scholarly journals 633. Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) Efficacy in Participants with Pre-Existing Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S376-S377
Author(s):  
Michelle L D’Antoni ◽  
Kristen Andreatta ◽  
Rima K Acosta ◽  
Silvia Chang ◽  
Ross Martin ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Pooled Analysis ◽  
Baseline Viral Load ◽  
Virologic Suppression ◽  
Strand Transfer ◽  
Viral Loads ◽  
Subtype B ◽  
Treatment Naïve ◽  
Inhibitor Resistance

Abstract Background Pre-existing drug resistance can affect the efficacy of antiretroviral therapy. Studies in treatment-naïve and virologically suppressed participants have demonstrated safety and efficacy of B/F/TAF, including in patients with M184V/I mutations. In this pooled analysis, we investigated virologic outcomes after 48 weeks of B/F/TAF treatment in individuals with pre-existing integrase strand transfer inhibitor resistance (INSTI-R). Methods Although INSTI-R was prohibited per study entry criteria, pre-existing INSTI-R (T66A/I/K, E92G/Q, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H/S, R263K) was evaluated in participants from studies 1489, 1490, 1844, 1878, 4030. INSTI-R was assessed by historical genotypes and/or retrospective deepType HIV assay (Seq-IT, Germany), GenoSure IN, GenoSure Archive (Monogram Biosciences). Virologic outcomes were defined by last on-treatment observation carried forward (LOCF) method. Results Pre-existing primary INSTI-R substitutions were detected in 20/1907 participants (1.0%) after enrolment. Of the 20, 75% were male, 30% white, and 85% had HIV-1 subtype B, baseline median CD4 counts of 594 (IQR 517, 700), and median age of 52 (43, 59) years. One participant was treatment-naïve with a baseline viral load of 30,000 copies/ml and had Q148H (+ G140S on plasma RNA genotype) and was sensitive to bictegravir (< 2.5-fold change). The other 19 participants were virologically suppressed and had E92G (n=3), Y143C (n=2), Y143H (n=4), S147G (n=2), N155S (n=1), Q148H (n=3), Q148K (n=1), Q148R (n=1), or R263K (n=2) INSTI-R mutations by DNA genotype. The treatment-naïve individual was suppressed by Week 4 and maintained viral loads of < 50 copies/mL through Week 48. All suppressed participants had HIV RNA < 50 copies/mL throughout Week 48. All study participants had virologic success by LOCF (< 50 copies/mL) at Week 48. Conclusion Participants with primary INSTI-R substitutions had or maintained virologic suppression through 48 weeks of B/F/TAF treatment. Consistent with the potent in vitro activity of bictegravir against many INSTI-R mutations, these virologic outcomes suggest that B/F/TAF may have potential as a treatment option for some patients with pre-existing INSTI-R, if confirmed by further studies. Disclosures Michelle L. D’Antoni, PhD, Gilead Sciences (Employee, Shareholder) Kristen Andreatta, MSc, Gilead Sciences (Employee, Shareholder) Rima K. Acosta, BS, Gilead Sciences, Inc. (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc. (Employee, Shareholder)

scholarly journals Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Rima K. Acosta ◽  
Madeleine Willkom ◽  
Ross Martin ◽  
Silvia Chang ◽  
Xuelian Wei ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Virologic Suppression ◽  
Strand Transfer ◽  
Primary Drug Resistance ◽  
Treatment Naïve ◽  
Tenofovir Alafenamide ◽  
Inhibitor Resistance ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravir-abacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTG+F-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.

Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir

2020 ◽  
Author(s):  
Hanh T Pham ◽  
Brunna M Alves ◽  
Sunbin Yoo ◽  
Meng A Xiao ◽  
Jing Leng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Binding ◽  
Drug Resistant ◽  
Strand Transfer ◽  
Viral Genomes ◽  
Proviral Dna ◽  
Viral Loads ◽  
Subtype B ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract Objectives The development of HIV drug resistance against the integrase strand transfer inhibitor dolutegravir is rare. We report here the transient detection, by near full-genome ultradeep sequencing, of minority HIV-1 subtype B variants bearing the S153F and R263K integrase substitutions in the proviral DNA from blood cells of one patient who successfully initiated dolutegravir-based ART, over 24 weeks. Our objective was to study the effects of these substitutions. Methods Strand transfer and DNA-binding activities of recombinant integrase proteins were measured in cell-free assays. Cell-based resistance, infectivity and replicative capacities were measured using molecular clones. Structural modelling was performed to understand experimental results. Results R263K emerged first, followed by the addition of S153F at Week 12. By Week 24, both mutations remained present, but at lower prevalence. We confirmed the coexistence of S153F and R263K on single viral genomes. Combining S153F or S153Y with R263K decreased integration and viral replicative capacity and conferred high levels of drug resistance against all integrase inhibitors. Alone, S153Y and S153F did little to infectivity or dolutegravir resistance. We identified altered DNA binding as a mechanism of resistance. The patient remained with undetectable viral loads at all timepoints. Conclusions Drug-resistant minority variants have often been reported under suppressive ART. Our study adds to these observations by unravelling a progression towards higher levels of resistance through a novel pathway despite continuous undetectable viral loads. Poorly replicative HIV drug-resistant minority proviral variants did not compromise viral suppression in one individual treated with dolutegravir.

scholarly journals Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor

2010 ◽  
Vol 84 (18) ◽  
pp. 9210-9216 ◽  
Author(s):  
Tamara Bar-Magen ◽  
Richard D. Sloan ◽  
Daniel A. Donahue ◽  
Björn D. Kuhl ◽  
Alexandra Zabeida ◽  
...  
Keyword(s):  
Viral Replication ◽  
First Generation ◽  
Second Generation ◽  
Integrase Inhibitor ◽  
Replication Capacity ◽  
Strand Transfer ◽  
Viral Replication Capacity ◽  
Transfer Inhibitor ◽  
Potential Basis

ABSTRACT MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected in vitro and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to ≈13% of wt levels and increased resistance to MK-2048 to ≈8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer “off” rate of MK-2048. In silico structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg2+ binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.

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.

scholarly journals Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Said A. Hassounah ◽  
Ahmad Alikhani ◽  
Maureen Oliveira ◽  
Simrat Bharaj ◽  
Ruxandra-Ilinca Ibanescu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Fold Increase ◽  
Integrase Inhibitor ◽  
Antiretroviral Drugs ◽  
Strand Transfer ◽  
Single Cycle ◽  
Genetic Barrier ◽  
Hiv 1

ABSTRACT Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development. Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 integrase (IN) mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with 50% effective concentrations (EC50s) in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R, or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC50), whereas G118R and R263K conferred ∼14-fold and ∼6-fold increases in EC50, respectively. In both single and multiple rounds of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC50). In multiple rounds of infection, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in nonhuman primate models of HIV infection.

scholarly journals Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage

2016 ◽  
Vol 60 (7) ◽  
pp. 3956-3969 ◽  
Author(s):  
Beata Nowicka-Sans ◽  
Tricia Protack ◽  
Zeyu Lin ◽  
Zhufang Li ◽  
Sharon Zhang ◽  
...  
Keyword(s):  
Human Serum ◽  
Second Generation ◽  
Mononuclear Cells ◽  
Integrase Inhibitor ◽  
Wild Type Virus ◽  
Peripheral Blood Mononuclear ◽  
Subtype B ◽  
Maturation Inhibitor ◽  
Hiv 1

ABSTRACTBMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n= 87) ofgag/prrecombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to anin vitromeasurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally,in vitrocombination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potentin vitroanti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat.

scholarly journals Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

2014 ◽  
Vol 59 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Tomokazu Yoshinaga ◽  
Masanori Kobayashi ◽  
Takahiro Seki ◽  
Shigeru Miki ◽  
Chiaki Wakasa-Morimoto ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Integrase Inhibitor ◽  
Culture Conditions ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Hiv Replication ◽  
Data Set ◽  
Long Acting ◽  
Anti Hiv

ABSTRACTGSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. Thein vitroantiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

scholarly journals HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Steven J. Smith ◽  
Xue Zhi Zhao ◽  
Dario Oliveira Passos ◽  
Dmitry Lyumkis ◽  
Terrence R. Burke ◽  
...  
Keyword(s):  
Strand Transfer ◽  
First Line ◽  
Preclinical Development ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Resistant Mutants ◽  
Hiv 1

ABSTRACT The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro. Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

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