Moving towards a reliable HIV incidence test – current status, resources available, future directions and challenges ahead

Abstract

In 2011 the Incidence Assay Critical Path Working Group reviewed the current state of HIV incidence assays and helped to determine a critical path to the introduction of an HIV incidence assay. At that time the Consortium for Evaluation and Performance of HIV Incidence Assays (CEPHIA) was formed to spur progress and raise standards among assay developers, scientists and laboratories involved in HIV incidence measurement and to structure and conduct a direct independent comparative evaluation of the performance of 10 existing HIV incidence assays, to be considered singly and in combinations as recent infection test algorithms. In this paper we report on a new framework for HIV incidence assay evaluation that has emerged from this effort over the past 5 years, which includes a preliminary target product profile for an incidence assay, a consensus around key performance metrics along with analytical tools and deployment of a standardized approach for incidence assay evaluation. The specimen panels for this evaluation have been collected in large volumes, characterized using a novel approach for infection dating rules and assembled into panels designed to assess the impact of important sources of measurement error with incidence assays such as viral subtype, elite host control of viraemia and antiretroviral treatment. We present the specific rationale for several of these innovations, and discuss important resources for assay developers and researchers that have recently become available. Finally, we summarize the key remaining steps on the path to development and implementation of reliable assays for monitoring HIV incidence at a population level.

Computational analysis of antibody dynamics identifies recent HIV-1 infection

“…The analysis includes the presence or absence of the response along with the magnitude and avidity of the antibody response when present. We evaluated plasma from 70 recent and 66 longstanding HIV-1 infections ("training panel") of multiple subtypes (A, AE, B, C) from the Center for HIV/AIDS Vaccine Immunology (CHAVI) 001 cohort (27), the US Military HIV Research Program (USMHRP) RV217 cohort (28), and the Consortium for the Development and Performance of HIV Incidence Assays (CEPHIA) repository (29), including specimens from 39 patients on antiretroviral therapy (Table 1). A recency cutoff of 9 months (270 days) was used to train the model for this analysis based upon initial characterization of candidate biomarkers using samples from the CEPHIA repository and CHAVI 001 acute infection cohorts (data not shown).…”

“…The complexity of early pathogenesis, including diversity in antibody responses among individuals and HIV subtypes, regional viral genetic diversity, HIV disease state, and ART, use has limited progress in novel assay development for incidence estimation (12,14). In particular, leading candidate assays all appear to require explicit viral load testing to reduce otherwise unacceptably high FRRs among treated individuals and elite controllers, both of which are enriched in populations with mature epidemics.…”

“…In particular, leading candidate assays all appear to require explicit viral load testing to reduce otherwise unacceptably high FRRs among treated individuals and elite controllers, both of which are enriched in populations with mature epidemics. Improvements in HIV-1 incidence estimation can be achieved through combining multiple tests into a multiassay algorithm, including antibody measurements, p24 antigen, viral diversity, and/or viral load determination (12). Recent infection testing algorithms, including serologic testing algorithm for recent HIV seroconversion (31)(32)(33)(34), have also been used in combination to refine estimates of incidence, with varying degrees of success (6,31).…”

“…This is often due to a high false recent rate (FRR) (i.e., specimens infected for more than a recency time cutoff time "T," often chosen to be 2 years, that are classified as recently infected) (6) and a mean duration of recent infection (MDRI) of approximately 4-5 months (6,11). Thus, the number of persons that must be surveyed in order to generate incidence estimates with a useful level of precision is unmanageably large in all but a small number of high incidence countries (12,13). Development of HIV-1 incidence assays using novel biomarkers must meet several key criteria for assay performance, including a longer MDRI and decreased FRR.…”

Tracking tuberculosis incidence: time to tool up

“…There are hints that the new QuantiFERON-TB Gold Plus test may be better able to identify recent infection; 4 but we are still largely looking to the future, whereas the development of HIV incidence assays and methodological work supporting their use in surveillance is much further progressed. 5 TB control is entering an exciting era. Achieving the End TB targets will require new tools; but effort to develop new methods of monitoring our progress will also be required.…”