Provider Attitudes Toward Risk-Based Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis in the United States.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers' opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patient's HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patient's HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001). CONCLUSIONS: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients' estimated HCC risk, instead of our current "one-size-fits all" strategy.

The COVID-19 Pandemic Highlights Opportunities to Improve Hepatocellular Carcinoma Screening and Diagnosis in a National Health System.

INTRODUCTION: We evaluated the coronavirus disease 2019 (COVID-19) pandemic's impact on hepatocellular carcinoma (HCC) screening and diagnosis among patients with cirrhosis in the Veterans Health Administration. METHODS: Rates and predictors of screening and diagnosis were reviewed September 1, 2019-February 29, 2020 ("pre-COVID-19," N = 94,612) and April 1, 2020-September 30, 2020 ("post-COVID-19," N = 88,073). RESULTS: Screening and diagnosis rates declined by 44% and 13%, respectively, after the COVID-19 pandemic. Screening declined irrespective of liver disease severity, but diagnosis declined only in Model for End Stage Liver Disease-Sodium score <20 or Fibrosis-4 score <3.25. Fibrosis-4 score ≥3.25 and HCC risk ≥1.5%/year strongly predicted HCC diagnosis but only moderately predicted receipt of screening. DISCUSSION: Screening and diagnosis rates declined after the COVID-19 pandemic. Prioritizing screening for patients at greatest risk for HCC may reduce delays in diagnosis.

Rates and Predictors of Undergoing Different Hepatocellular Carcinoma Screening Tests in Patients With Cirrhosis.

INTRODUCTION: We aimed to assess rates and predictors of hepatocellular carcinoma (HCC) screening among patients with cirrhosis. METHODS: We reviewed electronic health records of 11,361 patients with cirrhosis from 11 U.S. Veterans Health Administration facilities for receipt of HCC screening in the 6 months preceding October 1, 2019. RESULTS: Nearly half of the cohort (46%) received HCC screening over a 6-month period. Screening rates and modalities (ultrasound, computed tomography, magnetic resonance imaging, serum alpha fetoprotein) varied by facility. Screening was associated with race/ethnicity, body mass index ≥ 25, cirrhosis etiology, thrombocytopenia, Fibrosis-4 ≥ 3.25, and lower Model for End-Stage Liver Disease-Sodium. DISCUSSION: HCC screening rates varied by facility. Higher risk patients were more likely to receive screening.

Increased HCV Screening Yields Discordant Gains in Diagnoses Among Urban and Rural Veteran Populations in Texas: Results of a Statewide Quality Improvement Initiative.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a significant health burden among military veterans. Our goals were to increase monthly HCV screenings, diagnoses, and sustained virologic responses (SVR) among 88,652 unscreened birth cohort Veterans in Texas. METHODS: The interventions were enabled within six of the eight healthcare systems (HCSs) that compose Veteran's Integrated Service Network 17. The remaining two HCSs served as controls. The HCSs were separated into two groups: urban and rural; each composed of a control and three interventional HCSs. Decision support programming was embedded within the Computerized Patient Record System that prompted HCV screening among previously unscreened birth cohort patients. Clinical process design and educational efforts were enacted to enhance treatment capacity. RESULTS: Monthly screenings increased 4.89 times (p < 0.001) and 2.97 times (p < 0.001) during the postinterventional period relative to control for urban and rural HCSs, respectively. For urban HCSs, diagnoses increased 1.58 (p < 0.001) times more than the control group during the postinterventional period, but there was no difference in number of diagnoses in the rural HCSs (p = 0.86). Monthly SVR increased 2.69 times more than the control group during the postinterventional period (p < 0.001). CONCLUSION: Decision support improved HCV screening among birth cohort patients in both urban and rural HCSs. Increased screening boosted the monthly number of diagnoses in the urban HCSs, but not in the rural HCSs; which rebuts the utility of birth cohort screening among rurally residing veterans. These interventions significantly improved the rate of SVR achievement relative to control.

Increasing access for veterans with hepatitis C by enhancing use of clinical pharmacy specialists.

OBJECTIVES: To increase access to hepatitis C virus (HCV) care and cure by deploying clinical pharmacy specialist (CPS) providers across the largest integrated health care system in the United States. SETTING: National integrated health care system. PRACTICE DESCRIPTION: In late 2016, the Department of Veterans Affairs (VA) Pharmacy Benefits Management Clinical Pharmacy Practice Office (CPPO) partnered with the VA HIV, Hepatitis, and Related Conditions Program with the central priority of expanding veteran access to novel HCV treatments and timely cure to ultimately prevent morbidity and mortality associated with HCV disease progression. This successful collaboration resulted in clinical resource funding to bolster access to HCV treatment through the deployment of CPS providers. This enterprise-wide initiative to expand clinical pharmacy services for unmet health care needs in HCV treatment resulted in 52 VA facilities submitting full-time employment equivalent (FTEE) funding requests totaling more than $10 million dollars. Facilities may have requested funding for 1 or more FTEEs. RESULTS: Facilities hired 47 CPS providers and 5 clinical pharmacy technicians. CPS providers in this project recorded 24,888 patient care encounters providing care for 9593 unique patients and initiated new HCV treatment for 1191 treatment-naïve patients. For an additional 8402 patients, the CPS provided HCV care activities such as evaluation and monitoring before, during, and after treatment. CPPO estimates that the same care delivered by nonpharmacist provider specialists (e.g., specialty physicians) cost an additional $936,535, or 48% more. CONCLUSION: The deployment of HCV CPS resulted in a significant number of new HCV patients being screened and treated within the VA system.

Risk of Hepatitis B Reactivation in Patients Receiving Ibrutinib: The National Veterans Affairs Cohort.

Background: Ibrutinib has been a first-line treatment for chronic lymphocytic leukemia since 2014. Case reports of hepatitis B virus (HBV) reactivation after ibrutinib initiation have been presented. The association between the risk of HBV reactivation and ibrutinib initiation remains unclear. This nationwide study aimed to estimate the incidence of HBV reactivation after ibrutinib initiation. Method: This study included patients who received ibrutinib between 1 February 2014 and 31 October 2019. Possible reactivations were searched by (1) changes in HBV surface antigen or HBV DNA from no data or negative status to positive after ibrutinib initiation, (2) alanine aminotransferase levels that were at least 3 times the baseline value after ibrutinib initiation, and (3) new antiviral prescriptions against HBV after ibrutinib initiation. Individual chart reviews were conducted to identify HBV reactivation attributed to ibrutinib. The cumulative incidence of HBV reactivation was calculated. Results: A total 4130 patients were eligible during the study period. Of these, patients with negative HBV core antibody (anti-HBcAb; n = 1670) and patients who were taking antivirals against HBV (n = 60) were excluded. There were 2219 patients without anti-HBcAb testing results. Among the remaining 181 patients with positive anti-HBcAb, 7 HBV reactivations were directly attributable to ibrutinib treatment after chart review, for a 3.9% cumulative incidence. Conclusions: Our study revealed a low cumulative incidence of HBV reactivation after ibrutinib initiation among patients with previous anti-HBcAb positivity, indicating a moderate risk of HBV reactivation.

Etoposide catechol is an oxidizable topoisomerase II poison.

Topoisomerase II regulates DNA topology by generating transient double-stranded breaks. The anticancer drug etoposide targets topoisomerase II and is associated with the formation of secondary leukemias in patients. The quinone and catechol metabolites of etoposide may contribute to strand breaks that trigger leukemic translocations. To further analyze the characteristics of etoposide metabolites, we extend our previous analysis of etoposide quinone to the catechol. We demonstrate that the catechol is ∼2-3-fold more potent than etoposide and under oxidative reaction conditions induces high levels of double-stranded DNA cleavage. These results support a role for etoposide catechol in contributing to therapy-induced DNA damage.

User experience of a hepatitis c population management dashboard in the Department of Veterans Affairs.

BACKGROUND: The Veterans Health Administration (VA) is the largest integrated healthcare organization in the US and cares for the largest cohort of individuals with hepatitis C (HCV). A national HCV population management dashboard enabled rapid identification and treatment uptake with direct acting antiviral agents across VA hospitals. We describe the HCV dashboard (HCVDB) and evaluate its use and user experience. METHODS: A user-centered design approach created the HCVDB to include reports based on the HCV care continuum: 1) 1945-1965 birth cohort high-risk screening, 2) linkage to care and treatment of chronic HCV, 3) treatment monitoring, 4) post-treatment to confirm cure (i.e., sustained virologic response), and 5) special populations of unstably housed Veterans. We evaluated frequency of usage and user experience with the System Usability Score (SUS) and Unified Theory of Acceptance and Use of Technology 2 (UTAUT2) instruments. RESULTS: Between November 2016 and July 2021, 1302 unique users accessed the HCVDB a total of 163,836 times. The linkage report was used most frequently (71%), followed by screening (13%), sustained virologic response (11%), on-treatment (4%), and special populations (<1%). Based on user feedback (n = 105), the mean SUS score was 73±16, indicating a good user experience. Overall acceptability was high with the following UTAUT2 rated from highest to least: Price Value, Performance Expectancy, Social Influence, and Facilitating Conditions. CONCLUSIONS: The HCVDB had rapid and widespread uptake, met provider needs, and scored highly on user experience measures. Collaboration between clinicians, clinical informatics, and population health experts was essential for dashboard design and sustained use. Population health management tools have the potential for large-scale impacts on care timeliness and efficiency.

Microglia as a cellular target of diclofenac therapy in Alzheimer's disease.

Alzheimer's disease (AD) is an untreatable cause of dementia, and new therapeutic approaches are urgently needed. AD pathology is defined by extracellular amyloid plaques and intracellular neurofibrillary tangles. Research of the past decades has suggested that neuroinflammation plays a critical role in the pathophysiology of AD. This has led to the idea that anti-inflammatory treatments might be beneficial. Early studies investigated non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, celecoxib, ibuprofen, and naproxen, which had no benefit. More recently, protective effects of diclofenac and NSAIDs in the fenamate group have been reported. Diclofenac decreased the frequency of AD significantly compared to other NSAIDs in a large retrospective cohort study. Diclofenac and fenamates share similar chemical structures, and evidence from cell and mouse models suggests that they inhibit the release of pro-inflammatory mediators from microglia with leads to the reduction of AD pathology. Here, we review the potential role of diclofenac and NSAIDs in the fenamate group for targeting AD pathology with a focus on its potential effects on microglia.

Impact of proton pump inhibitors on sustained virologic response in veterans treated with sofosbuvir/velpatasvir for chronic hepatitis C virus: A retrospective cohort study.

STUDY OBJECTIVE: The objective of this study was to determine the clinical relationship between proton pump inhibitor (PPI) use and sustained virologic response (SVR) in patients treated with sofosbuvir/velpatasvir (SOF/VEL) for chronic hepatitis C virus (HCV) infection. DESIGN: This was a multicenter retrospective cohort study. SETTING: Data was collected on patients from 128 Veterans Affairs Medical Centers throughout the United States. PATIENTS: This study included veterans aged 18-89 years with viremic HCV who received a full course of SOF/VEL treatment from June 2016 - July 2017. INTERVENTION: Sustained viral response was compared in patients taking SOF/VEL with or without concurrent PPI prescriptions. MEASUREMENTS AND MAIN RESULTS: Analysis of the primary outcome was completed utilizing logistic regression. The relationship between SVR and PPI use was adjusted for African-American race, presence of cirrhosis, prior treatment, BMI greater than 30 kg/m2, and HCV genotype. The final analysis included 4,008 veterans, 830 with concomitant PPI use and 3,178 without PPI use. After adjustment for other variables in the logistic model, there was no statistically significant association between PPI use and lower SVR (odds ratio 0.67; 95%CI: 0.42, 1.06; p = 0.087). CONCLUSION: Concomitant PPI treatment adjusted for other variables did not significantly impact success or failure of SOF/VEL treatment of chronic HCV. Despite the lack of significant association identified in this study, in efforts to provide the best care possible, it remains prudent to proceed with caution in patients desiring to use PPI therapy while receiving SOF/VEL, and ensure prescribing instructions are closely followed in regard to concomitant PPI use, especially in patients with other risk factors for decreased SVR.

Etoposide quinone is a redox-dependent topoisomerase II poison.

Etoposide is a topoisomerase II poison that is used to treat a variety of human cancers. Unfortunately, 2-3% of patients treated with etoposide develop treatment-related leukemias characterized by 11q23 chromosomal rearrangements. The molecular basis for etoposide-induced leukemogenesis is not understood but is associated with enzyme-mediated DNA cleavage. Etoposide is metabolized by CYP3A4 to etoposide catechol, which can be further oxidized to etoposide quinone. A CYP3A4 variant is associated with a lower risk of etoposide-related leukemias, suggesting that etoposide metabolites may be involved in leukemogenesis. Although etoposide acts at the enzyme-DNA interface, several quinones poison topoisomerase II via redox-dependent protein adduction. The effects of etoposide quinone on topoisomerase IIα-mediated DNA cleavage have been examined previously. Although findings suggest that the activity of the quinone is slightly greater than that of etoposide, these studies were carried out in the presence of significant levels of reducing agents (which should reduce etoposide quinone to the catechol). Therefore, we examined the ability of etoposide quinone to poison human topoisomerase IIα in the absence of reducing agents. Under these conditions, etoposide quinone was ∼5-fold more active than etoposide at inducing enzyme-mediated DNA cleavage. Consistent with other redox-dependent poisons, etoposide quinone inactivated topoisomerase IIα when incubated with the protein prior to DNA and lost activity in the presence of dithiothreitol. Unlike etoposide, the quinone metabolite did not require ATP for maximal activity and induced a high ratio of double-stranded DNA breaks. Our results support the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis.

Diclofenac reduces the risk of Alzheimer's disease: a pilot analysis of NSAIDs in two US veteran populations.

BACKGROUND: Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer's disease (AD). MATERIALS AND METHODS: Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates. RESULTS: Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84-1.20, p = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09-0.68, p <0.01). After site effects were controlled for, age at end of the study (HR = 1.08, 95% CI: 1.07-1.09, p <0.001) was also found to influence the development of AD, and the medication-based disease burden index was a strong predictor for AD, HR 5.17 (95% CI: 4.60-5.81) indicating that as comorbidities increase, the risk for AD increases very significantly. CONCLUSION: Diclofenac, which has been shown to have active transport into the central nervous system, and which has been shown to lower amyloid beta and interleukin 1 beta, is associated with a significantly lower frequency of AD compared with etodolac and naproxen. These results are compelling, and parallel animal studies of the closely related fenamate NSAID drug class.