Recalibration of the limiting antigen avidity EIA to determine mean duration of recent infection in divergent HIV-1 subtypes

Abstract

Background: Mean duration of recent infection (MDRI) and misclassification of long-term HIV-1 infections, as proportion false recent (PFR), are critical parameters for laboratory-based assays for estimating HIV-1 incidence. Recent review of the data by us and others indicated that MDRI of LAg-Avidity EIA estimated previously required recalibration. We present here results of recalibration efforts using >250 seroconversion panels and multiple statistical methods to ensure accuracy and consensus.

Methods: A total of 2737 longitudinal specimens collected from 259 seroconverting individuals infected with diverse HIV-1 subtypes were tested with the LAg-Avidity EIA as previously described. Data were analyzed for determination of MDRI at ODn cutoffs of 1.0 to 2.0 using 7 statistical approaches and sub-analyzed by HIV-1 subtypes. In addition, 3740 specimens from individuals with infection >1 year, including 488 from patients with AIDS, were tested for PFR at varying cutoffs.

Results: Using different statistical methods, MDRI values ranged from 88-94 days at cutoff ODn = 1.0 to 177-183 days at ODn = 2.0. The MDRI values were similar by different methods suggesting coherence of different approaches. Testing for misclassification among long-term infections indicated that overall PFRs were 0.6% to 2.5% at increasing cutoffs of 1.0 to 2.0, respectively. Balancing the need for a longer MDRI and smaller PFR (<2.0%) suggests that a cutoff ODn = 1.5, corresponding to an MDRI of 130 days should be used for cross-sectional application. The MDRI varied among subtypes from 109 days (subtype A&D) to 152 days (subtype C).

Conclusions: Based on the new data and revised analysis, we recommend an ODn cutoff = 1.5 to classify recent and long-term infections, corresponding to an MDRI of 130 days (118-142). Determination of revised parameters for estimation of HIV-1 incidence should facilitate application of the LAg-Avidity EIA for worldwide use.

Fig 1. A: Changes in antibody avidity as measured by LAg-Avidity EIA post-seroconversion for all 259 seroconversion panels.

For the purpose of these plots, midpoint of last negative and first positive dates for each panel was used as the seroconversion date to calculate days post-seroconversion (X-axis). B: Changes in avidity for 176 panels after exclusion of suboptimal panels as required by some methods. C: Changes in avidity as depicted for suboptimal panels that were excluded for some methods.

Fig 2. Mean duration of recency at cutoff ODn of 1.5 by subtype or geographic region as determined by bionomial regression method that uses all specimens without any exclusion criteria.

Closed diamonds represent MDRI for different subtypes and vertical lines represent upper and lower 95% CI. The horizontal line represents overall mean MDRI of 130 days.

Fig 3. Close-up view of changes in avidity with overlap of MDRI at cutoffs of 1.0 to 2.0 as determined by binomial regression method.

The red lines represent 95% bounds around MDRI.