Hepatitis B.

Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.

Hepatitis B RNA and Core-Related Antigen Provide Value Beyond DNA in Evaluating e But Not Surface Antigen Clearance.

In chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) clearance are important milestones toward immune control.1 A drop in HBV DNA is an established correlate of both HBeAg and HBsAg clearance.2 We evaluated changes in HBV RNA and hepatitis B core-related antigen (HBcrAg) levels, markers of transcriptional activity of covalently closed circular DNA (cccDNA),3,4 with HBeAg and HBsAg clearance, and compared them with changes in HBV DNA level among adult participants in the Hepatitis B Research Network (HBRN).

How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?

Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.

Appropriate and Potentially Inappropriate Medication Use in Decompensated Cirrhosis.

BACKGROUND AND AIMS: Patients with decompensated cirrhosis are prescribed numerous medications. Data are limited as to whether patients are receiving medications they need and avoiding those they do not. We examined a large national claims database (2010-2015) to characterize the complete medication profile as well as the factors associated with appropriate and potentially inappropriate medication use in 12,621 patients with decompensated cirrhosis. APPROACH AND RESULTS: Clinical guidelines and existing literature were used to determine appropriate and potentially inappropriate medications in decompensated cirrhosis. The total medication days' supply was calculated from pharmacy data and divided by the follow-up period for each decompensation. Ascites was the most common (86.5%), followed by hepatic encephalopathy (HE; 37.8%), variceal bleeding (VB; 17.5%), hepatorenal syndrome (6.3%), and spontaneous bacterial peritonitis (SBP; 6.1%). For patients with ascites, 55.8% filled a diuretic. For patients with HE, 32.4% and 63.3% filled rifaximin and lactulose, respectively. After VB, 60.3% of patients filled a nonselective beta blocker, and after an episode of SBP, 48.0% of patients filled an antibiotic for prophylaxis. The minority (4.5%-17.3%) had enough medication to cover >50% follow-up days. Potentially inappropriate medication use was common: 53.2% filled an opiate, 46.0% proton pump inhibitors, 14.2% benzodiazepines, and 10.1% nonsteroidal anti-inflammatory drugs. Disease severity markers were associated with more appropriate mediation use but not consistently associated with less inappropriate medication use. CONCLUSIONS: Patients with decompensated cirrhosis are not filling indicated medications as often or as long as is recommended and are also filling medications that are potentially harmful. Future steps include integrating pharmacy records with medical records to obtain a complete medication list and counseling on medication use with patients at each visit.

The 2020 Nobel Prize for Medicine or Physiology for the Discovery of Hepatitis C Virus: A Triumph of Curiosity and Persistence.

The 2020 Nobel Prize in Medicine or Physiology was awarded to Drs. Harvey Alter, Michael Houghton, and Charles Rice for their contributions to the discovery and characterization of the hepatitis C virus (HCV). Their achievements represent a remarkable triumph of biomedical science which allowed the development of curative therapy for HCV, that will save countless lives. This tribute provides a historical perspective of the laureates' seminal work leading to the discovery of the HCV and a synopsis of a forum hosted by the American Association for the Study of Liver Diseases to honor the laureates in which they offered their perspectives, advice for young investigators and what's left to accomplish in the field. Finally, others in the research community who have worked closely with one or more of the laureates, share some of their personal reflections and anecdotes.

Comparison of HBV RNA and Hepatitis B Core Related Antigen With Conventional HBV Markers Among Untreated Adults With Chronic Hepatitis B in North America.

BACKGROUND AND AIMS: The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear. APPROACH AND RESULTS: Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log10 IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg+ and 58% of HBeAg- participants; HBcrAg was quantifiable in 20% of HBeAg+ (above linear range in the other 80%) and 51% of HBeAg- participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg+ and HBeAg- immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg+ and HBeAg- phases (HBV RNA: e+ ρ = 0.84; e- ρ = 0.78; HBcrAg: e+ ρ = 0.66; e- ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg+ phases only (HBV RNA: e+ ρ = 0.71; P < 0.001; e- ρ = 0.18; P = 0.56; HBcrAg: e+ ρ = 0.51; P < 0.001; e- ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg- , but not HBeAg+ , phases. CONCLUSIONS: Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators.

A multivariate parametric empirical Bayes screening approach for early detection of hepatocellular carcinoma using multiple longitudinal biomarkers.

The early detection of hepatocellular carcinoma (HCC) is critical to improving outcomes since advanced HCC has limited treatment options. Current guidelines recommend HCC ultrasound surveillance every 6 months in high-risk patients however the sensitivity for detecting early stage HCC in clinical practice is poor. Blood-based biomarkers are a promising direction since they are more easily standardized and less resource intensive. Combining of multiple biomarkers is more likely to achieve the sensitivity required for a clinically useful screening algorithm and the longitudinal trajectory of biomarkers contains valuable information that should be utilized. We propose a multivariate parametric empirical Bayes (mPEB) screening approach that defines personalized thresholds for each patient at each screening visit to identify significant deviations that trigger additional testing with more sensitive imaging. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial provides a valuable source of data to study HCC screening algorithms. We study the performance of the mPEB algorithm applied to serum α -fetoprotein, a widely used HCC surveillance biomarker, and des- γ carboxy prothrombin, an HCC risk biomarker that is FDA approved but not used in practice in the United States. Using cross-validation, we found that the mPEB algorithm demonstrated moderate but improved sensitivity compared to alternative screening approaches. Future research will validate the clinical utility of the approach in larger cohort studies with additional biomarkers.

Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B.

Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1+ and Vδ2+γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3hiCD4- Vδ2+γδT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vδ2+γδT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vδ1+γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2+γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1+γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2+γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.

Bariatric surgery and the risk of alcohol-related cirrhosis and alcohol misuse.

BACKGROUND & AIMS: Bariatric surgery is common, but alcohol misuse has been reported following these procedures. We aimed to determine if bariatric surgery is associated with increased risk of alcohol-related cirrhosis (AC) and alcohol misuse. METHODS: Retrospective observational analysis of obese adults with employer-sponsored insurance administrative claims from 2008 to 2016. Subjects with diagnosis codes for bariatric surgery were included. Primary outcome was risk of AC. Secondary outcome was risk of alcohol misuse. Bariatric surgery was divided into before 2008 and after 2008 to account for patients who had a procedure during the study period. Cox proportional hazard regression models using age as the time variable were used with interaction analyses for bariatric surgery and gender. RESULTS: A total of 194 130 had surgery from 2008 to 2016 while 209 090 patients had bariatric surgery prior to 2008. Age was 44.1 years, 61% women and enrolment was 3.7 years. A total of 4774 (0.07%) had AC. Overall risk of AC was lower for those who received sleeve gastrectomy and laparoscopic banding during the study period (HR 0.4, P <.001; HR 0.43, P =.02) and alcohol misuse increased for Roux-en-Y and sleeve gastrectomy recipients (HR 1.86 and 1.35, P <.001, respectively). In those who had surgery before 2008, women had increased risk of AC and alcohol misuse compared to women without bariatric surgery (HR 2.1 [95% CI: 1.79-2.41] for AC; HR 1.98 [95% CI 1.93-2.04]). CONCLUSIONS: Bariatric surgery is associated with a short-term decreased risk of AC but potential long-term increased risk of AC in women. Post-operative alcohol surveillance is necessary to reduce this risk.

Prevalence and clinical features of patients with concurrent HBsAg and anti-HBs: Evaluation of the hepatitis B research network cohort.

The prevalence of concurrent HBsAg and anti-HBs in plasma of persons with chronic hepatitis B virus (HBV) infection is variable and its clinical significance enigmatic. We examined the prevalence and clinical and virological features of concurrent HBsAg and anti-HBs in children and adults with chronic HBV infection living in North America. A total of 1462 HBsAg positive participants in the Hepatitis B Research Network paediatric and adult cohorts were included (median age 41 (range 4-80) years, 48% female, 11% white, 13% black, 73% Asians). Only 18 (1.2%) were found to be anti-HBs positive (≥10 mIU/mL) at initial study evaluation. Distributions of sex, race, HBV genotype and ALT were similar between participants with and without concurrent anti-HBs. Those who were anti-HBs positive appeared to be older (median age 50 vs 41 years, P = .06), have lower platelet counts (median 197 vs 222 × 103/mm3 , P = .07) and have higher prevalence of HBeAg (44% vs 26%, P = .10). They also had lower HBsAg levels (median 2.0 vs 3.5 log10 IU/mL, P = .02). Testing of follow-up samples after a median of 4 years (range 1-6) in 12 of the 18 participants with initial concurrent anti-HBs showed anti-HBs became undetectable in 6, decreased to <10 mIU/mL in 1 and remained positive in 5 participants. Two patients lost HBsAg during follow-up. In conclusion, prevalence of concurrent HBsAg and anti-HBs was low at 1.2%, with anti-HBs disappearing in some during follow-up, in this large cohort of racially diverse children and adults with chronic HBV infection living in North America. Presence of concurrent HBsAg and anti-HBs did not identify a specific phenotype of chronic hepatitis B, nor did it appear to affect clinical outcomes.

A risk score to predict the development of hepatic encephalopathy in a population-based cohort of patients with cirrhosis.

Over 40% of patients with cirrhosis will develop hepatic encephalopathy (HE). HE is associated with decreased survival, falls, motor vehicle accidents, and frequent hospitalization. Accordingly, we aimed to develop a tool to risk-stratify patients for HE development. We studied a population-based cohort of all patients with cirrhosis without baseline HE (n = 1,979) from the Veterans Administration from Michigan, Indiana, and Ohio (January 1, 2005-December 31, 2010) using demographic, clinical, laboratory, and pharmacy data. The primary outcome was the development of HE. Risk scores were constructed with both baseline and longitudinal data (annually updated parameters) and validated using bootstrapping. The cohort had a mean age of 58.0 ± 8.3 years, 36% had hepatitis C, and 17% had ascites. Opiates, benzodiazepines, statins, and nonselective beta-blockers were taken at baseline by 24%, 13%, 17%, and 12%, respectively. Overall, 863 (43.7%) developed HE within 5 years. In multivariable models, risk factors (hazard ratio, 95% confidence interval) for HE included higher bilirubin (1.07, 1.05-1.09) and nonselective beta-blocker use (1.34, 1.09-1.64), while higher albumin (0.54, 0.48-0.59) and statin use (0.80, 0.65-0.98) were protective. Other clinical factors, including opiate and benzodiazepine use, were not predictive. The areas under the receiver operating characteristics curve for HE using the four significant variables in baseline and longitudinal models were 0.68 (0.66-0.70) and 0.73 (0.71-0.75), respectively. Model effects were validated and converted into a risk score. A score ≤0 in our longitudinal model assigns a 6% 1-year probability of HE, while a score >20 assigns a 38% 1-year risk. CONCLUSION: Patients with cirrhosis can be stratified by a simple risk score for HE that accounts for changing clinical data; our data also highlight a role for statins in reducing cirrhosis complications including HE. (Hepatology 2017).

The high burden of alcoholic cirrhosis in privately insured persons in the United States.

Alcoholic cirrhosis (AC) is a major cause of liver-related morbidity and mortality in the United States. Rising rates of alcohol use disorders in the United States will likely result in more alcoholic liver disease. Our aim was to determine the prevalence, health care use, and costs of AC among privately insured persons in the United States. We collected data from persons aged 18-64 with AC (identified by codes from the International Classification of Diseases, Ninth and Tenth Revisions) enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009-2015). We determined yearly prevalence, weighted to the national employer-sponsored, privately insured population. Using competing risk analysis, we estimated event rates for portal hypertensive complications and estimated the association between AC and costs as well as admissions and readmissions. In 2015, 294,215 people had cirrhosis and 105,871 (36%) had AC. Mean age at AC diagnosis was 53.5 years, and 32% were women. Over the 7 years queried, estimated national cirrhosis prevalence rose from 0.19% to 0.27% (P < 0.001) and for AC from 0.07% to 0.10% (P < 0.001). Compared to non-AC, AC enrollees were significantly more likely to have portal hypertensive complications at diagnosis and higher yearly cirrhosis and alcohol-related admissions (25 excess cirrhosis admissions and 6.3 excess alcohol-related admissions per 100 enrollees) as well as all-cause readmissions. Per-person costs in the first year after diagnosis nearly doubled for AC versus non-AC persons (US$ 44,835 versus 23,319). CONCLUSION: In a nationally representative cohort of privately insured persons, AC enrollees were disproportionately sicker at presentation, were admitted and readmitted more often, and incurred nearly double the per-person health care costs compared to those with non-AC. (Hepatology 2018).

Gender Disparities in Alcohol Use Disorder Treatment Among Privately Insured Patients with Alcohol-Associated Cirrhosis.

BACKGROUND: The burden of alcohol-associated cirrhosis (AC) is high, and though alcohol cessation improves mortality, many patients fail to engage in alcohol use disorder (AUD) treatment and continue drinking. Our aim was to determine rates, predictors, and outcomes of AUD treatment utilization in AC patients with private insurance. METHODS: We collected data from persons with AC (diagnosed by ICD-9/ICD-10 codes), aged 18 to 64 years, enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009 to 2016). We determined rates and predictors of substance abuse treatment visits as well as rates of alcohol relapse prevention medication prescriptions, weighted to the national employer-sponsored insured population. Effects of AUD treatment utilization on decompensation rates were calculated using proportional hazards regression with propensity score adjustment. RESULTS: A total of 66,053 AC patients were identified, 32% were female, and mean age at diagnosis was 54.5 years. About 72% had insurance coverage for substance abuse treatment. Overall, AUD treatment utilization rates were low, with only 10% receiving a face-to-face mental health or substance abuse visit and only 0.8% receiving a Food and Drug Administration (FDA)-approved relapse prevention medication within 1 year of index diagnosis. Women were less likely to receive a face-to-face visit (hazard ratio [HR] 0.84, p < 0.001) or an FDA-approved relapse prevention medication (0.89, p = 0.05) than men. AC patients who had a clinic visit for AUD treatment or used FDA-approved relapse medication showed decreased risk of decompensation at 1 year (HR 0.85, p < 0.001 for either). CONCLUSIONS: AUD treatment utilization is associated with lower decompensation rates among privately insured patients with AC. Women were less likely to utilize AUD treatment visits. Efforts to reduce gender-specific barriers to treatment are urgently needed to improve outcomes.

Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment With Tumor Necrosis Factor Antagonists.

BACKGROUND & AIMS: Tumor necrosis factor (TNF) antagonists are the first-line treatment for many autoimmune diseases. However, they have been associated with reactivation of hepatitis B virus (HBV). We determined the rate of HBV reactivation and hepatotoxicity grade 3 or 4 (HT ≥3) in patients treated with an anti-TNF agent for an autoimmune disease. METHODS: We collected data from 8887 adult patients in the Kaiser Permanente Northern California database who began treatment with TNF antagonists for autoimmune diseases (dermatologic, rheumatologic, or gastrointestinal) from 2001 through 2010, followed through December 2012. We obtained data on HBV infection (52% of patients were screened for HBV before treatment), demographic features, comorbidities, and use of immunosuppressive agents. HBV reactivation was defined as 1 of the following: >1 log increase in HBV DNA, HBV DNA-positive when previously negative, HBV DNA >2000 IU/mL if no baseline level was available, or reverse seroconversion. HT ≥3 was defined according to the National Cancer Institute Common Toxicity Criteria. We performed multivariable logistic regression to identify factors associated with HT ≥3. RESULTS: Twenty-three patients tested positive for HB surface antigen (HBsAg) at baseline and 9 of these had HBV reactivation; of the 4267 patients with unknown HBV status at baseline, 2 had HBV reactivation. None of the 178 patients who were HBsAg negative and positive for the hepatitis B core antibody (anti-HBc+) had HBV reactivation. HBV reactivation occurred in 1/5 HBsAg+ patients who received prophylactic antiviral therapy and 8/18 who did not (P = .61). No one with HBV reactivation had liver failure. HT ≥3 occurred in 273 patients (2.7%), but only 3 cases were attributed to HBV. Cirrhosis was significantly associated with HT ≥3 (P < .001). CONCLUSION: In a retrospective analysis of patients treated with TNF antagonists for autoimmune diseases, we found HBV reactivation in 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy. Patients should be screened for HBV infection before anti-TNF therapy; HBsAg+ patients should receive prophylactic antiviral therapy, but not HBsAg-negative, anti-HBc+ patients.

Diagnosis of Minimal Hepatic Encephalopathy: A Systematic Review of Point-of-Care Diagnostic Tests.

OBJECTIVES: Minimal hepatic encephalopathy (HE) is common, characterized by deficits in reaction time and executive function, and strongly associated with disability and mortality. Point-of-care diagnostics performed without specialized skills or equipment are now available, albeit with limited data regarding their generalizability. METHODS: We systematically reviewed MEDLINE, EMBASE, Cochrane Library, and Scopus for diagnostic studies of MHE using broad search terms including HE and minimal, covert, or the names of published diagnostic modalities. We included tests that provide results during clinical visits without requiring neuropsychologists to administer and/or special equipment. These include the Inhibitory Control Test (ICT, n=16), EncephalApp Stroop (n=3), an algorithm based on the Sickness Impact Profile (n=2), and the Animal Naming Test (ANT, n=1). RESULTS: The populations enrolled in the included study were highly selected, excluding patients with recent (6-months) alcohol or psychoactive medications use. Cutoffs for MHE for each test varied widely. For the ICT, the optimal cutoffs for MHE varied by 300%, whereas healthy control performance varied >400%. The optimal cutoffs for the EncephalApp also varied (by 50%). The gold standards for MHE varied substantially between studies, and clinical outcomes were never used to develop test cutoffs. Data comparing the performance of each modality are lacking. Longitudinal data are limited but suggest that good performance on the ICT, EncephalApp or ANT is associated with reduced risk of developing overt HE. CONCLUSION: The point-of-care tests for MHE are promising tools. However, additional longitudinal studies are needed in clinically representative populations of at-risk patients with cutoffs validated based on the development of clinical outcomes.

Impact of an electronic health record alert in primary care on increasing hepatitis c screening and curative treatment for baby boomers.

Despite effective treatment for chronic hepatitis C, deficiencies in diagnosis and access to care preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record-based prompt on hepatitis C virus (HCV) screening rates in baby boomers in primary care and access to specialty care and treatment among those newly diagnosed. We implemented an electronic health record-based "best practice advisory" (BPA) that prompted primary care providers to perform HCV screening for patients seen in primary care clinic (1) born between 1945 and 1965, (2) who lacked a prior diagnosis of HCV infection, and (3) who lacked prior documented anti-HCV testing. The BPA had associated educational materials, order set, and streamlined access to specialty care for newly diagnosed patients. Pre-BPA and post-BPA screening rates were compared, and care of newly diagnosed patients was analyzed. In the 3 years prior to BPA implementation, 52,660 baby boomers were seen in primary care clinics and 28% were screened. HCV screening increased from 7.6% for patients with a primary care provider visit in the 6 months prior to BPA to 72% over the 1 year post-BPA. Of 53 newly diagnosed patients, all were referred for specialty care, 11 had advanced fibrosis or cirrhosis, 20 started treatment, and 9 achieved sustained virologic response thus far. CONCLUSION: Implementation of an electronic health record-based prompt increased HCV screening rates among baby boomers in primary care by 5-fold due to efficiency in determining needs for HCV screening and workflow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into electronic health record systems to increase HCV diagnosis and linkage to care. (Hepatology 2017;66:1805-1813).

A Bayesian screening approach for hepatocellular carcinoma using multiple longitudinal biomarkers.

Advanced hepatocellular carcinoma (HCC) has limited treatment options and poor survival, therefore early detection is critical to improving the survival of patients with HCC. Current guidelines for high-risk patients include ultrasound screenings every six months, but ultrasounds are operator dependent and not sensitive for early HCC. Serum α-Fetoprotein (AFP) is a widely used diagnostic biomarker, but it has limited sensitivity and is not elevated in all HCC cases so, we incorporate a second blood-based biomarker, des'γ carboxy-prothrombin (DCP), that has shown potential as a screening marker for HCC. The data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a valuable source of data to study biomarker screening for HCC. We assume the trajectories of AFP and DCP follow a joint hierarchical mixture model with random changepoints that allows for distinct changepoint times and subsequent trajectories of each biomarker. The changepoint indicators are jointly modeled with a Markov Random Field distribution to help detect borderline changepoints. Markov chain Monte Carlo methods are used to calculate posterior distributions, which are used in risk calculations among future patients and determine whether a patient has a positive screen. The screening algorithm was compared to alternatives in simulations studies under a range of possible scenarios and in the HALT-C Trial using cross-validation.