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A care cascade is a critical tool for evaluating delivery of care for chronic infections across sequential stages, starting with diagnosis and ending with viral suppression. However, there have been few data describing the hepatitis B virus (HBV) care cascade among people living with HIV infection who have HBV coinfection. We conducted a cross-sectional study among people living with HIV and HBV coinfection receiving care between January 1, 2012 and December 31, 2016 within 13 United States and Canadian clinical cohorts contributing data to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). We evaluated each of the steps in this cascade, including: 1) laboratory-confirmed HBV infection, 2) tenofovir-based or entecavir-based HBV therapy prescribed, 3) HBV DNA measured during treatment, and 4) viral suppression achieved via undetectable HBV DNA. Among 3,953 persons with laboratory-confirmed HBV (median age, 50 years; 6.5% female; 43.8% were Black; 7.1% were Hispanic), 3,592 (90.9%; 95% confidence interval, 90.0–91.8%) were prescribed tenofovir-based antiretroviral therapy or entecavir along with their antiretroviral therapy regimen, 2,281 (57.7%; 95% confidence interval, 56.2–59.2%) had HBV DNA measured while on therapy, and 1,624 (41.1%; 95% confidence interval, 39.5–42.6) achieved an undetectable HBV DNA during HBV treatment. Our study identified significant gaps in measurement of HBV DNA and suppression of HBV viremia among people living with HIV and HBV coinfection in the United States and Canada. Periodic evaluation of the HBV care cascade among persons with HIV/HBV will be critical to monitoring success in completion of each step. [ABSTRACT FROM AUTHOR]

Background and Aim: Chronic hepatitis C virus (HCV) infection, long‐term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene–environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome‐wide association study (GWAS). Methods: Two case‐control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results: In this GWAS, we found that two SNPs were associated with HCC at P < 5E‐8 and six SNPs at P < 5E‐6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case‐control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta‐analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. Conclusions: SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated. [ABSTRACT FROM AUTHOR]

In the United States, Black people are disproportionately diagnosed with hepatitis C virus (HCV) compared with White people but are under‐represented in HCV studies. In this US‐based cross‐sectional telephone survey study, we assessed willingness to participate (WTP) in health/medical research and attitudes and beliefs that may influence WTP among Black patients with HCV. Two hundred participants who had current or prior HCV diagnosis and self‐identified as Black or African American were recruited from a national HCV cohort study and an outpatient hepatology clinic. WTP responses ranged from 1 (not at all willing) to 5 (very willing). Multivariable models were used to identify factors associated with the overall mean WTP score. In addition, an open‐ended question solicited strategies to help increase research participation from the Black community. Overall, participants reported moderate WTP in research (Mean [95% Confidence Interval (CI)] = 3.78 [3.68, 3.88]). Of 13 types of research presented, participants reported lowest WTP for randomized controlled trials of medications (Mean [95% CI] = 2.31 [2.11, 2.50]). The initial multivariable model identified higher subjective knowledge of research as positively associated with WTP (Parameter estimate [95% CI] = 0.15 [0.02, 0.27]). Sensitivity analyses also identified higher perceived benefits of research as an additional factor associated with WTP. Qualitative findings indicate that greater community‐based outreach efforts would increase accessibility of research opportunities. When given the opportunity to participate, Black participants with HCV reported moderate WTP in health/medical research. Research sponsors and investigators should employ community‐based outreach to expand access and awareness of research opportunities. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is associated with significant morbidity and mortality due to liver cirrhosis, liver failure, and hepatocellular carcinoma, and represents a leading indication for liver transplantation in the United States (U.S.). A growing spectrum of novel therapies are currently in clinical development and target several mechanisms of action which address hepatic steatosis, steatohepatitis, and hepatic fibrosis. Cenicriviroc (Allergan, Dublin, Ireland) is a novel oral antagonist of CC-motif chemokine receptors 2 and 5 (CCR2/5) which have demonstrated expression on circulating monocytes and Kupffer cells. Preclinical models have confirmed that CCR2/5 antagonism may block fat accumulation and Kupffer cell activation and disrupt monocyte/macrophage recruitment and hepatic stellate cell activation responsible for fibrogenesis. Herein we review results from the phase 2b CENTAUR trial and study designs for the phase 2b TANDEM and phase 3 AURORA trials and discuss the potential role of cenicriviroc in future pharmacotherapy for NASH fibrosis. [ABSTRACT FROM AUTHOR]

Background: Despite increasing incidence of hepatocellular carcinoma (HCC) among HIV-infected patients, it remains unclear if HIV-related factors contribute to development of HCC. We examined if higher or prolonged HIV viremia and lower CD4+ cell percentage were associated with HCC.Methods: We conducted a cohort study of HIV-infected individuals who had HIV RNA, CD4+, and CD8+ cell counts and percentages assessed in the Veterans Aging Cohort Study (1999-2015). HCC was ascertained using Veterans Health Administration cancer registries and electronic records. Cox regression was used to determine hazard ratios (HR, 95% confidence interval [CI]) of HCC associated with higher current HIV RNA, longer duration of detectable HIV viremia (≥500 copies/mL), and current CD4+ cell percentage less than 14%, adjusting for traditional HCC risk factors. Analyses were stratified by previously validated diagnoses of cirrhosis prior to start of follow-up.Results: Among 35 659 HIV-infected patients, 302 (0.8%) developed HCC over 281 441 person-years (incidence rate = 107.3 per 100 000 person-years). Among patients without baseline cirrhosis, higher HIV RNA (HR = 1.25, 95% CI = 1.12 to 1.40, per 1.0 log10 copies/mL) and 12 or more months of detectable HIV (HR = 1.47, 95% CI = 1.02 to 2.11) were independently associated with higher risk of HCC. CD4+ percentage less than 14% was not associated with HCC in any model. Hepatitis C coinfection was a statistically significant predictor of HCC regardless of baseline cirrhosis status.Conclusion: Among HIV-infected patients without baseline cirrhosis, higher HIV RNA and longer duration of HIV viremia increased risk of HCC, independent of traditional HCC risk factors. This is the strongest evidence to date that HIV viremia contributes to risk of HCC in this group. [ABSTRACT FROM AUTHOR]

Background: Cure from chronic hepatitis C virus (HCV) infection is readily achievable with direct-acting antivirals (DAA), but little is known about optimal management after treatment. Weight gained after DAA treatment may mitigate benefits or increase risk for liver disease progression. As the single largest sample of HCV-infected individuals receiving DAA treatment in the United States, the Veterans Affairs (VA) Birth Cohort is an ideal setting to assess weight gain after DAA treatment. Methods: We performed a prospective study of patients dispensed DAA therapy from January 2014 to June 2015. Weight change was calculated as the difference in weight from sustained virologic response (SVR) determination to 2 years later. Demographic, weight, height, prescription, laboratory, and diagnosis code data were used for covariate definitions. We used multiple logistic regression to assess the association between candidate predictors and excess weight gain (≥ 10 lbs) after 2 years. Results: Among 11,469 patients, 78.0% of patients were already overweight or obese at treatment initiation. Overall, SVR was achieved in 97.0% of patients. After 2 years, 52.6% of patients gained weight and 19.8% gained excess weight. In those with SVR, weight gain was as high as 38.2 lbs, with the top 10% gaining ≥ 16.5 lbs. Only 1% of those with obesity at treatment initiation normalized their weight class after 2 years. Significant predictors of post-SVR weight gain were SVR achievement, lower age, high FIB-4 score, cirrhosis, and weight class at treatment initiation. Conclusion: Weight gain is common after DAA treatment, even among those who are overweight or obese prior to treatment. Major predictors include age, baseline weight, alcohol, cirrhosis, and SVR. Everyone receiving DAAs should be counseled against weight gain with a particular emphasis among those at higher risk. [ABSTRACT FROM AUTHOR]

Background and Aims: The management of chronic hepatitis B patients is not well characterized in real-world practice. We compared baseline characteristics of CHB patients on entecavir, the frequency of on-treatment monitoring, and the effectiveness of ETV treatment between academic and community practices.Methods: Treatment-naïve CHB patients ≥18 years old, treated with ETV for ≥12 months from 2005 to 2013, in 26 community and academic practices throughout the USA were retrospectively evaluated.Results: Of 841 patients enrolled, 658 (65% male, 83% Asian, median age 47, 9% with cirrhosis) met inclusion criteria. Half of the patients (52%) were from community practices. A lower percentage of patients in community practices had cirrhosis or liver cancer (5 vs. 14%). Community practices more often treated patients with baseline ALT < 2 × ULN. Over a median follow-up of 4 years, community practices were more likely to discontinue ETV with less frequent laboratory monitoring compared to academic practices. The 5-year cumulative probability of ALT normalization was greater among patients treated in community practices (70 vs. 50%, p < 0.001), but the 5-year cumulative probability of undetectable HBV DNA was lower (45 vs. 70%, p < 0.001) than those treated in academic practices.Conclusion: Academic practices saw CHB patients with more advanced liver disease, more often followed AASLD guidelines, and monitored patients on ETV treatment more frequently than community practices. While patients in community practices were less likely to achieve undetectable HBV DNA and more likely to achieve ALT normalization, the rates of HBeAg loss and seroconversion as well as HBsAg loss were similar. [ABSTRACT FROM AUTHOR]

Presents an editorial on graduate medical education research in the 21st century. Comments on a report in this issue on residency burnout; Belief that the methodological weakness of the evidence leaves as many questions as answers; Increase in studies of graduate medical students over the years but need for much more; Questions on who will fund the needed research; Changes in medical education over the years; Recent rulings on work hours and the National Resident Matching Program; Commitment of this magazine to advancing the science of post-graduate medical training; Encouragement for students, residents and others to submit papers on the topic.

Discusses tobacco use, the leading cause of preventable deaths in the United States. Emphasis on intervention at a young age as seen in the Campaign for Tobacco-Free Kids by the American Medical Association; Need for physicians to counsel patients to quit smoking; Discussion of lack of physician knowledge in this area; Recommendation for smoking-cessation training.

Background and Aims: HDV leads to the most severe form of viral hepatitis; however, the prevalence of HDV is not well understood. Using real-world data from the All-Payer Claims Database, this study estimates the prevalence of HBV/HDV infection among the chronic HBV population and describes patient/clinical characteristics for adults with HBV/HDV infection in the United States., Approach and Results: Adults (≥18 years) with ≥1 inpatient claim or ≥2 outpatient claims for HDV infection or HBV in the All-Payer Claims Database from January 1, 2014, to December 31, 2020, were identified. HDV prevalence was calculated as the proportion of patients with HBV/HDV infection among total patients with HBV infection. Patient characteristics, socioeconomic status, advanced liver complications (eg, cirrhosis, HCC), and comorbidities were assessed. A total of 6719 patients were diagnosed with HBV/HDV among 144,975 with HBV and 12 months of continuous data, for a prevalence of 4.6%. At diagnosis, 31.7% of patients with HBV/HDV had advanced liver complications, including compensated cirrhosis (16.3%) and decompensated cirrhosis (10.4%). Diabetes (50.5%), hypertension (49.8%), and HIV infection (30.9%) were the top 3 comorbidities., Conclusions: In a large database capturing approximately 80% of the US-insured population, HBV/HDV infection prevalence was 4.6% among adults infected with HBV. Patients infected with HDV had high rates of baseline liver complications and other comorbidities at the time of diagnosis, suggesting potentially delayed diagnosis and/or treatment. Earlier identification of HBV/HDV infection among the population with HBV may provide opportunities to improve linkage to care and treatment, thereby reducing the risk of liver-related morbidity and mortality., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: In the US, the prevalence of hepatitis C virus (HCV) is 1.8% among people who are Black and 0.8% among people who are not Black. Mortality rates due to HCV are 5.01/100 000 among people who are Black and 2.98/100 000 among people who are White., Observations: While people of all races and ethnicities experienced increased rates of incident HCV between 2015 and 2021, Black individuals experienced the largest percentage increase of 0.3 to 1.4/100 000 (367%) compared with 1.8 to 2.7/100 000 among American Indian/Alaska Native (50%), 0.3 to 0.9/100 000 among Hispanic (200%), and 0.9 to 1.6/100 000 among White (78%) populations. Among 47 687 persons diagnosed with HCV in 2019-2020, including 37 877 (79%) covered by Medicaid (7666 Black and 24 374 White individuals), 23.5% of Black people and 23.7% of White people with Medicaid insurance initiated HCV treatment. Strategies to increase HCV screening include electronic health record prompts for universal HCV screening, which increased screening tests from 2052/month to 4169/month in an outpatient setting. Awareness of HCV status can be increased through point-of-care testing in community-based settings, which was associated with increased likelihood of receiving HCV test results compared with referral for testing off-site (69% on-site vs 19% off-site, P < .001). Access to HCV care can be facilitated by patient navigation, in which an individual is assigned to work with a patient to help them access care and treatments; this was associated with greater likelihood of HCV care access (odds ratio, 3.7 [95% CI, 2.9-4.8]) and treatment initiation within 6 months (odds ratio, 3.2 [95% CI, 2.3-4.2]) in a public health system providing health care to individuals regardless of their insurance status or ability to pay compared with usual care. Eliminating Medicaid's HCV treatment restrictions, including removal of a requirement for advanced fibrosis or a specialist prescriber, was associated with increased treatment rates from 2.4 persons per month to 72.3 persons per month in a retrospective study of 10 336 adults with HCV with no significant difference by race (526/1388 [37.8%] for Black vs 2706/8277 [32.6%] for White patients; adjusted odds ratio, 1.02 [95% CI, 0.8-1.3])., Conclusions and Relevance: In the US, the prevalence of HCV is higher in people who are Black than in people who are not Black. Point-of-care HCV tests, patient navigation, electronic health record prompts, and unrestricted access to HCV treatment in community-based settings have potential to increase diagnosis and treatment of HCV and improve outcomes in people who are Black.

To determine whether the Veterans Health Administration's (VHA) hepatitis C (HCV) treatment campaign reached marginalized populations, we compared HCV care by previous incarceration status with Veterans Aging Cohort Study data. Of those with and those without previous incarceration, respectively, 40% and 21% had detectable HCV, 59% and 65% underwent treatment ( P  = .07); 92% and 94% of those who completed treatment achieved sustained virologic response. The VHA HCV treatment effort was successful and other systems should replicate those efforts. ( Am J Public Health. 2023;113(2):162-165. https://doi.org/10.2105/AJPH.2022.307152).

Background: Gut microbial alterations have been linked to chronic liver disease and hepatocellular carcinoma (HCC). The role of the oral microbiome in liver cancer development has not been widely investigated., Methods: Bacterial 16S rRNA sequences were evaluated in oral samples from 90 HCC cases and 90 controls who were a part of a larger U.S. case-control study of HCC among patients diagnosed from 2011 to 2016., Results: The oral microbiome of HCC cases showed significantly reduced alpha diversity compared with controls (Shannon P = 0.002; Simpson P = 0.049), and beta diversity significantly differed (weighted Unifrac P = 0.004). The relative abundance of 30 taxa significantly varied including Cyanobacteria, which was enriched in cases compared with controls ( P = 0.018). Cyanobacteria was positively associated with HCC [OR, 8.71; 95% confidence interval (CI), 1.22-62.00; P = 0.031] after adjustment for age, race, birthplace, education, smoking, alcohol, obesity, type 2 diabetes, Hepatitis C virus (HCV), Hepatitis B virus (HBV), fatty liver disease, aspirin use, other NSAID use, laboratory batch, and other significant taxa. When stratified by HCC risk factors, significant associations of Cyanobacteria with HCC were exclusively observed among individuals with negative histories of established risk factors as well as females and college graduates. Cyanobacterial genes positively associated with HCC were specific to taxa producing microcystin, the hepatotoxic tumor promotor, and other genes known to be upregulated with microcystin exposure., Conclusions: Our study provides novel evidence that oral Cyanobacteria may be an independent risk factor for HCC., Impact: These findings support future studies to further examine the causal relationship between oral Cyanobacteria and HCC risk., (©2021 American Association for Cancer Research.)

Background & Aims: Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs., Methods: We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25)., Results: Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group., Lay Summary: Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens., Competing Interests: Conflict of interest D.B. has received research support to the NIH AIDS Clinical Trials Group (ACTG) from Abbvie and Regeneron for an ACTG-sponsored trial. All other authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Published by Elsevier B.V.)

Background & Aims: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for oncology, leading to durable remissions in a subset of patients, but also a broad range of potentially life-threatening inflammatory toxicities, many of which involve the gastrointestinal (GI) tract and liver. The purpose of this expert review was to update gastroenterologists on the gastrointestinal and hepatic toxicities of ICIs and provide best practice advice on their diagnosis and management., Methods: The evidence reviewed in this work combines the expert clinical opinion of the authors with a comprehensive search of several English-language databases and a manual review of relevant publications., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Importance: People with HIV (PWH) are often coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), leading to increased risk of developing hepatocellular carcinoma (HCC), but few cohort studies have had sufficient power to describe the trends of HCC incidence and risk among PWH in the combination antiretroviral therapy (cART) era., Objective: To determine the temporal trends of HCC incidence rates (IRs) and to compare rates by risk factors among PWH in the cART era., Design, Setting, and Participants: This cohort study used data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study, which was conducted between 1996 and 2015. NA-ACCORD pooled individual-level data from 22 HIV clinical and interval cohorts of PWH in the US and Canada. PWH aged 18 years or older with available CD4 cell counts and HIV RNA data were enrolled. Data analyses were completed in March 2020., Exposures: HBV infection was defined as detection of either HBV surface antigen, HBV e antigen, or HBV DNA in serum or plasma any time during observation. HCV infection was defined by detection of anti-HCV seropositivity, HCV RNA, or detectable genotype in serum or plasma at any time under observation., Main Outcomes and Measures: HCC diagnoses were identified on the basis of review of medical records or cancer registry linkage., Results: Of 109 283 PWH with 723 441 person-years of follow-up, the median (interquartile range) age at baseline was 43 (36-51) years, 93 017 (85.1%) were male, 44 752 (40.9%) were White, 44 322 (40.6%) were Black, 21 343 (19.5%) had HCV coinfection, 6348 (5.8%) had HBV coinfection, and 2082 (1.9%) had triple infection; 451 individuals received a diagnosis of HCC by 2015. Between the early (1996-2000) and modern (2006-2015) cART eras, the crude HCC IR increased from 0.28 to 0.75 case per 1000 person-years. HCC IRs remained constant among HIV-monoinfected persons or those coinfected with HBV, but from 1996 to 2015, IRs increased among PWH coinfected with HCV (from 0.34 cases/1000 person-years in 1996 to 2.39 cases/1000 person-years in 2015) or those with triple infection (from 0.65 cases/1000 person-years in 1996 to 4.49 cases/1000 person-years in 2015). Recent HIV RNA levels greater than or equal to 500 copies/mL (IR ratio, 1.8; 95% CI, 1.4-2.4) and CD4 cell counts less than or equal to 500 cells/μL (IR ratio, 1.3; 95% CI, 1.0-1.6) were associated with higher HCC risk in the modern cART era. People who injected drugs had higher HCC risk compared with men who had sex with men (IR ratio, 2.0; 95% CI, 1.3-2.9), adjusted for HBV-HCV coinfection., Conclusions and Relevance: HCC rates among PWH increased significantly over time from 1996 to 2015. PWH coinfected with viral hepatitis, those with higher HIV RNA levels or lower CD4 cell counts, and those who inject drugs had higher HCC risk.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease, with global public health impact affecting more than 25% of the global population. NAFLD is associated with significant morbidity and mortality from cirrhosis, hepatocellular carcinoma, solid organ malignancies, diabetes mellitus, cardiovascular disease, and obstructive sleep apnea, resulting in significant health care resource use and decreased health-related quality of life. NAFLD cirrhosis is a leading indication for liver transplantation in the United States. Lifestyle modification to achieve weight loss remains a first-line intervention in patients with NAFLD. We summarize evidence-based interventions for lifestyle modification in the treatment of NAFLD and provided best practice advice statements to address key issues in clinical management., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatitis C virus (HCV) may increase pulmonary hypertension (PH) risk among people living with HIV (PLWH). Prior studies on this topic have been relatively small and examined selected populations. We determine whether HIV/HCV coinfection is associated with higher pulmonary artery systolic pressure (PASP) and prevalent echocardiographic PH. We performed a cross-sectional analysis of 6032 (16% HIV/HCV coinfected) Veterans Aging Cohort Study participants enrolled 4/1/2003-9/30/2012 with echocardiographic PASP measures. We performed multiple linear and logistic regression analyses to determine whether HIV/HCV mono- or co-infection were associated with PASP and PH compared to uninfected individuals. Individuals with HIV/HCV coinfection displayed a higher PASP than uninfected individuals ([Formula: see text]=1.10, 95% CI 0.01, 2.20) but there was no association between HIV/HCV coinfection and prevalent PH. Subset analyses examined HIV and HCV disease severity markers separately and jointly. Among PLWH, HCV coinfection ([Formula: see text]=1.47, 95% CI 0.26, 2.67) and CD4 + cell count ([Formula: see text]= - 0.68, 95% CI - 1.10, - 0.27), but not HIV viral load nor ART regimen, were associated with PASP. Among people with HCV, neither HIV coinfection nor HCV biomarkers were associated with PASP. Among US veterans referred for echocardiography, HIV/HCV coinfection was not associated with a clinically significant elevation in pulmonary pressure. Lower absolute CD4 + T-cell count was inversely associated with PASP which warrants further investigation in prospective studies.

Chronic hepatitis B virus (HBV) infection represents a major global health problem, affecting an estimated 257-291 million persons worldwide and is associated with substantial morbidity and mortality because of clinical complications, such as liver cirrhosis and hepatocellular carcinoma. Despite existing resources for vaccination, screening, and treatment, the burden of chronic HBV remains significant within the United States (US). Both the World Health Organization (WHO) and US Department of Health and Human Services (DHHS) have articulated formal hepatitis elimination plans, although an updated assessment of the epidemiology and prevalence of chronic HBV is needed to inform these initiatives. The Chronic Liver Disease Foundation (CLDF), a nonprofit 501(c)(3) educational organization dedicated to raising awareness of liver disease, partnered with a panel of leading US hepatologists to conduct an updated literature review to develop a contemporary HBV prevalence range estimate. Panel members researched and evaluated the peer-reviewed literature on HBV prevalence and, in May 2019, discussed their findings during a live HBV epidemiology workshop. The panel proposed an overall estimated prevalence for chronic HBV infection in the US of 1.59 million persons (range 1.25-2.49 million). This review provides a summary of the workshop findings and conclusions, which may serve to inform future initiatives focused on HBV screening and prevention in the US.

Background & Aims: Multiple gastrointestinal (GI) symptoms, including diarrhea, nausea/vomiting, and abdominal pain, as well as liver enzyme abnormalities, have been variably reported in patients with coronavirus disease 2019 (COVID-19). This document provides best practice statements and recommendations for consultative management based on a systematic review and meta-analysis of international data on GI and liver manifestations of COVID-19., Methods: We performed a systematic literature search to identify published and unpublished studies using OVID Medline and preprint servers (medRxiv, LitCovid, and SSRN) up until April 5, 2020; major journal sites were monitored for US publications until April 19, 2020. We pooled the prevalence of diarrhea, nausea, vomiting, and abdominal pain, as well as liver function tests abnormalities, using a fixed-effect model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework., Results: We identified 118 studies and used a hierarchal study selection process to identify unique cohorts. We performed a meta-analysis of 47 studies including 10,890 unique patients. Pooled prevalence estimates of GI symptoms were as follows: diarrhea 7.7% (95% confidence interval [CI], 7.2%-8.2%), nausea/vomiting 7.8% (95% CI, 7.1%-8.5%), and abdominal pain 2.7% (95% CI, 2.0%-3.4%). Most studies reported on hospitalized patients. The pooled prevalence estimates of elevated liver abnormalities were as follows: aspartate transaminase 15.0% (95% CI, 13.6%-16.5%) and alanine transaminase 15.0% (95% CI, 13.6%-16.4%). When we compared studies from China to studies from other countries in subgroup analyses, diarrhea, nausea/vomiting, and liver abnormalities were more prevalent outside of China, with diarrhea reported in 18.3% (95% CI, 16.6%-20.1%). Isolated GI symptoms were reported rarely. We also summarized the Gl and liver adverse effects of the most commonly utilized medications for COVID-19., Conclusions: GI symptoms are associated with COVID-19 in <10% of patients. In studies outside of China, estimates are higher. Further studies are needed with standardized GI symptoms questionnaires and liver function test checks on admission to better quantify and qualify the association of these symptoms with COVID-19. Based on findings from our meta-analysis, we provide several Best Practice Statements for the consultative management of COVID-19., (Copyright © 2020. Published by Elsevier Inc.)

Background: Despite increasing incidence of hepatocellular carcinoma (HCC) among HIV-infected patients, it remains unclear if HIV-related factors contribute to development of HCC. We examined if higher or prolonged HIV viremia and lower CD4+ cell percentage were associated with HCC., Methods: We conducted a cohort study of HIV-infected individuals who had HIV RNA, CD4+, and CD8+ cell counts and percentages assessed in the Veterans Aging Cohort Study (1999-2015). HCC was ascertained using Veterans Health Administration cancer registries and electronic records. Cox regression was used to determine hazard ratios (HR, 95% confidence interval [CI]) of HCC associated with higher current HIV RNA, longer duration of detectable HIV viremia (≥500 copies/mL), and current CD4+ cell percentage less than 14%, adjusting for traditional HCC risk factors. Analyses were stratified by previously validated diagnoses of cirrhosis prior to start of follow-up., Results: Among 35 659 HIV-infected patients, 302 (0.8%) developed HCC over 281 441 person-years (incidence rate = 107.3 per 100 000 person-years). Among patients without baseline cirrhosis, higher HIV RNA (HR = 1.25, 95% CI = 1.12 to 1.40, per 1.0 log10 copies/mL) and 12 or more months of detectable HIV (HR = 1.47, 95% CI = 1.02 to 2.11) were independently associated with higher risk of HCC. CD4+ percentage less than 14% was not associated with HCC in any model. Hepatitis C coinfection was a statistically significant predictor of HCC regardless of baseline cirrhosis status., Conclusion: Among HIV-infected patients without baseline cirrhosis, higher HIV RNA and longer duration of HIV viremia increased risk of HCC, independent of traditional HCC risk factors. This is the strongest evidence to date that HIV viremia contributes to risk of HCC in this group., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Nonalcoholic fatty liver disease (NAFLD) is a leading etiology for chronic liver disease with an immense public health impact and affects >25% of the US and global population. Up to 1 in 4 NAFLD patients may have nonalcoholic steatohepatitis (NASH). NASH is associated with significant morbidity and mortality due to complications of liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). Recent data confirm that HCC represents the fifth most common cancer and is the second leading cause of cancer-related death worldwide, and NAFLD has been identified as a rapidly emerging risk factor for this malignancy. NAFLD-associated liver complications are projected to become the leading indication for liver transplantation in the next decade. Despite evidence that NAFLD-associated HCC may arise in the absence of cirrhosis, is often diagnosed at advanced stages, and is associated with lower receipt of curative therapy and with poorer survival, current society guidelines provide limited guidance/recommendations addressing HCC surveillance in patients with NAFLD outside the context of established cirrhosis. Limited data are presently available to guide clinicians with respect to which patients with NAFLD should undergo HCC surveillance, optimal screening tools, frequency of monitoring, and the influence of coexisting host- and disease-related risk factors. Herein we present an evidence-based review addressing HCC risk in patients with NAFLD and provide Best Practice Advice statements to address key issues in clinical management., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Liver fibrosis, is independently associated with incident heart failure (HF). Investigating the association between liver fibrosis and type of HF, specifically HF with reduced ejection fraction (EF; HFrEF) or HF with preserved ejection fraction (HFpEF), may provide mechanistic insight into this association. We sought to determine the association between liver fibrosis score (FIB-4) and type of HF, and to assess whether HIV or hepatitis C status modified this association., Methods: We included patients alive on or after 4/1/2003 from the Veterans Aging Cohort Study. We followed patients without prevalent cardiovascular disease until their first HF event, death, last clinic visit, or 9/30/2015. We defined liver fibrosis as: likely advanced fibrosis (FIB-4 > 3.25), indeterminate (FIB-4 range 1.45-3.25), unlikely advanced fibrosis (FIB-4 < 1.45). Primary outcomes were HFrEF and HFpEF (defined using ICD-9 diagnoses for HF, and EF extracted from electronic medical records using natural language processing). Cox proportional hazards models were adjusted for potential confounders and used to estimate hazard ratios (HR)., Results: Among 108,708 predominantly male (96%) participants mean age was 49 years. Likely advanced fibrosis was present in 4% at baseline and was associated with an increased risk of HFpEF [HR (95% confidence interval)] [1.70 (1.3-2.3)]; and non-significantly with HFrEF [1.20 (0.9-1.7)]. These associations were not modified by HIV or hepatitis C status., Conclusion: Likely advanced fibrosis was independently associated with incident HFpEF but not HFrEF. This suggests that risk factors and/or mechanisms for liver fibrosis may have greater overlap with those for HFpEF than HFrEF., (Copyright © 2020. Published by Elsevier Inc.)

Background: Hepatitis B virus (HBV) infection is a leading cause of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) in HIV. Factors contributing to the high rates of liver complications among HIV/HBV-coinfected individuals remain unknown., Setting: North American AIDS Cohort Collaboration on Research and Design., Methods: We performed a retrospective cohort study among HIV/HBV-coinfected patients in 10 US and Canadian cohorts of the North American AIDS Cohort Collaboration on Research and Design that validated ESLD (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, and/or hepatic encephalopathy) and HCC diagnoses from 1996 to 2010. Multivariable Cox regression was used to examine adjusted hazard ratios [aHRs with 95% confidence interval (CIs)] of liver complications (first occurrence of ESLD or HCC) associated with hypothesized determinants and with increasing durations of HIV suppression (≤500 copies/mL)., Results: Among 3573 HIV/HBV patients with 13,790 person-years of follow-up, 111 liver complications occurred (incidence rate = 8.0 [95% CI: 6.6 to 9.7] events/1000 person-years). Rates of liver complication were increased with non-black/non-Hispanic race [aHR = 1.76 (1.13-2.74)], diabetes mellitus [aHR = 2.07 (1.20-3.57)], lower time-updated CD4 cell count [<200 cells/mm: aHR = 2.59 (1.36-4.91); 201-499 cells/mm: aHR = 1.75 (1.01-3.06) versus ≥500 cells/mm], heavy alcohol use [aHR = 1.58 (1.04-2.39)], and higher FIB-4 at start of follow-up [>3.25: aHR = 9.79 (5.73-16.74); 1.45-3.25: aHR = 3.20 (1.87-5.47) versus FIB-4 <1.45]. HIV suppression for ≥6 months was associated with lower liver complication rates compared with those with unsuppressed HIV [aHR = 0.56 (0.35-0.91)]., Conclusions: Non-black/non-Hispanic race, diabetes, lower CD4 cell count, heavy alcohol use, and advanced liver fibrosis were determinants of liver complications among HIV/HBV patients. Sustained HIV suppression should be a focus for HIV/HBV-coinfected patients to reduce the risks of ESLD/HCC.

Background: Hepatic steatosis is prevalent in Western countries, but few studies have evaluated whether the frequency and severity of steatosis are greater in the setting of HIV infection. We compared the prevalence and severity of hepatic steatosis between HIV-infected (HIV+) and uninfected persons and identified factors associated with greater steatosis severity within both groups., Methods: We performed a cross-sectional study among participants without cardiovascular disease who participated in a substudy of the Veterans Aging Cohort Study. Hepatic steatosis was defined by noncontrast computed tomography (CT) liver-to-spleen (L/S) attenuation ratio < 1.0. Multivariable linear regression was used to: 1) evaluate the association between HIV infection and severity of hepatic steatosis, as measured by absolute liver attenuation, and 2) identify factors associated with greater severity of steatosis, by HIV status., Results: Among 268 participants (median age, 55 years; 99% male; 79% black; 23% obese; 64% HIV+ [91% on antiretroviral therapy]), the overall prevalence of steatosis was 7.8% and was similar between HIV+ and uninfected individuals (13 [7.6%] versus 8 [8.2%], respectively; p = 0.85). Participants with HIV, the majority of whom received antiretroviral therapy, had a higher mean absolute liver attenuation (mean difference, 5.68 Hounsfield units; p < 0.001), correlating with lesser hepatic steatosis severity, compared to uninfected participants. After adjusting for covariates, only advanced hepatic fibrosis was associated with greater severity of steatosis in HIV+ persons (p = 0.03) and uninfected individuals (p < 0.001)., Conclusions: In this sample of participants without cardiovascular disease, the prevalence of hepatic steatosis by noncontrast abdominal CT was not different by HIV status. Increasing severity of steatosis was independently associated with advanced hepatic fibrosis in both groups.

Chronic hepatitis B (CHB) comorbidity data are limited. Using insurance claims databases, our aims were to determine the prevalence and incidence of nonliver comorbidities in CHB patients over time and the predictors of select comorbidities in CHB patients. Patients were adults with continuous coverage (commercial/Medicare or Medicaid) 6 months prior to and after the first CHB diagnosis and matched non-CHB patients. Deyo-Charlson Comorbidity Index (DCCI) and comorbidities were analyzed (cardiovascular disease [CVD], carcinoma, diabetes mellitus [DM], obesity, hypertension [HTN], hyperlipidemia, alcohol use, renal impairment, chronic kidney disease [CKD], and osteoporosis/fracture [OF]). The study population included 44,026 CHB cases and 121,568 matched controls. CHB patient mean age increased from 48.1 ± 11.9 years in 2006 to 51.8 ± 12.4 years in 2015 for commercial/Medicare and from 44.1 ± 11.1 years to 50.2 ± 10.2 years for Medicaid (P < 0.001 for both). The Medicaid CHB cohort was the sickest (DCCI, 2.6, P < 0.001). The commercial/Medicare 2006 CKD prevalence rate was 36.1/1,000 in CHB patients and 10.2/1,000 in controls, increasing to 97.6 and 38.8 in 2015, respectively. The 2006 CKD incidence (per 1,000 person-years) was 10.3 and 4.8 and 15.2 and 11.3 by 2015, respectively (P < 0.05 for all). The strongest predictors for CKD were DM (hazard ratio [HR], 2.48), HTN (HR, 3.29), and CVD (HR, 2.61) (all P < 0.0001). Similar prevalence and incidence changes were observed for OF. The strongest predictors for OF were female gender (HR, 2.22), alcohol use (HR, 2.02), and viral coinfection (HR, 1.37) (all P < 0.0001). Conclusion: Insured CHB patients were older, had more comorbidities, and experienced higher incidence and prevalence of CKD and OF than controls., (© 2018 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Chronic hepatitis B (CHB) affects over 2 million people in the US, with little reported on healthcare utilization and cost. We aimed to quantify annual CHB utilization and costs by disease severity and payer type., Methods: Using Commercial, Medicare, and Medicaid databases from 2004 to 2015 and ICD9 codes, we retrospectively identified adults with CHB, analyzing all-cause inpatient, outpatient, and pharmaceutical utilization and costs by disease severity. We compared healthcare utilization and costs between patients with CHB, without advanced liver disease, and matched non-CHB controls. All-cause inpatient, outpatient, and pharmaceutical utilization and costs were reported for each year and adjusted to 2015 dollars., Results: Our sample consisted of 33,904 CHB cases and 86,072 non-CHB controls. All-cause inpatient admissions (average stay 6-10 days) were more frequent in advanced liver disease states. Across all payers, patients with decompensated cirrhosis had the highest emergency department utilization (1.6-2.8 annual visits) and highest mean annual costs. The largest all-cause cost components for Commercial and Medicaid were inpatient costs for all advanced liver disease groups (Commercial: 62%, 47%, 68%; Medicaid: 81%, 72%, 74%, respectively), and decompensated cirrhosis and hepatocellular carcinoma groups for Medicare (Medicare 49% and 48%). In addition, patients with compensated liver disease incurred costs 3 times higher than non-CHB controls., Conclusion: Patients with CHB, regardless of payer, who experienced decompensated cirrhosis, hepatocellular carcinoma, or a liver transplant incurred the highest annual costs and utilization of healthcare resources, but even patients with CHB and compensated liver disease incurred higher costs than those without CHB. All stakeholders in disease management need to combine efforts to prevent infection and advanced liver disease through improved vaccination rates, earlier diagnosis, and treatment., Lay Summary: Hepatitis B virus can be a progressive disease leading to cirrhosis, hepatocellular carcinoma, liver transplant, and death. These progressive disease states are associated with a higher rate of hospitalizations, emergency room visits, outpatient visits, and costs compared to similar patients without hepatitis B. The most ill patients have the highest costs, but even patients who are less sick experience higher costs than patients without hepatitis B., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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)., Competing Interests: Donna M. Evon has received research funding from Gilead. Michael Fried has received research funding from and served as a consultant for AbbVie, BMS, Gilead, and Merck, and TARGET PharmaSolutions. Stock in TARGET PharmaSolutions is held in an independently managed trust. Anna S. Lok has received research support from AbbVie, BMS, Gilead, and Merck; and served as an advisor for Gilead. Richard K. Sterling has received research support from AbbVie, BMS, Gilead, Merck, and Roche and served as a consultant for Merck, Bayer, Salix, AbbVie, Gilead, Jansen, ViiV, Baxter, and Pfizer. Joseph K. Lim has received research support (paid to Yale University) and served as a consultant for Bristol-Myers Squibb and Gilead. Nancy Reau has received research funding (paid to Rush) from AbbVie and Intercept and has served as a consultant for AbbVie, Gilead, Merck, and BMS. Souvik Sarkar served on a Gilead and Abbvie Advisory Board. David R. Nelson has received research grant support from AbbVie, BMS, Gilead, Janssen, and Merck. K. Rajender Reddy is an Ad-Hoc Advisor to Gilead, BMS, Janssen, Merck, and Abbvie and has received research support from Gilead, BMS, Janssen, Merck, and AbbVie (paid to the University of Pennsylvania). Adrian M. Di Bisceglie has received research support from AbbVie, BMS and Gilead and has served on advisory boards for AbbVie, BMS and Merck. Paul Stewart has served as a consultant to TARGET PharmaSolutions. Jipcy Amador served as a biostatistics intern at TARGET PharmaSolutions in 2017. Carol E. Golin and Bryce Reeve declare that they have no conflict of interests to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Bilirubin may protect against cardiovascular disease (CVD) by reducing oxidative stress. Whether elevated bilirubin reduces the risk of CVD events among HIV + individuals and if this differs from uninfected individuals remain unclear. We assessed whether bilirubin independently predicted the risk of CVD events among HIV + and uninfected participants in VACS (Veterans Aging Cohort Study)., Methods and Results: We conducted a prospective cohort study using VACS participants free of baseline CVD. Total bilirubin was categorized by quartiles. CVD as well as acute myocardial infarction, heart failure, and ischemic stroke events were assessed. Cox regression was used to evaluate hazard ratios of outcomes associated with quartiles of total bilirubin in HIV + and uninfected people after adjusting for multiple risk factors. There were 96 381 participants (30 427 HIV + ); mean age was 48 years, 48% were black, and 97% were men. There were 6603 total incident CVD events over a mean of 5.7 years. In adjusted models, increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80-0.91). Among HIV + participants, results persisted for heart failure, ischemic stroke, and total CVD, but nonsignificant associations were observed for acute myocardial infarction., Conclusions: VACS participants (regardless of HIV status) with elevated bilirubin levels had a lower risk of incident total CVD, acute myocardial infarction, heart failure, and ischemic stroke events after adjusting for known risk factors. Future studies should investigate how this apparently protective effect of elevated bilirubin could be harnessed to reduce CVD risk or improve risk estimation among HIV + individuals., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Cancer patients receiving chemotherapy face an increased risk of reactivation of chronic hepatitis B virus infection., Aim: To determine the HBV screening rate in patients receiving cancer chemotherapy in various clinical settings., Method: We identified 11,959 adult cancer patients (age ≥ 18 years) receiving parenteral chemotherapy between 2012 and 2015 within a major US hospital network, including a large university hospital, community teaching hospitals, and community oncology clinics., Result: Two thousand and forty-five patients (17.1%) were screened for either HBV surface antigen (HBsAg) or HBV core antibody (HBcAb) before chemotherapy, and 1850 patients (15.5%) had both HBsAg and HBcAb tested before chemotherapy. 8.4% were exposed to HBV, and 0.9% had chronic HBV infection (both HBsAg/HBcAb positive). Patients with hematologic tumor were more often screened than with solid tumor (55.6 vs. 8.3%, p < 0.001). Patients receiving chemotherapy with higher HBV reactivation risk had higher yet suboptimal HBV screening rate (41.1% B-depleting agents, 21.5% anthracycline, 14.9% steroid, 64.7% anti-TNF alpha and 18.6% other chemotherapy, p < 0.001). Patients with age ≥ 50 years (old 16.2% vs. young 23.9%, p < 0.001) and Asian ethnicity (Asian 13.6 vs. Caucasian 16.6%, p < 0.001) were screened less for HBV despite higher prevalence of HBV exposure (old 9.3% vs. young 4.3%, p < 0.001 and Asian 27.8% vs. Caucasian 6.4%, p < 0.001). Patients receiving chemotherapy in community oncology clinics were less screened versus community teaching hospitals or university hospital (12.7 vs. 19.1 vs. 19.7%, p < 0.001), despite similar prevalence of HBV infection. On multivariate analysis, receiving chemotherapy at a community oncology clinic [odds ratio (OR) 0.57, 95% confidence interval (CI) 0.45-0.72, p < 0.001] was independently associated with less HBV screening compared to receiving chemotherapy at a university or community teaching hospital., Conclusion: HBV screening among patients undergoing cancer chemotherapy was suboptimal and less commonly performed in community oncology clinics compared to teaching hospitals.

Goals/background: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality., Study: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared., Results: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%., Conclusions: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

Prisoners bear much of the burden of the hepatitis C epidemic in the United States. Yet little is known about the scope and cost of treating hepatitis C in state prisons-particularly since the release of direct-acting antiviral medications. In the forty-one states whose departments of corrections reported data, 106,266 inmates (10 percent of their prisoners) were known to have hepatitis C on or about January 1, 2015. Only 949 (0.89 percent) of those inmates were being treated. Prices for a twelve-week course of direct-acting antivirals such as sofosbuvir and the combination drug ledipasvir/sofosbuvir varied widely as of September 30, 2015 ($43,418-$84,000 and $44,421-$94,500, respectively). Numerous corrections departments received smaller discounts than other government agencies did. To reduce the hepatitis C epidemic, state governments should increase funding for treating infected inmates. State departments of corrections should consider collaborating with other government agencies to negotiate discounts with pharmaceutical companies and with qualified health care facilities to provide medications through the federal 340B Drug Discount Program. Helping inmates transition to providers in the community upon release can enhance the gains achieved by treating hepatitis C in prison., (Project HOPE—The People-to-People Health Foundation, Inc.)

Background: New treatments for hepatitis C (HCV) infection hold great promise for cure, but numerous challenges to diagnosing, establishing care, and receiving therapy exist. There are limited data on insurance authorization for these medications., Materials and Methods: We performed a retrospective chart review of patients receiving sofosbuvir/ledipasvir (SOF/LED) from October 11-December 31, 2014 to determine rates and timing of drug authorization. We also determined predictors of approval, and those factors associated with faster decision and approval times., Results: Of 174 patients prescribed HCV therapy during this period, 129 requests were made for SOF/LED, of whom 100 (77.5%) received initial approval, and an additional 17 patients (13.9%) ultimately received approval through the appeals process. Faster approval times were seen in patients with Child-Pugh Class B disease (14.4 vs. 24.7 days, p = 0.048). A higher proportion of patients were initially approved in those with Medicare/Medicaid coverage (92.2% vs. 71.4%, p = 0.002) and those with baseline viral load ≥ 6 million IU/mL (84.1% vs. 62.5%, p = 0.040). Linear regression modeling identified advanced fibrosis, high Model of End Stage Liver Disease (MELD) score, and female gender as significant predictors of shorter decision and approval times. On logistic regression, Medicare/Medicaid coverage (OR 5.96, 95% CI 1.66-21.48) and high viral load (OR 4.52, 95% CI 1.08-19.08) were significant predictors for initial approval., Conclusions: Early analysis of real-world drug authorization outcomes between October-December 2014 reveals that nearly one in four patients are initially denied access to SOF/LED upon initial prescription, although most patients are eventually approved through appeal, which delays treatment initiation. Having Medicare/Medicaid and advanced liver disease resulted in a higher likelihood of approval as well as earlier decision and approval times. More studies are needed to determine factors resulting in higher likelihood of denial and to evaluate approval rates and times after implementation of restrictive prior authorization guidelines.

Unlabelled: The rise in incidence of hepatocellular carcinoma (HCC) in the United States has been well documented. The purpose of this analysis was to examine temporal trends in HCC incidence, mortality, and survival within the U.S. population. The Surveillance, Epidemiology, and End Results data were used to examine incidence and incidence-based (IB) mortality in HCC from 1973 to 2011. Secular trends in age-adjusted incidence and IB mortality by sex and cancer stage were characterized using the Joinpoint Regression program. In 1973, HCC incidence was 1.51 cases per 100,000, whereas in 2011, HCC incidence was 6.20 cases per 100,000. Although HCC incidence continues to increase, a slowing of the rate of increase occurs around 2006. In a sensitivity analysis, there was no significant increase in incidence and IB mortality from 2009 to 2011. There was a significant increase in overall median survival from the 1970s to 2000s (2 vs. 8 months; P < 0.001). On multivariable Cox's regression analysis, age, sex, race, tumor grade, stage at diagnosis, lymph/vascular invasion, number of primary tumors, tumor size, and liver transplant were independently associated with mortality., Conclusion: Our results indicate a deceleration in the incidence of HCC around 2006. Since 2009 and for the first time in four decades, there is no increase in IB mortality and incidence rates for HCC in the U.S. population. The nonsignificant increase in incidence and IB mortality in recent years suggest that the peak of the HCC epidemic may be near. A significant survival improvement in HCC was also noted from 1973 to 2010, which seems to be driven by earlier detection of HCC at a curative stage and greater utilization of curative modalities (especially transplant)., (© 2014 by the American Association for the Study of Liver Diseases.)

Background: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV., Methods: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770., Findings: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups., Interpretation: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection., Funding: Bristol-Myers Squibb., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: The absence of validated methods to identify hepatic decompensation in cohort studies has prevented a full understanding of the natural history of chronic liver diseases and impact of medications on this outcome. We determined the ability of diagnostic codes and liver-related laboratory abnormalities to identify hepatic decompensation events within the Veterans Aging Cohort Study (VACS)., Methods: Medical records of patients with hepatic decompensation codes and/or laboratory abnormalities of liver dysfunction (total bilirubin ≥ 5.0 g/dL, albumin ≤ 2.0 g/dL, INR ≥ 1.7) recorded 1 year before through 6 months after VACS entry were reviewed to identify decompensation events (i.e., ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, hepatocellular carcinoma) at VACS enrollment. Positive predictive values (PPVs) of diagnostic codes, laboratory abnormalities, and their combinations for confirmed outcomes were determined., Results: Among 137 patients with a hepatic decompensation code and 197 with a laboratory abnormality, the diagnosis was confirmed in 57 (PPV, 42%; 95%CI, 33%-50%) and 56 (PPV, 28%; 95%CI, 22%-35%) patients, respectively. The combination of any code plus laboratory abnormality increased PPV (64%; 95%CI, 47%-79%). One inpatient or ≥2 outpatient diagnostic codes for ascites, spontaneous bacterial peritonitis, or variceal hemorrhage had high PPV (91%; 95%CI, 77%-98%) for confirmed hepatic decompensation events., Conclusion: An algorithm of 1 inpatient or ≥ 2 outpatient codes for ascites, peritonitis, or variceal hemorrhage has sufficiently high PPV for hepatic decompensation to enable its use for epidemiologic research in VACS. This algorithm may be applicable to other cohorts., (Copyright © 2011 John Wiley & Sons, Ltd.)

Cirrhosis represents the end stage of any chronic liver disease. Hepatitis C and alcohol are currently the main causes of cirrhosis in the United States. Although initially cirrhosis is compensated, it eventually becomes decompensated, as defined by the presence of ascites, variceal hemorrhage, encephalopathy, and/or jaundice. These management recommendations are divided according to the status, compensated or decompensated, of the cirrhotic patient, with a separate section for the screening, diagnosis, and management of hepatocellular carcinoma (HCC), as this applies to patients with both compensated and decompensated cirrhosis. In the compensated patient, the main objective is to prevent variceal hemorrhage and any practice that could lead to decompensation. In the decompensated patient, acute variceal hemorrhage and spontaneous bacterial peritonitis are severe complications that require hospitalization. Hepatorenal syndrome is also a severe complication of cirrhosis but one that usually occurs in patients who are already in the hospital and, as it represents an extreme of the hemodynamic alterations that lead to ascites formation, it is placed under treatment of ascites. Recent advances in the pathophysiology of the complications of cirrhosis have allowed for a more rational management of cirrhosis and also for the stratification of patients into different risk groups that require different management. These recommendations are based on evidence in the literature, mainly from randomized clinical trials and meta-analyses of these trials. When few or no data exist from well-designed prospective trials, emphasis is given to results from large series and consensus conferences with involvement of recognized experts. A rational management of cirrhosis will result in improvements in quality of life, treatment adherence, and, ultimately, in outcomes.