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