Antiviral activity of HIV‐1 integrase strand‐transfer inhibitors against mutants with integrase resistance‐associated mutations and their frequency in treatment‐naïve individuals

2019 ◽  
Vol 91 (12) ◽  
pp. 2188-2194 ◽  
Author(s):  
Nicolas A. Margot ◽  
Renee R. Ram ◽  
Kirsten L. White ◽  
Michael E. Abram ◽  
Christian Callebaut
Keyword(s):  
Antiviral Activity ◽  
Strand Transfer ◽  
Integrase Strand Transfer Inhibitors ◽  
Treatment Naïve ◽  
Hiv 1

scholarly journals Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

2016 ◽  
pp. AAC.01474-16 ◽  
Author(s):  
Manuel Tsiang ◽  
Gregg S. Jones ◽  
Joshua Goldsmith ◽  
Andrew Mulato ◽  
Derek Hansen ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Clinical Investigation ◽  
Cross Resistance ◽  
Strand Transfer ◽  
Resistance Profile ◽  
Drug Concentrations ◽  
Treatment Naïve ◽  
T Cell Lines ◽  
Hiv 1

Bictegravir (BIC; GS-9883), a novel potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN) specifically targets IN strand transfer activity (IC50= 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selectivein vitroantiretroviral activity in both T-cell lines and primary human T-lymphocytes with EC50values ranging from 1.5 to 2.4 nM and selectivity indices up to 8800 relative to cytotoxicity. BIC exhibits synergisticin vitroantiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals. BIC displayed anin vitroresistance profile markedly improved compared to the integrase strand transfer inhibitors (INSTIs) raltegravir (RAL) and elvitegravir (EVG), and comparable to that of dolutegravir (DTG), against nine INSTI-resistant site-directed HIV-1 mutants. BIC displayed statistically improved antiviral activity relative to EVG, RAL, and DTG against a panel of 47 patient-derived HIV-1 isolates with high-level INSTI resistance; 13 of 47 tested isolates exhibited >2-fold lower resistance to BIC compared to DTG. In dose-escalation experiments conductedin vitro, BIC and DTG exhibited higher barriers to resistance than EVG, selecting for HIV-1 variants with reduced phenotypic susceptibility at days 71, 87, and 20, respectively. A recombinant virus with the BIC-selected dual mutations M50I+R263K in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to WT virus (2.8-fold). All BIC-selected variants exhibited low to intermediate level cross-resistance to RAL, DTG, and EVG (<8-fold), but remained susceptible to other classes of antiretrovirals. A high barrier toin vitroresistance emergence for both BIC and DTG was also observed in viral breakthrough studies in the presence of constant clinically relevant drug concentrations. The overall virologic profile of BIC supports its ongoing clinical investigation in combination with other antiretroviral agents for both treatment-naïve and experienced HIV-infected patients.

scholarly journals Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Prats ◽  
Ignacio Martínez-Zalacaín ◽  
Beatriz Mothe ◽  
Eugènia Negredo ◽  
Núria Pérez-Álvarez ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Integrase Inhibitor ◽  
Strand Transfer ◽  
Cognitive Differences ◽  
Integrase Strand Transfer Inhibitors ◽  
Initiation Of Therapy ◽  
Main Component ◽  
Living With Hiv ◽  
The Impact ◽  
Hiv 1

AbstractIntegrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks.

scholarly journals Study on Suitable Analysis Method for HIV-1 Non-catalytic Integrase Inhibitor

2020 ◽  
Author(s):  
Ki Hoon Park ◽  
Minjee Kim ◽  
Seoung Eun Bae ◽  
Hee Jung Lee ◽  
Kyung-Chang Kim ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Integrase Inhibitor ◽  
Treatment Method ◽  
Strand Transfer ◽  
Inhibition Assay ◽  
Analysis Method ◽  
Catalytic Core ◽  
Host Chromosome ◽  
Inconsistent Result ◽  
Hiv 1

Abstract Background: Integrase (IN) is an essential protein for HIV replication that catalyzes insertion of the reverse-transcribed viral genome into the host chromosome during the early steps of viral infection. Highly active anti-retroviral therapy (HAART) is a HIV/AIDS treatment method that combines three or more antiviral drugs often formulated from compounds that inhibit the activities of viral reverse transcriptase and protease enzymes. Early IN inhibitors (INIs) mainly serve as integrase strand transfer inhibitors (INSTI) that disrupt strand transfer by binding the catalytic core domain (CCD) of IN. However, mutations of IN can confer resistance to INSTI. Therefore, non-catalytic integrase inhibitors (NCINI) have been developed as next-generation INIs. Methods: In this study, we evaluated and compared the activity of INSTI and NCINI according to the analysis method. Antiviral activity was compared using p24 ELISA with MT2 cell and TZM-bl luciferase system with TZM-bl cell. Each drug was serially diluted and treated to MT2 and TZM-b1 cells, infected with HIV-1 AD8 strain and incubated for 5 and 2 days, respectively. Additionally, to analyze properties of INSTI and NCINI, transfer inhibition assay and 3'-processing inhibition assay were performed. Results: During screening of INIs using the p24 ELISA and TZM-bl luciferase systems, we found an inconsistent result with INSTI and NCINI drugs. Following infection of MT2 and TZM-bl cells with T-tropic HIV-1 strain, both INSTI and NCINI treatments induced significant p24 reduction in MT2 cells. However, NCINI showed no antiviral activity in the TZM-bl luciferase system, indicating that this widely used and convenient antiretroviral assay is not suitable for screening of NCINI compounds that target the second round of HIV-1 replication. Conclusion: Accordingly, we recommend application of other assay procedures, such as p24 ELISA or reverse transcription activity, in lieu of the TZM-bl luciferase system for preliminary NCINI drug screening. Utilization of appropriate analytical methods based on underlying mechanisms is necessary for accurate assessment of drug efficacy.

scholarly journals Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor

2014 ◽  
Vol 58 (6) ◽  
pp. 3233-3244 ◽  
Author(s):  
Craig Fenwick ◽  
Ma'an Amad ◽  
Murray D. Bailey ◽  
Richard Bethell ◽  
Michael Bös ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Phase 1 ◽  
Integrase Inhibitor ◽  
Parallel Synthesis ◽  
Cell Permeability ◽  
Strand Transfer ◽  
Primary Resistance ◽  
Catalytic Core ◽  
Hiv 1

ABSTRACTBI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3′-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 μM. BI 224436 also has a low, ∼2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-likein vitroabsorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%;F, 82%), and dog (CL, 8%;F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.

Susceptibility to HIV-1 integrase strand transfer inhibitors (INSTIs) in highly treatment-experienced patients who failed an INSTI-based regimen

2020 ◽  
Vol 56 (1) ◽  
pp. 106027
Author(s):  
Maria M. Santoro ◽  
Chiara Fornabaio ◽  
Marina Malena ◽  
Laura Galli ◽  
Andrea Poli ◽  
...  
Keyword(s):  
Strand Transfer ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv 1

Integrase Strand Transfer Inhibitors (INSTIs) Resistance Mutations in HIV-1 Infected Turkish Patients

2016 ◽  
Vol 17 (3) ◽  
pp. 109-113 ◽  
Author(s):  
M. Sayan ◽  
A. Gündüz ◽  
G. Ersöz ◽  
A. İnan ◽  
A. Deveci ◽  
...  
Keyword(s):  
Strand Transfer ◽  
Resistance Mutations ◽  
Integrase Strand Transfer Inhibitors ◽  
Turkish Patients ◽  
Hiv 1

Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors

2020 ◽  
Vol 30 (3) ◽  
pp. 126784 ◽  
Author(s):  
Kevin M. Peese ◽  
B. Narasimhulu Naidu ◽  
Manoj Patel ◽  
Chen Li ◽  
David R. Langley ◽  
...  
Keyword(s):  
Strand Transfer ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv 1

scholarly journals INSTI-Based Triple Regimens in Treatment-Naïve HIV-Infected Patients Are Associated With HIV-RNA Viral Load Suppression at Ultralow Levels

2019 ◽  
Vol 6 (5) ◽  
Author(s):  
Sidonie Lambert-Niclot ◽  
Anders Boyd ◽  
Djeneba Fofana ◽  
Nadia Valin ◽  
Marc Wirden ◽  
...  
Keyword(s):  
Multivariable Analysis ◽  
Female Gender ◽  
Strand Transfer ◽  
University Hospitals ◽  
Viral Load Suppression ◽  
Hiv Rna ◽  
Art Initiation ◽  
Treatment Naïve ◽  
Hiv 1

Abstract Background During antiretroviral therapy (ART), HIV-1-infected patients may present with ultralow (UL) HIV-RNA viral loads (VLs) below quantification levels of current assays. Reasons for UL-VL detection and its relation to virological rebound (VR) are unclear. Methods HIV-1-infected, ART-naïve patients followed at 2 university hospitals were included. All participants had an HIV-RNA &gt;200 copies/mL at ART initiation and achieved a VL &lt;50 copies/mL during ART. UL-VL was determined by the presence/absence of polymerase chain reaction signal detected using a commercially available assay (COBAS, TaqMan, Roche). Random-effects Poisson regression was used for assessing determinants of UL-VL not detected overtime and conditional risk set analysis for VR (1 VL &gt; 200 copies/mL or 2 VL &gt; 50 copies/mL) while accounting for frequency of VL measurements. Results Between 2009 and 2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) plus a non-NRTI (29.4%), a protease inhibitor (58.4%), or an integrase-strand transfer inhibitor (INSTI; 12.1%). During a median (interquartile range) 3.4 (2.3–4.6) years, 676 (94.3%) patients achieved UL-VL not detected. In multivariable analysis, UL-VL not detected overtime was associated with younger age (P &lt; .001), female gender (P = .04), lower baseline VL (P &lt; .001), baseline CD4+ &gt;500 vs &lt;350/mm3 (P &lt; .001), and INSTI-containing ART (P = .009). One hundred thirty-one (18.3%) patients had VR during follow-up, which was independently associated with a CD4/CD8 ratio &lt;0.8 during follow-up (P = .01) and time spent with UL-VL not detected (P &lt; .001). When UL-VL not detected occurred for ≥50% of the follow-up duration (n = 290), faster time to reach UL-VL not detected (P &lt; .001), faster CD4+ T-cell count increase (P = .03), and faster CD4/CD8 ratio increase (P = .001) were observed. Conclusions VL suppression at an ultralow level is associated with INSTI-class ART initiation. Extensive VL suppression below ultralow detection could improve immune reconstitution.

Primary resistance to integrase strand transfer inhibitors in Spain using ultrasensitive HIV-1 genotyping

2020 ◽  
Vol 75 (12) ◽  
pp. 3517-3524
Author(s):  
M Casadellà ◽  
J R Santos ◽  
M Noguera-Julian ◽  
R Micán-Rivera ◽  
P Domingo ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Low Frequency ◽  
Transmitted Drug Resistance ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
First Line ◽  
Primary Resistance ◽  
Integrase Strand Transfer Inhibitors ◽  
Virological Outcomes ◽  
Hiv 1

Abstract Background Transmission of resistance mutations to integrase strand transfer inhibitors (INSTIs) in HIV-infected patients may compromise the efficacy of first-line antiretroviral regimens currently recommended worldwide. Continued surveillance of transmitted drug resistance (TDR) is thus warranted. Objectives We evaluated the rates and effects on virological outcomes of TDR in a 96 week prospective multicentre cohort study of ART-naive HIV-1-infected subjects initiating INSTI-based ART in Spain between April 2015 and December 2016. Methods Pre-ART plasma samples were genotyped for integrase, protease and reverse transcriptase resistance using Sanger population sequencing or MiSeq™ using a ≥ 20% mutant sensitivity cut-off. Those present at 1%–19% of the virus population were considered to be low-frequency variants. Results From a total of 214 available samples, 173 (80.8%), 210 (98.1%) and 214 (100.0%) were successfully amplified for integrase, reverse transcriptase and protease genes, respectively. Using a Sanger-like cut-off, the overall prevalence of any TDR, INSTI-, NRTI-, NNRTI- and protease inhibitor (PI)-associated mutations was 13.1%, 1.7%, 3.8%, 7.1% and 0.9%, respectively. Only three (1.7%) subjects had INSTI TDR (R263K, E138K and G163R), while minority variants with integrase TDR were detected in 9.6% of subjects. There were no virological failures during 96 weeks of follow-up in subjects harbouring TDR as majority variants. Conclusions Transmitted INSTI resistance remains rare in Spain and, to date, is not associated with virological failure to first-line INSTI-based regimens.

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