Prevalence in the USA of rilpivirine resistance-associated mutations in clinical samples and effects on phenotypic susceptibility to rilpivirine and etravirine.
BACKGROUND
The prevalence of rilpivirine resistance-associated mutations (RAMs) in the USA, and their effect on phenotypic susceptibility to rilpivirine and etravirine, was evaluated in clinical samples from HIV-1-infected patients.


METHODS
In total, 15,991 samples submitted to Monogram Biosciences (South San Francisco, CA, USA) for routine resistance testing between January 2010 and June 2011 were assessed for the presence of known rilpivirine RAMs K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L; non-nucleoside reverse transcriptase inhibitor (NNRTI) RAMs K103N, L100I and L100I+K103N; and the nucleoside reverse transcriptase inhibitor (NRTI) RAMs M184I/V and their combinations with rilpivirine RAMs. Phenotypic susceptibility (PhenoSenseGT(®) assay; Monogram Biosciences) was evaluated, with reduced susceptibility defined as fold change (FC) in 50% inhibitory concentration (IC50)>2.0 for rilpivirine and FC>2.9 for etravirine.


RESULTS
Of the 15,991 samples, 17% harboured ≥1 rilpivirine RAMs. The prevalence of most rilpivirine RAMs and combinations of NNRTI RAMs of interest was low (≤3%), except for Y181C (7%). Rilpivirine RAMs were often associated with reduced rilpivirine phenotypic susceptibility. Median FC values >2.0 were observed for clinical isolates with rilpivirine RAMs K101P, E138Q/R, Y181C/I/V, Y188L or M230L, and for the combination of E138K with M184I/V, and K101E with M184I. Most rilpivirine FC values >2.0 were associated with etravirine FC values >2.9 for individual rilpivirine RAMs and those combined with M184I/V. There was no relationship between the presence of K103N and rilpivirine FC. However, the L100I+K103N combination (without rilpivirine RAMs), at <2% prevalence, was associated with a rilpivirine FC>2.0.


CONCLUSIONS
Based on 15,991 US clinical samples from HIV-1-infected patients, the frequency of most known rilpivirine RAMs apart from Y181C was low.
Janssen Research & Development LLC, Titusville, NJ, USA.
Gaston R
GR
Picchio
Laurence T
LT
Rimsky
Veerle
V
Van Eygen
Mojgan
M
Haddad
Laura A
LA
Napolitano
Johan
J
Vingerhoets
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000453:epidemiology* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D015995:Prevalence; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D000068696:Rilpivirine; D014481:United States / Q000453:epidemiology
D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D000068696:Rilpivirine