Insights about minority HIV-1 strains in transmitted drug resistance mutation dynamics and disease progression

Léda, Ana Rachel; Hunter, James R.; Oliveira, Ursula Castro de; Azevedo, Inacio Junqueira; Sucupira, Maria Cecília Araripe; Diaz, Ricardo Sobhie

doi:10.1093/jac/dky132

Cited by 7 publications

(4 citation statements)

References 21 publications

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“…Additional articles were identified by experts in the field. We screened out 1330 studies after removing duplicates, and 140 articles were downloaded for full-length screening, of which 39 articles were kept [ 6 , 17 , 24 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

Ouyang,

Yuan,

Zhai

et al. 2024

Viruses

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Background: There are an increasing number of articles focused on the prevalence and clinical impact of pretreatment HIV drug resistance (PDR) detected by Sanger sequencing (SGS). PDR may contribute to the increased likelihood of virologic failure and the emergence of new resistance mutations. As SGS is gradually replaced by next-generation sequencing (NGS), it is necessary to assess the levels of PDR using NGS in ART-naïve patients systematically. NGS can detect the viral variants (low-abundance drug-resistant HIV-1 variants (LA-DRVs)) of virus quasi-species at levels below 20% that SGS may fail to detect. NGS has the potential to optimize current HIV drug resistance surveillance methods and inform future research directions. As the NGS technique has high sensitivity, it is highly likely that the level of pretreatment resistance would be underestimated using conventional techniques. Methods: For the systematic review and meta-analysis, we searched for original studies published in PubMed, Web of Science, Scopus, and Embase before 30 March 2023 that focused exclusively on the application of NGS in the detection of HIV drug resistance. Pooled prevalence estimates were calculated using a random effects model using the ‘meta’ package in R (version 4.2.3). We described drug resistance detected at five thresholds (>1%, 2%, 5%, 10%, and 20% of virus quasi-species). Chi-squared tests were used to analyze differences between the overall prevalence of PDR reported by SGS and NGS. Results: A total of 39 eligible studies were selected. The studies included a total of 15,242 ART-naïve individuals living with HIV. The prevalence of PDR was inversely correlated with the mutation detection threshold. The overall prevalence of PDR was 29.74% at the 1% threshold, 22.43% at the 2% threshold, 15.47% at the 5% threshold, 12.95% at the 10% threshold, and 11.08% at the 20% threshold. The prevalence of PDR to INSTIs was 1.22% (95%CI: 0.58–2.57), which is the lowest among the values for all antiretroviral drugs. The prevalence of LA-DRVs was 9.45%. At the 2% and 20% detection threshold, the prevalence of PDR was 22.43% and 11.08%, respectively. Resistance to PIs and INSTIs increased 5.52-fold and 7.08-fold, respectively, in those with a PDR threshold of 2% compared with those with PDR at 20%. However, resistance to NRTIs and NNRTIs increased 2.50-fold and 2.37-fold, respectively. There was a significant difference between the 2% and 5% threshold for detecting HIV drug resistance. There was no statistically significant difference between the results reported by SGS and NGS when using the 20% threshold for reporting resistance mutations. Conclusion: In this study, we found that next-generation sequencing facilitates a more sensitive detection of HIV-1 drug resistance than SGS. The high prevalence of PDR emphasizes the importance of baseline resistance and assessing the threshold for optimal clinical detection using NGS.

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Section: Resultsmentioning

confidence: 99%

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

Ouyang,

Yuan,

Zhai

et al. 2024

Viruses

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“…We recognize that a more detailed analysis of HIV quasispecies in this study would greatly benefit from single-genome amplification or next-generation sequencing tools. It has recently been demonstrated using next-generation sequencing (NGS) that transmitted drug-resistance mutations representing small percentages of the viral population do not persist during infection because they are negatively selected in the first year after HIV-1 seroconversion [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral Drug-Resistance Mutations on the Gag Gene: Mutation Dynamics during Analytic Treatment Interruption among Individuals Experiencing Virologic Failure

et al. 2022

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We describe drug-resistance mutation dynamics of the gag gene among individuals under antiretroviral virologic failure who underwent analytical treatment interruption (ATI). These mutations occur in and around the cleavage sites that form the particles that become the mature HIV-1 virus. The study involved a 12-week interruption in antiretroviral therapy (ART) and sequencing of the gag gene in 38 individuals experiencing virologic failure and harboring triple-class resistant HIV strains. Regions of the gag gene surrounding the NC-p2 and p1-p6 cleavage sites were sequenced at baseline before ATI and after 12 weeks from plasma HIV RNA using population-based Sanger sequencing. Fourteen of the sixteen patients sequenced presented at least one mutation in the gag gene at baseline, with an average of 4.93 mutations per patient. All the mutations had reverted to the wild type by the end of the study. Mutations in the gag gene complement mutations in the pol gene to restore HIV fitness. Those mutations around cleavage sites and within substrates contribute to protease inhibitor resistance and difficulty in re-establishing effective virologic suppression. ART interruption in the presence of antiretroviral resistant HIV strains was used here as a practical measure for more adapted HIV profiles in the absence of ART selective pressure.

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“…Of the PI codons on the IAS list, we initially had data on 22. These were codons 10, 20, 24,30,32,36,46,47,48,50,53,54,63,71,73,77,82,84,85,88, 89, 90, and 93. We eliminated codons 32, 47, and 50 from our analysis as they either had 0 or 1 tests that showed that mutation and therefore did not allow comparison.…”

Section: Protease Inhibitor (Pi) Mutations At Dna Levelmentioning

confidence: 99%

“…We recognize that a more detailed analysis of HIV quasispecies in this study would greatly benefit from single genome amplification or next-generation sequencing (NGS) tools. It has been recently demonstrated using NGS that transmitted drug resistance mutations representing small percentages of the viral population do not persist during infection because they are negatively selected in the first year after HIV-1 seroconversion [48]. In this context, a recent study exploring the extinction dynamics of transmitted drug resistance mutations using next-generation sequencing showed that these mutations are rare at a 20% threshold of detection [49].…”

Section: M184v As a Special Case Of Mutationmentioning

confidence: 99%

Fitness Cost of Antiretroviral Drug Resistance Mutations on the pol Gene during Analytical Antiretroviral Treatment Interruption among Individuals Experiencing Virological Failure

et al. 2021

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HIV cure studies require patients to enter an analytical treatment interruption (ATI). Here, we describe previously unanalyzed data that sheds light on ATI dynamics in PLHIV (People Living with HIV). We present drug resistance mutation dynamics on the pol gene among individuals with antiretroviral virological failure who underwent ATI. The study involved a 12-week interruption in antiretroviral therapy (ART), monitoring of viral load, CD4+/CD8+ T cell counts, and sequencing of the pol gene from 38 individuals experiencing virological failure and harboring 3-class resistant HIV strains: nucleoside reverse transcriptase inhibitors (NRTI) non-nucleoside inhibitors (NNRTI), and protease inhibitors (PI). Protease and reverse transcriptase regions of the pol gene were sequenced at baseline before ATI and every four weeks thereafter from PBMCs and at baseline and after 12 weeks from plasma HIV RNA using population-based Sanger sequencing. Average viral load increased 0.559 log10 copies per milliliter. CD4+ T cell count decreased as soon as ART was withdrawn, an average loss of 99.0 cells/mL. Forty-three percent of the mutations associated with antiretroviral resistance in PBMCs disappeared and fifty-seven percent of the mutations in plasma reverted to wild type, which was less than the 100% reversion expected. In PBMC, the PI mutations reverted more slowly than reverse transcriptase mutations. The patients were projected to need an average of 33.7 weeks for PI to revert compared with 20.9 weeks for NRTI and 19.8 weeks for NNRTI. Mutations in the pol gene can cause virological failure and difficulty in re-establishing effective virological suppression.

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Insights about minority HIV-1 strains in transmitted drug resistance mutation dynamics and disease progression

Abstract: Transmitted drug resistance mutations representing small percentages of the viral population do not persist during infection because they are negatively selected in the first year after HIV-1 seroconversion.

Cited by 7 publications

References 21 publications

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

Antiretroviral Drug-Resistance Mutations on the Gag Gene: Mutation Dynamics during Analytic Treatment Interruption among Individuals Experiencing Virologic Failure

Fitness Cost of Antiretroviral Drug Resistance Mutations on the pol Gene during Analytical Antiretroviral Treatment Interruption among Individuals Experiencing Virological Failure

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