CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

825 Needle Autopsies Highlight Challenges in Defining HIV+ TB Deaths Using Verbal Autopsy Aaron Karat 1 ; MphoTlali 2 ; Salome Charalambous 2 ; Kerrigan McCarthy 2 ;Violet Chihota 2 ; Gavin Churchyard 2 ; Katherine Fielding 1 ; Kathleen Kahn 3 ;Tanvier Omar 4 ; Alison Grant 1 1 London School of Hygiene and Tropical Medicine, London, United Kingdom; 2 The Aurum Institute, Johannesburg, South Africa; 3 University of the Witwatersrand, Johannesburg, South Africa; 4 National Health Laboratory Service, Wits School of Public Health, Johannesburg, South Africa Background: Cause of death data are crucial to guide public health policy. Verbal autopsy (VA) is widely used to collect these data, but has mostly been validated against gold standards of variable quality, generated from hospital notes. Full post-mortem is the best way to determine cause of death, though needle autopsy (NA) is more acceptable to relatives and can provide high quality information. In HIV+ individuals, differentiating between deaths due to tuberculosis (TB) and advanced HIV is difficult, but important to guide interventions to reduce early mortality. This ongoing cross-sectional study, nested within the TB Fast Track trial in South Africa, compared causes of death assigned by VA and NA in adults with advanced HIV. Methods: Adult trial participants had a CD4 count of ≤ 150 cells/ μ L and were not taking TB treatment or antiretroviral therapy (ART). Consent for NA was obtained from participants at enrolment or from families after death (if participant not asked). NAs involved biopsies of liver, spleen, and lungs; aspiration of CSF; and broncheo-alveolar lavage. Laboratory tests included: histology; GeneXpert MTB/RIF; and MGIT, bacterial, and fungal cultures. Preliminary NA causes of death were assigned by investigators using demographic and NA data. VAs were performed within one year of death by lay-workers using the 2012 WHO tool; causes of death assigned by InterVA-4 and SmartVA software (using health care experience and narrative data). For comparison, causes of death were categorised as TB, AIDS/HIV-related (not TB), or ‘other’. Cohen’s kappa coefficient was used to measure inter-rater agreement. Results: The first 20 decedents with NA and VA data were included in the analysis. 12/20 (60%) were female, with median: age at death 37.8 (interquartile range [IQR] 31-44) years; CD4 count at enrolment 31 (IQR 14-56) cells/mL; time from enrolment to death 45 (IQR 20-103) days; time from death to NA 4.5 (IQR 3-7) days; and time from death to VA 106.5 (IQR 60-178) days. Causes of death assigned by NA and VA are shown in Table 1. Agreement, expected agreement and kappa between: NA and InterVA-4 were 40.0%, 42.0%, and 0.00; and NA and SmartVA were 50.0%, 50.0% and 0.00, respectively.

Poster Abstracts

Table 1: Causes of death assigned by needle autopsy and by verbal autopsy as interpreted by InterVA-4 and SmartVA Conclusions: These preliminary data suggest that current VA tools do not performwell at distinguishing between deaths due to TB vs. other HIV-related causes among individuals with advanced HIV disease. Alternative methods should be explored so that the burden of TB mortality can be more accurately recorded. 826 Delta-Like 1 Protein, Vitamin D Binding Protein, and Fetuin Measurement in Cerebrospinal Fluid for Detection of Mycobacterium tuberculosis Meningitis Nathan C. Bahr 1 ; Ryan Halupnick; Grace Linder; Reuben Kiggundu 2 ; HenryW. Nabeta 2 ; DarlishaWilliams 1 ; Srinand Srevatsan 3 ; Joshua Rhein 1 ; David B. Meya 2 ; David R. Boulware 1 1 University of Minnesota, Minneapolis, MN, US; 2 Makerere University College of Health Sciences, Kampala, Uganda; 3 University of Minnesota, Minneapolis, MN, US Background: Tuberculosis meningitis (TBM) diagnosis is notoriously difficult, new biomarkers are needed. We evaluated the diagnostic utility of 3 novel biomarkers, 1) delta-like 1 protein (DLL1), a Notch ligand, which selectively drives antigen-specific CD4 T helper type-1 (Th1) responses; 2) vitamin D binding protein (VDBP); 3) fetuin. VDBP and fetuin are promising biomarkers of bovine tuberculosis. Methods: Biomarker concentrations were measured by ELISA in cryopreserved CSF from 139 HIV-infected Ugandan patients with meningitis. TBMwas diagnosed by GeneXpert MTB/Rif assay and/or mycobacterial culture. Cohort diagnoses included TBM (n=21), cryptococcal meningitis (n=71), and aseptic ‘other’ meningitis (n=47) among those testing negative for TB, Cryptococcus , and bacteria. We evaluated the diagnostic performance of DLL1 (n=136), VDBP (n=130), and fetuin (n=130) for TBM. Results: Patient characteristics were similar at diagnosis except for sex, CD4 count, CSF WBC count, and CSF protein. DLL, VDBP, and fetuin CSF concentrations were significantly higher in patients with TBM than cryptococcal or ‘other’ meningitis (Table 1) . Using logistic regression, DLL1 alone provided 33% sensitivity, 98% specificity, 78% positive predictive value (PPV), and 88% negative predictive value (NPV). Combining DLL1 with interferon gamma (IFNg) and cryptococcal antigen testing improved sensitivity to 62% with slightly decreased specificity of 95%, PPV of 72% and NPV of 93%. For every two-fold increase in DLL1, the odds of TBM increased (adjusted Odds Ratio=2.6, 95%CI: 1.2-5.5; P=.011) in the multivariable logistic model (P<0.001 in univariate analysis). Further incorporating fetuin, VDBP, CSF white cell count, or CSF protein into a predictive model did not improve diagnostic performance. Among the 5 putative false positives as classified by the DLL1, IFNg, CRAG model, 2 had a clinical TBM diagnosis during hospitalization without

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CROI 2015