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.

FIG 1

Resistance profile of BIC and other INSTIs against 47 HIV-1 patient-derived isolates with INSTI resistance mutations. (A) Bar graph of fold change in resistance. (B) Stratification of the clinical isolates based on fold change in resistance. Primary and other INSTI resistance mutations are listed. Primary INSTI resistance mutations are T66I/A/K, E92Q/G, T97A, Y143C/H/R, S147G, Q148H/K/R, and N155H, and other INSTI resistance mutations are H51Y, L68I/V, V72A/N/T, L74M, Q95K/R, F121C/Y, A128T, E138A/K, G140A/C/S, P145S, Q146I/K/L/P/R, V151L/A, S153A/F/Y, E157K/Q, G163K/R, E170A, and R263K in IN. Susceptibility was determined as the fold change in EC₅₀ versus that of the NL4-3 wild-type vector by Monogram Biosciences, Inc. The biological or lower clinical cutoffs for reduced susceptibility in this assay are 4.0 for DTG, 1.5 for RAL, and 2.5 for EVG. No cutoff has been determined for BIC.

FIG 2

Progress of BIC, DTG, and EVG resistance selection with HIV-1 IIIb. A horizontal line connecting two closed circles represents one passage of the infected cell culture. A vertical line connecting two closed circles represents a transfer of cell-free virus supernatant to fresh uninfected cell culture with either a 1.5-fold or 2-fold increase of the drug concentration. The culture supernatant from the last infected cell culture (black circle) was used for population sequencing, and the mutations identified in the integrase region are indicated. In addition, the viral pool from the last passage of each drug selection was used for clonal sequencing to determine the percentage of clones containing each identified mutation.

FIG 3

HIV-1 IIIb resistance breakthrough in MT-2 cells. Viral resistance breakthrough for each drug was tested in four independent infected cultures in the presence of constant drug pressure for up to 35 days. The number of cultures with replicating virus based on the observed cytopathic effect was scored at each time point. (A) Viral breakthrough control compounds included emtricitabine (FTC), tested at 4× EC₉₅, and elvitegravir (EVG), tested at a C_min of 5× EC₉₅. (B) Dolutegravir (DTG) and bictegravir (BIC) also were tested at 2.5× and 5× EC₉₅.