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Resistance to Darunavir Falling Since Approval of the Protease Inhibitor in 2006
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20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
In the first half of 2012, 2.3% of viral samples in the entire sample set had phenotypic resistance to darunavir.
Mark Mascolini
Genotypic and phenotypic resistance to darunavir fell significantly since approval of this protease inhibitor (PI) in 2006, according to analysis of almost 79,000 clinical viral samples submitted to Monogram Biosciences for resistance testing [1]. Rates of phenotypic resistance to darunavir were lower than for any other PI.
A high barrier to resistance has been a hallmark of ritonavir-boosted PIs. Previous research found a low prevalence of darunavir resistance mutations in treated people [2,3]. Eleven mutations are associated with resistance to darunavir; three or more of these mutations compromise virologic efficacy of this PI.
The new analysis focused on 78,843 clinical isolates sent to Monogram for routine resistance testing from January 2006 to June 2012. Thus the study sample could be expected to have a higher overall resistance prevalence than the general population of antiretroviral-treated people. The investigators defined genotypic resistance to darunavir by detection of one of the 11 darunavir-associated mutations (list in poster linked below), and they defined phenotypic resistance (loss of viral susceptibility) by accepted cutoffs in fold change in 50% inhibitory concentration.
The average number of all primary PI-associated resistance mutations in the 78,843-isolate sample set dropped from 1.0 in 2006 to 0.32 in the first half of 2012 (2012 H1). Percentage of viral samples with no darunavir mutations climbed from 77.7% in 2006 to 92.8% in 2012 H1, a highly significant change (P = 0.0008). Prevalence of viral isolates with three or more darunavir mutations slumped from 7.5% in 2006 to 2.6% in 2010 H1 (P = 0.002). Prevalence of each of the 11 darunavir-associated mutations also fell during the study period. And prevalence of the most frequently detected darunavir mutation, L33F, waned from 11.2% in 2006 to 3.9% in 2012 H1.
Among 15,932 viral samples with phenotypic resistance to any PI, the proportion of isolates with no darunavir-associated mutations rose significantly from 39.9% in 2006 to 55.0% in 2012 H1 (P = 0.005). The proportion of isolates with three or more darunavir mutations did not change significantly over this period, drifting from 21.7% in 2006 to 19.2% in 2012 H1 (P = 0.27). In this sample set, prevalence of the two most frequent darunavir mutations, L33F and I84V, fell during the study period, from 31.7% to 27.1% and from 30.8% to 20.7%.
In the overall sample set, median fold change in susceptibility to darunavir remained low and stable over the study period (0.84 in 2006 to 0.76 in 2012 H1, P = 0.38). In the set of viral isolates with phenotypic resistance to any PI, fold change in susceptibility to darunavir eased significantly from 2.20 in 2006 to 1.51 in 2012 H1 (P = 0.012). In the overall sample set, prevalence of partial to full phenotypic resistance to darunavir dropped significantly from 8.2% in 2006 to 2.3% in 2012 H1 (P = 0.002). In the set of isolates phenotypically resistance to any PI, prevalence of phenotypic resistance to darunavir fell significantly from 23.9% in 2006 to 17.1% in 2012 H1 (P = 0.025).
Prevalence of phenotypic resistance to darunavir was lower than prevalence of phenotypic resistance to any other PI in the entire sample set (P < 0.001) and in the set of samples with phenotypic resistance to any PI (P < 0.001). In the first half of 2012, 2.3% of viral samples in the entire sample set had phenotypic resistance to darunavir, while 17.1% in the resistant sample set had phenotypic resistance to darunavir.
References
1. Lathouwers E, Kambili C, Haddad M, Paquet A, De Meyer S, Baugh B. Trends in darunavir resistance-associated mutations and phenotypic resistance: US, 2006 to 2012. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 590. http://www.retroconference.org/2013b/PDFs/590.pdf
2. Mitsuya Y, Liu TF, Rhee SY, Fessel WJ, Shafer RW. Prevalence of darunavir resistance-associated mutations: patterns of occurrence and association with past treatment. J Infect Dis. 2007;196:1177-1179. http://jid.oxfordjournals.org/content/196/8/1177.long
3. Llibre JM, Schapiro JM, Clotet B. Clinical implications of genotypic resistance to the newer antiretroviral drugs in HIV-1-infected patients with virological failure. Clin Infect Dis. 2010;50:872-881. http://cid.oxfordjournals.org/content/50/6/872.long
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