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.
Highlights
Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), targets IN strand transfer activity (50% inhibitory concentration [IC50] of 7.5 ؎ 0.3 nM) and HIV-1 integration in cells
DTG must be dosed twice daily when coadministered with cytochrome P450 (CYP) and/or UDP glucuronosyltransferase (UGT) inducers and in patients with documented or suspected integrase strand transfer inhibitors (INSTIs)-associated resistance [24, 26]
Bictegravir differs from previously known structures in that it contains a unique bridged bicyclic ring and a distinct benzyl tail consisting of a trisubstituted 2,4,6-trifluorobenzyl moiety
Summary
Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), targets IN strand transfer activity (50% inhibitory concentration [IC50] of 7.5 ؎ 0.3 nM) and HIV-1 integration in cells. 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. Dolutegravir (DTG) was subsequently approved for treatment of HIV-1 in 2013 It is an unboosted INSTI with a higher barrier to resistance development and improved resistance profile relative to RAL and EVG and is dosed once daily for many patients [16,17,18,19]. We describe the in vitro biological characterization of BIC and show its potent activity against laboratory strains and clinical isolates of HIV-1, a higher barrier to resistance development than RAL and EVG, and a statistically improved resistance profile compared to those of RAL, EVG, and DTG against a set of patientderived INSTI-resistant viral isolates
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