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

Sutherland, K.A., Parry, C.M., McCormick, A.L., Kapaata, A., Lyagoba, F., Kaleebu, P., Gilks, C.F., Goodall, R., Spyer, M., Kityo, C., Pillay, D., Gupta, R.K. and DART Virology Group 2015. Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial. PLoS ONE. 10 (9). doi:10.1371/journal.pone.0137834

TitleEvidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
AuthorsSutherland, K.A., Parry, C.M., McCormick, A.L., Kapaata, A., Lyagoba, F., Kaleebu, P., Gilks, C.F., Goodall, R., Spyer, M., Kityo, C., Pillay, D., Gupta, R.K. and DART Virology Group
Abstract

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.

KeywordsHIV, human immunodeficiency virus; LPV, lopinavir; LPV/r, ritonavir boosted lopinavir; DRV, darunavir, PI–protease inhibitor; Gag, Group antigen, Pro–protease; SARA, The Boosted Protease Inhibitor Monotherapy as Maintenance Second-line Anti-retroviral therapy in Africa; RTI, reverse transcriptase inhibitor
Article number e0137834
JournalPLoS ONE
Journal citation10 (9)
ISSN1932-6203
Year2015
PublisherPublic Library of Science
Publisher's versionSutherland_etal_PLoSONE_2015pdf.pdf
Digital Object Identifier (DOI)doi:10.1371/journal.pone.0137834
Publication dates
Published18 Sep 2015

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