Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Abstract

Doravirine (DOR), which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI). DOR exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC50s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). To assess the potential for DOR to suppress NNRTI-associated and rilpivirine (RPV)-specific mutants at concentrations achieved in the clinic setting, inhibitory quotients (IQs) were calculated by determining the ratio of the clinical trough concentration over the antiviral IC50for each virus with DOR and RPV and efavirenz (EFV). DOR displayed IQs of 39, 27, and 25 against the K103N, Y181C, and K103N/Y181C mutants, respectively. In contrast, RPV exhibited IQs of 4.6, 1.4, and 0.8, and EFV showed IQs of 2.5, 60, and 1.9 against these viruses, respectively. DOR also displayed higher IQs than those of RPV and EFV against other prevalent NNRTI-associated mutants, with the exception of Y188L. Both DOR and EFV exhibited higher IQs than RPV when analyzed with RPV-associated mutants. Resistance selections were conducted with K103N, Y181C, G190A, and K103N/Y181C mutants at clinically relevant concentrations of DOR, RPV, and EFV. No viral breakthrough was observed with DOR, whereas breakthrough viruses were readily detected with RPV and EFV against Y181C and K103N viruses, respectively. These data suggest that DOR should impose a higher barrier to the development of resistance than RPV and EFV at the concentrations achieved in the clinic setting.

FIG 1

Titration curves for the antiviral activities of DOR, RPV, and EFV against WT virus, K103N, Y181C, and K103N/Y181C mutants in the presence of 100% NHS (open square, DOR; filled diamond, RPV; filled circle, EFV). The potencies (IC₅₀s) is as follows: WT virus: DOR, 12 ± 4.2 nM; RPV, 58 ± 15 nM; EFV, 30 ± 8.7 nM); for the K103N mutant: DOR, 21 ± 6.8 nM; RPV, 56 ± 15 nM; EFV, 1,173 ± 448 nM); Y181C mutant: DOR, 31 ± 10 nM; RPV, 169 ± 45 nM; EFV, 90 ± 21 nM). K103N/Y181C mutant: DOR, 33 ± 5.4 nM; RPV, 318 ± 62 nM; EFV, 3,119 ± 920 nM). [M], concentration of NNRTIs. The data are represented as the means ± standard deviations from the results of >3 replicates.

FIG 2

Antiviral activities (IC₅₀s) (A) and inhibitory quotients (IQs) (B) of DOR, RPV, and EFV against prevalent NNRTI-associated mutants in the presence of 100% NHS. The data are represented as the means ± standard deviations from the results of >3 replicates.

FIG 3

Antiviral activities (IC₅₀s) (A) and inhibitory quotients (IQs) (B) of DOR, RPV, and EFV against RPV-associated mutants in the presence of 100% NHS. The data are represented as the means ± standard deviations from the results of >3 replicates.

FIG 4

In vitro resistance selection with prevalent NNRTI-associated mutants. (A) Plate layout. 1× represents the concentration (conc.) selected for resistance selection based on the calculation from Table 1. Each concentration was included in two columns (16 replicates). (B1) K103N mutant (columns 1 to 6) and Y181C mutant (columns 7 to 12). (B2) G190A mutant (columns 1 to 6) and K103N/Y181C mutant (columns 7 to 12). P, passage number.