Abstract
BackgroundProtease inhibitors (PI) are especially important in salvage therapy. Previous treatment failure with a PI containing regimen may elicit resistance mutations, reducing PI susceptibility and limiting treatment options. The aim of this study was to describe major PI mutations among patients exposed to at least one PI to evaluate predictors of mutation emergence and the impact of subtypes on resistance.MethodologyPartial HIV-1 pol sequences (Sanger Sequencing) from patients exposed to PI with virological failure were genotyped from January 2014 to December 2017. Drug resistance mutations (DRM), antiretroviral susceptibility (GSS) and subtypes, along clinical and laboratory parameters, were evaluated using logistic regression to access the predictors of mutation emergence.ResultsIn 27.5% (466/1696) of the cases at least one major PI mutations was identified, most commonly M46 (14.7%), V82 (13.8%) and I54 (13.3%). Mutations to NRTI and NNRTI were observed in 69.6% and 59.9%, respectively, of the 1696 sequences. Full activity to darunavir was predicted in 88% (1496/1696), but was only 57% among those with at least one PI-DRM. Subtype C sequences had less major PI-DRMs (10%, 9/87) compared to B (28%, 338/1216) or F (35%, 58/168) (p <0.001) but adjusted analysis suggested that this association is not independent from a shorter treatment time and fewer regimens (OR 0.59, Confidence Interval 95: 0.2–2.5, p = 0.48). Subtype F, together with NRTI mutations and longer time on treatment was associated to presence of PI-DRM, to a lower darunavir GSS and to mutations at codon I50.ConclusionsAmong patients with PI-DRM, full activity to darunavir was compromised in almost half of the cases and efforts to detect failure at earlier time are warranted, particularly for HIV-1 subtype F that showed association to the emergence of resistance, with potential impact in protease inhibitors sequencing. Furthermore, NRTI mutations may serve as an indicative of sufficient adherence to allow PI-DRM emergence.
Highlights
Information on protease inhibitor drug resistance mutations (PI-Drug resistance mutations (DRM)) is an important component in the planning of salvage therapy
Mutations to nucleotide analog reverse transcriptase inhibitor (NRTI) and nucleoside reverse transcriptase inhibitor (NNRTI) were observed in 69.6% and 59.9%, respectively, of the 1696 sequences
Full activity to darunavir was predicted in 88% (1496/1696), but was only 57% among those with at least one PIDRM
Summary
Information on protease inhibitor drug resistance mutations (PI-DRM) is an important component in the planning of salvage therapy. Contrary to NRTI drugs, where resistance may not be an impediment for drug recycling in second-line therapy [1,2,3], and to first generation NNRTI drugs, that should be avoided in exposed patients even without detectable mutations, detection of PI-DRM may help in the selection of PI drugs to be used as part of salvage regimens. The recommended first ARV regimens in Brazil at the time of the study was efavirenz plus two NRTI, PI could be used as an alternative as first line (lopinavir or atazanavir) and at second and subsequent regimens at physician’s discretion. The aim of this study was to describe major PI mutations among patients exposed to at least one PI to evaluate predictors of mutation emergence and the impact of subtypes on resistance.
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