Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis

Sterrantino, Gaetana; Zaccarelli, Mauro; Colao, G; Baldanti, Fausto; Giambenedetto, Simona Di; Carli, Tiziana; Maggiolo, Franco; Zazzi, Maurizio

doi:10.1007/s15010-011-0237-y

Cited by 20 publications

(20 citation statements)

References 28 publications

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“…Darunavir effectively binds wild type protease; however V32I, I47V, I50V, V82F, or I84V mutations cause resistance to the drug and attenuated binding. [127–130] In this cross-docking family, the ligand darunavir is represented 7 times, and receptors with at least one of the above mutations are represented 16 times, providing 7×16=112 combinations of darunavir and darunavir-resistant receptors. The remaining 43 receptors provide 7×43=301 combinations of darunavir and wild type or non-resistant mutant receptors.…”

Section: Results Ii: Current Docking Performancementioning

confidence: 99%

DOCK 6: Impact of new features and current docking performance

et al. 2015

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This manuscript presents the latest algorithmic and methodological developments to the structure-based design program DOCK 6.7 focused on an updated internal energy function, new anchor selection control, enhanced minimization options, a footprint similarity scoring function, a symmetry-corrected RMSD algorithm, a database filter, and docking forensic tools. An important strategy during development involved use of three orthogonal metrics for assessment and validation: pose reproduction over a large database of 1043 protein-ligand complexes (SB2012 test set), cross-docking to 24 drug-target protein families, and database enrichment using large active and decoy data sets (DUD-E test set) for 5 important proteins including HIV protease and IGF-1R. Relative to earlier versions, a key outcome of the work is a significant increase in pose reproduction success in going from DOCK 4.0.2 (51.4%) → 5.4 (65.2%) → 6.7 (73.3%) as a result of significant decreases in failure arising from both sampling 24.1% → 13.6% → 9.1% and scoring 24.4% → 21.1% → 17.5%. Companion cross-docking and enrichment studies with the new version highlight other strengths and remaining areas for improvement, especially for systems containing metal ions. The source code for DOCK 6.7 is available for download and free for academic users at http://dock.compbio.ucsf.edu/.

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Section: Results Ii: Current Docking Performancementioning

confidence: 99%

DOCK 6: Impact of new features and current docking performance

et al. 2015

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“…Thus, darunavir resistance observed in 2004 was mainly due to cross-resistance. In 2009, in addition to cross-resistance mutations, specific darunavir resistance mutations (V11I and T74P), frequently selected during darunavir failure, 16 contributed to the increase in resistance observed in 2009.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL: a 2014 French nationwide study

Assoumou

Charpentier

Recordon-Pinson

et al. 2017

Journal of Antimicrobial Chemotherapy

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Background: Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) .50 copies/ mL. Methods: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.Results: 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. Conclusion: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.

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“…However, the emergence of DRV-resistant HIV-1 variants has been reported in in vitro and in vivo (21)(22)(23)(24)(25)(26); hence, more potent PIs are needed to intercept the replication of such DRV-resistant HIV-1 variants. In regard to in vitro DRV-selected HIV-1 variants, we previously selected highly DRV-resistant HIV-1 variants using a mixture of 8 multidrugresistant HIV-1 strains in vitro (21), which had significantly reduced sensitivity against all of four FDA-approved PIs, DRV as well as APV, LPV, and ATV, as illustrated in Table 2.…”

Section: Discussionmentioning

confidence: 99%

“…It is also known that DRV has a high genetic barrier against HIV-1 development of resistance (referred to here as a genetic barrier) apparently because of its dual antiviral activity, enzymatic inhibition activity, and dimerization inhibition activity of HIV-1 protease (16)(17)(18)(19)(20). However, the emergence of DRV-resistant HIV-1 variants has been reported both in vitro and in vivo, and patients with such DRV-resistant HIV-1 variants have experienced treatment failure (21)(22)(23)(24)(25)(26). Hence, continuous efforts to develop more potent drugs with higher genetic barriers are required to combat such DRVresistant HIV-1 variants.…”

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confidence: 99%

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

Aoki

Hayashi

Yedidi

et al. 2016

J Virol

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We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1 WT ), with 50% effective concentrations (EC 50 s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC 50 ) for GRL-015, -085, and -097 of 80, >100, and >100 M,

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Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis

Abstract: The HIV-DB interpretation algorithm identified few patients with full DRV resistance at baseline and few patients developed full resistance at DRV failure, indicating that complete resistance to DRV is uncommon.

Cited by 20 publications

References 28 publications

DOCK 6: Impact of new features and current docking performance

DOCK 6: Impact of new features and current docking performance

Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL: a 2014 French nationwide study

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

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