Clinical and analytical relevance of NNRTIs minority mutations on viral failure in HIV‐1 infected patients

Mohamed, Sofiane; Ravet, Sophie; Camus, Claire; Khiri, Hacène; Olive, Daniel; Halfon, Philippe

doi:10.1002/jmv.23853

Cited by 11 publications

(9 citation statements)

References 58 publications

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“…Previous studies [27–39] have reported that individuals initiating cART with preexisting HIV low-frequency DRMs have a higher likelihood of VF, particularly among those initiating NNRTIs. It has also been reported that individuals with preexisting low-frequency DRMs at baseline have the same DRMs at the time of VF.…”

Section: Introductionmentioning

confidence: 99%

Low-frequency HIV-1 drug resistance mutations in antiretroviral naïve individuals in Botswana

et al. 2022

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Background: Individuals living with human immunodeficiency virus (HIV) who experience virological failure (VF) after combination antiretroviral therapy (cART) initiation may have had low-frequency drug resistance mutations (DRMs) at cART initiation. There are no data on low-frequency DRMs among cART-naïve HIV-positive individuals in Botswana.Methods: We evaluated the prevalence of low-frequency DRMs among cART-naïve individuals previously sequenced using Sanger sequencing. The generated pol amplicons were sequenced by next-generation sequencing.Results: We observed low-frequency DRMs (detected at <20% in 33/103 (32%) of the successfully sequenced individuals, of whom four also had mutations detected at >20%. K65R was the most common low-frequency DRM detected in 8 individuals. Eighty-two of the 103 individuals had follow-up viral load data while on cART. Twenty-seven of the 82 individuals harbored lowfrequency DRMs. Only 12 of 82 individuals experienced VF. The following low-frequency DRMs were observed in four individuals experiencing VF: K65R, K103N, V108I, and Y188C. No statistically significant difference was observed in the prevalence of lowfrequency DRMs between individuals experiencing VF (4/12) and those not experiencing VF (23/70) (P = .97). However, individuals with non-nucleoside reverse transcriptase inhibitors-associated low-frequency DRMs were 2.68 times more likely to experience VF (odds ratio, 2.68; 95% confidential interval, 0.4-13.9) compared with those without (P = .22). Conclusion:Next-generation sequencing was able to detect low-frequency DRMs in this cohort in Botswana, but these DRMs did not contribute significantly to VF. Abbreviations: ANCs = antenatal clinics, BHP = Botswana Harvard AIDS Partnership, cART = combination antiretroviral therapy, DRMs = drug resistance mutations, DTG = dolutegravir, EFV = efavirenz, FTC = emtricitabine, HIV = human immunodeficiency virus, IDCC = infectious disease care clinics, KRISP = Kwazulu-Natal Research Innovation and Sequencing Platform, NGS = next generation sequencing, NNRTI = non-nucleoside reverse transcriptase inhibitors, NRTI = nucleoside reverse transcriptase inhitors, OR = odds ratio, PASeq = polymorphism analysis sequencing, PCR = polymerase chain reaction, PI = protease inhibitors, PR = protease, RNA = ribonucleic acid, RT = reverse transcriptase, TB = tuberculosis, TDF = tenofovir disoproxil fumarate, VF = virological failure, VL = viral load.

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Section: Introductionmentioning

confidence: 99%

Low-frequency HIV-1 drug resistance mutations in antiretroviral naïve individuals in Botswana

et al. 2022

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“…Retrieving HIV resistance data from PBMC may be less expensive, but the clinical significance of DRM in proviral DNA remains controversial [ 9 , 15 – 17 ]. Moreover, consensus genotype from plasma RNA or proviral DNA does not detect DRM as minority variants <20% [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

HIV Drug Resistance Mutations in Proviral DNA from a Community Treatment Program

et al. 2015

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BackgroundDrug resistance mutations archived in resting memory CD4+ cells may persist despite suppression of HIV RNA to <50 copies/ml. We sequenced pol gene from proviral DNA among viremic and suppressed patients to identify drug resistance mutations.MethodsThe Peninsula AIDS Research Cohort study enrolled and followed over 2 years 120 HIV infected patients from San Mateo and San Francisco Counties. HIV-1 pol genotyping by bulk sequencing was performed on 38 DNA and RNA from viremic patients and DNA only among 82 suppressed patients at baseline. Antiretroviral susceptibility was predicted by HIVDB.stanford.edu.ResultsAmong 120 subjects, 81% were on antiretroviral therapy and had been treated for a median time of 7 years. Thirty-two viremic patients showed concordant RNA and DNA genotypes (84%); the discordant profiles were mainly observed in patients with low-level viremia. Among suppressed patients, 21 had drug resistance mutations in proviral DNA (26%) with potential resistance to one, two or three ARV classes in 16, 4 and 1 samples respectively.ConclusionsThe high level of genotype concordance between DNA and RNA in viremic patients suggested that DNA genotyping might be used to assess drug resistance in resource-limited settings, and further investigation of extracted DNA from dried blood spots is needed. Drug resistance mutations in proviral DNA in 26% of subjects with less than 50 copies/ml pose a risk for the transmission of drug resistant virus with virologic failure, treatment interruption or decreased adherence.

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“…By comparison with cloning and sequencing, we estimate that at least 20% mutant was necessary in the patient’s specimens to be detected by the PCR-SSOP-Luminex assay. The sensitivity of detection by Sanger sequencing has been reported to be ∼20% [33] , [34] . Sanger sequencing and PCR-SSOP-Luminex had approximately the same detection sensitivity on patient materials.…”

Section: Discussionmentioning

confidence: 99%

Development and Customization of a Color-Coded Microbeads-Based Assay for Drug Resistance in HIV-1 Reverse Transcriptase

Kawana-Tachikawa

Shiino

et al. 2014

PLoS ONE

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BackgroundDrug resistance (DR) of HIV-1 can be examined genotypically or phenotypically. Although sequencing is the gold standard of the genotypic resistance testing (GRT), high-throughput GRT targeted to the codons responsible for DR may be more appropriate for epidemiological studies and public health research.MethodsWe used a Japanese database to design and synthesize sequence-specific oligonucleotide probes (SSOP) for the detection of wild-type sequences and 6 DR mutations in the clade B HIV-1 reverse transcriptase region. We coupled SSOP to microbeads of the Luminex 100 xMAP system and developed a GRT based on the polymerase chain reaction (PCR)-SSOP-Luminex method.ResultsSixteen oligoprobes for discriminating DR mutations from wild-type sequences at 6 loci were designed and synthesized, and their sensitivity and specificity were confirmed using isogenic plasmids. The PCR-SSOP-Luminex DR assay was then compared to direct sequencing using 74 plasma specimens from treatment-naïve patients or those on failing treatment. In the majority of specimens, the results of the PCR-SSOP-Luminex DR assay were concordant with sequencing results: 62/74 (83.8%) for M41, 43/74 (58.1%) for K65, 70/74 (94.6%) for K70, 55/73 (75.3%) for K103, 63/73 (86.3%) for M184 and 68/73 (93.2%) for T215. There were a number of specimens without any positive signals, especially for K65. The nucleotide position of A2723G, A2747G and C2750T were frequent polymorphisms for the wild-type amino acids K65, K66 and D67, respectively, and 14 specimens had the D67N mutation encoded by G2748A. We synthesized 14 additional oligoprobes for K65, and the sensitivity for K65 loci improved from 43/74 (58.1%) to 68/74 (91.9%).ConclusionsWe developed a rapid high-throughput assay for clade B HIV-1 DR mutations, which could be customized by synthesizing oligoprobes suitable for the circulating viruses. The assay could be a useful tool especially for public health research in both resource-rich and resource-limited settings.

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Clinical and analytical relevance of NNRTIs minority mutations on viral failure in HIV‐1 infected patients

Cited by 11 publications

References 58 publications

Low-frequency HIV-1 drug resistance mutations in antiretroviral naïve individuals in Botswana

Low-frequency HIV-1 drug resistance mutations in antiretroviral naïve individuals in Botswana

HIV Drug Resistance Mutations in Proviral DNA from a Community Treatment Program

Development and Customization of a Color-Coded Microbeads-Based Assay for Drug Resistance in HIV-1 Reverse Transcriptase

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