Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Abstract

We compared the activity of the integrase inhibitor bictegravir against HIV-1 and HIV-2 using a culture-based, single-cycle assay. Values of 50% effective concentrations ranged from 1.2 to 2.5 nM for 9 HIV-1 isolates and 1.4 to 5.6 nM for 15 HIV-2 isolates. HIV-2 integrase mutants G140S/Q148R and G140S/Q148H were 34- and 110-fold resistant to bictegravir, respectively; other resistance-associated mutations conferred ≤5-fold changes in bictegravir susceptibility. Our findings indicate that bictegravir-based antiretroviral therapy should be evaluated in HIV-2-infected individuals.

Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes

“…All currently approved INSTIs share a common pharmacophore consisting of a metal binding scaffold that effectively chelates the two active site catalytic Mg 2+ ions and prevents terminal viral nucleotide 3'OH nucleophilic attack on the host DNA, thereby blocking integration (Table 1). These INSTIs show potent inhibition of HIV-1 replication in cells, however, there are distinct differences in their chemical structures, interaction with HIV-1 IN-DNA complexes, resistance profiles, and dissociation rates from complexes of IN bound to double-stranded DNA (IN-DNA complexes) (2)(3)(4)(5)(6)(7)(8)(9). The apparent dissociation rate constant of DTG from IN-DNA complexes was previously shown to be longer than RAL and EVG and was predicted to correlate with potent antiretroviral activity and a higher genetic barrier to resistance, but direct comparison to BIC has not been investigated (2,3).…”

“…INSTI potency against WT HIV-1 have been well studied and, for the compounds described here, fall into the single digit nM range (Table 1). BIC and DTG retain antiviral activity against many viral strains with INSTI resistance-associated mutations but show reduced activity against some complex mutants (4)(5)(6)(7)(8)(9). The clinically relevant G140S+Q148H confers high-level resistance to RAL and EVG, 4.3-fold reduced susceptibility to DTG, and 2.1-fold on March 14, 2021 by guest http://aac.asm.org/ Downloaded from reduced susceptibility to BIC.…”

Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials

“…As observed in the viremic individual in this study, BIC has broader phenotypic activity than other INSTIs, including DTG, against clinical isolates with Q148H + G140S combinations. 36,47,48 Substitutions associated with BIC, which have been selected in vivo and in vitro, can lead to a range of phenotypic changes. For example, the combination of Q148H/K/R and G140A/C/S in the presence of additional substitutions can cause high-level resistance to BIC (.10fold change in phenotype compared with wild type) but as was seen with the naive case presented in this study, the Q148H+G140S pattern can also be susceptible to BIC.…”

“…As observed in the viremic individual in this study, BIC has broader phenotypic activity than other INSTIs, including DTG, against clinical isolates with Q148H + G140S combinations. 36,47,48…”

British HIV Association guidelines for the management of HIV‐2 2021

“…Bictegravir is highly potent in vitro against HIV‐2 although there are no published data on the clinical use of bictegravir in individuals with untreated HIV‐2 infection [127]. Bictegravir is only available in a single tablet containing emtricitabine and tenofovir AF.…”