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 (IC 50 s) 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 IC 50 for 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.T he introduction of highly active antiretroviral therapy (HAART) in 1996 has significantly reduced the morbidity and mortality associated with HIV-1 infection (1, 2). However, the clinical and immunologic benefits of antiretroviral therapy can be compromised by the emergence of drug-resistant viruses due to suboptimal treatment or adherence.Drug-resistant mutants can be transmitted to an uninfected individual. Transmitted drug-resistant (TDR) mutants limit the choice of first-line combination antiretroviral therapy, decrease the efficacy of subsequent antiretroviral regimens, and increase the risk of treatment failure (3-5). TDR mutants have been documented among treatment-naive patients, with prevalences ranging from 3% to 24%, depending on the cohort and geographic characteristics (6). Importantly, transmitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants are of particular concern, as they have the ability to persist for years after initial infection, suggesting the low impact of NNRTI-resistant mutations on viral fitness (7-9). The persistence of NNRTI-associated mutants after the discontinuation of an NNRTI-containing regimen may contribute to the prevalence of NNRTI-associated TDR mutants.Three mutants, K103N, Y181C, and G190A, account for Ͼ90% of the NNRTI-associated TDR mutants in the United States (10). K103N, Y181C, and K103N/Y181...

Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir

“…Blood for elbasvir and grazoprevir plasma analysis was collected on day 10 of period 2 and day 5 of period 3 at the following time points: predose and at 0. 5,1,2,3,4,5,6,8,12,16, and 24 h postdose.…”

In Vitro Evaluation of the Drug Interaction Potential of Doravirine

“…dine and tenofovir disoproxil fumarate (TDF) (4,5). In vitro, doravirine has similar activity against HIV-1 wild-type virus and the K103N, Y181C, and K103N/Y181C mutants (6). Previously reported results showed that doravirine is metabolized primarily to an oxidative metabolite, M9, by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by CYP3A5 ( Fig.…”

Mechanistic Study of Common Non-Nucleoside Reverse Transcriptase Inhibitor-Resistant Mutations with K103N and Y181C Substitutions

“…This mutation confers a high degree of resistance to both NVP and DLV and a moderate resistance to rilpivirine RPV [11]. A relatively rare mutation of Y188L was also identified in viruses from patients who have failed with NNRTI-containing regimens.…”