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New Assay Probing HIV DNA Detects Mutations Found Earlier in Plasma RNA
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ICAAC 2015, September 17-21, 2015, San Diego
Mark Mascolini
An assay probing for resistance mutations in HIV DNA from latently infected cells saw mutation patterns highly concordant with each person's historical plasma RNA resistance profile [1]. The findings suggest Monogram's GenoSure Archive assay could be a useful clinical tool in people with a long antiretroviral history and a currently low viral load.
Monogram Biosciences researchers who conducted this study noted that suppressive antiretroviral regimens given to people with a record of previous treatment must sometimes be changed because of toxicity, cost, convenience, drug-drug interactions, and other factors. Because the new regimen must suppress HIV bearing archived resistance mutations, Monogram developed the GenoSure Archive assay to scout for resistant virus sequestered in latently infected cells but invisible to genotypic assays looking for resistant virus in plasma. An online summary explains how the assay works and how samples should be collected [2].
The study presented at ICAAC 2015 aimed to assess the correlation between drug-resistant HIV archived in the latent reservoir (identified by GenoSure Archive) and historical resistance profiles derived from previous plasma RNA genotyping. The analysis focused on 48 people in San Francisco's SCOPE cohort who had (1) a documented history of resistance to antiretrovirals, (2) durable virologic suppression, and (3) peripheral blood mononuclear cell (PBMC) aliquots available during a period of antiretroviral-induced viral suppression. Monogram technicians extracted cellular DNA from 4.5 million PBMCs per sample for the GenoSure Archive probe.
Most study participants (89%) were men, and most began antiretroviral therapy (ART) before 2001. Age averaged 49 years, and current CD4 count averaged 686. These people had taken an average of 5 regimens and had a current undetectable viral load for an average 3.9 years. Almost all (90%) had a record of nucleoside (NRTI) resistance, two thirds had resistance to protease inhibitors (PIs), and half had resistance to nonnucleosides (NNRTIs). One third had two-class resistance and 42% had three-class resistance.
The Monogram team collated historical plasma RNA genotypic results from each patient to create a cumulative resistance profile. Participants had an average of 7 previous genotypic results combined in this cumulative profile. The investigators considered GenoSure Archive results concordant when they matched drug resistance calls in the cumulative resistance profile. Results were discordant when GenoSure missed mutations seen in plasma RNA. Resistance variants detected by GenoSure but absent from the plasma RNA profile did not render the two resistance sets discordant. The analysis compared GenoSure and plasma RNA resistance calls for 21 antiretrovirals. Assay concordance assessment involved 11 major resistance-associated positions in HIV protease and 20 positions in reverse transcriptase.
Sensitivity (GenoSure's ability to detect plasma genotype-identified resistance to individual antiretrovirals) proved highest for NRTIs (93%), followed by NNRTIs (91%), and PIs (83%). Overall sensitivity measured 89% (95% confidence interval [CI] 86% to 91%). Sensitivity in detecting major resistance-associated mutations proved highest with NRTI mutations (89%), followed by NNRTI mutations (82%) and PI mutations (77%). Overall resistance mutation sensitivity measured 85% (95% CI 80% to 89%).
Concordance of GenoSure results and historical resistance calls for individual antiretrovirals stood at 85% (95% CI 81% to 88%), with concordance highest for resistance to NNRTIs (93%) and lower for resistance to PIs (84%) and NRTIs (76%). GenoSure accurately identified major wild-type (nonmutant) variants at a rate of 97% (98% for NNRTI mutations, 96% for NRTI mutations, and 96% for PI mutations). The false omission rate (how often a resistant variant seen in the historical genotype is called wild-type by GenoSure) was only 3% for all resistant variants assessed.
On the basis of these findings, the Monogram investigators proposed that GenoSure Archive "may serve as a source of additional guidance to aid in suppression management by contributing to a cumulative resistance profile when comprehensive historical resistance information is unavailable."
References
1. Toma J, Tan Y, Cai S, et al. Drug resistance profiles derived from HIV-1 DNA in ARV suppressed patients correlate with historical resistance profiles obtained from HIV-1 plasma RNA. ICAAC 2015, September 17-21, 2015, San Diego.
2. Monogram Biosciences. GenoSure Archive: HIV-1 next generation DNA sequencing assay. http://www.monogrambio.com/hiv-tests/suppression-management/genosure-archive
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