title: 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.
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Meizhen
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Sachs
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Grobler
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Wade
authors.initials: W
authors.lastname: Blair
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA mingtain_lai@merck.com.
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression; D057809:HEK293 Cells; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation; D011728:Pyridones / Q000494:pharmacology*; D000068696:Rilpivirine / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D011728:Pyridones; D014230:Triazoles; C000592662:doravirine; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine; C098320:efavirenz
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