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Darunavir Mutation Rate Dropping in Large Clinical Sample Survey
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Tenth International Congress on Drug Therapy in HIV Infection, November 7-11, 2010, Glasgow
Mark Mascolini
Prevalence of darunavir-associated mutations dropped from 2003 through 2009 in several analyses of the vast Virco database, despite growing use of the protease inhibitor (PI) over those years [1]. Darunavir mutation rates fell in all samples sent to Virco for resistance testing in those years, and in all Virco samples bearing any PI-related mutations.
Researchers from Tibotec (maker of darunavir) and Virco analyzed 232,273 routine clinical samples sent to Virco for testing between January 2003 and December 2009. The investigators excluded samples from research studies and clinical trials. They checked samples for 11 darunavir-associated resistance mutations listed on the IAS-USA resistance tables, dividing samples into those with no darunavir mutations, or one, two, or three or more mutations. Darunavir mutations are V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, and L89V.
Over the study period, the proportion of clinical samples with no darunavir mutations rose from 86.3% in 2003 to 93.9% in 2009. Proportions with one, two, or three or more darunavir mutations fell from 7.9% to 3.3%, from 3.3% to 1.3%, and from 2.5% to 1.5%.
Looking only at clinical samples that carried any PI mutation (according to the US FDA mutation list), the investigators charted the following proportions with 0, 1, 2, or 3 or more darunavir mutations:
-- 0 darunavir mutations: 72.7% in 2003 to 86.3% in 2009
-- 1 darunavir mutation: 15.5% in 2003 to 7.1% in 2009
-- 2 darunavir mutations: 6.7% in 2003 to 3.0% in 2009
-- 3 darunavir mutations: 5.1% in 2003 to 3.5% in 2009
Next the researchers counted darunavir resistance mutations in clinical isolates with phenotypic evidence of resistance to any PI according to Virco fold-change cutoffs. Again, the proportion of samples with no darunavir mutations rose, while proportions with 1, 2, or 3 or more mutations fell:
-- 0 darunavir mutations: 71.3% in 2003 to 82.6% in 2009
-- 1 darunavir mutation: 16.3% in 2003 to 8.8% in 2009
-- 2 darunavir mutations: 7.0% in 2003 to 3.9% in 2009
-- 3 darunavir mutations: 5.4% in 2003 to 4.6% in 2009
Prevalence of four darunavir mutations (V32I, L33F, I54L, and I184V) rose from 2003 through 2009, while rates of I47V and I54M fell. Rates of V32I and I54L climbed most throughout the study period. The investigators believe those findings "suggest that these two mutations potentially play a more predominant role in conferring resistance to darunavir today than before launch." They proposed that overall declining darunavir mutation rates could be explained by pharmacologic pressure on the mutation rate and/or darunavir's high genetic barrier to resistance.
Reference
1. De La Rosa G, Pattery T, Picchio G, et al. Changing prevalence of darunavir-associated mutations in clinical samples received for routine resistance testing: 2003-2009. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract P132.
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