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Medically tailored meals for food insecurity and type 2 diabetes: Protocol for the Food as Medicine for Diabetes (FAME-D) trial.
Berkowitz, SA, Kruse, GR, Ball Ricks, KA, Burch, J, Ouimet, E, Kitzis, B, Forrest, C, Terranova, J, Stewart, PW, Buse, JB, et al
Contemporary clinical trials. 2023;:107039
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Abstract
BACKGROUND Food insecurity is associated with worse glycemic management for individuals with type 2 diabetes mellitus (T2DM), but whether medically tailored meals (MTM), a food insecurity intervention, can improve glycemic management is unclear. OBJECTIVE To describe the protocol for a trial assessing whether an MTM plus lifestyle intervention improves hemoglobin A1c (HbA1c) and participant-reported outcomes, relative to a food subsidy (money that can be spent on foods participants choose), for adults with both T2DM and food insecurity. METHODS The Food as Medicine for Diabetes (FAME-D) randomized clinical trial (goal n = 200) is a pragmatic trial with an active comparator. Participants, who will have T2DM and report food insecurity, will be randomly assigned to a 6-month MTM plus telephone-delivered lifestyle change intervention, or a 6-month food subsidy ($40/month). The primary outcome is HbA1c at 6 months. Secondary outcomes include HbA1c at 12 months to assess whether the intervention effect (if any) is sustained, along with weight, food insecurity, diabetes distress, and health-related quality of life. Qualitative analyses of semi-structured interviews will help understand why, how, and under what circumstances the intervention achieved its observed results. CONCLUSION Results from FAME-D will help inform clinical management of food insecurity when it co-occurs with T2DM. Further, results may be useful as healthcare payors are considering coverage for MTM interventions. CLINICALTRIALS gov: NCT04828785.
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Sustainable and equivalent improvements in symptoms and functional well-being following viral cure from ledipasvir/sofosbuvir versus elbasvir/grazoprevir for chronic hepatitis C infection: Findings from the randomized PRIORITIZE trial.
Evon, DM, Dong, M, Reeve, BB, Peter, J, Michael, L, Lok, AS, Nelson, DR, Stewart, PW
Journal of viral hepatitis. 2022;(9):795-806
Abstract
The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.
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Patient-reported outcomes 12 months after hepatitis C treatment with direct-acting antivirals: Results from the PROP UP study.
Serper, M, Evon, DM, Amador, J, Stewart, PW, Sarkar, S, Lok, AS, Sterling, RK, Reeve, BB, Golin, CE, Rajender Reddy, K, et al
Liver international : official journal of the International Association for the Study of the Liver. 2021;(4):692-704
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Abstract
BACKGROUND & AIMS The long-term impact of hepatitis C virus (HCV) therapy with all-oral direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) has not been well-described. We characterized changes in PROs from pre-treatment to 12 months post-treatment in a real-world cohort. METHODS PROP UP was a multi-centre observational cohort study of 1601 patients treated with DAAs at 11 US gastroenterology/hepatology practices from 2015 to 2017. PROs were evaluated pre-treatment (T1) and 12 months post-treatment (T5). A minimally important change (MIC) threshold was prespecified as >5% change in PRO scores from T1 to T5. Multivariable analyses identified predictors of change. RESULTS Three-quarters of patients were 55 or older; 45% were female, 60% were white, 33% were black, nearly half had cirrhosis. The most commonly-prescribed DAA regimens were sofosbuvir-based (83%) and grazoprevir/elbasvir (11%). Study retention was >95%. On average, small improvements were observed at 3 months post-treatment in all PROs and sustained at 12 months post-treatment among patients with sustained virologic response (SVR). Clinically meaningful improvements were achieved in fatigue (mean change score: -3.7 [-4.2, -3.1]), sleep (mean change score: -3.1 [-3.7, -2.5]), abdominal pain (mean change score: -2.6 [-3.3, -1.9]) and functional well-being (mean change score: -7.0 [-6.0, -8.0]). Symptom improvements were generally not sustained with no SVR (n = 52). Patients with cirrhosis and MELD ≥12 had the greatest improvements in functional well-being (-12.9 [-17.6, -8.1]). CONCLUSIONS The improvements in patient-reported outcomes reported by patients who achieved SVR following HCV DAA therapy were durable at 12 months post-treatment.
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Medication Non-adherence in a Prospective, Multi-center Cohort Treated with Hepatitis C Direct-Acting Antivirals.
Serper, M, Evon, DM, Stewart, PW, Lok, AS, Amador, J, Reeve, BB, Golin, CE, Fried, MW, Reddy, KR, Sterling, RK, et al
Journal of general internal medicine. 2020;(4):1011-1020
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Abstract
BACKGROUND The prevalence and risk factors for non-adherence to direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) in clinical practice settings are under-studied. OBJECTIVES (1) To quantify DAA non-adherence in the total cohort and among subgroups with and without mental health conditions, alcohol use, and substance use, and (2) to investigate patient- and treatment-level risk factor non-adherence. DESIGN Prospective, observational cohort study. PARTICIPANTS A total of 1562 patients receiving DAAs between January 2016 and October 2017 at 11 US medical centers including academic and community practices. MAIN MEASURES Self-reported medication non-adherence, defined as any missed doses in the past 7 days, surveyed early (T2: at 4 ± 2 weeks) and late in treatment (T3: 2-3 weeks prior to end of treatment). Non-adherence to post-treatment follow-up visits was defined as absence of lab results after DAA therapy completion. KEY RESULTS Of 1447 patients, 162 (11%) reported non-adherence at T2 or T3. Medical records indicated 262 (17%) of the 1562 participants had not returned for post-treatment visits. At baseline, 37% of patients reported mental health conditions, 15% reported alcohol use, and 23% reported using substances in the previous year. Baseline characteristics associated with DAA non-adherence included alcohol use (OR 1.96), younger age (< 35 years vs. > 55 years: OR 3.40), non-white race (OR > 2.26), and DAA treatment cohort, but not substance use or mental health condition. Non-adherence to follow-up exhibited association with younger age and a higher baseline overall symptom burden. Among 1287 patients with evaluable sustained virologic response (SVR) data, 53 patients (4%) did not achieve SVR. The bivariate correlation between adherence and SVR was negligible (r = 0.01). CONCLUSIONS DAA non-adherence was low and SVR rates were high. Mental health conditions, substance use, and alcohol use should not disqualify patients from DAA therapy. Patients with alcohol use disorder before DAA therapy initiation may benefit from targeted on-treatment support.
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The Type and Amount of Dietary Fat Affect Plasma Factor VIIc, Fibrinogen, and PAI-1 in Healthy Individuals and Individuals at High Cardiovascular Disease Risk: 2 Randomized Controlled Trials.
Kris-Etherton, PM, Stewart, PW, Ginsberg, HN, Tracy, RP, Lefevre, M, Elmer, PJ, Berglund, L, Ershow, AG, Pearson, TA, Ramakrishnan, R, et al
The Journal of nutrition. 2020;(8):2089-2100
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BACKGROUND Factor VIIc, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) are cardiovascular disease (CVD) risk factors and are modulated, in part, by fat type and amount. OBJECTIVE We evaluated fat type and amount on the primary outcomes: factor VIIc, fibrinogen, and PAI-1. METHODS In the Dietary Effects on Lipoproteins and Thrombogenic Activity (DELTA) Trial, 2 controlled crossover feeding studies evaluated substituting carbohydrate or MUFAs for SFAs. Study 1: healthy participants (n = 103) were provided with (8 wk) an average American diet [AAD; designed to provide 37% of energy (%E) as fat, 16% SFA], a Step 1 diet (30%E fat, 9% SFA), and a diet low in SFA (Low-Sat; 26%E fat, 5% SFA). Study 2: participants (n = 85) at risk for CVD and metabolic syndrome (MetSyn) were provided with (7 wk) an AAD, a step 1 diet, and a high-MUFA diet (designed to provide 37%E fat, 8% SFA, 22% MUFA). RESULTS Study 1: compared with AAD, the Step 1 and Low-Sat diets decreased mean factor VIIc by 1.8% and 2.6% (overall P = 0.0001), increased mean fibrinogen by 1.2% and 2.8% (P = 0.0141), and increased mean square root PAI-1 by 0.0% and 6.0% (P = 0.0037), respectively. Study 2: compared with AAD, the Step 1 and high-MUFA diets decreased mean factor VIIc by 4.1% and 3.2% (overall P < 0.0001), increased mean fibrinogen by 3.9% and 1.5% (P = 0.0083), and increased mean square-root PAI-1 by 2.0% and 5.8% (P = 0.1319), respectively. CONCLUSIONS Replacing SFA with carbohydrate decreased factor VIIc and increased fibrinogen in healthy and metabolically unhealthy individuals and also increased PAI-1 in healthy subjects. Replacing SFA with MUFA decreased factor VIIc and increased fibrinogen but less than carbohydrate. Our results indicate an uncertain effect of replacing SFA with carbohydrate or MUFA on cardiometabolic risk because of small changes in hemostatic factors and directionally different responses to decreasing SFA. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT00000538?term=NCT00000538&rank=1 as NCT00000538.
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Patient-reported symptoms during and after direct-acting antiviral therapies for chronic hepatitis C: The PROP UP study.
Evon, DM, Sarkar, S, Amador, J, Lok, AS, Sterling, RK, Stewart, PW, Reeve, BB, Serper, M, Reau, N, Rajender Reddy, K, et al
Journal of hepatology. 2019;(3):486-497
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Abstract
BACKGROUND & AIMS A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs. METHODS PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment. RESULTS Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements. CONCLUSIONS In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities. LAY SUMMARY Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.
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Probe Cocktail to Assess Transporter Function in Sandwich-Cultured Human Hepatocytes.
Guo, C, Brouwer, KR, Stewart, PW, Mosley, C, Brouwer, KLR
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2019;(1):567-575
Abstract
PURPOSE Probe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH. METHODS Rosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate. RESULTS For rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive. CONCLUSIONS These data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.
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A comprehensive assessment of patient reported symptom burden, medical comorbidities, and functional well being in patients initiating direct acting antiviral therapy for chronic hepatitis C: Results from a large US multi-center observational study.
Evon, DM, Stewart, PW, Amador, J, Serper, M, Lok, AS, Sterling, RK, Sarkar, S, Golin, CE, Reeve, BB, Nelson, DR, et al
PloS one. 2018;(8):e0196908
Abstract
BACKGROUND Symptom burden, medical comorbidities, and functional well-being of patients with chronic hepatitis C virus (HCV) initiating direct acting antiviral (DAA) therapy in real-world clinical settings are not known. We characterized these patient-reported outcomes (PROs) among HCV-infected patients and explored associations with sociodemographic, liver disease, and psychiatric/substance abuse variables. METHODS AND FINDINGS PROP UP is a large US multicenter observational study that enrolled 1,600 patients with chronic HCV in 2016-2017. Data collected prior to initiating DAA therapy assessed the following PROs: number of medical comorbidities; neuropsychiatric, somatic, gastrointestinal symptoms (PROMIS surveys); overall symptom burden (Memorial Symptom Assessment Scale); and functional well-being (HCV-PRO). Candidate predictors included liver disease markers and patient-reported sociodemographic, psychiatric, and alcohol/drug use features. Predictive models were explored using a random selection of 700 participants; models were then validated with data from the remaining 900 participants. The cohort was 55% male, 39% non-white, 48% had cirrhosis (12% with advanced cirrhosis); 52% were disabled or unemployed; 63% were on public health insurance or uninsured; and over 40% had markers of psychiatric illness. The median number of medical comorbidities was 4 (range: 0-15), with sleep disorders, chronic pain, diabetes, joint pain and muscle aches being present in 20-50%. Fatigue, sleep disturbance, pain and neuropsychiatric symptoms were present in over 60% and gastrointestinal symptoms in 40-50%. In multivariable validation models, the strongest and most frequent predictors of worse PROs were disability, unemployment, and use of psychiatric medications, while liver markers generally were not. CONCLUSIONS This large multi-center cohort study provides a comprehensive and contemporary assessment of the symptom burden and comorbid medical conditions in patients with HCV treated in real world settings. Pain, fatigue, and sleep disturbance were common and often severe. Sociodemographic and psychiatric markers were the most robust predictors of PROs. Future research that includes a rapidly changing population of HCV-infected individuals needs to evaluate how DAA therapy affects PROs and elucidate which symptoms resolve with viral eradication. TRIAL REGISTRATION (Clinicaltrial.gov: NCT02601820).
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Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis.
Ferslew, BC, Xie, G, Johnston, CK, Su, M, Stewart, PW, Jia, W, Brouwer, KL, Barritt, AS
Digestive diseases and sciences. 2015;(11):3318-28
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BACKGROUND AND AIMS The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. METHODS Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. RESULTS Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595-3549 µM and healthy 1171-1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444-5898 µM and healthy 2634-2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. CONCLUSIONS Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.
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Monthly haemostatic factor variability in women and men.
Hill, AM, Stewart, PW, Fung, MK, Kris-Etherton, PM, Ginsberg, HN, Tracy, RP, Pearson, TA, Lefevre, M, Reed, RG, Elmer, PJ, et al
European journal of clinical investigation. 2014;(3):309-18
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BACKGROUND Hormonal status influences haemostatic factors including fibrinogen, factor VII and plasminogen activator inhibitor (PAI-1), and concentrations differ among men, premenopausal and postmenopausal women. This study examines how phases of the menstrual cycle influence variability of fibrinogen, factor VII and PAI-1. DESIGN We studied 103 subjects (39 premenopausal women, 18 postmenopausal women and 46 men) during three, randomized, 8-week energy- and nutrient-controlled experimental diets in the Dietary Effects on Lipids and Thrombogenic Activity (DELTA) Study. Fasting blood samples were collected weekly during the last 4 weeks of each diet period, and haemostatic factors were quantified. Two linear mixed-effects models were used for fibrinogen, factor VII and PAI-1: one to estimate and compare group-specific components of variance, and the other to estimate additional fixed effects representing cyclical functions of day of menstrual cycle in premenopausal women. RESULTS Systematic cyclical variation with day of menstrual cycle was observed for fibrinogen (P < 0.0001), factor VII (P = 0.0012) and PAI-1 (P = 0.0024) in premenopausal women. However, the amplitude of cycling was small relative to the total magnitude of intra-individual variability. In addition, the intra-individual variance and corresponding coefficient of variation observed in premenopausal women did not differ from postmenopausal women and men. CONCLUSIONS The variability in haemostatic factors in premenopausal women is no greater than for postmenopausal women or men. Consequently, premenopausal women can be included in studies investigating haemostatic factor responses without controlling for stage of menstrual cycle.