Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA TrialReport as inadecuate




Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial - Download this document for free, or read online. Document in PDF available to download.

Background

Major 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.

Methods

Samples 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.

Results

We 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.

Conclusions

Here 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.



Author: Katherine A. Sutherland, Chris M. Parry, Adele McCormick, Anne Kapaata, Fred Lyagoba, Pontiano Kaleebu, Charles F. Gilks, Ruth Go

Source: http://plos.srce.hr/



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