Clinically relevant thresholds for ultrasensitive HIV drug resistance testing: a multi-country nested case-control study

Inzaule, Seth; Hamers, Raph L; Noguera-Julián, Marc; Casadellà, María; Parera, Mariona; Kityo, Cissy; Steegen, Kim; Naniche, Denise; Clotet, Bonaventura; Wit, Tobias F. Rinke de; Paredes, Roger; Osibogun, Akin; Wallis, Carole L.; Nalubwama, Cathy; Letsoalo, Esrom; Senono, Fred; Adelabu, Hameed; Kakooza, Hanipha; Namata, Harriet; Sanne, Ian; Nankya, Immaculate; Menke, Jack; Lange, Joep M. A.; Sigaloff, Kim C.E.; Mandaliya, Kishor; Hardman, M.; Siwale, Margaret; Jager, Marleen de; Dolan, Marian; Botes, Mariëtte E.; O'Mello, Martin; Wellington, Maureen; Mutebi, Miiro; Nakitto, Miriam; Labib, Moheb; Pakker, Nadine; Ondoa, Pascale; Mugyenyi, Peter; Ive, Prudence; Nakanjako, Ritah; Schuurman, Rob; Lüthy, Ruedi; Balinda, Sheila N.; Akanmu, Alani S; Boender, T. Sonia; Adeyemo, Titilope A.; Rodoye, Tope; Stevens, Wendy; Namala, Winnie

doi:10.1016/s2352-3018(18)30177-2

Cited by 63 publications

(45 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…The worst-case strategy, however, performs worse compared to both other strategies and there is no scenario where this strategy seems to be reasonable. A recent study suggests that lowering the threshold of resistance testing might come with a reduction of specificity in HIV-1 resistance testing, but increases the identification of people at risk of virological failure, i.e., sensitivity 20 . So far there are cases where patients experienced therapy failure during a co-receptor antagonist, while the X4 ratio was beneath the threshold of phenotypic testing 11 .…”

Section: Discussionmentioning

confidence: 99%

Comparative analyses of error handling strategies for next-generation sequencing in precision medicine

Löchel

Heider

2020

Sci Rep

View full text Add to dashboard Cite

Next-generation sequencing (NGS) offers the opportunity to sequence millions and billions of DNA sequences in a short period, leading to novel applications in personalized medicine, such as cancer diagnostics or antiviral therapy. Nevertheless, sequencing technologies have different error rates, which occur during the sequencing process. If the NGS data is used for diagnostics, these sequences with errors are typically neglected or a worst-case scenario is assumed. In the current study, we focused on the impact of ambiguous bases on therapy recommendations for Human Immunodeficiency Virus 1 (HIV-1) patients. Concretely, we analyzed the treatment recommendation with entry blockers based on prediction models for co-receptor tropism. We compared three different error handling strategies that have been used in the literature, namely (i) neglection, (ii) worst-case assumption, and (iii) deconvolution with a majority vote. We could show that for two or more ambiguous positions per sequence a reliable prediction is generally no longer possible. Moreover, also the position of ambiguity plays a crucial role. Thus, we analyzed the error probability distributions of existing sequencing technologies, e.g., Illumina MiSeq or PacBio, with respect to the aforementioned error handling strategies and it turned out that neglection outperforms the other strategies in the case where no systematic errors are present. In other cases, the deconvolution strategy with the majority vote should be preferred. MethodOn DNA level X4 sequences R5 sequences Scientific RepoRtS | (2020) 10:5750 | https://doi.

show abstract

“…A meta-analysis has shown that so-called minority virus strains (virus strains that constitute <20% of the virus population) can affect treatment outcome, especially for NNRTI-based treatment (see also Section Resistance testing) [46]. However, data suggest that if the resistant virus accounts for less than 5% of the virus population, the risk of treatment failure is not increased [47]. Further studies are needed to more accurately assess the relevance of resistance in smaller virus populations for different mutations and different medicines.…”

Section: Treatment Goals and Monitoringmentioning

confidence: 99%

Antiretroviral treatment for HIV infection: Swedish recommendations 2019

Eriksen

Carlander

Albert

et al. 2020

Infectious Diseases

View full text Add to dashboard Cite

The Swedish Reference Group for Antiviral Therapy (RAV) published recommendations for the treatment of HIV infection in this journal most recently in 2017. An expert group under the guidance of RAV here provides updated recommendations. The most important updates in the present guidelines are the following: (a) The risk of HIV transmission through condomless sex from individuals with fully suppressed HIV viral load is effectively zero. (b) Pre-exposure prophylaxis (PrEP) is recommended for groups with a high risk of HIV infection. (c) Since the last update, two new substances have been registered: bictegravir and doravirine. (d) Dual treatment may be an alternative in selected patients, using lamivudine þ dolutegravir or lamivudine þ boosted darunavir/atazanavir. As with previous publications, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine. This document does not cover treatment of opportunistic infections and tumours.

show abstract

Clinically relevant thresholds for ultrasensitive HIV drug resistance testing: a multi-country nested case-control study

Cited by 63 publications

References 17 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

Comparative analyses of error handling strategies for next-generation sequencing in precision medicine

Antiretroviral treatment for HIV infection: Swedish recommendations 2019

Contact Info

Product

Resources

About