title: Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile.
abstract: Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), specifically targets IN strand transfer activity (50% inhibitory concentration [IC50] of 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selective in vitro antiretroviral activity in both T-cell lines and primary human T lymphocytes, with 50% effective concentrations ranging from 1.5 to 2.4 nM and selectivity indices up to 8,700 relative to cytotoxicity. BIC exhibits synergistic in vitro antiviral 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 an in vitro resistance profile that was 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 than DTG. In dose-escalation experiments conducted in 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 M50I/R263K dual mutations in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to wild-type virus. All BIC-selected variants exhibited low to intermediate levels of cross-resistance to RAL, DTG, and EVG (<8-fold) but remained susceptible to other classes of antiretrovirals. A high barrier to in vitro resistance 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-naive and -experienced HIV-infected patients.
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tsiang
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Gregg S
authors.initials: GS
authors.lastname: Jones
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Goldsmith
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mulato
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Hansen
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Kan
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Luong
authors.initials: L
authors.lastname: Tsai
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Rujuta A
authors.initials: RA
authors.lastname: Bam
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Stepan
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Stray
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Niedziela-Majka
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Yant
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Yu
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Lazerwith
authors.affiliation: Gilead Sciences, Foster City, California, USA Kirsten.white@gilead.com.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: White
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Haolun
authors.initials: H
authors.lastname: Jin
mesh_terms: D000577:Amides; D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects*; D004357:Drug Synergism; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium / Q000494:pharmacology; D000099226:Dolutegravir
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C000620396:bictegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1