Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL in 2009: a French nationwide study
Lambert AssoumouDiane DescampsSabine YerlyGeorges Dos SantosAnne‐Geneviève MarcelinConstance DelaugerreLaurence Morand‐JoubertAnnick RuffaultJ. IzopetJean‐Christophe PlantierSophie PakianatherB. MontesMarie‐Laure ChaixMarc WirdenDominique CostagliolaBernard Masquelier
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Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) >50 copies/mL. The protease and reverse transcriptase (RT) genes were systematically sequenced in samples from 756 patients with VL >50 copies/mL in 2009. The genotyping results were interpreted for each antiretroviral drug (ARV) by using the ANRS algorithm v21. Weighted analyses were used to derive representative estimates of percentages of patients. Prevalence rates were compared with those obtained in 2004 among patients with VL >1000 copies/mL. Sequences were obtained for 506 patients. Sequencing was successful in 45%, 80% and 96% of samples with VL of 51-500, 501-1000 and >1000 copies/mL, respectively. Resistance or possible resistance to at least one ARV was observed in 59% of samples. Overall, 0.9% of samples contained viruses resistant to all drugs belonging to at least three drug classes. All resistance prevalence rates were significantly lower in 2009 than in 2004. In France, where 86% of patients were receiving combination antiretroviral therapy in 2009, only 15.0% of patients had a VL >50 copies/mL, suggesting that only 8.9% of treated patients could potentially transmit resistant viruses. Only 0.08% of patients harboured viruses fully resistant to at least three antiretroviral drug classes. Further studies are needed to determine whether resistance continues to decline over time.Keywords:
HIV drug resistance
We compared the two commercially available sequencing kits for HIV-1 drug resistance testing, the ViroSeq Genotyping System (Applied Biosystems, Foster City, CA, U.S.A.) and the TRUGENE HIV-1 Genotyping Kit (Visible Genetics, Inc., Toronto, Ontario, Canada), with our in-house genotyping system. Fifteen viral isolates from African patients (6 treated and 9 untreated) covering a panel of HIV-1 subtypes A through J and 7 plasma samples from Belgian and African patients (2 treated and 5 untreated) were tested. All the samples could be amplified and sequenced by the three systems; however, for all systems, alternative amplification/sequencing primers had to be used for some samples belonging to subtype B as well as to other subtypes. The consensus sequence was partially derived from only one strand for the in-house system and for the ViroSeq Genotyping System. The TRUGENE HIV-1 Genotyping Kit scored the highest number of ambiguities, followed by the ViroSeq Genotyping System and the in-house system. For 11 samples, these differences in reporting mixtures affected 14 resistance-related positions, which altered the interpretation toward protease inhibitors for 2 samples when using version 1.2 RetroGram software (Virology Networks, Utrecht, The Netherlands). All three systems were able to sequence diluted samples with a viral load down to 103 or 104 RNA copies/ml. Our data therefore suggest that the performance of amplification and sequencing primers must be improved to allow fast and reliable resistance testing for all HIV-1 subtypes.
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HIV reverse transcriptase (RT) is an enzyme that plays a major role in the replication cycle of HIV and has been a key target of anti-HIV drug development efforts. Because of the high genetic diversity of the virus, mutations in RT can impart resistance to various RT inhibitors. As the prevalence of drug resistance mutations is on the rise, it is necessary to design strategies that will lead to drugs less susceptible to resistance. Here we provide an in-depth review of HIV reverse transcriptase, current RT inhibitors, novel RT inhibitors, and mechanisms of drug resistance. We also present novel strategies that can be useful to overcome RT's ability to escape therapies through drug resistance. While resistance may not be completely avoidable, designing drugs based on the strategies and principles discussed in this review could decrease the prevalence of drug resistance.
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Objective To apply HIV-1 genotyping in the surveillance of subjects infected with HIV-1 drug resistant strains,and to investigate if there are drug-resistant HIV-1 strains transmitted among infected subjects before antiretroviral therapy in Guangdong Province.Methods Viral RNA samples were collected from the sera of subjects infected with HIV-1 without receiving HAART intervetion,and were amplified by nested PCR;then the amplified fragments were sequenced and analyzed.Result HIV-1 drug resistance genotyping can be applied in targeted gene fragments obtained from samples in which the viral load is more than 1000 copies/ml and CD_4 is less than 400.Among 50 untreated cases,2 cases had low to median mutations associated with resistance,and the rate was 4%,none of which had high mutations associated with resistance.Two cases had general mutations associated with resistance,with a rate of 4%.Conclusion HIV-1 genotyping is an effective tool for the surveillance of HIV-1 drug resistant strains.These tests are accurate and reliable.The results of the study confirm the hypothesis that there are natural drug resistant mutants in the infected subjects even without receiving antiretroviral regimens.
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To evaluate the virological outcomes in children and adolescents infected with HIV-1 in Salvador, Bahia according to genotyping results.We retrospectively evaluated the rates of virological suppression of children and adolescents submitted to HIV-1 genotyping test from January/2008 to December/2012. The participants were followed in the two referral centers for pediatric AIDS care, in Salvador, Brazil. Resistance mutations, drug sensitivity profiles, and viral subtypes were analyzed using the Stanford HIV-1 Drug Resistance Database. Adherence was estimated by drugs withdrawal at pharmacies of the two sites.101 subjects were included: 35 (34.6%) were drug-naïve, and the remaining 66 were failing ART. In drug-naïve group, 3 (8.6%), presented with NNRTIs resistance mutations, along with polymorphic mutations to PIs in most (82.8%) of them. Among the failing therapy group, we detected a high frequency (89.4%) of resistance mutations to PIs, NRTI (84.8%), and NNRTI (59.1%). Virological suppression after introduction/modification of genotyping-guided ART was achieved only for patients (53.1%) with drug withdrawal over 95%. Main detected HIV-1 subtypes were B (67.3%), F (7.9), C (1.9%), and recombinant forms (22.9%).Despite the use of genotyping tests in guidance of a more effective antiretroviral regimen, poor adherence to ART seems to be the main determinant of low virological suppression rate for children and adolescents, in Salvador, Brazil.
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Abstract Objectives To evaluate the performance of a high-throughput research assay for HIV drug resistance testing based on whole genome next-generation sequencing (NGS) that also quantifies HIV viral load. Methods Plasma samples (n = 145) were obtained from HIV-positive MSM (HPTN 078). Samples were analysed using clinical assays (the ViroSeq HIV-1 Genotyping System and the Abbott RealTime HIV-1 Viral Load assay) and a research assay based on whole-genome NGS (veSEQ-HIV). Results HIV protease and reverse transcriptase sequences (n = 142) and integrase sequences (n = 138) were obtained using ViroSeq. Sequences from all three regions were obtained for 100 (70.4%) of the 142 samples using veSEQ-HIV; results were obtained more frequently for samples with higher viral loads (93.5% for 93 samples with >5000 copies/mL; 50.0% for 26 samples with 1000–5000 copies/mL; 0% for 23 samples with <1000 copies/mL). For samples with results from both methods, drug resistance mutations (DRMs) were detected in 33 samples using ViroSeq and 42 samples using veSEQ-HIV (detection threshold: 5.0%). Overall, 146 major DRMs were detected; 107 were detected by both methods, 37 were detected by veSEQ-HIV only (frequency range: 5.0%–30.6%) and two were detected by ViroSeq only. HIV viral loads estimated by veSEQ-HIV strongly correlated with results from the Abbott RealTime Viral Load assay (R2 = 0.85; n = 142). Conclusions The NGS-based veSEQ-HIV method provided results for most samples with higher viral loads, was accurate for detecting major DRMs, and detected mutations at lower levels compared with a method based on population sequencing. The veSEQ-HIV method also provided HIV viral load data.
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The ViroSeq (Celera Diagnostics) and Trugene (Bayer HealthCare) HIV-1 genotyping systems are widely used today in world clinical practice to detect drug resistance mutations resulting from ineffective treatment for HIV infection. Only the former test has gained acceptance. The present study has compared ViroSeq and Trugene genotyping systems used to identify both mutations of drug resistance and those of polymorphism in the HIV variants circulating in Russia where the unique strain IDU-A prevails. Analysis of 18 samples from HIV-infected patients who received and did not receive specific therapy has demonstrated that the agreement of the results of the tests was 95% (180 of the 190 mutations). At the same time, the results of resistance mutation detection by the ViroSeq and Trugene HIV-1 genotyping systems coincided completely. The fact that the Trugene HIV-1 genotyping system may be used along with the ViroSeq test system in clinical diagnostic laboratories is shown in the paper.
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Abstract Background: HIV-1 drug resistance genotyping is critical to the monitoring of antiretroviral treatment. Data on HIV-1 genotyping success rates of different laboratory specimen types from multiple sources is still scarce. Methods: In this cross-sectional study, we determined the laboratory genotyping success rates (GSR) and assessed the correlates of genotyping failure of 6837 unpaired dried blood spot (DBS) and plasma specimens from multiple studies/sources. Specimens from multiple studies in a resource-constrained setting were analysed in our laboratory between 2016 and 2019. Results: We noted an overall GSR of 65.7% and specific overall GSR for DBS and plasma of 49.8% and 85.9% respectively. The correlates of genotyping failure were viral load (VL) <10,000 copies/mL (aOR 0.3 95% CI: 0.24-0.38; p<0.0001), lack of viral load testing prior to genotyping (OR 0.85 95% CI: 0.77-0.94; p=0.002), use of DBS specimens (aOR 0.10 95% CI: 0.08-0.14; p<0.0001) and specimens from routine clinical diagnosis (aOR 1.4 95% CI: 1.10-1.75; p=0.005). Conclusions: We report rapidly decreasing HIV-1 genotyping success rates between 2016 and 2019 with increased use of DBS specimens for genotyping and note decreasing median viral loads over the years. We recommend improvement in DBS handling, viral load testing prior to genotyping and development of more sensitive assays to genotype specimens with low or undetectable viral load, especially in this era where virological suppression rates are rising due to increased antiretroviral therapy roll-out.
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ABSTRACT The ViroSeq HIV-1 genotyping system is used in many African countries for drug resistance testing. In this study, we used a panel of diverse HIV-1 group M isolates circulating in Cameroon to show that the performance of this assay can be altered by the sequence variation of non-B HIV-1 strains that predominate in African settings.
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