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Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy.

Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy.
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Dunn DT, Stöhr W, Arenas-Pinto A, Tostevin A, Mbisa JL, Paton NI, ,


Dunn DT, Stöhr W, Arenas-Pinto A, Tostevin A, Mbisa JL, Paton NI, , (click to view)

Dunn DT, Stöhr W, Arenas-Pinto A, Tostevin A, Mbisa JL, Paton NI, ,

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Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 2018 02 05101() 63-65 pii 10.1016/j.jcv.2018.02.003

Abstract
BACKGROUND
The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug.

OBJECTIVES
To assess if we had missed low frequency mutations, using a more sensitive methodology.

STUDY DESIGN
We performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method. Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm.

RESULTS
17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome.

DISCUSSION
This report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations.

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