Transmission of HIV drug resistance

Geretti, Anna María; Paredes, Roger; Kozal, Michael J.

doi:10.1097/qco.0000000000000136

Cited by 12 publications

(8 citation statements)

References 36 publications

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“…Consensus sequences and frequencies of reads were produced as previously described; reads were analysed applying a 1% interpretative cut-off. 19 , 20 RAMs considered major in the resistance analysis are reported in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring

Villa

Phillips

Smith

et al. 2018

Journal of Antimicrobial Chemotherapy

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ObjectivesThe resistance profiles of patients receiving long-term ART in sub-Saharan Africa have been poorly described. This study obtained a sensitive assessment of the resistance patterns associated with long-term tenofovir-based ART in a programmatic setting where virological monitoring is yet to become part of routine care.MethodsWe studied subjects who, after a median of 4.2 years of ART, replaced zidovudine or stavudine with tenofovir disoproxil fumarate while continuing lamivudine and an NNRTI. Using deep sequencing, resistance-associated mutations (RAMs) were detected in stored samples collected at tenofovir introduction (T0) and after a median of 4.0 years (T1).ResultsAt T0, 19/87 (21.8%) subjects showed a detectable viral load and 8/87 (9.2%) had one or more major NNRTI RAMs, whereas 82/87 (94.3%) retained full tenofovir susceptibility. At T1, 79/87 (90.8%) subjects remained on NNRTI-based ART, 5/87 (5.7%) had introduced lopinavir/ritonavir due to immunological failure, and 3/87 (3.4%) had interrupted ART. Whilst 68/87 (78.2%) subjects maintained or achieved virological suppression between T0 and T1, a detectable viral load with NNRTI RAMs at T0 predicted lack of virological suppression at T1. Each treatment interruption, usually reflecting unavailability of the dispensary, doubled the risk of T1 viraemia. Tenofovir, lamivudine and efavirenz selected for K65R, K70E/T, L74I/V and Y115F, alongside M184V and multiple NNRTI RAMs; this resistance profile was accompanied by high viral loads and low CD4 cell counts.ConclusionsViraemia on tenofovir, lamivudine and efavirenz led to complex resistance patterns with implications for continued drug activity and risk of onward transmission.

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Section: Methodsmentioning

confidence: 99%

Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring

Villa

Phillips

Smith

et al. 2018

Journal of Antimicrobial Chemotherapy

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“…For the purpose of discussion in this paper, we reported a variant detection limit of >1% as resistant variants at this level have been shown to be clinically relevant [ 10 , 32 – 34 ]. In addition, the level of >1% was chosen as the 454 platform used in this study has demonstrated high intralaboratory and interlaboratory consistency in the detection of mutants present at a frequency between 1 and 10% in a large multicentre evaluations [ 35 – 37 ]…”

Section: Methodsmentioning

confidence: 99%

HIV Drug Resistance Mutations (DRMs) Detected by Deep Sequencing in Virologic Failure Subjects on Therapy from Hunan Province, China

Chen

Zou

et al. 2016

PLoS ONE

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ObjectiveDetermine HIV drug resistance mutations (DRMs) prevalence at low and high levels in ART-experienced patients experiencing virologic failure (VF).Methods29 subjects from 18 counties in Hunan Province that experienced VF were evaluated for the prevalence of DRMs (Stanford DRMs with an algorithm value ≥15, include low-, intermediate and high-level resistance) by both Sanger sequencing (SS) and deep sequencing (DS) to 1% frequency levels.ResultsDS was performed on samples from 29 ART-experienced subjects; the median viral load 4.95×104 c/ml; 82.76% subtype CRF01_AE. 58 DRMs were detected by DS. 18 DRMs were detected by SS. Of the 58 mutations detected by DS, 40 were at levels <20% frequency (26 NNRTI, 12 NRTI and 2 PI) and the majority of these 95.00% (38/40) were not detected by standard genotyping. Of these 40 low-level DRMs, 16 (40%) were detected at frequency levels of 1–4% and 24 (60%) at levels of 5–19%. SS detected 15 of 17 (88.24%) DRMs at levels ≥ 20% that were detected by DS. The only variable associated with the detection of DRMs by DS was ART adherence (missed doses in the prior 7 days); all patients that reported missing a dose in the last 7 days had DRMs detected by DS.ConclusionsDS of VF samples from treatment experienced subjects infected with primarily AE subtype frequently identified Stanford HIVdb NRTI and NNRTI resistance mutations with an algorithm value 15. Low frequency level resistant variants detected by DS were frequently missed by standard genotyping in VF specimens from antiretroviral-experienced subjects.

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“…It has been shown that low-frequency variants with mutations affecting the NNRTIs, and to a lesser extent the NRTIs, significantly reduce responses to first-line therapy with two NRTIs plus one NNRTI, while showing no appreciable effect on bPI-based regimens. 17–20 However, transmission is unlikely to be a source of the large majority of these low-frequency variants in individuals who have recently acquired HIV and consequently would have minimal to no impact on treatment outcome as they would not have been selected under drug pressure. 21 …”

Section: Introductionmentioning

confidence: 99%

Surveillance of HIV-1 transmitted integrase strand transfer inhibitor resistance in the UK

Mbisa

Ledesma

Kirwan

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background HIV treatment guidelines have traditionally recommended that all HIV-positive individuals are tested for evidence of drug resistance prior to starting ART. Testing for resistance to reverse transcriptase inhibitors and PIs is well established in routine care. However, testing for integrase strand transfer inhibitor (InSTI) resistance is less consistent. Objectives To inform treatment guidelines by determining the prevalence of InSTI resistance in a national cohort of recently infected individuals. Patients and methods Recent (within 4 months) HIV-1 infections were identified using a Recent Infection Testing Algorithm of new HIV-1 diagnoses in the UK. Resistance-associated mutations (RAMs) in integrase, protease and reverse transcriptase were detected by ultradeep sequencing, which allows for the sensitive estimation of the frequency of each resistant variant in a sample. Results The analysis included 655 randomly selected individuals (median age = 33 years, 95% male, 83% MSM, 78% white) sampled in the period 2014 to 2016 and determined to have a recent infection. These comprised 320, 138 and 197 samples from 2014, 2015 and 2016, respectively. None of the samples had major InSTI RAMs occurring at high variant frequency (≥20%). A subset (25/640, 3.9%) had major InSTI RAMs occurring only as low-frequency variants (2%–20%). In contrast, 47/588 (8.0%) had major reverse transcriptase inhibitor and PI RAMs at high frequency. Conclusions Between 2014 and 2016, major InSTI RAMs were uncommon in adults with recent HIV-1 infection, only occurring as low-frequency variants of doubtful clinical significance. Continued surveillance of newly diagnosed patients for evidence of transmitted InSTI resistance is recommended to inform clinical practice.

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Transmission of HIV drug resistance

Cited by 12 publications

References 36 publications

Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring

Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring

HIV Drug Resistance Mutations (DRMs) Detected by Deep Sequencing in Virologic Failure Subjects on Therapy from Hunan Province, China

Surveillance of HIV-1 transmitted integrase strand transfer inhibitor resistance in the UK

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