Novel mutations and shifting susceptibility to darunavir and tipranavir

Prevalence of mutations conferring resistance to the protease inhibitors (PIs) darunavir and tipranavir has dropped in recent years, according to an analysis of Monogram Sciences resistance database [1].

The study also identified novel darunavir and tipranavir mutations and correlated declining susceptibility to darunavir with rising prevalence of mutations that make virus more susceptible to tipranavir.

Monogram researchers plumbed their database for viral samples with matched genotypic and phenotypic data, then used univariate and multivariate analyses to pinpoint mutations strongly associated with susceptibility to darunavir or tipranavir (measured as fold-change in 50% inhibitory concentration).

The investigators further assessed the potential impact of each mutation with in silico site-directed mutagenesis, a technique that identifies paired viral samples with matched amino acids at relevant resistance positions but with a single mutation at a specified position. For the 2141 darunavir-resistant samples, the Monogram team evaluated temporal trends in resistance from 2006 through 2009.

Three novel mutations were strongly associated with resistance to both darunavir and tipranavir: E35N, I47A, and V82L. Three other mutations – L10F, G48M, and V82F – were linked to resistance to darunavir only. And three other mutations – I54S, I84A, and I84C – were tied to resistance to tipranavir only. Overall prevalence of mutations associated with resistance to darunavir and tipranavir dropped from 2006 through 2009.

Among darunavir-resistant viral samples, average resistance to darunavir climbed from 38-fold to 50-fold over the study period. This jump in fold change correlated closely with a decrease in average tipranavir fold change from 7.6 to 4.3; the r(2) value for this inverse correlation was 0.99.

During the study period, prevalence of three darunavir-related mutations in the Monogram database rose – I50V from 11% to 15%, I54L from 17% to 33%, and L76V from 5% to 9%. Earlier studies found that these mutations make HIV more susceptible to tipranavir. The Monogram genotypic-phenotypic analysis confirmed the impact of these mutations on susceptibility to tipranavir.

The Monogram investigators suggested that increasing resistance to darunavir (measured as fold-change in susceptibility) appears to be strongly associated with selection of mutations associated with darunavir resistance that have [a] sensitising effect on tipranavir. The researchers proposed that continued crutiny of resistance databases is essential to detect emerging trends in drug resistance and to identify novel mutations that improve the accuracy of genotypic interpretation algorithms.