Doravirine resistance/cross-resistance profile
Doravirine resistance/cross-resistance profile
Resistance profile in two 48-week studies in treatment-naïve patients with HIV-1
7 patients in the doravirine treatment arms of the treatment-naïve trials DRIVE-FORWARD and DRIVE-AHEAD (n=747) in the resistance analysis subset (n=30) had doravirine resistance-associated substitutions (n=7) through Week 481
Emergent doravirine resistance-associated substitutions in RT included one or more of the following: A98G, V106A, V106I, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F.1
In the doravirine treatment-arm of DRIVE-FORWARD between Weeks 48 and 96, 1 patient developed RT V106A and P225H doravirine resistance-associated substitutions which conferred >95-fold reduction in doravirine susceptibility.
Cross-resistance*
In Phase 3 trials
The following amino acid substitutions were observed in clinical isolates obtained from patients with treatment failure who had both genotypic and phenotypic resistance data available: Y188L alone, F227C in combination with A98G, A98G/V106I/H221Y, V106I, V106I/H221Y or V106M; and V106A in combination with P225H and Y318F. These isolates showed >100X reduced susceptibility to doravirine.1
Treatment-emergent doravirine resistance-associated substitutions may confer cross-resistance to EFV, RVP, NVP, and ETR. Of the 8 virologic failure subjects who developed doravirine phenotypic resistance, all had phenotypic resistance to NVP, 6 to EFV, 4 to RVP, and 4 patients had partial resistance to ETR based on the Monogram Phenosense assay.1
Laboratory strains of NNRTI-associated mutations*
Common NNRTI-associated mutations include K103N, Y181C, or K103N/Y181C substitutions. Tests with laboratory strains of HIV-1 with these RT mutations showed a <3-fold decrease in susceptibility to doravirine compared to wild-type virus when evaluated in the presence of 100% NHS. Doravirine was able to suppress the following NNRTI-associated substitutions, K103N, Y181C, G190A, and E138K mutants under clinically relevant concentrations.1
Clinical isolates with NNRTI-associated mutations (a panel of 96 diverse clinical isolates)*
Isolates that showed potentially clinically meaningful reduced (>100X) susceptibility to doravirine contained the following substitutions: Y188L alone or with K103N or V106I; V106A in combination with G190A and F227L; and E138K in combination with Y181C and M230L.1
* Clinical significance has not been established.
RT=reverse-transcriptase; EFV=efavirenz; RVP=rilpivirine; NVP=nevirapine; ETR=etravirine; NNRTI=non-nucleoside reverse transcriptase inhibitor; NHS=normal human serum
Reference: 1. PIFELTRO® Product Monograph. Merck Canada Inc. December 10, 2024.
CA-DOR-00155