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.

Optimal HIV Postexposure Prophylaxis Regimen Completion With Single Tablet Daily Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine Compared With More Frequent Dosing Regimens

“…However, given that PEP use is only for 28 days, the differences and long term benefits between TAF and TDF may be negligible, particularly if generic TDF/FTC offers a cost advantage in the near term. Another promising regimen is the new INSTI, bictegravir, which has been co-formulated with TAF and FTC (31). Given that this INSTI does not require a metabolic booster such as cobicistat or ritonavir, this would minimize the likelihood of drug interactions, while still providing a safe and well tolerated once daily PEP pill.…”

Antiviral activity of HIV‐1 integrase strand‐transfer inhibitors against mutants with integrase resistance‐associated mutations and their frequency in treatment‐naïve individuals

“…A list of HIV‐1 integrase (IN) mutations associated with major resistance to the first‐generation INSTIs (raltegravir [RAL] and elvitegravir [EVG]) has been compiled (T66I/A/K, E92Q/G, F121Y, Y143R/H/C, S147G, Q148R/H/K, N155H, and R263K in HIV‐1 IN) based on resistance emergence in clinical trials upon treatment failure with RAL or EVG as well as in vitro resistance selection experiments and phenotypic testing . The absence of emergent HIV‐1 drug resistance in clinical trials of second‐generation inhibitors (dolutegravir [DTG] and bictegravir [BIC]) after 48 weeks has been attributed to the higher resistance barrier associated with DTG and BIC compared with the first‐generation inhibitors (RAL and EVG) . Incidentally, major INSTI drug resistance mutations (DRMs) have rarely been observed in ART‐naïve individuals, with only six literature cases reported to date .…”

“…12,13 The absence of emergent HIV-1 drug resistance in clinical trials of second-generation inhibitors (dolutegravir [DTG] and bictegravir [BIC]) after 48 weeks 3,5,14 has been attributed to the higher resistance barrier associated with DTG and BIC compared with the first-generation inhibitors (RAL and EVG). 15 Incidentally, major INSTI drug resistance mutations (DRMs) have rarely been observed in ART-naïve individuals, with only six literature cases reported to date. 10,[16][17][18][19] In contrast to the high degree of conservation found at amino acid residues associated with major INSTI resistance (INSTI-R) in the HIV-1 of ART-naïve patients, other HIV-1 IN amino acid residues are found to be polymorphic in INSTI-naïve patients, including at positions associated with minor INSTI-R. 8,20,21 In this report, the baseline IN sequence from 2177 ART-naïve subjects enrolled in recent clinical trials were surveyed to study the level of residue conservation across HIV-1 IN, including amino acid residues associated with major (eight residues) and minor (…”

Development of an HIV‐1 integrase genotyping assay for HIV‐1 subtype AE

“…Integrase strand transfer inhibitors (INSTIs) target the active site of human immunodeficiency virus (HIV)‐1 integrase (IN), an enzyme which mediates the integration of HIV‐1 DNA into the host genome . Raltegravir (RAL) was the first IN inhibitor approved by the Food and Drug Administration for use in treatment‐naïve and treatment experienced patients, followed by elvitegravir (EVG), dolutegravir (DTG), and more recently bictegravir . Primary INSTI resistance associated mutations have been identified in HIV‐1‐infected patients failing RAL or EVG‐containing regimens in clinical studies.…”

“…1,2 Raltegravir (RAL) was the first IN inhibitor approved by the Food and Drug Administration for use in treatment-naïve and treatment experienced patients, 3 followed by elvitegravir (EVG), 4 dolutegravir (DTG), 5 and more recently bictegravir. 6 Primary INSTI resistance associated mutations have been identified in HIV-1-infected patients failing RAL or EVG-containing regimens in clinical studies. For RAL, four major primary mutations in IN have been identified: F121Y, Y143R/H/C, Q148H/K/R, and N155H; for EVG, six primary mutations T66I, E92Q, F121Y, S147G, Q148/H/K/ R, and N155H have been identified.…”