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Novel Mutation Combinations Linked to Resistance to Rilpivirine
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53rd ICAAC, September 10-13, 2013, Denver
Mark Mascolini
Two previously unrecognized mutation combinations and one recognized mutation pair conferred resistance to the nonnucleoside rilpivirine in an analysis of almost 35,000 patient viral samples by researchers from Monogram Biosciences and Janssen [1]. The investigators recommended adding these mutation clusters to genotypic algorithms predicting resistance to rilpivirine.
Research has identified several reverse transcriptase mutations associated with resistance to rilpivirine, the most recently licensed nonnucleoside reverse transcriptase inhibitor: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C, and M230I/L. To refine the understanding of resistance to rilpivirine, the investigators analyzed pairs of reverse transcriptase genotypes and rilpivirine phenotypes in 34,907 viruses sent to Monogram for routine resistance testing.
The Monogram team aimed to identify samples that lacked standard genotypic evidence of rilpivirine resistance yet conferred reduced phenotypic susceptibility to rilpivirine, defined as a fold-change in 50% inhibitory concentration above the established biological resistance cutoff, which is 2-fold. They used site-directed mutagenesis to confirm reduced susceptibility to rilpivirine associated with these mutations.
Three resistance clusters were strongly associated with decreased susceptibility (resistance) to rilpivirine. The following list gives the mutation combination, the number of samples with that pattern, the median (and interquartile range [IQR]) fold-change in susceptibility, and the P value indicating the strength of the association:
L100I + K103N: n = 593, fold-change 9.1 (IQR 3.8 to 25), P = 0.000
L100I + K103R + V179D: n = 11, fold-change 4.6 (IQR 3.5 to 5.7), P = 0.000
L100I + K103S: n = 8, fold-change 5.8 (IQR 1 to 68.2), P = 0.002
Prior research disclosed the impact of L100I + K103N on resistance to rilpivirine [2]. The researchers found no samples with L100I + K103R alone. Samples harboring L100I, K103N, K103R, K103S, or V179D as single mutations did not significantly reduce viral susceptibility to rilpivirine.
Site-directed mutagenesis experiments confirmed reduced susceptibility to rilpivirine with the three identified mutation clusters. These three clusters conferred greater reductions in susceptibility to the early nonnucleosides efavirenz and nevirapine than to rilpivirine or etravirine.
The substantial impact of these mutation clusters on resistance to rilpivirine and the high prevalence of L100I + K103N led the investigators to propose that "incorporating these resistance-associated mutations into genotypic algorithms would be crucial for the accuracy of the predictions." They proposed that "periodic monitoring of large phenotype-genotype databases can improve the accuracy of genotypic predictions of drug resistance, especially in cases of recently approved agents."
References
1. Haddad M, Napolitano LA, Frantzell A, et al. Combinations of HIV-1 reverse transcriptase mutations L100I+K103N/S and L100I+K103R+V179D reduce susceptibility to rilpivirine. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-677.
2. Azijn H, Tirry I, Vingerhoets J, et al. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother. 2010;54:718-727. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812151/
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