Analysis of a panel-based pharmacogenomics testing program among members of a commercial and Medicare client of a pharmacy benefits manager.

BACKGROUND: Although the field of pharmacogenomics (PGx) has existed for decades, use of pharmacogenomic information by providers to optimize medication therapy for patients has had relatively slow adoption. There are many factors that have contributed to the slow adoption of PGx testing, but it is partially due to a lack of coverage by payers. If PGx testing is covered by payers, frequently only testing of a specific gene is covered, rather than a panel of many genes. As a result, little is known about how coverage of a panel-based PGx test will affect a member's medication therapy. OBJECTIVES: To determine how giving providers specific medication optimization recommendations, based on results of a panel-based PGx test, impacted members' medication regimens. METHODS: Pharmacy claims data were retrospectively reviewed for this exploratory study. Members who participated in PGx testing were in the intervention group and members who chose not to participate in the PGx testing, but who were eligible to participate, were in the control group. PGx test results, including suggested medication changes, were mailed to providers. To determine if providers adopted the suggested medication changes, pharmacy claims data were analyzed retrospectively for the 4-month period preceding and following the date from which recommendations were provided to prescribers. RESULTS: Of the 101 members included in the analysis, 50 were in the intervention group and 51 were in the control group. In the intervention group, members were taking in a total of 352 medications; 165 of the medications had PGx guidance. Based on the PGx test results, 62 of these medications (37.6%) had recommendations. Of members who received PGx testing, 76% had at least 1 recommended change. When pharmacist recommendations were made, a change was made to the medication 27% of the time. There was a statistically significant difference between the number of medication changes in the PGx group and the control group (P = 0.024). CONCLUSIONS: Recommendations based on PGx testing can lead to changes in medications and an optimized medication regimen for members. DISCLOSURES: The authors have no conflicts to disclose that may present a potential conflict of interest.

Effects of substitutions at the 4' and 2 positions on the bioactivity of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.

Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) form the backbone of most anti-HIV therapies. We have shown that 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a highly effective NRTI; however, the reasons for the potent antiviral activity of EFdA are not well understood. Here, we use a combination of structural, computational, and biochemical approaches to examine how substitutions in the sugar or adenine rings affect the incorporation of dA-based NRTIs like EFdA into DNA by HIV RT and their susceptibility to deamination by adenosine deaminase (ADA). Nuclear magnetic resonance (NMR) spectroscopy studies of 4'-substituted NRTIs show that ethynyl or cyano groups stabilize the sugar ring in the C-2'-exo/C-3'-endo (north) conformation. Steady-state kinetic analysis of the incorporation of 4'-substituted NRTIs by RT reveals a correlation between the north conformation of the NRTI sugar ring and efficiency of incorporation into the nascent DNA strand. Structural analysis and the kinetics of deamination by ADA demonstrate that 4'-ethynyl and cyano substitutions decrease the susceptibility of adenosine-based compounds to ADA through steric interactions at the active site. However, the major determinant for decreased susceptibility to ADA is the 2-halo substitution, which alters the pKa of N1 on the adenine base. These results provide insight into how NRTI structural attributes affect their antiviral activities through their interactions with the RT and ADA active sites.

Efficient and rapid identification of Candida albicans allelic status using SNP-RFLP.

Candida albicans is the most prevalent opportunistic fungal pathogen in the clinical setting, causing a wide spectrum of diseases ranging from superficial mucosal lesions to life-threatening deep-tissue infections. Recent studies provide strong evidence that C. albicans possesses an arsenal of genetic mechanisms promoting genome plasticity and that it uses these mechanisms under conditions of nutritional or antifungal drug stress. Two microarray-based methods, single nucleotide polymorphism (SNP) and comparative genome hybridization arrays, have been developed to study genome changes in C. albicans. However, array technologies can be relatively expensive and are not available to every laboratory. In addition, they often generate more data than needed to analyze specific genomic loci or regions. Here, we have developed a set of SNP-restriction fragment length polymorphism (RFLP) (or PCR-RFLP) markers, two per chromosome arm, for C. albicans. These markers can be used to rapidly and accurately detect large-scale changes in the C. albicans genome including loss of heterozygosity (LOH) at single loci, across chromosome arms or across whole chromosomes. Furthermore, skewed SNP-RFLP allelic ratios are indicative of trisomy at heterozygous loci. While less comprehensive than array-based approaches, we propose SNP-RFLP as an inexpensive, rapid, and reliable method to screen strains of interest for possible genome changes.