A new antibody/antigen combination rapid test to detect acute HIV infection: A synthesis of evidence

Background: Rapid and point-of-care diagnostics have expanded access to HIV testing, with fourth generation HIV rapid tests (Ag/Ab combo) now offering the potential of timely detection of acute HIV infection, when HIV is highly infectious. The aim of this thesis is to synthesize evidence on the global diagnostic performance of the only FDA-approved fourth generation rapid test, the Determine HIV 1/2 Ag/Ab Combo RT, to detect acute HIV in adults.Methods: We performed a systematic review and meta-analysis, searching Medline, Embase, PubMed, BIOSIS, The Cochrane Library, LILACS, and African Index Medicus, including conferences, bibliographies, and citations. Studies were included if they evaluated the Determine Combo Rapid Test in adults, against a reference standard. Two reviewers independently extracted data and assessed study quality with QUADAS-2. Our main outcomes of interest were sensitivity and specificity (overall, plus antigen and antibody components). Data from 17 studies (n=21599 patient samples) were pooled using a Bayesian hierarchical random effects meta-analysis model, which assumed a perfect gold standard was available for each study. To explore the extent to which the pooled estimates obtained through this model might differ under different assumptions, data were pooled using a hierarchical random effects model which assumed varying thresholds for positivity, allowing sensitivity and specificity to be correlated within each study. We analyzed subgroups by blood sample and study design for each model.Results: Using the Bayesian model which assumed a perfect gold standard, the overall pooled sensitivity for the device was 88.5%, 95% credible interval (CrI) [80.1 – 93.4], and overall pooled specificity was 99.1%, 95% CrI [97.3 – 99.8]. Pooled sensitivity of the antigen component was 12.3%, 95% CrI [1.1 – 44.2], with a pooled antigen specificity of 99.7%, 95% CrI [96.8 – 100]. Pooled sensitivity of the antibody component was 97.3%, 95% CrI [60.7 – 99.9], and pooled antibody specificity was 99.6%, 95% CrI [99.0 – 99.8]. Estimates using the continuous threshold model did not differ notably from the perfect gold standard model, giving us confidence that our estimates are robust. Individual study limitations included failure to blind reference standard results, and selecting patients or samples based on HIV status, resulting in potential for bias. None of the included studies were considered to have a low risk of bias. Data limitations prevented sub-group analyses by reference standards, and statistical exploration of the effect of patient case-mix on accuracy. Conclusions: HIV infection is accurately detected by the Determine HIV Combo in individuals who have seroconverted; however the diagnostic accuracy of the antigen component needs to be improved for detecting acute HIV infections at point-of-care.

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