Abstract
BackgroundMajor protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs.MethodsSamples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain.ResultsWe cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC50 to LPV was 4.07 fold (95% CI, 2.08–6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC50 to LPV was 4.25 fold (95% CI, 1.39–7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure.ConclusionsHere we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally.
Highlights
It is estimated that almost 15 million human immunodeficiency virus (HIV)-infected people in resource limited settings are currently being treated with antiretroviral therapy[1]
For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC50 to LPV was 4.07 fold at the pre-protease inhibitors (PI) timepoint
We observe in one patient the development of significantly reduced susceptibility conferred by changes in Group antigen (Gag) which may have contributed to treatment failure on a protease inhibitor containing regimen
Summary
It is estimated that almost 15 million HIV-infected people in resource limited settings are currently being treated with antiretroviral therapy[1]. The use of boosted protease inhibitor monotherapy (bPImono) as maintenance therapy has been investigated in a number of trials in resource-rich settings, which have suggested that this strategy can be considered under certain circumstances [3,4,5,6,7]. Major resistance mutations in protease [10] were detected in 5/20 (25%) bPImono participants with a VL>1000 copies/ml at 24 weeks/last time-point with successful genotyping (compared to 0/8 CT)[9]. The larger EARNEST trial ( conducted in sub Saharan Africa) showed inferiority of a PI monotherapy approach to triple therapy over 2 years of follow up [11], though detailed genotypic resistance data have not been published.
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