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Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants

Published on Dec 1, 2018in Retrovirology3.744
· DOI :10.1186/s12977-018-0420-7
Steven J. Smith16
Estimated H-index: 16
(NIH: National Institutes of Health),
Xue Zhi Zhao15
Estimated H-index: 15
(NIH: National Institutes of Health)
+ 1 AuthorsStephen H. Hughes31
Estimated H-index: 31
(NIH: National Institutes of Health)
Abstract
Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates. Two new INSTIs, Cabotegravir (CAB) and Bictegravir (BIC), are currently in late-stage clinical trials. Both CAB and BIC had much broader antiviral profiles than RAL and EVG against the INSTI-resistant single, double, and triple HIV-1 mutants used in this study. BIC was more effective than DTG against several INSTI-resistant mutants. Overall, in terms of their ability to inhibit a broad range of INSTI-resistant IN mutants, BIC was superior to DTG, and DTG was superior to CAB. Modeling the binding of CAB, BIC, and DTG within the active site of IN suggested that the “left side” of the INSTI pharmacophore (the side away from the viral DNA) was important in determining the ability of the compound to inhibit the IN mutants we tested. Of the two INSTIs in late stage clinical trials, BIC appears to be better able to inhibit the replication of a broad range of IN mutants. BIC retained potency against several of the INSTI-resistant mutants that caused a decrease in susceptibility to DTG.
  • References (58)
  • Citations (16)
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References58
Newest
#1Tomokazu YoshinagaH-Index: 17
#2Takahiro SekiH-Index: 12
Last. Tamio Fujiwara (CGD: Center for Global Development)H-Index: 6
view all 11 authors...
Abstract Cabotegravir (CAB, S/GSK1265744) is an investigational second-generation integrase strand transfer inhibitor (INSTI) with a chemical structure similar to dolutegravir. CAB is under development as a long-acting injectable formulation for treatment of HIV-1 infection and for pre-exposure prophylaxis. We conducted an in vitro passage study of raltegravir- or elvitegravir-resistant signature mutants in the presence of CAB to characterize the resistance profile of this drug. During passage w...
6 CitationsSource
#1Ujjwal NeogiH-Index: 17
#2Kamlendra SinghH-Index: 6
Last. Anders SönnerborgH-Index: 60
view all 8 authors...
OBJECTIVE:To determine the antiretroviral activity of the integrase strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), cabotegravir (CAB) and bictegravir (BIC), against different subtypes as well as primary and acquired drug resistance mutations (DRMs) in a patient-cohort infected with diverse subtypes. DESIGN:Biochemical and virological drug sensitivity analyses using patient-derived HIV type 1 (HIV-1) genes and cross-sectional/longitudinal clinical ...
15 CitationsSource
#1Xue Zhi ZhaoH-Index: 15
#2Steven J. SmithH-Index: 16
Last. Terrence R. BurkeH-Index: 50
view all 11 authors...
Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defin...
8 CitationsSource
#1David A. Margolis (RTP: Research Triangle Park)H-Index: 33
#2Juan González-García (Hospital Universitario La Paz)H-Index: 25
Last. William Spreen (RTP: Research Triangle Park)H-Index: 27
view all 24 authors...
Summary Background Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. Methods In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily. The objective of this study was to select an intram...
108 CitationsSource
#1Martin Markowitz (Aaron Diamond AIDS Research Center)H-Index: 66
#2Ian Frank (UPenn: University of Pennsylvania)H-Index: 44
Last. William Spreen (RTP: Research Triangle Park)H-Index: 27
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Summary Background Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection. Methods We did this multicentre, double-blind, randomised, placebo-controlled, ...
56 CitationsSource
: Objective: to evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (bic), a novel, potent hiv integrase strand-transfer inhibitor (insti) Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study HIV–infected adults not taking antiretroviral therapy were randomized to receive BIC (5, 25, 50, or 100 mg) or placebo once daily for 10 days. Primary endpoint was time-weighted average change from baseline to Day 11 (DA...
18 CitationsSource
#1Paul E. Sax (Brigham and Women's Hospital)H-Index: 52
#2Edwin DeJesusH-Index: 55
Last. Erin QuirkH-Index: 9
view all 14 authors...
Summary Background All recent treatment guidelines recommend integrase strand transfer inhibitors (INSTIs) as components of initial HIV therapy. Bictegravir, a novel, once-daily, unboosted INSTI, showed potent activity in a 10 day monotherapy study and has a high in-vitro resistance barrier. On the basis of these results, we did a phase 2 trial comparing bictegravir with dolutegravir. Methods In this randomised, double-blind, phase 2 trial, we recruited previously untreated adults (aged ≥18 year...
32 CitationsSource
#1D.O. Passos (Salk Institute for Biological Studies)H-Index: 4
#2Min Li (NIH: National Institutes of Health)H-Index: 10
Last. Dmitry Lyumkis (Salk Institute for Biological Studies)H-Index: 19
view all 10 authors...
Like all retroviruses, HIV-1 irreversibly inserts a viral DNA (vDNA) copy of its RNA genome into host target DNA (tDNA). The intasome, a higher-order nucleoprotein complex composed of viral integrase (IN) and the ends of linear vDNA, mediates integration. Productive integration into host chromatin results in the formation of the strand transfer complex (STC) containing catalytically joined vDNA and tDNA. HIV-1 intasomes have been refractory to high-resolution structural studies. We used a solubl...
55 CitationsSource
#1Steven J. Smith (NIH: National Institutes of Health)H-Index: 16
#2Gary T. Pauly (NIH: National Institutes of Health)H-Index: 14
Last. Stephen H. Hughes (NIH: National Institutes of Health)H-Index: 31
view all 10 authors...
Background Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 A from the polymerase active site. Binding of an NNRTI causes structural changes that perturb the alignment of the primer terminus and polymerase active site, preventing viral DNA synthesis. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to t...
6 CitationsSource
#1Janani Varadarajan (Vandy: Vanderbilt University)H-Index: 2
Last. Stephen H. HughesH-Index: 65
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Background HIV-1 integrase is the target for three FDA-approved drugs, raltegravir, elvitegravir, and dolutegravir. All three drugs bind at the active site of integrase and block the strand transfer step of integration. We previously showed that sub-optimal doses of the anti-HIV drug raltegravir can cause aberrant HIV integrations that are accompanied by a variety of deletions, duplications, insertions and inversions of the adjacent host sequences.
3 CitationsSource
Cited By16
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#1Alan Engelman (Harvard University)H-Index: 65
#2Peter Cherepanov (Imperial College London)H-Index: 37
Integrase strand transfer inhibitors (INSTIs) are important components of drug formulations that are used to treat people living with HIV, and second-generation INSTIs dolutegravir and bictegravir impart high barriers to the development of drug resistance. Reported 10 years ago, X-ray crystal structures of prototype foamy virus (PFV) intasome complexes explained how INSTIs bind integrase to inhibit strand transfer activity and provided initial glimpses into mechanisms of drug resistance. However...
Source
#1Anthony Markham (Springer Science+Business Media)H-Index: 13
A regimen comprising extended release injectable suspensions of cabotegravir and rilpivirine for concurrent administration (CABENUVA™) is being developed by ViiV Healthcare and Janssen Pharmaceutica (Janssen) as a complete regimen for HIV infection. Based on the results of the ATLAS and FLAIR trials, the regimen was recently approved in Canada for the treatment of HIV-1 infection in adults to replace current antiretroviral therapy in patients who are virologically stable and suppressed. This art...
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#1Stefano Aquaro (University of Calabria)H-Index: 33
#2Ana Borrajo (University of Rome Tor Vergata)H-Index: 1
Last. Valentina Svicher (University of Rome Tor Vergata)H-Index: 25
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Ongoing with current combinations of antiretroviral drugs for the treatment of Human Immunodeficiency Virus (HIV) infection can successfully maintain long-term suppression of HIV-1 replication in plasma. Still, none of these therapies is capable of extinguishing the virus from the long-lived cellular reservoir, including monocyte-derived macrophages (MDM), that means the principal obstacle to HIV cure. MDM are widely distributed in all tissues and organs, including central system nervous (CNS) w...
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#2Min Li (NIH: National Institutes of Health)H-Index: 24
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The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretrovirals, integrase (IN) strand transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo-electron microscopy (cryo-EM) structures of HIV i...
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Despite worldwide prescription, the mechanistic basis for superiority of second-generation HIV integrase (IN) strand transfer inhibitors (INSTIs) is poorly understood. We use single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near atomic resolution. Q148H/G140S amino acid substitutions in IN that pervade clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical sc...
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#1Lidija Kovač (University of Ljubljana)
#2Zdenko Časar (University of Ljubljana)H-Index: 12
AbstractIntroduction: Studies presented in the patent applications demonstrate that a new integrase strand transfer inhibitor cabotegravir might be used as long-acting antiretroviral formulation or...
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#1Ana Belén LozanoH-Index: 6
#2Natalia ChuecaH-Index: 12
Last. Federico García-GarcíaH-Index: 27
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Abstract We present here one of the first cases of virological failure in real world during treatment with bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy®). On March 2019, an antiretroviral-experienced HIV-infected patient was admitted to hospital because of cerebral toxoplasmosis. After undergoing treatment with sulfadiazine-pyrimethamine for two weeks, the patient initiated a Biktarvy® treatment, with 6.01 HIV RNA Log copies/mL, and 37 CD4 cells/μL. After two months under antiretrov...
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#1Jay Trivedi (UNMC: University of Nebraska Medical Center)H-Index: 2
#2Dinesh Mahajan (Translational Health Science and Technology Institute)H-Index: 8
Last. Siddappa N. Byrareddy (UNMC: University of Nebraska Medical Center)H-Index: 13
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The complex multistep life cycle of HIV allows it to proliferate within the host and integrate its genome in to the host chromosomal DNA. This provirus can remain dormant for an indefinite period. The process of integration, governed by integrase (IN), is highly conserved across the Retroviridae family. Hence, targeting integration is not only expected to block HIV replication but may also reveal new therapeutic strategies to treat HIV as well as other retrovirus infections. HIV integrase (IN) h...
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#1Arezoo Marjani (IUMS: Iran University of Medical Sciences)H-Index: 1
#2Farah Bokharaei-Salim (IUMS: Iran University of Medical Sciences)H-Index: 12
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The latest class of antiretrovirals (ARVs), including integrase strand transfer inhibitors (INSTIs), has been demonstrated to be effective for antiretroviral therapy (ART). Despite all the distinguishing characteristics of these drugs, including a high genetic barrier to resistance and lower toxicity than other ARVs, unfortunately, INSTI drug resistance mutations (DRMs) have occasionally been observed. The aim of this study was to investigate the presence of DRMs associated with INSTIs among tre...
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