had an SQ score of 1, 5.69% (43/756) 2, 63.76% (482/756) 3, and 22.22% (168/756) 4. CrAg SQ scores in plasma (Figure) and CSF positively correlated with QFCs. Increasing CrAg SQ scores in plasma were strongly associated with increasing mortality risk at 2- and 10-weeks. Mortality was 0% (0/22) in those with plasma SQ score of 1, 4.4% (1/23) 2, 13.9% (75/540) 3, and 34.55% (19/55) 4 (p for trend <0.001). Conclusion: Plasma CrAgSQ is a promising prognostic tool for 2-week mortality in patients with HIV-CM, making it a viable option for RLS. Further research is warranted to establish how it could be used to stratify management in individuals presenting with HIV-CM.

Poster Abstracts

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Histoplasmosis in Advanced HIV Disease: A Multi-Center Prospective Diagnostic Validation Study Hao T Nguyen 1 , Dieu Q. Nguyen 1 , Vo Trieu Ly 2 , Khanh H. Dang 1 , Phuong L. Trinh 1 , Thach N. Pham 3 , Nguyen Thanh Dung 2 , Nguyen Thi Lan 3 , Do Thi Le Na 3 , Nguyen Thanh Vinh 1 , Nguyen Phu Huong Lan 2 , Vu Quoc Dat 4 , H. Rogier van Doorn 1 , Thuy Le 5 , for the Talaromycosis Study Group 1 Oxford University Clinical Research Unit in Vietnam, Ho Chi Minh City, Vietnam, 2 Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, 3 National Hospital for Tropical Diseases, Hanoi, Vietnam, 4 Hanoi Medical University, Hanoi, Vietnam, 5 Duke University School of Medicine, Durham, NC, USA Background: Histoplasmosis burden in advanced HIV disease (AHD) in Southeast Asia is unknown due to the lack of diagnostics. We report results of an ongoing multi-center prospective histoplasmosis diagnostic validation study in patients with AHD in Vietnam. Methods: We recruited hospitalized HIV-infected adults, CD4 count ≤ 100 cells/µL or WHO stage 3 or 4 disease, ART-naive or on ART for ≤ 3 months or >12 months from 3 hospitals in Vietnam. All patients were screened for Histoplasma antigen using the IMMY Clarus Histoplasma GM enzyme immunoassay (HAg EIA) in urine and Myco/F Lytic blood culture (over 6 weeks), alongside conventional microscopy and cultures of other specimens as clinically indicated. Proven histoplasmosis was defined as culture-positive disease. Probable histoplasmosis was defined as a compatible clinical syndrome and resolution of HAg levels on antifungal therapy. Patients were followed up monthly for over 6 months. Results: 900 patients were recruited between 02/2021 and 08/2023. Overall prevalence of HAg positivity was 37/900 (4.1%) and was higher in southern vs. northern Vietnam, 30/581(5.2%) vs. 7/319 (2.2%), P= 0.035, Fisher Exact. Among the 37 HAg-positive patients, 15 (40.5%) had proven histoplasmosis; 13 (35.1%) had probable histoplasmosis; and 9 (24.3%) did not develop disease over 6 months. The median HAg EIA unit of proven and probable histoplasmosis patients was 35.84 (IQR 4.31 to 40.96) compared to -0.04 (IQR -0.08 to 0.03) of non-histoplasmosis patients, P<0.001, Mann-Whitney. At a cut-off EIA unit of 1.2, HAg EIA had 100% sensitivity (95% CI: 87.7% - 100%), 99% specificity (95% CI 98.1% - 99.5%), 75.7% positive predictive value (95% CI 61.9% - 85.6%), 100% negative predictive value (95% CI 99.6% - 100%), and an accuracy of 99.8% (95% CI: 99.7% – 100%). Among 28 histoplasmosis patients, the median CD4 count was 17 (IQR, 7 - 31) cells/μL. H. capsulatum was isolated from blood in 12 (42.9%), bone marrow in 11 (39.3%), skin lesions in 1 (3.6%) patients. Median

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NSE and UCHL1 as Prognostic Biomarkers for Mortality From Cryptococcal Meningitis Mary Foley 1 , F. Kathryn Boyd 1 , Ronan Doyle 1 , Kwana Lechiile 2 , Conrad Muzoora 3 , Cecilia Kanyama 4 , Graeme A. Meintjes 5 , David B. Meya 6 , Mosepele Mosepele 7 , Henry C. Mwandumba 8 , Chiratidzo Ndhlovu 9 , Thomas S. Harrison 10 , David S. Lawrence 1 , Joseph N. Jarvis 1 , for the AMBITION Study Group 1 London School of Hygiene & Tropical Medicine, London, United Kingdom, 2 Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana, 3 Infectious Disease Institute, Kampala, Uganda, 4 University of North Carolina Project–Malawi, Lilongwe, Malawi, 5 University of Cape Town, Cape Town, South Africa, 6 Makerere University, Kampala, Uganda, 7 University of Botswana, Gaborone, Botswana, 8 Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi, 9 University of Zimbabwe, Harare, Zimbabwe, 10 St George's University of London, London, United Kingdom Background: Despite new, more effective treatments, mortality due to HIV associated cryptococcal meningitis remains high. Markers that are associated with mortality may be helpful to identify individuals who would benefit from intensive management and monitoring, and also improve understanding of underlying disease pathology. The neurological biomarkers Neuron specific enolase (NSE), Ubiquitin C-terminal hydrolase-L1 (UCHL1), and Glial fibrillary acidic protein (GFAP) have been associated with traumatic brain injury but have never been studied in the context of cryptococcal meningitis. This exploratory study examined cerebrospinal fluid levels of these biomarkers in patients from the AMBITION-cm trial. It was hypothesized that UCHL1, NSE, and GFAP would be elevated in participants who died from cryptococcal meningitis.

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