Prevalence of Darunavir Resistance in the United States from 2010 to 2017

Abstract

The emergence and transmission of antiretroviral drug resistance have been and remain a concern among people living with human immunodeficiency virus (HIV)-1 infection. The protease inhibitor (PI) darunavir has been approved for use in the United States for more than 10 years and has demonstrated a high barrier to resistance. Previous analyses identified significant reductions in the prevalence of samples with darunavir resistance-associated mutations (RAMs) and with phenotypic resistance to darunavir and other PIs between 2006 and 2012. This analysis extends those findings by evaluating darunavir and PI resistance among clinical samples submitted for routine drug resistance testing (combined genotyping and phenotyping) in the United States from 2010 to 2017. Frequencies of 11 darunavir and 23 primary PI RAMs, and phenotypic susceptibility, were assessed yearly among all samples and in a subset of samples with distinct phenotypic resistance to one or more PIs. Among all samples (N = 60,760), the proportion with 0 darunavir RAMs was 91.7% in 2010 and 95.8% in 2017. The proportions of all samples with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 97.4%, 94.2%, and 94.7% in 2010 and 98.6%, 97.7%, and 97.5% in 2017. Among the 4,799 samples with phenotypic resistance to one or more PIs, the proportions with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 73.3%, 41.5%, and 46.0% in 2010 and 70.7%, 53.7%, and 48.8% in 2017. The prevalence of darunavir RAMs among commercially tested HIV-1 samples remained low and generally stable from 2010 to 2017, and high proportions showed phenotypic darunavir susceptibility.

HIV-1 resistance rarely observed in subjects using darunavir once-daily regimens across clinical studies

“…5,27 The overall prevalence of darunavir RAMs among these submitted samples decreased over time; a corresponding decrease in darunavir phenotypic resistance was also observed. 5,27 The prevalence of darunavir phenotypic resistance remained lower than that of other PIs for each year during the analysis period. 5,27 n = 1) and lost emtricitabine phenotypic susceptibility.…”

“…5,27 The prevalence of darunavir phenotypic resistance remained lower than that of other PIs for each year during the analysis period. 5,27 n = 1) and lost emtricitabine phenotypic susceptibility. Two subjects from GS-US-216-0130, both of whom used emtricitabine and tenofovir disoproxil fumarate (1 treatment-naïve and 1 treatment-experienced), developed M184V and lost emtricitabine phenotypic susceptibility.…”

“…25,26 The rare development of darunavir resistance upon virologic failure, as seen in the current analysis, is consistent with findings based on a database analysis of US clinical samples. 5,27 Samples (from patients receiving varying ARV/PI regimens and with different treatment experiences and histories of resistance [no prior treatment information was available]) had been submitted for resistance testing (combined genotypic and phenotypic resistance testing) to Monogram Biosciences and were collected from 2006 through 2015. 5,27 The overall prevalence of darunavir RAMs among these submitted samples decreased over time; a corresponding decrease in darunavir phenotypic resistance was also observed.…”

“…5,27 Samples (from patients receiving varying ARV/PI regimens and with different treatment experiences and histories of resistance [no prior treatment information was available]) had been submitted for resistance testing (combined genotypic and phenotypic resistance testing) to Monogram Biosciences and were collected from 2006 through 2015. 5,27 The overall prevalence of darunavir RAMs among these submitted samples decreased over time; a corresponding decrease in darunavir phenotypic resistance was also observed. 5,27 The prevalence of darunavir phenotypic resistance remained lower than that of other PIs for each year during the analysis period.…”

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

“…However, the number of direct hydrogen bond interactions between PR with the GRL-142 derivatives containing the crn-THF moiety discussed in www.nature.com/scientificreports www.nature.com/scientificreports/ the present work is greater than that with tipranavir (11 versus 9) 16 . The oxygen atoms of the crn-THF moiety form three direct hydrogen bonds to the main chain N-H of Asp29 and Asp30 residues in a similar manner as observed with the bis-THF moiety of DRV 7,17 . Fig.…”