Precision medication: An illustrative case series guiding the clinical application of multi-drug interactions and pharmacogenomics.

Precision medication entails selecting the precise medication, dose, and timing of administration. Multi-drug interactions and genetics significantly affect precision medication. In this article, we present two simulated cases for real-world applications of precision medication. Clinicians may need to acquire additional skills to apply the principles illustrated by these cases.

Genetic variants and interactions from a pharmacist-led pharmacogenomics service for PACE.

Aim: Evaluate results of pharmacogenomics testing for participants enrolled in the Program of All-inclusive Care for the Elderly (PACE). Materials & methods: A convenience sample of 100 participants from the PHARM-GENOME-PACE study. Genetic variants were determined by pharmacogenomics testing. Drug-gene interactions (DGIs), drug-drug-gene interactions (DDGIs) and phenoconversions were interrogated from a clinical decision support system. Results: In total, 146 genetic variants, 169 DGIs and 125 DDGIs were detected. DGIs and DDGIs occurred most commonly with the CYP2D6 gene (36.1 and 39.2%, respectively). There were 280 instances of phenoconversions; majority (62.9%) affecting the CYP3A4 isoenzyme. Conclusion: Prevalence of exposures to DGIs and DDGIs among PACE participants is high. Pharmacists using a clinical decision support system can support PACE practitioners with assessing multidrug simultaneous interactions. Clinical trial registration: NCT03257605.

Long HIV type 1 reverse transcripts can accumulate stably within resting CD4+ T cells while short ones are degraded.

We utilized quantitative methods to compare the efficiency of reverse transcription and stability of viral DNA within resting and activated T cells. Highly purified resting CD4(+) T cells and activated T cells from healthy donors were spinoculated with HIV-1(YU-2), then cultured in conditions that maintain both the viability and the quiescence of the resting cells. Spreading infection was suppressed, then kinetic PCR was used to relate the rates of synthesis of short (strong-stop, RU5) and long (gag or U3-gag second strand transfer) viral DNA to the mean number of virions initially bound to each type of cell. As shown previously, activated cells support an initial burst of high-level reverse transcription, which is then followed by a approximately 10-fold decay in cDNA levels over 4.5 days. In resting T cells, although the synthesis of late reverse transcripts was initially approximately 1000-fold less efficient than in activated T cells, the number of these cDNAs per bound input virion rose 10-fold as culture was extended to 4.5 days. The number of late reverse transcripts remained constant for 3 days after the addition of efavirinez, reflecting enhanced stability. In contrast, the short strong-step reverse transcripts were mostly degraded. Thus, late HIV-1 reverse transcripts can accumulate stably in resting T cells in the absence of detectable T cell activation. Defining the underlying basis for the stabilization of late reverse transcripts, and their associated nucleoprotein complexes, may be pertinent to the accumulation of reservoirs of latent HIV-1 in patients, and could provide a target for future therapies.

A sensitive, quantitative assay for human immunodeficiency virus type 1 integration.

Quantitative methods to measure human immunodeficiency virus type 1 (HIV-1) integration promise to be important tools in dissecting the mechanisms whereby latent reservoirs of provirus are established, most notably in the resting T cells of patients receiving antiretroviral therapy. Here we describe a fluorescence-monitored, nested PCR assay that is able to quantify the relatively rare integration events that occur within these cells. Following DNA extraction, a nonkinetic preamplification step is performed with primers that bind genomic Alu elements and HIV-1 gag sequences, under conditions where primers, deoxynucleoside triphosphates, and enzyme are not limiting. This is followed by a kinetic PCR that quantitates HIV-1 long terminal repeat sequences. A T-cell-based integration standard which reflects the randomness of HIV-1 integration is also described. The assay is 10 to 100 times more sensitive than previously reported quantitative Alu PCR-based integration assays. It is specific for integration events, since no proviruses are detected in cells infected either in the presence of an integrase inhibitor or with an integrase-deficient virus. This method promises to provide important new insights into the processes underlying the accumulation and persistence of latent HIV-1 reservoirs and may eventually be useful clinically in monitoring the eradication of latent virus by novel therapies.