Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial

Derache, Anne; Iwuji, Collins; Harling, Guy; Danaviah, Siva; Marcelin, Anne‐Geneviève; Cálvez, Vincent; Oliveira, Túlio de; Dabis, François; Porter, Kholoud; Pillay, Deenan

doi:10.1093/cid/ciy881

Cited by 59 publications

(66 citation statements)

References 33 publications

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“…Sanger-based HIVDR genotyping reports DRM data as dichotomous (present or absent), whereas NGS-based HIVDR genotyping also reports DRMs as numerical data (relative abundance). This additional information strengthens our ability to assess the clinical impact of a given DRM and to determine and track its overall frequency within a population, which may significantly impact drug regimens and public health approaches to control and reduce HIV transmission 10,14,[49][50][51][52] . Notably, while many NGS HIVDR data analysis pipelines exist 25,[31][32][33][34][35][36][37][38][39] , their design and implementation was conducted independently by different research groups with little coordination among the developers.…”

Section: Discussionmentioning

confidence: 81%

Performance comparison of next generation sequencing analysis pipelines for HIV-1 drug resistance testing

Lee

Parkin

Jennings

et al. 2020

Sci Rep

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Next generation sequencing (NGS) is a trending new standard for genotypic HIV-1 drug resistance (HIVDR) testing. Many NGS HIVDR data analysis pipelines have been independently developed, each with variable outputs and data management protocols. Standardization of such analytical methods and comparison of available pipelines are lacking, yet may impact subsequent HIVDR interpretation and other downstream applications. Here we compared the performance of five NGS HIVDR pipelines using proficiency panel samples from NIAID Virology Quality Assurance (VQA) program. Ten VQA panel specimens were genotyped by each of six international laboratories using their own in-house NGS assays. Raw NGS data were then processed using each of the five different pipelines including HyDRA, MiCall, PASeq, Hivmmer and DEEPGEN. All pipelines detected amino acid variants (AAVs) at full range of frequencies (1~100%) and demonstrated good linearity as compared to the reference frequency values. While the sensitivity in detecting low abundance AAVs, with frequencies between 1~20%, is less a concern for all pipelines, their specificity dramatically decreased at AAV frequencies <2%, suggesting that 2% threshold may be a more reliable reporting threshold for ensured specificity in AAV calling and reporting. More variations were observed among the pipelines when low abundance AAVs are concerned, likely due to differences in their NGS read quality control strategies. Findings from this study highlight the need for standardized strategies for NGS HIVDR data analysis, especially for the detection of minority HiVDR variants.Genotypic HIV drug resistance (HIVDR) testing not only guides effective clinical care of HIV-infected patients but also serves to provide surveillance of transmitted HIVDR in the population. Treatment guidelines in resource-permitted settings advocate the use of HIVDR monitoring both prior to ART initiation and when treatment failure is suspected 1,2 . There is increasing evidence showing that the presence of minority resistance variants open Scientific RepoRtS | (2020) 10:1634 | https://doi.org/10.1038/s41598-020-58544-z www.nature.com/scientificreports www.nature.com/scientificreports/ (MRV) in the HIV quasispecies (i.e., a swarm of highly-related but genotypically different viral variants) may be clinically significant and increase the risk of virological failure, impair immune recovery, lead to accumulation of drug resistance, increase risk of treatment switches and death [3][4][5][6][7][8] . A nationwide study in Mexico focusing on pretreatment drug resistance (PDR) found that lowering the detection threshold for PDR to 5% versus the conventional 20% improved the ability to identify patients with virological failure 6 . In addition, a European wide study found that pre-existing minority drug-resistant HIV-1 variants more than doubled the risk of virological failure to first-line NNRTI-based ART 9 . A more recent African study also reported similar findings, suggesting lowering the threshold below 20% improved the ability to i...

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Section: Discussionmentioning

confidence: 81%

Performance comparison of next generation sequencing analysis pipelines for HIV-1 drug resistance testing

Lee

Parkin

Jennings

et al. 2020

Sci Rep

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“…[12][13][14] By contrast, the ANRS 12249 Treatment as Prevention Trial 15 reported that the most common NNRTI mutation, K103N, when detected alone, was not associated with increased risk of VF on an NNRTI-based single tablet regimen containing tenofovir, emtricitabine and efavirenz. 16 A study in Kenya similarly suggested isolated K103N might have limited impact on EFV-based ART. 17 These con icting data have generated controversy in the eld on optimal rst-line regimens to balance safety, tolerability, cost, and the impact of circulating NNRTI drug resistance on virologic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Siedner¹,

Moorhouse²,

Simmons³

et al. 2020

Preprint

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Background: Little is known about the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second generation integrase inhibitors, now the standard of care drug class for HIV-1 treatment globally.Methods: We conducted next-generation sequencing on stored plasma specimens from the ADVANCE trial collected prior to treatment initiation. Our primary outcome was 96-week virologic success, defined as achievement of a viral load < 1000 copies/mL from 12 weeks, < 200 copies/mL from 24 weeks, and < 50 copies/mL from 48 through 96 weeks. We estimated the impact of PDR, defined by the presence of drug resistance on the World Health Organization (WHO) mutation list, on virologic outcomes in the entire cohort, and stratified by EFV-based versus DTG-based regimens. In sensitivity analyses, we allowed virologic failure with re-suppression, assessed FDA 48 and 96-week Snapshot outcomes, and considered minority resistance mutations (5–20% frequency).Results: Of 1,053 trial participants, 873 (83%) had plasma available and successful sequencing completed. Of these, 288 (33%) were randomized to an EFV-based regimen and 585 (67%) were randomized to a DTG-based regimen. Fourteen percent (122/873) had at least one WHO-defined mutation, of which over 98% (120/122) had NNRTI mutations. NRTI mutations were rare (20/873, 2%). Rates of virologic suppression were significantly lower in those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001). This phenomenon was consistent for both EFV-based (60% [12/20] versus 86% [214/248], P = 0.002) and DTG-based ART (61/92 [66%] versus 84% [391/465] P < 0.001, P for interaction by regimen 0.49). In multivariable models adjusted for clinical characteristics and treatment adherence, PDR strongly predicted failure [adjusted OR 0.38 (0.23–0.61), P < 0.001]. Although suppression rates were greater when allowing for non-consecutive visits with failure, PDR significantly predicted greater risk of failure for both regimens in all outcome definitions. We found no effect of mutations at frequencies 5–20% on any of our outcomes.Interpretation: NNRTI resistance prior to treatment initiation is associated with failure of integrase inhibitor-containing first-line regimens. These results portend high rates of first-line treatment failure in sub Saharan Africa, where circulating NNRTI resistance is common.

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“…The study by Derache and colleagues is the largest to assess the effect of baseline NNRTI resistance on the virological response to the fixed-dose combination of TDF/emtricitabine (FTC)/efavirenz (EFV), one of the WHO-recommended first-line ART regimens [3]. It is also one of the largest studies to quantify PDR prevalence using a next-generation sequencing technology, Illumina MiSeq, in place of the more common dideoxynucleoside Sanger sequencing technology.…”

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confidence: 99%

The Clinical Implications of Pretreatment Drug Resistance—A Moving Target

Shafer

Frenkel

2018

Clinical Infectious Diseases

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Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial

Cited by 59 publications

References 33 publications

Performance comparison of next generation sequencing analysis pipelines for HIV-1 drug resistance testing

Performance comparison of next generation sequencing analysis pipelines for HIV-1 drug resistance testing

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

The Clinical Implications of Pretreatment Drug Resistance—A Moving Target

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