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A number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 CG single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD.To enable mechanistic dissection, we developed a human pluripotent stem cell (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first applied this liver culture to model NAFLD by utilising a lipotoxic milieu reflecting the circulating levels of disease risk factors in affected individuals. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotype development.Our hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL-6/signal transducer and activator of transcription 3 (STAT3) activity in liver cultures, consistent with transcriptomic data of liver biopsies from individuals carrying the rs738409 SNP. Dampening IL-6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, whereas boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL-6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-κB activity.Our study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD.An increasing number of genetic variants manifest in non-alcoholic fatty liver disease (NAFLD) development and progression; however, the underlying mechanisms remain elusive. To study these variants in human-relevant systems, we developed an induced pluripotent stem cell-derived multicellular liver culture and focused on a common genetic variant (i.e. rs738409 in PNPLA3). Our findings not only provide mechanistic insight, but also a potential therapeutic strategy for NAFLD driven by this genetic variant in PNPLA3. Our liver culture is therefore a useful platform for exploring genetic variants in NAFLD development.

Supplementary Data from Mutations in the Hepatitis C Virus core Gene Are Associated with Advanced Liver Disease and Hepatocellular Carcinoma

Purpose: Hepatitis C virus (HCV) infection can promote the development of hepatocellular carcinoma (HCC). Published data implicate the HCV core gene in oncogenesis. We tested the hypothesis that core gene sequences from HCC patients differ from those of patients without cirrhosis/HCC.Experimental Design: Full-length HCV sequences from HCC patients and controls were obtained from the investigators and GenBank and compared with each other. A logistic regression model was developed to predict the HCC risk of individual point mutations and other sequence features. Mutations in partial sequences (bases 36-288) from HCC patients and controls were also analyzed. The first base of the AUG start codon was designated position 1.Results: A logistic regression model developed through analysis of full-length core gene sequences identified seven polymorphisms significantly associated with increased HCC risk (36G/C, 209A, 271U/C, 309A/C, 435A/C, 481A, and 546A/C) and an interaction term (for 209A-271U/C) that had an odds ratio Conclusions: HCV core genes from patients with and without HCC differ at several positions. Of interest, 209A has been associated with IFN resistance and HCC in previous studies. Our findings suggest that HCV core gene sequence data might provide useful information about HCC risk. Prospective investigation is needed to establish the temporal relationship between appearance of the viral mutations and development of HCC.

There is mounting evidence that Black patients develop more advanced liver cancers with less advanced liver disease. These findings have important implications for the future of liver cancer screening.

There is constant remodeling in a cirrhotic liver resulting in cirrhosis being spatially heterogeneous. The Laennec system, and, more recently the Beijing classification, have been used to sub-classify various degrees of cirrhosis. It is unknown how these two schemes compare with each other, how they are impacted by geographic variation, and how they correlate with clinical outcomes. Five needle biopsies were obtained from 20 explanted cirrhotic HCV livers at the time of transplantation. Collagen proportionate area (CPA) was measured by computerized quantitative morphometry. The Laennec system (4A-4C indicating increasing degrees of cirrhosis) and Beijing classification (P-progressive, R-regressive, I-indeterminate) were assessed and then correlated with CPA. Geographical variation using CPAs was calculated by the coefficient of variation (CoV). CPA of Laennec 4C cirrhosis was higher than 4A (p = 0.00008) or 4B (p = 0.0002). The CPA of the P pattern was greater than the R (p = 0.002) or I patterns (p = 0.037). The mean CoV of the five CPAs was 47.3 ± 4.5%, suggesting a significant degree of geographic variation. There was 100% overlap between the Beijing R pattern and Laennec 4A, and 80% overlap between the P pattern and Laennec 4C. Patients' platelet counts of P pattern were lower than R pattern (p = 0.008) or I pattern (p = 0.024), while Laennec 4C was lower than 4A (p = 0.036) and 4B patients (p = 0.7). There was no correlation between CPA, Laennec stage, or Beijing classification and MELD score, liver weights, total bilirubin, or albumin levels. The Laennec system and the Beijing classification are highly correlated with CPA in cirrhosis. This study confirms that there is a significant degree of geographic variation in terms of fibrosis content and cirrhosis morphology throughout the liver.

Background and aimsThe prevalence and etiology of liver fibrosis vary over time and impact racial/ethnic groups unevenly. This study measured time-trends and identified factors associated with advanced liver fibrosis in the U.S.MethodsStandardized methods were used to analyze data on 47,422 participants (≥ 20 years) in the National Health and Nutrition Examination Survey (1999-2018). Advanced liver fibrosis was defined as Fibrosis-4 ≥2.67 and/or Forns Index ≥6.9 and elevated ALT.ResultsThe estimated number of people with advanced liver fibrosis increased from 1.3 million (95% CI, 0.8-1.9) to 3.5 million (95% CI, 2.8-4.2), a nearly 3-fold increase. Prevalence was higher in non-Hispanic Black and Mexican American persons than in non-Hispanic White persons. In multivariable logistic regression analysis, cadmium was an independent risk factor in all racial/ethnic groups. Smoking and current excessive alcohol use were risk factors in most. Importantly, non-Hispanic Black persons had a distinctive set of risk factors compared to non-Hispanic White persons that included poverty (OR = 2.09; 95%CI, 1.44-3.03), and susceptibility to lead exposure (OR = 3.25; 95%CI, 1.95-5.43), but did not include diabetes (OR = 0.88; 95% CI, 0.61-1.27, P =0.52). Non-Hispanic Black persons were more likely to have high exposure to lead, cadmium, polychlorinated biphenyls, and poverty than Non-Hispanic White persons.ConclusionsThe number of people with advanced liver fibrosis has increased, creating a need to expand the liver care workforce. The risk factors for advanced fibrosis varied by racial/ethnicity. These variations provide useful information for the design of screening programs. Poverty and toxic exposures were associated with the high prevalence of advanced liver fibrosis in non-Hispanic Black persons and need to be addressed.Lay summaryBecause liver disease often produces few warning signs, simple and inexpensive screening tests that can be performed by non-specialists are needed to allow timely detection and linkage to care. This study shows that non-Hispanic Black persons have a distinctive set of risk factors that need to be taken into account when designing liver disease screening tests. Exposure to exogenous toxins may be especially important risk factors for advanced liver fibrosis in non-Hispanic Black persons.

Genetic variants affecting liver disease risk vary among racial and ethnic groups. Hispanics/Latinos in the U.S. have a high prevalence of PNPLA3 I148M, which increases liver disease risk, and a low prevalence of HSD17B13 predicted loss-of-function (pLoF) variants, which reduce risk. Less is known about the prevalence of liver disease-associated variants among Hispanic/Latino subpopulations defined by country-of-origin and genetic ancestry. We evaluated the prevalence of HSD17B13 pLoF variants and PNPLA3 I148M, and their associations with quantitative liver phenotypes in Hispanic/Latino participants of an electronic health record-linked biobank in New York City.This study included 8,739 adult Hispanic/Latino participants of the BioMe biobank with genotyping and exome sequencing data. We estimated the prevalence of Hispanic/Latino individuals harboring HSD17B13 and PNPLA3 variants, stratified by genetic ancestry, and performed association analyses between variants and liver enzymes and Fibrosis-4 (FIB-4) scores.Individuals with ancestry from Ecuador and Mexico had the lowest frequency of HSD17B13 pLoF variants (10%/7%) and the highest frequency of PNPLA3 I148M (54%/65%). These ancestry groups had the highest outpatient alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and largest proportion of individuals with a FIB-4 score2.67. HSD17B13 pLoF variants were associated with reduced ALT (p = 0.002), AST (p =0.001), and FIB-4 score (p = 0.045). PNPLA3 I148M was associated with increased ALT, AST, and FIB-4 score (p0.001 for all). HSD17B13 pLoF variants mitigated the increase in ALT conferred by PNPLA3 I148M (p = 0.006).Variation in HSD17B13 and PNPLA3 variants across genetic ancestry groups may contribute to differential risk for liver fibrosis among Hispanic/Latino individuals.

Viral hepatitis leads to immune-mediated liver injury. The rate of disease progression varies between individuals. We aimed to phenotype immune cells associated with preservation of normal liver function during hepatitis C virus (HCV) infection. Clinical data and specimens were obtained from 19 HCV-infected patients undergoing liver transplantation. Liver and peripheral blood mononuclear cells were isolated and eight subsets of innate immune cells were delineated by multiparameter flow cytometry. Cytokine assays and microarrays were performed. Intrahepatic CD56Bright/CD16- natural killer (NK) cells comprised the only subset correlating with better liver function, i.e., lower bilirubin (p = 0.0002) and lower model for end stage of liver disease scores (p = 0.03). The signature of liver NK cells from HCV-infected patients included genes expressed by NK cells in normal liver and by decidual NK cells. Portal vein blood had a higher concentration of interleukin (IL)-10 than peripheral blood (p = 0.03). LMCs were less responsive to toll-like receptor (TLR) stimulation than PBMCs, with fewer pro-inflammatory gene-expression pathways up-regulated after in vitro exposure to lipopolysaccharide and a TLR-7/8 agonist. Hepatic CD56Bright/CD16- NK cells may be critical for maintaining liver homeostasis. Portal vein IL-10 may prime inhibitory pathways, attenuating TLR signaling and reducing responsiveness to pro-inflammatory stimuli.

Coronavirus disease 2019 (COVID‐19) has created an emergency of epic proportions. While a vaccine may be forthcoming, this is not guaranteed, as discussed herein. The potential problems and ominous signs include (1) lung injury that developed in animals given an experimental vaccine for the severe acute respiratory syndrome coronavirus (SARS‐CoV)‐1; (2) a perversion of adaptive immune responses called antibody‐dependent enhancement of infection that occurs in SARS‐CoV‐1 and that may occur in people vaccinated for COVID‐19; (3) the frequent and recurrent infections that are caused by respiratory coronaviruses; and (4) the appearance of mutations in SARS‐CoV‐2 proteins, which raise the specter of vaccine escape mutants. Because success is uncertain, alternatives to vaccines need to be vigorously pursued during this critical moment in the pandemic. Alternatives include (1) engineered monoclonal antibodies that do not cause antibody‐dependent enhancement; (2) cocktails of antiviral drugs and inhibitors of the cellular proteins required for SARS‐CoV‐2 replication; (3) interferons; and (4) anticoagulants, antioxidants, and immune modulators. To organize and coordinate the systematic investigation of existing therapies and new therapies (as they emerge), a Covid‐19 clinical trials network is needed to provide (1) robust funding (on a par with vaccine funding) and administration; (2) an adaptive trial design committee to prioritize interventions and review results in real time; (3) a computer interface to facilitate patient enrollment, make data available to investigators, and present findings; (4) a practice guidelines study group; and (5) a mobile corps of COVID‐19 experts available for rapid deployment, to assist local health care providers and enroll patients in trials as outbreaks occur. To combat the COVID‐19 pandemic and future mass contagions, the network would be a cornerstone of a comprehensive infectious diseases research program.

Background Currently, there are no recognized or validated biomarkers to identify hepatocellular carcinoma patients (HCC) likely to benefit from anti–PD‐1 therapy. We evaluated the relationship between neutrophil‐lymphocyte ratio (NLR) and platelet‐lymphocyte ratio (PLR) and survival outcomes, pretreatment and after three doses (posttreatment) of nivolumab in HCC patients. Methods Medical records of HCC patients treated with nivolumab between June 2016 and July 2018 were reviewed. Kaplan‐Meier analysis and the log‐rank test were used to calculate and compare overall survival between NLR, In this study evaluating 103 patients with advanced hepatocellular carcinoma, lower neutrophil‐lymphocyte ratio (NLR) and platelet‐lymphocyte ratio (PLR) were both strongly predictive of improved survival after three cycles of nivolumab. Baseline NLR was not associated with survival. An elevated NLR and PLR in the posttreatment setting may be an early sign of treatment failure and may warrant consideration for early change in therapy.

Hepatocellular carcinoma (HCC) incidence and mortality vary by race/ethnicity and both are higher in Black patients than in Whites. For HCC surveillance, all cirrhotic patients are advised to undergo lifelong twice-annual abdominal imaging. We investigated factors associated with surveillance and HCC incidence in a diverse HCC risk group, cirrhotic patients recently cured of hepatitis C virus (HCV) infection.In this observational cohort study, all participants (n = 357) had advanced fibrosis/cirrhosis and were cured of HCV with antiviral treatment. None had Liver Imaging Reporting and Data System (LI-RADS) 2-5 lesions prior to HCV cure. Ultrasound, computed tomography, and/or magnetic resonance imaging were used for surveillance.At a median follow-up of 40 months [interquartile range (IQR) = 28-48], the median percentage of time up-to-date with surveillance was 49% (IQR) = 30%-71%. The likelihood of receiving a first surveillance examination was not significantly associated with race/ethnicity, but was higher for patients with more advanced cirrhosis, for example, bilirubin [odds ratio (OR) = 3.8/mg/dL, p = 0.002], private insurance (OR = 3.4, p = 0.006), and women (OR = 2.3, p = 0.008). The likelihood of receiving two or three examinations was significantly lower for non-Hispanic Blacks and Hispanics versus non-Hispanic Whites (OR = 0.39, and OR = 0.40, respectively, p 0.005 for both) and for patients with higher platelet counts (OR = 0.99/10,000 cells/µl, p = 0.01), but higher for patients with private insurance (OR = 2.8, p 0.001). Incident HCC was associated with higher bilirubin (OR = 1.7, p = 0.02) and lower lymphocyte counts (OR = 0.16, p = 0.01).Contrary to best practices, HCC surveillance was associated with sociodemographic factors (insurance status and race/ethnicity) among patients cured of HCV. Guideline-concordant surveillance is needed to address healthcare disparities.

We previously reported a higher incidence of non-albumin proteinuria and a small but significant decline in estimated glomerular filtration rate (eGFR) among HIV-negative adults randomized to emtricitabine/tenofovir disoproxil fumarate preexposure prophylaxis (FTC/TDF PrEP) versus placebo. In a nested case--control study among participants randomized to FTC/TDF PrEP, established kidney injury biomarkers measured at 12 months were not significantly different between participants who subsequently experienced one of these kidney endpoints and randomly selected controls who did not.

Background & Aims Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). Methods We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. Results Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29–4.55), decompensated cirrhosis (HR 2.91 [1.70–5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53–7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47–3.70]) and decompensated cirrhosis (OR 2.50 [1.20–5.21]) were independently associated with risk for severe COVID-19. Conclusions The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084

BACKGROUND AND AIMS Although chronic HCV infection increases mortality, thousands of patients remain diagnosed-but-untreated (DBU). We aimed to (1) develop a DBU phenotyping algorithm, (2) use it to facilitate case finding and linkage to care, and (3) identify barriers to successful treatment. APPROACH AND RESULTS We developed a phenotyping algorithm using Java and SQL and applied it to ~2.5 million EPIC electronic medical records (EMRs; data entered January 2003 to December 2017). Approximately 72,000 EMRs contained an HCV International Classification of Diseases code and/or diagnostic test. The algorithm classified 10,614 cases as DBU (HCV-RNA positive and alive). Its positive and negative predictive values were 88% and 97%, respectively, as determined by manual review of 500 EMRs randomly selected from the ~72,000. Navigators reviewed the charts of 6,187 algorithm-defined DBUs and they attempted to contact potential treatment candidates by phone. By June 2020, 30% (n = 1,862) had completed an HCV-related appointment. Outcomes analysis revealed that DBU patients enrolled in our care coordination program were more likely to complete treatment (72% [n = 219] vs. 54% [n = 256]; P

BACKGROUND The World Trade Center (WTC) attack exposed thousands of workers to toxic chemicals that have been linked to liver diseases and cancers. This study examined the relationship between the intensity of WTC dust exposure and the risk of hepatic steatosis in the WTC General Responders Cohort (GRC). METHODS All low-dose computed tomography (CT) scans of the chest performed on the WTC GRC between September 11, 2001 and December 31, 2018, collected as part of the World Trade Center Health Program, were reviewed. WTC dust exposure was categorized into five groups based on WTC arrival time. CT liver density was estimated using an automated algorithm, statistics-based liver density estimation from imaging. The relationship between the intensity of WTC dust exposure and the risk of hepatic steatosis was examined using univariate and multivariable regression analyses. RESULTS Of the 1788 WTC responders, 258 (14.4%) had liver attenuation less than 40 Hounsfield units (HU

Guidelines recommend hepatitis B (HBV) testing in individuals from endemic areas, and if positive, screening for hepatocellular carcinoma (HCC). While screening programs are well established in the Asian immigrant population in New York City (NYC), less is known about the characteristics of HBV/HCC among the African immigrant community. A retrospective review was performed of HCC cases from 2005 to 2018 at our institution. Country of origin was not documented in the electronic medical record; therefore, African immigrant status was approximated using self-identified race/ethnicity, positive HBV status, and an online registry to determine country of origin based on last name. Surnames with the greatest prevalence or density in an African country were considered. Among 4400 patients with HCC, 472 identified as non-Hispanic Black; of these, 86 were HBV+. Based on surname, it was estimated that 33 individuals were likely immigrants from Africa. In this group, median age of HCC diagnosis was 48 years (IQR 43–55). In patients with an available date of HBV diagnosis (n = 24), 17 (71%) were unaware of their HBV status when they presented with HCC. Zero patients were diagnosed with HCC through routine screening, most patients (66%) were diagnosed upon imaging evaluation of symptoms. Twelve patients (36%) underwent resection or transplantation; the remaining 64% were ineligible for surgical treatment. Of the 26 patients with follow-up data, 18 (69%) died of disease or were critically ill at last encounter, and of these, 14 (77%) died within 1 year of HCC diagnosis. In conclusion, African immigrants in NYC with HBV/HCC are at high risk of HCC related mortality at a young age. Most were unaware of their hepatitis status at the time of HCC diagnosis. No patients were enrolled in routine HCC screening; the majority were diagnosed based on imaging obtained for symptoms. Most individuals presented with inoperable disease, and the majority died within months of diagnosis. Awareness of these findings may help healthcare providers improve patient outcomes.

There is constant remodeling in a cirrhotic liver resulting in cirrhosis being spatially heterogeneous. The Laennec system, and, more recently the Beijing classification, have been used to sub-classify various degrees of cirrhosis. It is unknown how these two schemes compare with each other, how they are impacted by geographic variation, and how they correlate with clinical outcomes. Five needle biopsies were obtained from 20 explanted cirrhotic HCV livers at the time of transplantation. Collagen proportionate area (CPA) was measured by computerized quantitative morphometry. The Laennec system (4A-4C indicating increasing degrees of cirrhosis) and Beijing classification (P-progressive, R-regressive, I-indeterminate) were assessed and then correlated with CPA. Geographical variation using CPAs was calculated by the coefficient of variation (CoV). CPA of Laennec 4C cirrhosis was higher than 4A (p = 0.00008) or 4B (p = 0.0002). The CPA of the P pattern was greater than the R (p = 0.002) or I patterns (p = 0.037). The mean CoV of the five CPAs was 47.3 ± 4.5%, suggesting a significant degree of geographic variation. There was 100% overlap between the Beijing R pattern and Laennec 4A, and 80% overlap between the P pattern and Laennec 4C. Patients' platelet counts of P pattern were lower than R pattern (p = 0.008) or I pattern (p = 0.024), while Laennec 4C was lower than 4A (p = 0.036) and 4B patients (p = 0.7). There was no correlation between CPA, Laennec stage, or Beijing classification and MELD score, liver weights, total bilirubin, or albumin levels. The Laennec system and the Beijing classification are highly correlated with CPA in cirrhosis. This study confirms that there is a significant degree of geographic variation in terms of fibrosis content and cirrhosis morphology throughout the liver.

BACKGROUND In the United States, mortality after a diagnosis of hepatocellular carcinoma (HCC) is higher in patients who are Black than in patients of other racial groups. The objective of this study was to clarify factors contributing to this disparity by analyzing liver and tumor characteristics in patients with HCC who have a history of hepatitis C virus (HCV) infection. METHODS Records of patients with HCV and HCC at the authors' institution from 2003 to 2018 were retrospectively reviewed. Race and ethnicity were self-identified. Imaging, laboratory, and pathologic features were compared between Black and non-Black cohorts. RESULTS Among 1195 individuals with HCC, 390 identified as Black. At the time of HCC diagnosis, Black patients had better liver function, as measured by Child-Pugh score, Model of End-Stage Liver Disease score, histology of nontumor tissue, and fibrosis-4 (FIB-4) score (all P < .05). FIB-4 scores were

Purpose In this study, we describe the patterns of hepatocellular carcinoma (HCC) screening with imaging and factors associated with imaging modality selection in a tertiary care transplant center. Methods This was a retrospective study where all adult patients with cirrhosis and/or chronic hepatitis B virus infection referred for HCC screening with ultrasound (US), CT or MRI were identified during 2017. The association between imaging methods, demographic/clinical data were analyzed by uni- and multivariate analysis. Results A total of 1437 patients were included (median age 61y, 59% male, median BMI 27.5 kg/m(2), median AFP 3.4 ng/mL, 37% with HCV and 87% with cirrhosis). Index screening imaging method utilization included MRI (51%), US (33%) and CT (16%). Use of US as the index imaging modality for screening was significantly associated with race/ethnicity [Odds Ratio (OR) 1.71-2.01, all p < 0.05] in multivariate analysis. Presence of cirrhosis (OR 0.29, p < 0.001) and referral by a hepatologist (OR 0.23, p < 0.001) were associated with screening with MRI in the multivariate analysis; while gender, age, BMI, etiology and income at ZIP code of residence were not significantly associated with imaging modality selection. HCC was observed in 62 patients (prevalence 4.3%). Rate of HCC detection was significantly higher with MRI vs US (5.9% vs. 1.5%, p = 0.001). Conclusion MRI was the most frequently used modality (> 50%) for HCC screening in our tertiary care center, in contrast with the current practice guidelines. Race/ethnicity, cirrhosis and referral by a hepatologist were associated with the imaging method used for HCC screening.

New therapies offer hope for a cure to millions of persons living with hepatitis C virus (HCV) infection. HCV elimination is a global goal that will be difficult to achieve using the traditional paradigms of diagnosis and care. The current standard has evolved toward universal HCV screening and treatment, to achieve elimination goals. There are several steps between HCV diagnosis and cure with major barriers along the way. Innovative models of care can address barriers to better serve hardly reached populations and scale national efforts in the United States and abroad. Herein, we highlight innovative models of HCV care that aid in our progress toward HCV elimination.

ImportanceThere is an urgent need to understand patient characteristics of having COVID-19 disease and evaluate markers of critical illness and mortality.ObjectiveTo assess association of clinical features on patient outcomes.Design, Setting, and ParticipantsIn this observational case series, patient-level data were extracted from electronic medical records for 28,336 patients tested for SARS-CoV-2 at the Mount Sinai Health System from 2/24/ to 4/15/2020, including 6,158 laboratory-confirmed cases.ExposuresConfirmed COVID-19 diagnosis by RT-PCR assay from nasal swabs.Main Outcomes and MeasuresEffects of race on positive test rates and mortality were assessed. Among positive cases admitted to the hospital (N = 3,273), effects of patient demographics, hospital site and unit, social behavior, vital signs, lab results, and disease comorbidities on discharge and death were estimated.ResultsHispanics (29%) and African Americans (25%) had disproportionately high positive case rates relative to population base rates (ppConclusions and RelevanceWhile race was associated with higher risk of infection, we did not find a racial disparity in inpatient mortality suggesting that outcomes in a single tertiary care health system are comparable across races. We identified clinical features associated with reduced mortality and discharge. These findings could help to identify which COVID-19 patients are at greatest risk and evaluate the impact on survival.

Andrea D. Branch discusses the challenges of eliminating the burden of disease caused by HCV infection, despite the availability of curative antiviral treatments., Eliminating the burden of disease caused by hepatitis C virus infection is proving difficult, despite the availability of curative drug treatments. Progress will require innovations in healthcare delivery and a deeper understanding of how the liver and other vital organs survive damage caused by chronic injury.

BACKGROUND AND AIMS: To determine the prevalence of moderate-to-severe hepatic steatosis (HS) and associated risk factors in members of the World Trade Center (WTC) General Responder Cohort (GRC) who qualify for low-dose non-contrast computed tomography for lung cancer screening and compare them to non-WTC participants in the same screening program. METHODS: All participants gave written informed consent before participating in this IRB-approved study. Clinical variables and laboratory values were recorded. Hepatic attenuation measurement (Hounsfield unit; HU) was measured on low-dose computed tomography (LDCT) and a threshold attenuation value

Hepatitis C virus (HCV) is one of the most prevalent causes of chronic blood-borne infections worldwide. Despite developments of highly effective treatments, most infected individuals are unaware of their infection. Approximately 75% of infections are in low- and middle-income countries; therefore, continuing research in HCV molecular virology and the development of vaccines and affordable diagnostics is required to reduce the global burden. Various intracellular forms of the HCV nucleocapsid (core) protein are produced in cell culture; these comprise the conventional p21 core and the newly discovered shorter isoforms (minicores). Minicores lack the N-terminus of p21 core. This study was conducted to determine if minicores are secreted in cell culture and more importantly if they circulate in the blood of individuals infected with HCV. We also developed a new monoclonal antibody that detects minicores targeting a C-terminal region common to p21 core and minicores. Direct evidence of minicores requires western blot analysis to distinguish the detection of p21 core from minicores. However, the sensitivity for western blot detection of HCV proteins from blood is nil without their prior purification/enrichment from blood. Therefore, we developed a purification method based on a heparin/Mn+2 precipitation of apolipoprotein B-containing lipoproteins because HCV is thought to circulate as a hybrid lipoviral particle. Minicores are secreted in culture when cells are grown in the presence of human serum. The heparin/Mn+2 precipitate from HCV-infected cell culture supernatants and from the blood of 4 patients with high-titer genotype-1 HCV contained minicores. Conclusion: Minicores are major newly discovered HCV proteins that are secreted and circulate in blood during natural infections. Minicore proteins have translational potential as targets in diagnostic assays and in vaccine development. (Hepatology Communications 2018;2:21-28).

AIM To assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection. METHODS The real-world performance of patients treated with SMV/SOF ± ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer’s perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression. RESULTS SVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF ± RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: ± $18588) for SMV/SOF ± RBV; $223003 (± $77946) for SOF/RBV; and $126496 (± $31052) for SOF/PEG/RBV. Among patients on SMV/SOF ± RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score ≥ 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV. CONCLUSION SVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs.

Determine the frequency of moderate-to-severe hepatic steatosis (HS) in asymptomatic participants in a low-dose CT (LDCT) screening program for lung cancer, to identify risk factors, and develop recommendations.Baseline LDCT scans of the chest of 170 participants in an IRB-approved study between August 2011 and April 2016 were reviewed. Demographic variables, comorbidities, and liver function tests were documented. Hepatic and splenic attenuation values hounsfield unit (HU) were measured. Regression analyses were performed.Average liver attenuation was 57.6HU (standard deviation (SD) 9.3) and average liver/spleen (L/S) ratio was 1.3 (SD 0.3). Liver attenuation was40HU for 9 (5.3%), liver/spleen (L/S) ratio0.8 for 6 (3.5%), and either40HU or L/S ratio0.8 for 9 (5.3%). Male sex (p=0.004), diabetes (p=0.0005), emphysema (p=0.03), and high BMI (p=0.0006) were significant predictors of HS. Aspartate aminotransferase (p=0.0018) and alanine aminotransferase (p=0.012) were negatively correlated with liver attenuation. Reduced serum levels of alpha-1-antitrypsin may be a common factor of emphysema and HS.LDCT can detect HS in asymptomatic participants with frequencies similar to previous reports. If liver attenuation is below 40HU and/or L/S ratio below 0.8, further evaluation of HS to the primary care physician or liver specialist is recommended.

Patient-reported outcomes (PROs) are important measures of quality of life. Direct-acting antiviral (DAA) drugs for hepatitis C virus (HCV) improved PROs in clinical trials. We prospectively evaluated the impact of DAA-based HCV cure on PROs and liver-related outcomes in real-world patients at a large urban medical center. The short form (SF)-36 and three additional validated instruments were used. F3-4 fibrosis was defined as > 9.6 kPa by transient elastography (TE); S2-3 steatosis was defined as > 270 dB/m by TE-controlled attenuation parameter (CAP). Data were analysed by paired and unpaired t tests. Patients (n = 16) who did not achieve a sustained virologic response at 12 weeks (SVR12) were excluded. The study achieved its primary endpoint and showed a significant 30% improvement in the SF-36 vitality score, measured baseline to SVR12: 63 versus 82, P < .001 (n = 111). Scores in 24 of 25 PRO domains improved at SVR12 (P < .05). Nearly all gains exceeded 5%, indicating their clinical significance. Transaminase values and liver stiffness improved (decreased) significantly, baseline to SVR12 (P < .005), but steatosis was unchanged (P = .58). Patients with baseline F0-2 fibrosis and those with F3-F4 fibrosis both improved in 22 domains. Patients with baseline S0-S1 steatosis improved in more domains (23) than patients with S2-S3 steatosis (19). At baseline, patients with F3-F4 fibrosis and patients with S2-3 steatosis had worse scores in certain PRO domains than patients with F0-2 fibrosis or S0-S1 steatosis, but this difference resolved by SVR12. HCV cure led to meaningful gains in PROs, and these findings may encourage patients to seek treatment.

End-stage liver disease is a common cause of non-AIDS-related mortality in HIV+ patients, despite effective anti-retroviral therapies (ARTs). HIV-1 infection causes gut CD4 depletion and is thought to contribute to increased gut permeability, bacterial translocation, and immune activation. Microbial products drain from the gut into the liver via the portal vein where Kupffer cells (KCs), the resident liver macrophage, clear translocated microbial products. As bacterial translocation is implicated in fibrogenesis in HIV patients through unclear mechanisms, we tested the hypothesis that HIV infection of KCs alters their response to LPS in a TLR4-dependent manner. We showed that HIV-1 productively infected KCs, enhanced cell-surface TLR4 and CD14 expression, and increased IL-6 and TNF-α expression, which was blocked by a small molecule TLR4 inhibitor. Our study demonstrated that HIV infection sensitizes KCs to the proinflammatory effects of LPS in a TLR4-dependent manner. These findings suggest that HIV-1-infected KCs and their dysregulated innate immune response to LPS may play a role in hepatic inflammation and fibrosis and represent a novel target for therapy.

Non-alcoholic fatty liver disease (NAFLD) is a complex heterogeneous disease which affects more than 20% of the population worldwide. Some subtypes of NAFLD have been clinically identified using hypothesis-driven methods. In this study, we used data mining techniques to search for subtypes in an unbiased fashion. Using electronic signatures of the disease, we identified a cohort of 13,290 patients with NAFLD from a hospital database. We gathered clinical data from multiple sources and applied unsupervised clustering to identify five subtypes among this cohort. Descriptive statistics and survival analysis showed that the subtypes were clinically distinct and were associated with different rates of death, cirrhosis, hepatocellular carcinoma, chronic kidney disease, cardiovascular disease, and myocardial infarction. Novel disease subtypes identified in this manner could be used to risk-stratify patients and guide management.

Background Pre-exposure prophylaxis (PrEP) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) reduces the risk of HIV seroconversion but may promote bone mineral density (BMD) decline. The mechanisms of BMD decline with FTC/TDF remain unclear, and studies in HIV-positive individuals have been confounded by the effects of HIV and concomitant antiretroviral medications. We evaluated the impact of FTC/TDF on biomarkers of bone remodeling and bone mineral metabolism in HIV-negative men and women enrolled in the Partners PrEP Study. Methods In a random sample of HIV-negative participants randomized to FTC/TDF PrEP (n = 50) or placebo (n = 50), serum parathyroid hormone (PTH), bone biomarkers (C-telopeptide, procollagen 1 intact N-terminal propeptide, and sclerostin), and plasma fibroblast growth factor 23 were measured at baseline and month 24, and the percentage change was compared between groups. In a complementary analysis, we compared the change in biomarkers between participants with and without a 25% decline in glomerular filtration rate (GFR) on FTC/TDF. Results Baseline characteristics were similar between the groups (median age, 38 years; 40% women). Vitamin D insufficiency was common, but baseline GFR and PTH were in the normal range. We observed a significantly greater percent increase in serum C-telopeptide in participants randomized to FTC/TDF vs placebo (P = .03), suggesting an increase in bone remodeling. We observed no differences in the other biomarkers, or in a separate analysis comparing participants with and without a decline in GFR. Conclusions Increased bone remodeling may mediate the BMD decline observed with tenofovir-containing PrEP and antiretroviral therapy, independent of a TDF-mediated decrease in kidney function.

Plasmacytoid dendritic cells (pDCs) are “natural” interferon α (IFNα)-producing cells. Despite their importance to antiviral defense, autoimmunity, and ischemic liver graft injury, because DC subsets are rare and heterogeneous, basic questions about liver pDC function and capacity to make cytokines remain unanswered. Previous investigations failed to consistently detect IFNα mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFNα. We used a combination of molecular, biochemical, cytometric, and high-dimensional techniques to analyze DC frequencies/functions in liver and peripheral blood mononuclear cells (PBMCs) of hepatitis C virus (HCV)-infected patients, to examine correlations between DC function and gene expression of matched whole liver tissue and liver mononuclear cells (LMCs), and to determine if pDCs can produce multiple cytokines. T cells often produce multiple cytokines/chemokines but until recently technical limitations have precluded tests of polyfunctionality in individual pDCs. Mass cytometry (CyTOF) revealed that liver pDCs are the only LMC that produces detectable amounts of IFNα in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFNα (~2 million molecules of IFNα/cell/hour) and produced more IFNα than PBMCs after stimulation, p = 0.0001. LMCs secreted >14-fold more IFNα than IFNλ in 4 hours. Liver pDC frequency positively correlated with whole liver expression of “IFNα-response” pathway (R2 = 0.58, p = 0.007) and “monocyte surface” signature (R2 = 0.54, p = 0.01). Mass cytometry revealed that IFNα-producing pDCs were highly polyfunctional; >90% also made 2–4 additional cytokines/chemokines of our test set of 10. Liver BDCA1 DCs, but not BDCA3 DCs, were similarly polyfunctional. pDCs from a healthy liver were also polyfunctional. Our data show that liver pDCs retain the ability to make abundant IFNα during chronic HCV infection and produce many other immune modulators. Polyfunctional liver pDCs are likely to be key drivers of inflammation and immune activation during chronic HCV infection., Author summary This is a detailed characterization of human liver plasmacytoid dendritic cells from patients with a chronic viral infection. It revealed that these rare innate immune cells can become point sources of multiple immune activators and pro-inflammatory mediators. This study adds new information about the fundamental properties of pDCs, which are traditionally known as “natural interferon producing cells.” In fact, these cells produce an array of bioactive molecules and may play an important role in organizing the liver’s immune response.

Background & Aims There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. Methods We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). Results Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70–1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70–1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. Conclusion In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

IL-1β is an important mediator of innate inflammatory responses and has been shown to contribute to liver injury in a number of etiologies. HIV patients have increased necroinflammation and more rapid fibrosis progression in chronic liver injury compared to non-HIV-infected patients. As the resident liver macrophage is critical to the IL-1β response to microbial translocation in chronic liver disease, we aim to examine the impact of HIV-1 and LPS stimulation on the IL-1β response of the resident hepatic macrophages. We isolated primary human liver macrophages from liver resection specimens, treated them with HIV-1BaL and/or LPS ex vivo, examined the IL-1β response, and then studied underlying mechanisms. Furthermore, we examined IL-1β expression in liver tissues derived from HIV-1 patients compared to those with no underlying liver disease. HIV-1 up-regulated TLR4 and CD14 expression on isolated primary CD68+ human liver macrophages and contributed to the IL-1β response to LPS stimulation as evidenced by TLR4 blocking. Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) was shown to be involved in the IL-1β response of liver macrophages to HIV-1 infection and NLRP3 blocking experiments in primary CD68+ liver macrophages confirmed the contribution of the NLRP3-caspase 1 inflammatory signaling pathway in the IL-1β response. High in situ IL-1β expression was found in CD68+ cells in human liver tissues from HIV-1-infected patients, suggesting a critical role of IL-1β responses in patients infected by HIV. HIV infection sensitizes the IL-1β response of liver macrophages to LPS through up-regulation of CD14 and TLR4 expression and downstream activation of the NLRP3-caspase 1 pathway. These findings have implications for enhanced immune activation in HIV+ patients and mechanisms for rapid fibrosis progression in patients with chronic liver injury. Resident liver macrophages infected by HIV-1 demonstrate an increased IL-1β response to LPS that is mediated by TLR4 and downstream activation of the caspase1-NLRP3 pathway.

Background & Aim: To better understand the clinical significance of drug induced liver injury (DILI) during chemotherapy, we examined the epidemiology, incidence, and treatment effects of DILI in patients undergoing chemotherapy for genitourinary malignancies over a twoyear period. Methods: We conducted a retrospective review of 284 patients who underwent chemotherapy for prostate, bladder, testicular and renal cell carcinomas over a two year period. Those with abnormal or absent liver test (LT) results prior to chemotherapy initiation were excluded. Post chemotherapy LT results were defined as DILI if ALT>3x ULN and/or total bilirubin (TB)>2x ULN, in the absence of other more likely causes of elevated LT. Results: The cumulative incidence of DILI in the total study population was 6.1% (17/284), and in the population who had appropriate LT performed it increased to 18.9% (17/90). Chemotherapeutic agents were determined to be the cause of DILI in 82% (14/17) of patients, and the treatment plans were changed in 59% (10/17) of patients. Conclusion: In this real world study, the cumulative incidence of DILI was higher than commonly reported in clinical trials, and the majority of affected patients had to have their cancer treatment altered or interrupted.

Hepatitis C virus (HCV) is unique among RNA viruses in its ability to establish chronic infection in the majority of exposed adults. HCV persists in the liver despite interferon (IFN)‐stimulated gene (ISG) induction; robust induction actually predicts treatment failure and viral persistence. It is unclear which forms of HCV RNA are associated with ISG induction and IFN resistance during natural infections. To thoroughly delineate HCV RNA populations, we developed conditions that fully separate the strands of long double‐stranded RNA (dsRNA) and allow the released RNAs to be quantified in reverse transcription/polymerase chain reaction assays. These methods revealed that dsRNA, a pathogen‐associated molecular pattern (PAMP), comprised 52% (standard deviation, 28%) of the HCV RNA in the livers of patients with chronic infection. HCV dsRNA was proportionally higher in patients with the unfavorable IL28B TT (rs12979860) genotype. Higher ratios of HCV double‐stranded to single‐stranded RNA (ssRNA) correlated positively with ISG induction. In Huh‐7.5 cells, IFN treatment increased the total amount of HCV dsRNA through a process that required de novo viral RNA synthesis and shifted the ratio of viral dsRNA/ssRNA in favor of dsRNA. This shift was blocked by ribavirin (RBV), an antiviral drug that reduces relapse in HCV patients. Northern blotting established that HCV dsRNA contained genome‐length minus strands. Conclusion: HCV dsRNA is the predominant form in the HCV‐infected liver and has features of both a PAMP and a genomic reservoir. Interferon treatment increased rather than decreased HCV dsRNA. This unexpected finding suggests that HCV produces dsRNA in response to IFN, potentially to antagonize antiviral defenses. (Hepatology 2017;66:357–370).

Hepatitis C virus (HCV) recurrence after liver transplant (LT) is associated with worse outcomes. Ledipasvir and sofosbuvir (LDV/SOF) has been approved for HCV treatment after LT, but there is limited data on the effectiveness and safety of LDV/SOF in the “real world” setting. This multi-center study is the largest report to date, on the effectiveness and safety of LDV/SOF in the post-LT setting. Two hundred and four patients (72% male, 68% Caucasian, 66% genotype 1a, 21% METAVIR F3-F4, 49% treatment-experienced) were treated with LDV/SOF. The mean duration from LT to treatment initiation was 4.8 years. The overall sustained virologic response rate 12 weeks after completion of therapy (SVR12) was 96%. Patients treated with 8 or 12 weeks of LDV/SOF without RBV experienced an SVR12 rate of 100% and 96%, respectively. Calcineurin inhibitors were used in 89% of patients and 32% of patients underwent adjustment in immunosuppression during treatment. One episode of mild rejection, responsive to an increase in immunosuppression dosage, was observed. There was no graft loss attributed to HCV treatment. Four deaths occurred unrelated to HCV treatment, and no significant serious adverse events were documented. Conclusion: Sofosbuvir and ledipasvir with or without RBV for 8, 12, or 24 weeks in post LT patients was effective and safe with a high SVR12 rate across a spectrum of genotypes and stages of fibrosis. This article is protected by copyright. All rights reserved.

To conduct surveillance and determine the safety profile of new hepatitis C virus treatments in real-world clinical practice. Hepatic decompensation and other serious adverse events were investigated in an observational cohort study of 511 patients treated with regimens containing sofosbuvir, December 2013-June 2014. Among 499 previously stable patients (no history of hepatic decompensation during the previous 12 months), a nested case-control study was performed to identify predictors of decompensation/serious adverse event. Cases and controls were matched 1:5 based on treatment regimen and duration. Matched conditional logistic regression was used for analysis. Providers scored the likelihood that events were treatment-related (scale = 0-4). The cumulative incidence of decompensation/events was 6.4% for the total cohort. Among 499 previously stable patients, the incidence of decompensation/events was 4.5%; the mortality rate was 0.6%. Sixteen of the 499 experienced one or more serious complications considered to be at least potentially treatment-related, and the sustained virological response rate was 7/16 (44%). Two cases, both on sofosbuvir/simeprevir (without interferon or ribavirin), had complications consistent with autoimmune events (score 3, 'likely treatment-related'), and one experienced a flare of autoimmune hepatitis. Compared to controls, cases had higher baseline median model for end-stage liver disease scores (14 vs 8, P < 0.01). Decompensation/events was independently associated with lower baseline albumin (OR = 0.12/g/dL, P = 0.01) and higher total bilirubin (OR = 4.31/mg/dL, P = 0.01). Reduced hepatic function at baseline increased the risk of liver decompensation/events.