Dual trajectories of antiretroviral therapy adherence and polypharmacy in women with HIV in the United States.

BACKGROUND: Polypharmacy, using five or more medications, may increase the risk of nonadherence to prescribed treatment. We aimed to identify the interrelationship between trajectories of adherence to antiretroviral therapy (ART) and polypharmacy. METHODS: We included women with HIV (aged ≥ 18) enrolled in the Women's Interagency HIV Study in the United States from 2014 to 2019. We used group-based trajectory modeling (GBTM) to identify trajectories of adherence to ART and polypharmacy and the dual GBTM to identify the interrelationship between adherence and polypharmacy. RESULTS: Overall, 1,538 were eligible (median age of 49 years). GBTM analysis revealed five latent trajectories of adherence with 42% of women grouped in the consistently moderate trajectory. GBTM identified four polypharmacy trajectories with 45% categorized in the consistently low group. CONCLUSIONS: The joint model did not reveal any interrelationship between ART adherence and polypharmacy trajectories. Future research should consider examining the interrelationship between both variables using objective measures of adherence.

Food Insecurity Is Associated With Lower Levels of Antiretroviral Drug Concentrations in Hair Among a Cohort of Women Living With Human Immunodeficiency Virus in the United States.

BACKGROUND: Food insecurity is a well-established determinant of suboptimal, self-reported antiretroviral therapy (ART) adherence, but few studies have investigated this association using objective adherence measures. We examined the association of food insecurity with levels of ART concentrations in hair among women living with human immunodeficiency virus (WLHIV) in the United States. METHODS: We analyzed longitudinal data collected semiannually from 2013 through 2015 from the Women's Interagency HIV Study, a multisite, prospective, cohort study of WLHIV and controls not living with HIV. Our sample comprised 1944 person-visits from 677 WLHIV. Food insecurity was measured using the US Household Food Security Survey Module. ART concentrations in hair, an objective and validated measure of drug adherence and exposure, were measured using high-performance liquid chromatography with mass spectrometry detection for regimens that included darunavir, atazanavir, raltegravir, or dolutegravir. We conducted multiple 3-level linear regressions that accounted for repeated measures and the ART medication(s) taken at each visit, adjusting for sociodemographic and clinical characteristics. RESULTS: At baseline, 67% of participants were virally suppressed and 35% reported food insecurity. In the base multivariable model, each 3-point increase in food insecurity was associated with 0.94-fold lower ART concentration in hair (95% confidence interval, 0.89 to 0.99). This effect remained unchanged after adjusting for self-reported adherence. CONCLUSIONS: Food insecurity was associated with lower ART concentrations in hair, suggesting that food insecurity may be associated with suboptimal ART adherence and/or drug absorption. Interventions seeking to improve ART adherence among WLHIV should consider and address the role of food insecurity.

Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine.

The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IMs; tenofovir diphosphate [TFVdp] and FTCtp) to their endogenous nucleotides (ENs; dATP and dCTP), a potential treatment efficacy marker, were assessed among participants of the Women's Interagency HIV Study (WIHS), who ranged from 25 to 75 years. Samples from women receiving TDF-FTC with viral loads of <200 copies/ml were dichotomized by age at collection into two groups (≤45 years and ≥60 years). IM/EN concentrations were measured in peripheral blood mononuclear cell (PBMC) pellets; interleukin-6 (IL-6) and sCD163 were measured in plasma; senescent CD8+ T cells were measured in viable PBMCs. The TFVdp:dATP and FTCtp:dCTP ratios had statistically significantly different distributions in older and younger women (log-rank test, P = 0.0023 and P = 0.032, respectively); in general, IM and EN concentrations were higher in the older women. After adjusting for potential confounders, these findings were not significant. In women aged ≤45 years, TFVdp was negatively associated with IL-6 and sCD163, while FTCtp was positively associated with sCD163 and IL-6 in women aged ≥60 years. Body mass index (BMI) was positively associated with IL-6 in both age groups and negatively associated with TFVdp in women aged ≤45 years. After adjustment, age remained significant for sCD163, while black race, BMI, and renal function remained significant for several IMs and ENs, suggesting that factors associated with aging, but not age itself, govern intracellular TDF-FTC pharmacology.

Development and validation of an LC-MS/MS assay for the quantification of dolutegravir extracted from human hair.

Measurement of drug concentrations in hair provides a non-invasive approach to assess drug adherence. Here, we report on the development and validation of a method for the quantification of the antiretroviral dolutegravir (DTG) extracted from human hair. DTG is extracted from hair samples by sonication and incubation in 50:50 methanol:acetonitrile with 2% formic acid overnight at 40 °C. Following extraction, samples are analyzed by reverse-phase chromatography on a Waters Atlantis T3 (50 × 2.1 mm, 3-µm particle size) column with subsequent detection by electrospray ionization in positive ion mode on an AB Sciex API-5000 triple quadrupole mass spectrometer. The stable, isotopically labeled 13C,d5-DTG is used as an internal standard in the assay. The calibration range is 5-10,000 pg DTG/mL of extraction solvent with the ability to extract between 1 and 10 mg of hair/mL of extraction solvent. The assay was linear, accurate (inter-assay %bias within ± 6.5%), and precise (inter-assay %CV ≤ 10.3%). The assay was successfully used to analyze clinical samples from subjects on DTG regimens. Analysis of clinical samples suggested the potential presence of a degradation product, which was subsequently confirmed to occur with exposure to sunlight. The degradation of DTG could complicate absolute interpretation of clinical results, but the presence of this degradation product is easily evaluated with this assay to aid in data interpretation.

OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis.

OBJECTIVE: Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. METHODS: This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. RESULTS: The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. CONCLUSION: Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.

Exploratory cohort study into underlying mechanism of differences in estrogen metabolism between Asian and Caucasian women during assisted reproductive technology treatment.

Objective: Explore whether racial differences in prevalence of CYP1A2∗1F polymorphism underlies estrogen metabolism differences among Asians and Caucasians. Design: Prospective cohort study. Setting: University-based fertility practice. Patients: Asian or Caucasian patients who underwent ovarian stimulation (OS) or programmed cycle frozen embryo transfer (FET) between October 2019 and April 2021. Interventions: None. Main Outcome Measures: Trigger-day serum E2 per oocyte retrieved in OS cycles, and E2 on day of lining check in FET cycles. Results: Seventy-one participants were enrolled, 55 in OS group (29 Caucasian and 26 Asian) and 16 in FET group (10 Caucasian and 6 Asian). Peak E2 per oocyte retrieved in the OS group (n = 48) differed by race, with significantly lower levels in Caucasians compared with Asians (177.5 ± 64.2 vs. 261.1 ± 139.5 pg/mL). Prevalence of CYP1A2∗1F polymorphism did not significantly differ by race. Compared using Kruskal-Wallis test, peak E2 per oocyte retrieved did not differ by CYP1A2∗1F genotype. In multivariate linear regression model, adjusting for body mass index, caffeine intake, and self-reported race, there remained no significant correlation. In FET group, serum E2 on day of lining check was also not significantly different by CYP1A2∗1F genotype. Conclusions: Although a consistent difference in serum E2 between Asians and Caucasians undergoing OS was noted, the CYP1A2∗1F polymorphism is unlikely the primary driver of this difference.

Dual Trajectories of Antiretroviral Therapy Adherence and Polypharmacy in Women with HIV in the United States.

Background Polypharmacy, using five or more medications, may increase the risk of nonadherence to prescribed treatment. We aimed to identify the interrelationship between trajectories of adherence to antiretroviral therapy (ART) and polypharmacy. Methods We included women with HIV (aged ≥ 18) enrolled in the Women's Interagency HIV Study in the United States from 2014 to 2019. We used group-based trajectory modeling (GBTM) to identify trajectories of adherence to ART and polypharmacy and the dual GBTM to identify the interrelationship between adherence and polypharmacy. Results Overall, 1,538 were eligible (median age of 49 years). GBTM analysis revealed five latent trajectories of adherence with 42% of women grouped in the consistently moderate trajectory. GBTM identified four polypharmacy trajectories with 45% categorized in the consistently low group. Conclusions The joint model did not reveal any interrelationship between ART adherence and polypharmacy trajectories. Future research should consider examining the interrelationship between both variables using objective measures of adherence.

Trajectories of Antiretroviral Therapy Adherence and Virologic Failure in Women With HIV in the United States.

BACKGROUND: Women with HIV (WHIV) in the United States face many challenges with adherence to antiretroviral therapy (ART), and suboptimal adherence often leads to virologic failure. This study aimed to determine the association between ART adherence trajectories and the risk of virologic failure. METHODS: We included WHIV (aged 18 years or older) enrolled in the Women's Interagency HIV Study in the United States from April 2014 to September 2019 who had at least 2 consecutive measurements of HIV RNA and ≥3 measurements of self-reported adherence. Group-based trajectory modeling was used to identify adherence trajectories. Cox proportional hazard ratios were used to measure the association. MAIN OUTCOME MEASURE: Virologic failure was defined as HIV RNA ≥200 copies/mL at 2 consecutive visits. RESULTS: We included 1437 WHIV (median age 49 years). Of all women, 173 (12.0%) experienced virologic failure. Four adherence trajectories were identified, namely "consistently high" (26.3%), "moderate increasing" (9.5%), "moderate decreasing" (30.6%), and "consistently low" (33.5%). Women in the consistently low adherence group consumed alcohol and experienced depression more than other groups. Compared with the "consistently high" trajectory, the risk of virologic failure was higher among women with "consistently low" [adjusted hazard ratio (aHR) 2.8; 95% confidence interval (CI): 1.6 to 4.9; P < 0.001] and "moderate decreasing" adherence trajectories (aHR 1.8; 95% CI: 1.0 to 3.2; P = 0.04), but it was similar to those with "moderate increasing" adherence trajectory (aHR 1.0; 95% CI: 0.4 to 2.5; P = 0.94). CONCLUSIONS: Adherence to ART remains a challenge among WHIV. Multilevel behavioral interventions to address poor adherence, alcohol consumption, and depression are needed.

A Patient Decision Aid (i.ARTs) to Facilitate Women's Choice Between Oral and Long-Acting Injectable Antiretroviral Treatment for HIV: Protocols for its Development and Randomized Controlled Pilot Trial.

BACKGROUND: Many women with HIV (WWH) have suboptimal adherence to oral antiretroviral therapy (ART) due to multilevel barriers to HIV care access and retention. A long-acting injectable (LAI) version of ART was approved by the US Food and Drug Administration in January 2021 and has the potential to overcome many of these barriers by eliminating the need for daily pill taking. However, it may not be optimal for all WWH. It is critical to develop tools that facilitate patient-provider shared decision making about oral versus LAI ART modalities to promote women's adherence and long-term HIV outcomes. OBJECTIVE: This study will develop and pilot test a web-based patient decision aid called i.ART+support (i.ARTs). This decision aid aims to support shared decision making between WWH and their providers, and help women choose between oral and LAI HIV treatment. METHODS: The study will occur in 3 phases. In phase 1, we will utilize a mixed methods approach to collect data from WWH and medical and social service providers to inform i.ARTs content. During phase 2, we will conduct focus groups with WWH and providers to refine i.ARTs content and develop the web-based decision aid. In phase 3, i.ARTs will be tested in a randomized controlled trial with 180 women in Miami, Florida, and assessed for feasibility, usability, and acceptability, as well as to evaluate the associations between receiving i.ARTs and viral suppression, ART pharmacy refills, and clinic attendance. RESULTS: This study was funded in March 2021. Columbia University's IRB approved the study protocols (approval number IRB-AAAT5314). Protocols for phase 1 interviews have been developed and interviews with service providers started in September 2021. We will apply for Clinicaltrials.gov registration prior to phase 3, which is when our first participant will be enrolled in the randomized controlled trial. This is anticipated to occur in April 2023. CONCLUSIONS: This study is the first to develop a web-based patient decision aid to support WWH choices between oral and LAI ART. Its strengths include the incorporation of both patient and provider perspectives, a mixed methods design, and implementation in a real-world clinical setting. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35646.

Degree of Polypharmacy and Cognitive Function in Older Women with HIV.

The number of people with HIV (PWH) experiencing age-associated comorbidities including those treated with medications and cognitive impairment is increasing. We examined associations between polypharmacy and cognition in older women with HIV (WWH) given their vulnerability to this comorbidity. Cross-sectional analysis capitalizing on Women's Interagency HIV Study data collected between 2014 and 2017. WWH meeting the following criteria were analyzed: age ≥50 years; availability of self-reported non-antiretroviral therapy (ART) medications data; and neuropsychological data. The number of non-ART medications used regularly in the prior 6 months was summed. Polypharmacy was categorized as none/low (0-4), moderate (5-9), or severe (≥10). Multivariable linear regression analyses examined polypharmacy-cognition (T-score) associations in the total sample and among virally suppressed (VS; < 20 copies/mL)-WWH after covariate adjustment for enrollment site, income, depressive symptoms, substance use (smoking, heavy alcohol, marijuana, crack, cocaine, and/or heroin), the Veterans Aging Cohort Study index (indicators of HIV disease and organ system function, hepatitis C virus serostatus), ART use, nadir CD4 count, and specific ART drugs (efavirenz, integrase inhibitors). We included 637 women (median age = 55 years; 72% Black). Ninety-four percent reported ART use in the past 6 months and 75% had HIV RNA <20 copies/mL. Comorbidity prevalence was high (61% hypertension; 26% diabetes). Moderate and severe polypharmacy in WWH were 34% and 24%. In WWH, severe polypharmacy was associated with poorer executive function (p = .007) and processing speed (p = .01). The same pattern of findings remained among VS-WWH. Moderate polypharmacy was not associated with cognition. Moderate and severe polypharmacy were common and associated with poorer executive function and processing speed in WWH. Severe polypharmacy may be a major contributor to the persistence of domain-specific cognitive complications in older WWH above and beyond the conditions that these medications are used to treat.

Polypharmacy Is Associated With Falls in Women With and Without HIV.

BACKGROUND: Aging in people with HIV is associated with increased risk of developing synergistic conditions such as neurocognitive impairment, polypharmacy, and falls. We assessed associations between polypharmacy (use of 5 or more non-ART medications), use of neurocognitive adverse effects (NCAE) medications, and odds of falls in women with HIV (WWH) and without HIV (HIV-). METHODS: Self-reported falls and medication use data were contributed semiannually by 1872 (1315 WWH and 557 HIV-) Women's Interagency HIV Study participants between 2014 and 2016. Polypharmacy and NCAE medication use were evaluated separately and jointly in multivariable models to assess their independent contributions to single and multiple falls risk. RESULTS: The proportion of women who reported any fall was similar by HIV status (19%). WWH reported both greater polypharmacy (51% vs. 41%; P < 0.001) and NCAE medication use (44% vs. 37%; P = 0.01) than HIV- women. Polypharmacy conferred elevated odds of single fall [adjusted odds ratio (aOR) 1.67, 95% CI: 1.36 to 2.06; P < 0.001] and multiple falls (aOR 2.31, 95% CI: 1.83 to 2.93; P < 0.001); the results for NCAE medications and falls were similar. Both polypharmacy and number of NCAE medications remained strongly and independently associated with falls in multivariable models adjusted for HIV serostatus, study site, sociodemographics, clinical characteristics, and substance use. CONCLUSIONS: Polypharmacy and NCAE medication use were greater among WWH compared with HIV-, and both were independently and incrementally related to falls. Deprescribing and avoidance of medications with NCAEs may be an important consideration for reducing fall risk among WWH and sociodemographically similar women without HIV.

Cerivastatin, genetic variants, and the risk of rhabdomyolysis.

OBJECTIVE: The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. METHODS: This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. RESULTS: Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63). CONCLUSION: We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.

Association Between Medication-Taking and Refractive Error in a Large General Population-Based Cohort.

Purpose: Refractive errors, particularly myopia, are common and a leading cause of blindness. This study aimed to explore associations between medications and refractive error in an aging adult cohort and to determine whether childhood-onset refractive errors predict future medication use to provide novel insights into disease mechanisms. Methods: The study compared the spherical equivalent values measured in 102,318 UK Biobank participants taking the 960 most commonly used medications. The strengths of associations were evaluated against the self-reported age of spectacle wear. The causality of refractive error changes was inferred using sensitivity and Mendelian randomization analyses. Results: Anti-glaucoma drugs were associated with 1 to 2 diopters greater myopic refraction, particularly in subjects who started wearing correction in the first two decades of life, potentially due to the association of higher intraocular pressure since early years with both myopia and, later in life, glaucoma. All classes of pain-control medications, including paracetamol, opiates, non-steroidal antiinflammatory drugs, and gabapentinoids, were associated with greater hyperopia (+0.68-1.15 diopters), after correction for deprivation, education, and polypharmacy and sensitivity analyses for common diagnoses. Oral hypoglycemics (metformin, gliburonide) were associated with myopia, as was allopurinol, and participants using bronchodilators (ipratropium and salbutamol) were more hyperopic. Conclusions: This study finds for the first time, to our knowledge, that medication use is associated with refractive error in adults. The novel finding that analgesics are associated with hyperopic refraction, and the possibility that multisite chronic pain predisposes to hyperopia, deserves further research. Some drugs, such as antihyperglycemic or bronchodilators, may directly alter refractive error. Intraocular pressure appears causative for myopia.

Cerivastatin in vitro metabolism by CYP2C8 variants found in patients experiencing rhabdomyolysis.

OBJECTIVES: Cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor withdrawn from the market because of serious adverse effects, is metabolized primarily by CYP2C8. The occurrence of associated myotoxicity and rhabdomyolysis were attributed to altered cerivastatin pharmacokinetics on account of gemfibrozil-inhibition or genetic variations in CYP2C8 and drug transporters involved in cerivastatin clearance. However, the effect of CYP2C8 genetic variation on cerivastatin metabolism has not been fully elucidated. METHODS: In this study, patients (n=126) with confirmed cases of rhabdomyolysis after cerivastatin administration had their CYP2C8 gene resequenced and the metabolism of cerivastatin by the discovered CYP2C8 variants was assessed in proteins expressed in Escherichia coli. RESULTS: In this unique patient population, 12 novel single nucleotide polymorphisms were discovered of which six were exclusively found in patients not using gemfibrozil. Three rare exonic variants resulted in amino acid substitutions and a frame shift deletion (V472fsL494 generating a defective mostly heme-free CYP2C8 protein). A particular promoter located deletion (-635_-634delTA) was tightly linked to CYP2C8*3. Heterologously expressed CYP2C8.3 and CYP2C8.4 displayed an increase in cerivastatin metabolic clearance of up to six-fold compared with the wild-type enzyme. Similarly, an independent sample of microsomes from human livers carrying the CYP2C8*3 and CYP2C8*4 alleles exhibited a 2-fold to 14-fold increase in normalized cerivastatin intrinsic clearance, compared with microsomes from livers carrying only the wild type allele. CONCLUSION: Gain or loss of catalytic function found in the CYP2C8 gene could certainly alter cerivastatin pharmacokinetics and may influence, at least in part, susceptibility to the development of myotoxicity.

Human subjects are protected from mast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations.

BACKGROUND: Mast cell tryptases have proposed roles in allergic inflammation and host defense against infection. Tryptase gene loci TPSAB1 and TPSB2 are known to be polymorphic, but the nature and extent of diversity at these loci have not been fully explored. OBJECTIVE: We sought to compare functional and nonfunctional tryptase allele frequencies and establish haplotypes in human populations. METHODS: Tryptase allele frequencies were determined by means of direct sequencing in 270 individuals from HapMap populations of European, African, Chinese, and Japanese ancestry. Haplotypes were predicted, validated in parent-child trios, and compared between populations. RESULTS: We identify a new frame-shifted tryptase allele (betaIII(FS)) carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. Homology models predict that betaIII(FS) is functionless. Our genotyping assay shows that allele and haplotype distributions in each population are unique. Strong linkage disequilibrium between TPSAB1 and TPSB2 (r(2)=0.83, D'=0.85) yields 2 major and 5 minor tryptase haplotypes. CONCLUSIONS: Tryptase deficiency alleles (alpha and the newly discovered betaIII(FS)) are common, causing the number of inherited active genes to range from a minimum of 2 to a maximum of 4, with major differences between populations in the proportion of individuals inheriting 2 versus 4 active alleles. African and Asian populations are especially enriched in genes encoding functional and nonfunctional tryptases, respectively. Strong linkage of TPSAB1 and TPSB2 and pairing of deficiency alleles with functional alleles in observed haplotypes protect human subjects from "knockout" genomes and indeed from inheritance of fewer than 2 active alleles.

CYP2C19 Allele Frequencies in Over 2.2 Million Direct-to-Consumer Genetics Research Participants and the Potential Implication for Prescriptions in a Large Health System.

Understanding the prevalence of clinically relevant pharmacogenetic variants using large unselected populations is critical for gauging the potential clinical impact of widespread preemptive pharmacogenetic testing. To this end, we assessed the frequencies and ethnic distribution of the three most common CYP2C19 alleles (*2, *3, and *17) in 2.29 million direct-to-consumer genetics research participants (23andMe, Sunnyvale, CA). The overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17, and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. To better understand how this high frequency might impact a real patient population, we examined the prescription rates (Rx) of high-pharmacogenetic-risk medications metabolized by CYP2C19 using the University of California at San Francisco (UCSF) health system's anonymized database of over 1.25 million patients. Between 2012 and 2019, a total of 151,068 UCSF patients (15.8%) representing 5 self-reported ethnicities were prescribed one or more high-pharmacogenetic-risk CYP2C19 medications: proton pump inhibitors (145,243 Rx), three selective serotonin reuptake inhibitor antidepressants (54,463 Rx), clopidogrel (14,376 Rx), and voriconazole (2,303 Rx).

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients.

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. Design, Setting, and Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Exposures: Prescription of 38 level A medications based on electronic health records. Main Outcomes and Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. Conclusions and Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.

Ascorbic acid metabolites are involved in intraocular pressure control in the general population.

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma.

A Practical First Step Using Needs Assessment and a Survey Approach to Implementing a Clinical Pharmacogenomics Consult Service.

INTRODUCTION: Genetic-guided selection of non-oncologic medications is not commonly practiced in general, and at University of California, San Francisco (UCSF) Health, specifically. Understanding the unique position of clinicians with respect to clinical pharmacogenetics (PG) at a specific institution or practice is fundamental for implementing a successful PG consult service. OBJECTIVES: To assess clinicians' current practices, needs, and interests with respect to clinical PG at UCSF Health, a large tertiary academic medical center. METHODS: A list of 42 target medications with clinical PG recommendations was complied. Clinical specialties that routinely used the target medications were identified. A 12-question survey focused on practice of PG for target medications was developed. Pharmacists and physicians were surveyed anonymously in several clinical specialties. Survey results were analyzed using descriptive statistics. RESULTS: Of the 396 clinicians surveyed, 76 physicians and 59 pharmacists participated, resulting in 27% and 50% average response rates, respectively. The current use of PG in clinical practice for physicians and pharmacists was 29% and 32%, respectively, however this number varied across clinical specialties from 0% to 80%. Of clinicians whom reported they do not currently apply PG, 63% of physicians and 54% of pharmacists expressed interest in integrating PG. However, the level of interest varied from 20% to 100% across specialties. Of the respondents, 64% of physicians and 56% of pharmacists elected to provide contact information to investigators to further discuss their interest related to clinical PG. CONCLUSIONS: While PG is not uniformly practiced at UCSF Health, there is considerable interest in utilizing PG by the respondents. Our approach was successful at identifying clinicians and services interested in PG for specific drug-gene pairs. This work has set a foundation for next steps to advance PG integration at UCSF Health. Clinicians can adopt our approach as preliminary work to build a clinical PG program at their institutions.