Independent assessment of candidate HIV incidence assays on specimens in the CEPHIA repository

Kassanjee, Reshma; Pilcher, Christopher D.; Keating, Sheila M.; Facente, Shelley N.; McKinney, Elaine; Price, Matthew A.; Martin, Jeffrey N.; Hecht, Frederick M.; Kallas, Esper G.; Welte, Alex; Busch, Michael P.; Murphy, Gary

doi:10.1097/qad.0000000000000429

Cited by 137 publications

(240 citation statements)

References 33 publications

(41 reference statements)

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“…5,6 An additional recommendation is the generation of a local false-recent rate (FRR), which is the fraction of longterm infected (>2 years) who test positive for the testing algorithm. 5,7,8 In this report, we present LAg-Avidity assay results from individuals in Guangxi province of China who have been infected a median of 5.4 years (range 2.0 to 13.5 years), based on prior HIV antibody testing. A total of 362 specimens from 341 individuals were tested; 320 individuals provided one time point, 19 individuals provided two time points, and 2 individuals provided three time points.…”

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confidence: 99%

Short Communication: Low False Recent Rate of Limiting-Antigen Avidity Assay Among Long-Term Infected Subjects from Guangxi, China

Laeyendecker

Wendel

et al. 2015

AIDS Research and Human Retroviruses

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Assays used for HIV cross-sectional incidence testing can misclassify some individuals with nonrecent HIV infection as recently infected, overestimating HIV incidence. We analyzed the frequency and factors associated with false-recent misclassification on subjects from Quangxi, China known to have long-term infection using the limited antigen-avidity assay (LAg-Avidity). Stored samples from treatment-naive individuals from Guangxi, China were tested using the LAg-Avidity. A total of 362 samples from individuals known to be infected 2 to 13.5 years were tested and the false-recent rate (FRR), the frequency of samples with a positive result, was determined at different cutoff values of the assay. Additionally, factors associated with misclassification were determined. The FRR of the LAg-Avidity was 1.1% (4/362) using a cutoff of 1.5 normalized optical density units (OD-n). All four samples had viral loads >1,000 copies/ml. Using a cutoff of 3.0 OD-n the FRR was 5.5% (20/362), with four samples having viral loads <1,000 copies/ml. Factors associated with a higher odds of misclassification were female gender (OR 7.7, 95% CI 1.0-56.4) and being a female sex worker (OR 31.3,. At the higher cutoff, being of Zhuang decent, relative to Han, had higher odds of misclassification (OR 6.2, 95% CI 1.99-19.0). The LAg-Avidity assay had a low FRR in this Chinese population. Further investigations of the higher frequency of low LAg-Avidity results seen in female sex workers and individuals of Zhuang descent should be explored in a larger study.

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confidence: 99%

Short Communication: Low False Recent Rate of Limiting-Antigen Avidity Assay Among Long-Term Infected Subjects from Guangxi, China

Laeyendecker

Wendel

et al. 2015

AIDS Research and Human Retroviruses

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“…17 In the CEPHIA evaluation, the FRR for individuals on ART was 50% for the CDC-modified Bio-Rad Avidity assay and 58.8% for LAg-Avidity assay; the FRR was 12.9% for elite suppressors for both assays. In contrast, none of the 23 elite suppressors evaluated in this report was misclassified as assay positive using the new Bio-Rad Combo Avidity assay.…”

Section: Discussionmentioning

confidence: 99%

“…Methods to calculate the MDRI using T = 2 have been described previously. 17,31 The FRR was determined using data obtained from samples from the ALIVE, ES, JHHCC, and MACS cohorts. The FRR (proportion of samples from individuals infected >2 years that were misclassified as recently infected) was determined using AI cutoffs of 20%-90%.…”

Section: Methodsmentioning

confidence: 99%

“…The performance of incidence assays can be characterized by two variables: the mean duration of recent infection (MDRI, the average amount of time individuals are considered recently infected for a given assay or algorithm), and the false recent rate (FRR, the frequency that individuals with long-term infection are misclassified as recently infected). [15][16][17] The WHO/UNAIDS Working Group on Incidence Assays recommends that incidence assays have an MDRI of >120 days with an FRR <2%. [18][19][20] A modified version of the third-generation Bio-Rad GS HIV-1/HIV-2 Plus O EIA is used in MAAs to estimate HIV incidence.…”

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confidence: 99%

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Development and Evaluation of a Modified Fourth-Generation Human Immunodeficiency Virus Enzyme Immunoassay for Cross-Sectional Incidence Estimation in Clade B Populations

Kirkpatrick

Patel

Celum

et al. 2016

AIDS Research and Human Retroviruses

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Background: Accurate methods for cross-sectional incidence estimation are needed for HIV surveillance and prevention research. We developed an avidity assay based on the fourth-generation Genetic Systems HIV Combo Ag/Ab EIA (Bio-Rad Combo assay) and evaluated its performance. Materials and Methods: The BioRad Combo assay was modified incubating samples with and without 0.025 M diethylamine (DEA). The avidity index (AI) was calculated as the ratio of the DEA-treated to untreated result for a specific sample. We analyzed 2,140 samples from 808 individuals from the United States with known duration of HIV infection. The mean duration of recent infection (MDRI) and the false-recent rate (FRR, fraction of samples from individuals known to be infected >2 years misclassified as recent) were calculated for AI cutoffs of 20%-90% for the avidity assay alone and in combination with a viral load assay (VL, limit of detection 400 copies/ml). Factors associated with misclassification of samples collected ‡2 years after infections were also evaluated. Results: The MDRI for the Bio-Rad Combo Avidity assay ranged from 50 days using an AI cutoff of 20% to 276 days using an AI cutoff of 90%; the FRR ranged from 0% to 9%. When samples with a VL <400 copies/ml were classified as nonrecent, the FRRs were reduced approximately twofold and the MDRI estimates were reduced by *20%. An AI cutoff of 50% provided an MDRI of 135 days with an FRR of 2.1%. All samples from elite suppressors had an AI >80%. In adjusted analysis, viral suppression and low CD4 cell count were significantly associated with misclassification among individuals infected >2 years. Conclusions: This modified Bio-Rad Combo Avidity assay may be a useful tool for cross-sectional HIV incidence estimation. Further research is needed to evaluate use of this assay in combination with other assays to accurately estimate population-level HIV incidence.

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“…Under a general framework for incidence estimation, two parameters are required (Kassanjee, McWalter & Barnighausen 2012): The Mean Duration of Recent Infection (MDRI) -the average time subjects spend 'recently' infected within some time post infection; and the FalseRecent Rate (FRR) -the probability that a subject who is infected for longer than will return a 'recent' result. While the FRR should ideally be zero, it is non-negligible for many currently available TRIs and is understood to vary by time and place (Busch, Pilcher & Mastro 2010;Hallett, Ghys & Barnighausen 2009;Kassanjee, Pilcher & Keating 2014;Le Vu, Pillonel & Semaille 2008;Longosz, Mehta & Kirk 2014;Mastro, Kim & Hallett 2010;Murphy & Parry 2008). The MDRI, typically required to be at least half a year for a TRI to begin to show promise (Incidence Assay Critical Path Working Group 2011), should ideally remain constant so that a once-calibrated TRI would be useful when transferred to other contexts.…”

Section: Introductionmentioning

confidence: 99%

Cross-Sectional HIV Incidence Surveillance: A Benchmarking of Approaches for Estimating the ‘Mean Duration of Recent Infection’

Kassanjee

Angelis

Farah

et al. 2017

Statistical Communications in Infectious Diseases

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Abstract:The application of biomarkers for 'recent' infection in cross-sectional HIV incidence surveillance requires the estimation of critical biomarker characteristics. Various approaches have been employed for using longitudinal data to estimate the Mean Duration of Recent Infection (MDRI) -the average time in the 'recent' state. In this systematic benchmarking of MDRI estimation approaches, a simulation platform was used to measure accuracy and precision of over twenty approaches, in thirty scenarios capturing various study designs, subject behaviors and test dynamics that may be encountered in practice. Results highlight that assuming a single continuous sojourn in the 'recent' state can produce substantial bias. Simple interpolation provides useful MDRI estimates provided subjects are tested at regular intervals. Regression performs the best -while 'random effects' describe the subject-clustering in the data, regression models without random effects proved easy to implement, stable, and of similar accuracy in scenarios considered; robustness to parametric assumptions was improved by regressing 'recent'/'non-recent' classifications rather than continuous biomarker readings. All approaches were vulnerable to incorrect assumptions about subjects' (unobserved) infection times. Results provided show the relationships between MDRI estimation performance and the number of subjects, inter-visit intervals, missed visits, loss to follow-up, and aspects of biomarker signal and noise.

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Independent assessment of candidate HIV incidence assays on specimens in the CEPHIA repository

Cited by 137 publications

References 33 publications

Short Communication: Low False Recent Rate of Limiting-Antigen Avidity Assay Among Long-Term Infected Subjects from Guangxi, China

Short Communication: Low False Recent Rate of Limiting-Antigen Avidity Assay Among Long-Term Infected Subjects from Guangxi, China

Development and Evaluation of a Modified Fourth-Generation Human Immunodeficiency Virus Enzyme Immunoassay for Cross-Sectional Incidence Estimation in Clade B Populations

Cross-Sectional HIV Incidence Surveillance: A Benchmarking of Approaches for Estimating the ‘Mean Duration of Recent Infection’

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