Viral load criteria and threshold optimization to improve HIV incidence assay characteristics

Abstract

Objective Assays for classifying HIV infections as ‘recent’ or ‘non-recent’ for incidence surveillance fail to simultaneously achieve large mean durations of ‘recent’ infection (MDRIs) and low ‘false-recent’ rates (FRRs), particularly in virally suppressed persons. The potential for optimizing recent infection testing algorithms (RITAs), by introducing viral load criteria and tuning thresholds used to dichotomize quantitative measures, is explored. Design The Consortium for the Evaluation and Performance of HIV Incidence Assays characterized over 2000 possible RITAs constructed from seven assays (LAg, BED, Less-sensitive Vitros, Vitros Avidity, BioRad Avidity, Architect Avidity and Geenius) applied to 2500 diverse specimens. Methods MDRIs were estimated using regression, and FRRs as observed ‘recent’ proportions, in various specimen sets. Context-specific FRRs were estimated for hypothetical scenarios. FRRs were made directly comparable by constructing RITAs with the same MDRI through the tuning of thresholds. RITA utility was summarized by the precision of incidence estimation. Results All assays produce high FRRs amongst treated subjects and elite controllers (10%-80%). Viral load testing reduces FRRs, but diminishes MDRIs. Context-specific FRRs vary substantially by scenario – BioRad Avidity and LAg provided the lowest FRRs and highest incidence precision in scenarios considered. Conclusions The introduction of a low viral load threshold provides crucial improvements in RITAs. However, it does not eliminate non-zero FRRs, and MDRIs must be consistently estimated. The tuning of thresholds is essential for comparing and optimizing the use of assays. The translation of directly measured FRRs into context-specific FRRs critically affects their magnitudes and our understanding of the utility of assays.

A comparison of self-report and antiretroviral detection to inform estimates of antiretroviral therapy coverage, viral load suppression and HIV incidence in Kwazulu-Natal, South Africa

“…Contextspecific FRR estimates for an algorithm consisting of LAg-Avidity EIA and viral load in a setting similar to the study population have been estimated as low as 0.2% [12]. Furthermore, benchmarking data are not available for quantifying the impact of including a measure of ARV use on the mean duration of recent infection (MDRI) and FRR.…”

“…We estimated Mean Duration of Recent Infection (MDRI) for this RITA at 184 days (95% CI: 159-219), based on a subtype C-specific estimate for the LAg-Avidity EIA and the sensitivity of the screening algorithm [11]. The False Recent Rate (FRR) was estimated in a similar context at 0.2% [12].…”

Viral and Host Characteristics of Recent and Established HIV-1 Infections in Kisumu based on a Multiassay Approach

“…Samples with missing values by any of the four parameters (three incidence assays or VL) were excluded from this analysis. We derived mean duration of recency (w) and 95% confidence intervals (95% CI) for the three assays from a previous publication49, and estimated percent incidence by individual assays and MAAs as previously described50, assuming missing at random to adjust for the samples missing incidence test data. We transformed the five parameters’ data into binomial values according to their respective cut-offs and generated heat maps using PermutMatrix-1.9.3 to evaluate the classification of samples by the five parameters.…”

Infection Staging and Incidence Surveillance Applications of High Dynamic Range Diagnostic Immuno-Assay Platforms

“…Performance of the VITROS and ARCHITECT avidity assays for use in cross-sectional incidence estimation has been investigated by the CEPHIA collaboration, as part of an independent evaluation of leading candidate HIV incidence assays (9,10). During application of the proposed procedures for recency ascertainment to the CEPHIA ‘evaluation panel’, these two-well avidity protocols additionally produced results from diluted (1:10) but otherwise unmodified runs.…”