Search

Objective: To apply the new nomenclature for steatotic liver diseases (SLD), replacing nonalcoholic fatty liver disease (NAFLD) with metabolic dysfunction-associated steatotic liver disease (MASLD), in adolescents using National Health and Nutrition Examination Survey (NHANES) data., Methods: Among 1410 adolescents (12-19 years) in NHANES (2017-March, 2020), the controlled attenuation parameter (CAP) of transient elastography (TE) was used to define steatosis and fibrosis (TE ≥ 7.4 kPa). Obesity and alanine aminotransferase (ALT) ≥ 80 U/L were used to identify adolescents qualifying for hepatology referral according to practice guidelines. NAFLD was defined as liver steatosis without a specific exposure; it has no cardiometabolic risk factor requirement, unlike MASLD., Results: Steatosis (yes/no) is the first decision point in the new diagnostic protocol; however, criteria for steatosis are undefined. At the supplier (EchoSens)-recommended CAP threshold of 240 dB/m, 30.5% (95% confidence interval [CI]: 27.1%-34.0%) of adolescents had SLD and about 85% of adolescents with NAFLD met criteria for MASLD. The other 15% would receive an ambiguous diagnosis of either cryptogenic SLD or possible MASLD. At higher CAP thresholds, MASLD/NAFLD concordance increased and approached 100%. Among adolescents with MASLD-fibrosis, only 8.8% (95% CI: 0%-19.3%) had overweight/obese and ALT ≥ 80 U/L., Conclusions: The new nomenclature highlights the high prevalence of liver steatosis. At the CAP threshold of 240 dB/m, however, approximately 15% of adolescents would receive an ambiguous diagnosis, which could lead to confusion and worry. Fewer than 10% of adolescents with MASLD-fibrosis had overweight/obese and ALT ≥ 80 U/L. Revised guidelines are needed to ensure that the other 90% receive appropriate referral and liver disease care., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Chronic HCV infection induces interferon and dysregulates immune responses through inflammation and chronic antigenic stimulation. Antiviral drugs can cure HCV, providing a unique opportunity to examine the immunological restoration that does and does not occur when a chronic viral infection is eradicated. We quantified blood cytokines levels and used mass cytometry to immunophenotype peripheral blood mononuclear cells before and after HCV cure in 2 groups of patients and controls. At baseline, serum interferon α and soluble CD163 (a macrophage product) were elevated in both liver transplant and nonliver transplant patients compared to controls; the frequencies of several peripheral blood mononuclear cell populations differed from controls; and programmed death protein 1-positivity was increased in nearly all T cell subsets. Many abnormalities persisted after HCV cure, including elevated programmed death protein 1 expression on CD4 naïve and central memory T cells, elevated soluble CD163, and expansion of the plasmablast/plasma cell compartment. Several myeloid-lineage subsets, including Ag-presenting dendritic cells, remained dysregulated. In mechanistic studies, interferon α treatment increased programmed death protein 1 on human T cells and increased T cell receptor signaling. The data identify immunological abnormalities that persist after curative HCV treatment. Before cure, high levels of interferon α may stimulate programmed death protein 1 expression on human T cells, causing persistent functional changes., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Patients with advanced liver disease often have vitamin D deficiency, but the daily dosages of vitamin D 3  needed to raise their serum 25-hydrodroxyvitamin D [25(OH)D] concentrations are unknown., Objective: We aimed to establish the dose-response relationship between vitamin D 3  and 25(OH)D in patients with liver cirrhosis., Design: An open-label study of orally-administered vitamin D 3  (gelcaps) was conducted in patients with liver cirrhosis using a tiered-dosing regimen: 4,000 IU/d for baseline 25(OH)D ≤ 15 ng/mL and 2,000 IU/d for baseline 25(OH)D > 15 to ≤ 25 ng/mL (NCT01575717). Supplementation continued for 6 months, or until liver transplantation. Changes in 25(OH)D were measured after ≥ 3 months. Dose-response data on 48 patients (21 receiving 4000 IU/d and 27 receiving 2,000 IU/d) reporting ≥ 80% adherence were analyzed using generalized estimating equations (GEE)., Results: Among the 48 patients, 39 (81%) had 25(OH)D > 20 ng/mL while on supplements, and none experienced hypercalcemia. The magnitude of the increase in 25(OH)D was approximately twofold greater in patients receiving the higher dose. The mean incremental increase was 5.1 ng/ml ± 3.9 of 25(OH)D per 1000 IU/d of vitamin D 3 . Multivariable models demonstrated a significant positive relationship between baseline 25(OH)D and serum albumin (p < 0.01) and hemoglobin (p = 0.01), and a negative relationship with the MELD score (p < 0.01) and total bilirubin (p < 0.01)., Conclusions: A two-tiered dosing regimen of daily oral vitamin D 3  supplementation safely raised 25(OH)D concentrations in the majority of adults with liver cirrhosis who were adherent to supplement use., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Black patients have higher hepatocellular carcinoma (HCC)-related mortality than White patients and more often develop HCC in non-cirrhotic liver. HCC surveillance is primarily directed toward cirrhotic patients. We aimed to characterize HCC in non-cirrhotic patients and to identify factors associated with HCC beyond Milan criteria., Methods: Demographic, imaging, laboratory, and pathology data of HCC patients at our institution, 2003-2018, were reviewed, retrospectively. Race/ethnicity were self-reported. Cirrhosis was defined as a Fibrosis-4 score ≥3.25., Results: Compared to 1146 cirrhotic patients, 411 non-cirrhotic patients had larger tumors (median 4.7 cm vs. 3.1 cm, p < 0.01) and were less likely to be within Milan criteria (42.6% vs. 57.7%, p < 0.01). Among non-cirrhotic patients, Black patients had larger tumors (4.9 cm vs. 4.3 cm, p < 0.01) and a higher percentage of poorly differentiated tumors (39.4% vs. 23.1%, p = 0.02). Among cirrhotic patients, Black patients had larger tumors (3.3 cm vs. 3.0 cm, p = 0.03) and were less likely to be within Milan criteria (52.3% vs. 83.2%, p < 0.01). In multivariable analysis, lack of commercial insurance (OR 1.45 [CI 95% 1.19-1.83], p < 0.01), male sex (OR 1.34 [CI 95% 1.05-1.70], p < 0.01), absence of cirrhosis (OR 1.58 [CI 95% 1.27-1.98], p < 0.01) and Black race/ethnicity (OR 1.34 [CI 95% 1.09-1.66], p = 0.01) were associated with HCC beyond Milan criteria. Black patients had lower survival rates than other patients (p < 0.01)., Conclusions: Non-cirrhotic patients had more advanced HCC than cirrhotic patients. Black patients (with or without cirrhosis) had more advanced HCC than comparable non-Black patients and higher mortality rates. Improved access to healthcare (commercial insurance) may increase early diagnosis (within Milan criteria) and reduce disparities., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background & Aims: Genetic variants affecting liver disease risk vary among racial and ethnic groups. Hispanics/Latinos in the United States 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 from an electronic health record-linked biobank in New York City., Methods: This study included 8739 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., Results: 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 the largest proportion of individuals with a FIB-4 score greater than 2.67. HSD17B13 pLoF variants were associated with reduced ALT level (P = .002), AST level (P < .001), and FIB-4 score (P = .045). PNPLA3 I148M was associated with increased ALT level, AST level, and FIB-4 score (P < .001 for all). HSD17B13 pLoF variants mitigated the increase in ALT conferred by PNPLA3 I148M (P = .006)., Conclusions: Variation in HSD17B13 and PNPLA3 variants across genetic ancestry groups may contribute to differential risk for liver fibrosis among Hispanic/Latino individuals., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Successful treatment of hepatitis C reduces liver inflammation and fibrosis; however, patients remain at risk of developing hepatocellular carcinoma (HCC)., Aims: To identify risk factors for new-onset HCC in patients cured of hepatitis C., Methods: Imaging, histological, and clinical data on patients whose first HCC was diagnosed >12 months of post-SVR were analyzed. Histology of 20 nontumor tissues was analyzed in a blinded manner using the Knodel/Ishak/HAI system for necroinflammation and fibrosis/cirrhosis stage and the Brunt system for steatosis/steatohepatitis. Factors associated with post-SVR HCC were identified by comparison with HALT-C participants who did not develop post-SVR HCC., Results: Hepatocellular carcinoma was diagnosed in 54 patients (45 M/9F), a median of 6 years of post-SVR [interquartile range (IQR) =1.4-10y] at a median age of 61 years (IQR, 59-67). Approximately one-third lacked cirrhosis, and only 11% had steatosis on imaging. The majority (60%) had no steatosis/steatohepatitis in histopathology. The median HAI score was 3 (1.25-4), indicating mild necroinflammation. In a multivariable logistic regression model, post-SVR HCC was positively associated with non-Caucasian race (p = 0.03), smoking (p = 0.03), age > 60 years at HCC diagnosis (p = 0.03), albumin<3.5 g/dL (p = 0.02), AST/ALT>1 (p = 0.05), and platelets <100 × 10 3 cells/μL (p < 0.001). Alpha fetoprotein ≥4.75 ng/mL had 90% specificity and 71% sensitivity for HCC occurrence. Noncirrhotic patients had larger tumors (p = 0.002) and a higher prevalence of vascular invasion (p = 0.016) than cirrhotic patients., Conclusions: One-third of patients with post-SVR HCC did not have liver cirrhosis; most had no steatosis/steatohepatitis. Hepatocellular carcinomas were more advanced in noncirrhotic patients. Results support AFP as a promising marker of post-SVR HCC risk., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background & Aims: The prevalence and aetiology 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 United States., Methods: Standardised methods were used to analyse data on 47,422 participants (≥20 years old) 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 alanine aminotransferase., Results: The 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 threefold 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, compared with non-Hispanic White persons, non-Hispanic Black persons had a distinctive set of risk factors that included poverty (odds ratio [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., Conclusions: The number of people with advanced liver fibrosis has increased, creating a need to expand the liver care workforce. The risk factors for advanced fibrosis vary by race/ethnicity. These differences provide useful information for designing screening programmes. Poverty and toxic exposures were associated with the high prevalence of advanced liver fibrosis in non-Hispanic Black persons and need to be addressed., Impact and Implications: Because liver disease often produces few warning signs, simple and inexpensive screening tests that can be performed by non-specialists are needed to allow timely diagnosis 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 programs. Exposure to exogenous toxins may be especially important risk factors for advanced liver fibrosis in non-Hispanic Black persons., Competing Interests: All authors declare no relevant or material financial interests that relate to the research described in this paper. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background & Aims: 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 C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD., Methods: 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., Results: 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., Conclusions: Our study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD., Impact and Implications: 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., Competing Interests: Conflicts of interest CMR is a founder of Apath LLC; a Scientific Advisory Board member of Imvaq Therapeutics, Vir Biotechnology, and Arbutus Biopharma; and an advisor for Regulus Therapeutics and Pfizer. CEM is a cofounder of Onegevity. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: The Diabetes Prevention Program (DPP) is the gold standard lifestyle modification program that reduces incident type 2 diabetes mellitus. Patients with prediabetes and patients with non-alcoholic fatty liver disease (NAFLD) often share metabolic features; we hypothesized that the DPP could be adapted and used to improve outcomes in patients with NAFLD., Methods: NAFLD patients were recruited into a 1 year modified DPP. Demographics, medical comorbidities, and clinical laboratory values were collected at baseline, 6 and 12 months. The primary endpoint was change in weight at 12 months. Secondary endpoints were changes in hepatic steatosis, metabolic comorbidities, and liver enzymes (per-protocol basis) and retention at 6 and 12 months., Results: Fourteen NAFLD patients enrolled; three dropped out before 6 months. From baseline to 12 months, hepatic steatosis ( p  = 0.03), alanine aminotransferase ( p  = 0.02), aspartate aminotransferase ( p = 0.02), high-density lipoprotein ( p  = 0.01) and NAFLD fibrosis score ( p  < 0.001) improved, but low-density lipoprotein worsened ( p  = 0.04)., Conclusion: Seventy-nine percent of patients completed the modified DPP. Patients lost weight and had improvements in five out of six indicators of liver injury and lipid metabolism., Clinical Trial Registry Number: NCT04988204., Competing Interests: The authors declare no other conflict of interest., (© 2022 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: 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., Methods: 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., Results: 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)., Conclusions: 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., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

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 < 0.001) and to have a verified sustained virological response (67% vs. 46%; P < 0.001) than other patients. Forty-eight percent (n = 2,992) of DBU patients could not be reached by phone, which was a major barrier to engagement. Nearly half of these patients had Fibrosis-4 scores ≥ 2.67, indicating significant fibrosis. Multivariable logistic regression showed that DBUs who could not be contacted were less likely to have private insurance than those who could (18% vs. 50%; P < 0.001)., Conclusions: The digital DBU case-finding algorithm efficiently identified potential HCV treatment candidates, freeing resources for navigation and coordination. The algorithm is portable and accelerated HCV elimination when incorporated in our comprehensive program., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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 < 40) on their earliest CT. Median time after September 11, 2001 and the earliest available CT was 11.3 years (interquartile range: 8.0-14.9 years). Prevalence of liver attenuation less than 40 HU was 17.0% for arrivals on September 11, 2001, 16.0% for arrivals on (September 12, 2001 or September 13, 2001), 10.9% for arrivals on September 14-30, 2001, and 9.0% for arrivals on January 10, 2001 or later (p = 0.0015). A statistically significant trend of increasing liver steatosis was observed with earlier arrival times (p < 0.0001). WTC arrival time remained a significant independent factor for decreased liver attenuation after controlling for other covariates., Conclusions: Early arrival at the WTC site was significantly associated with increasing hepatic steatosis., (© 2021 Wiley Periodicals LLC.)

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., (Copyright © 2021 AGA Institute. All rights reserved.)

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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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 <3.25 in 31% of Black patients. In addition, Black patients had less early stage HCC (20.2% vs 32.3%; P < .05), larger tumors (median [interquartile range]: 3.5 cm [2.2-6.2 cm] vs 3.1 cm [2.1-5.1 cm]; P < .01), more multiple tumors (median, [interquartile range]: 1 tumor [1-3 tumors] vs 1 tumor [1-2 tumors]; P = .03), more poorly differentiated tumors (30.3% vs 20.5%; P < .05), and more microvascular invasion (67.2% vs 56.5%; P < .05)., Conclusions: Black patients with HCV exposure develop HCC at earlier stages of liver disease than members of other racial groups. Nearly one-third would not qualify for HCC screening using the common FIB-4 cirrhosis threshold. Practice guidelines that stress HCC surveillance for cirrhotic patients with HCV may need to be revised to be more inclusive for Black patients. In addition, tumors in Black patients carry worse prognostic features, and molecular studies are needed to characterize their biologic properties., (© 2021 American Cancer Society.)

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 CD56 Bright /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 CD56 Bright /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.

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., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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 centre. 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 vs 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<0.005), but steatosis was unchanged (p=0.58). 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., (© 2020 John Wiley & Sons Ltd.)

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., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

The epidemic of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men (MSM) is in its second decade, but the routes of transmission remain poorly understood. We hypothesized that by pairing single genome sequencing (SGS), to enumerate infecting HCV genomes (viruses), with detailed sexual and drug histories, we could gain insight into the routes of transmission among MSM. We used SGS to analyze blood specimens from eight HIV-infected MSM who had 10 episodes of acute (seronegative) or early HCV infections. Seven of eight men reported condomless receptive anal intercourse (CRAI), six with rectal exposure to semen, and all eight denied rectal trauma or bleeding. Of the 10 HCV infections, eight resulted from transmission of a single virus; one infection resulted from transmission of either one or a few (three or four) closely-related viruses; and one infection resulted from transmission of >10 distinct viruses. The participant infected by >10 viruses reported sharing injection equipment for methamphetamine during sex. Two other participants also injected methamphetamine during sex but they did not share injection equipment and were infected by a single virus. Conclusions: Most HCV infections of HIV-infected MSM without a history of either rectal trauma or bleeding or shared injection equipment were caused by a single virus. Intra-rectal exposure to semen during CRAI is therefore likely sufficient for HCV transmission among MSM. Conversely, rectal trauma or bleeding or shared injection equipment are not necessary for HCV transmission among MSM. These results help clarify routes of HCV transmission among MSM and can therefore help guide the design of much-needed behavioral and other interventions to prevent HCV transmission among MSM., Competing Interests: I have read the journal's policy and the following authors of this manuscript have the following competing interests: Kristen M. Marks: reports research funding paid to her institution outside the submitted work from Gilead Sciences, Merck, and Bristol-Myers Squibb Andrew H. Talal: reports having served as a speaker, a consultant, and an advisory board member for Abbott Laboratories, and has received research funding from Merck Inc, Gilead, Abbott Laboratories, AbbVie, Intercept, Conatus, and Bristol-Myers-Squibb. Bisher Akil: reports receiving contract, consultant, and speaker fees from ViiV Healthcare Andrea D. Branch: reports having served as a consultant to Boehringer Ingelheim and receiving research funding paid to her institution from Gilead Sciences Daniel S. Fierer: reports research funding paid to his institution outside the submitted work from Gilead Sciences and Merck. The following authors have declared that no competing interests exist: Hui Li; Wouter O. van Seggelen; Asa Radix; Shirish Huprikar; Shuyi Wang; George M. Shaw. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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 < 5 Vs ≥ 5 and among PLR tertiles., Results: A total of 103 patients were identified. Median age was 66 (29-89) years. Median treatment duration was 26 (2-149) weeks. Sixty-four (62%) patients had Child-Pugh class A (CP-A) liver function. Barcelona Clinic Liver Cancer stage was B in 20 (19%) and C in 83 (81%) patients. CP-A patients who achieved a partial or complete response had significantly lower posttreatment NLR and PLR (P < .001 for both) compared to patients who had stable disease or progression of disease. No relationship was observed between response and pretreatment NLR and PLR. NLR < 5 was associated with improved OS compared to NLR ≥ 5 both pretreatment (23 Vs10 months, P = .004) and posttreatment (35 Vs 9 months, P < .0001). Survival also differed significantly among PLR tertiles both pre- (P = .05) and posttreatment (P = .013). In a multivariable model, posttreatment NLR (HR = 1.10, P < .001) and PLR (HR = 1.002, P < .001) were strongly associated with survival. In a composite model of posttreatment NLR and PLR, a combination of high NLR and PLR was associated with an eightfold increased risk of death (HR = 8.3, P < .001)., Conclusions: This study suggests a strong predictive role of these inflammatory cell ratios in the posttreatment setting in HCC patients treated with anti anti-PD-1 therapy and should be evaluated in a larger cohort., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2019 John Wiley & Sons Ltd.)

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 <40HU indicated moderate-to-severe HS. Bivariate and multivariable linear and logistic regression analyses were performed. Propensity scores (PS) were calculated and inverse probability weighting (IPW) was used to adjust for potential confounders when comparing the WTC with non-WTC participants., Results: The prevalence of moderate-to-severe HS was 16.2% among 154 WTC participants compared to 5.3% among 170 non-WTC participants. In WTC members, moderate-to-severe HS was associated with higher BMI, higher laboratory liver function tests, and former smoking status. Using PS analysis and IPW to account for potential confounders, the odds ratio for moderate-to-severe HS was 3.4-fold higher (95% confidence interval: 1.7-6.7) in the WTC participants compared with non-WTC participants. Moderate-to-severe HS was also associated with higher BMI and former smoker status., Conclusion: Prevalence of moderate-to-severe HS was >3-fold higher in the WTC-GRC group than in other participants., Competing Interests: Declaration of competing interest Dr. Yankelevitz is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest including measurement of nodules. Some of these, which are owned by Cornell Research Foundation (CRF), are non-exclusively licensed to General Electric. As an inventor of these patents, Dr. Yankelevitz is entitled to a share of any compensation which CRF may receive from its commercialization of these patents. He is also an equity owner in Accumetra, a privately held technology company committed to improving the science and practice of image-based decision making (7 Corporate Drive, Clifton Park, NY 12065; Tel: 518–280-7530; http://accumetra.com/). Dr. Yankelevitz also serves on the advisory board of GRAIL (1525 O'Brien Drive, Menlo Park, CA 94025; Tel: 650–542-0372; https://grail.com/). Dr. Henschke is the President and serves on the board of the Early Diagnosis and Treatment Research Foundation. She receives no compensation from the Foundation. The Foundation is established to provide grants for projects, conferences, and public databases for research on early diagnosis and treatment of diseases. Dr. Claudia Henschke is also a named inventor on a number of patents and patent applications relating to the evaluation of pulmonary nodules on CT scans of the chest which are owned by Cornell Research Foundation (CRF). Since 2009, Dr. Henschke does not accept any financial benefit from these patents including royalties and any other proceeds related to the patents or patent applications owned by CRF. Other authors declare no conflicts of interest., (Copyright © 2019. Published by Elsevier Inc.)

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., Competing Interests: Disclosures: The author declares no competing interests exist., (© 2020 Branch.)

Purpose: Develop and validate an automated method for measuring liver attenuation in non-contrast low-dose chest CT (LDCT) scans and compare it to the standard manual method for identifying moderate-to-severe hepatic steatosis (HS)., Method: The automated method identifies a region below the right lung within the liver and uses statistical sampling techniques to exclude non-liver parenchyma. The method was used to assess moderate-to-severe HS on two IRB-approved cohorts: 1) 24 patients with liver disease examined between 1/2013-1/2017 with non-contrast chest CT and abdominal MRI scans obtained within three months of liver biopsy, and 2) 319 lung screening participants with baseline LDCT performed between 8/2011-1/2017. Agreement between the manual and automated CT methods, the manual MRI method, and pathology for determining moderate-to-severe HS was assessed using Cohen's Kappa by applying a 40 HU threshold to the CT method and 17.4% fat fraction to MRI. Agreement between the manual and automated CT methods was assessed using the intraclass correlation coefficient (ICC). Variability was assessed using Bland-Altman limits of agreement (LoA)., Results: In the first cohort, the manual and automated CT methods had almost perfect agreement (ICC = 0.97, κ = 1.00) with LoA of -7.6 to 4.7 HU. Both manual and automated CT methods had almost perfect agreement with MRI (κ = 0.90) and substantial agreement with pathology (κ = 0.77). In the second cohort, the manual and automated CT methods had almost perfect agreement (ICC = 0.94, κ = 0.87). LoA were -10.6 to 5.2 HU., Conclusion: Automated measurements of liver attenuation from LDCT scans can be used to identify moderate-to-severe HS on LDCT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background & Aims: There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy., Methods: We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting., Results: Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18-0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55-2.33)., Conclusions: In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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-1 BaL 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., (©2019 Society for Leukocyte Biology.)

Purpose: The objectives of our study included comparing reproductive histories and causes of infertility between patients with and without a hysterosalpingogram (HSG) investigation, and summarizing the prevalence and extent of tubal abnormalities among patients who underwent HSG. Outcomes following assisted reproductive technology (ART) were compared between HSG and non-HSG groups., Materials and Methods: A cross-sectional study was conducted to review the medical records of 200 Saudi women with subfertility. In addition to information on HSG, patient data extracted included age, body mass index (BMI), infertility duration, miscarriage experience, parity, cause of infertility, and history of previous surgery, ectopic pregnancy, endometriosis, tubal surgery, pelvic inflammatory disease (PID), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), pregnancy, and live birth., Results: One hundred and ninety six (98.0%) patients had either IVF (n=18; 9.0%) or ICSI (n=178; 89.0%) performed; ICSI was performed in 157 (90%) and 21 (81%) patients. Of the 12 women with tubal factor who did not undergo HSG, 3 (25.0%) became pregnant after ART, 8 (66.7%) did not, and the status of 1 (8.3%) is yet unknown., Conclusions: Our study aimed to contribute to resolving the debate regarding the continuing role of HSG in an environment where ART has become established as a successful approach to treat infertility. Most of the HSGs were done as per the attending physician's discretion, and not according to any specific policy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The complement system bridges innate and adaptive immunity against microbial infections, with viral infection being a major trigger. Activation of the classical, alternative, and lectin pathways have been reported in chronic hepatitis C virus (HCV) infection and/or cryoglobulinemia. HCV infection leads to dysregulation of complement-mediated immune responses. Clinical and experimental evidence support involvement of complement in intra- and extrahepatic manifestations of HCV infection, such as liver fibrosis and type II cryoglobulinemia. In this review, we summarize studies that have investigated the interplay between HCV and the complement system to establish chronic infection and autoimmunity, as well as the association between HCV pathogenesis and abnormal complement profiles. Several unanswered questions are highlighted which suggest additional informative lines of investigation.

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 two-year 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>3× ULN and/or total bilirubin (TB)>2× 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.

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., Competing Interests: Conflict-of-interest statement: Dr. Kian Bichoupan is a paid consultant for Gilead Sciences and Janssen Pharmaceuticals, Inc. Neeta Tandon is an employee of Johnson and Johnson. Dr. Andrea D Branch received research support from Gilead Sciences and Janssen Pharmaceuticals, Inc. Dr. Douglas T Dieterich serves as a paid lecturer, consultant and is a member on scientific advisory boards of companies which either develop or assess medicines used for the treatment of viral hepatitis. These companies include Gilead Sciences, Abbvie, Achillion, Bristol-Myers Squibb, Merck, and Janssen Pharmaceuticals, Inc. Dr. Thomas D Schiano is a paid consultant for Salix, Merck, Gilead, BMS, Novartis and Janssen and received research support from Mass biologics, Gilead, Merck, Biotest and Genentech. Michel Ng is a paid member of AbbVie’s Speakers bureau. Dr. Ponni V Perumalswami receives research support from Gilead Sciences. Dr. Keith M Sigel has served on an advisory board for Gilead Sciences. Dr. James Crismale, Dr Meena B Bansal, Dr. Joshua Hartman, Dr. Sweta Chekuri, Alyson Harty, Dr. Joseph A Odin, Dr. Priya Grewal, Dr. Nancy Bach, Dr. Lawrence Liu, Dr. Charissa Y Chang, Dr. Gene Y Im, Dr. Jennifer Leong, Dr. David Del Bello, Dr. Neal M Patel and Dr. Scott L Friedman do not have any relevant disclosures.

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).

Objective: 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., Methods: 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., Results: 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 was <40HU for 9 (5.3%), liver/spleen (L/S) ratio <0.8 for 6 (3.5%), and either <40HU or L/S ratio <0.8 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., Conclusion: 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., (Copyright © 2017. Published by Elsevier B.V.)

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)., (© 2016 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Aim: To evaluate new therapies for hepatitis C virus (HCV), data about real-world outcomes are needed., Methods: Outcomes of 223 patients with genotype 1 HCV who started telaprevir- or boceprevir-based triple therapy (May 2011-March 2012) at the Mount Sinai Medical Center were analyzed. Human immunodeficiency virus-positive patients and patients who received a liver transplant were excluded. Factors associated with sustained virological response (SVR24) and relapse were analyzed by univariable and multivariable logistic regression as well as classification and regression trees. Fast virological response (FVR) was defined as undetectable HCV RNA at week-4 (telaprevir) or week-8 (boceprevir)., Results: The median age was 57 years, 18% were black, 44% had advanced fibrosis/cirrhosis (FIB-4 ≥ 3.25). Only 42% (94/223) of patients achieved SVR24 on an intention-to-treat basis. In a model that included platelets, SVR24 was associated with white race [odds ratio (OR) = 5.92, 95% confidence interval (CI): 2.34-14.96], HCV sub-genotype 1b (OR = 2.81, 95%CI: 1.45-5.44), platelet count (OR = 1.10, per x 10 4 cells/μL, 95%CI: 1.05-1.16), and IL28B CC genotype (OR = 3.54, 95%CI: 1.19-10.53). Platelet counts > 135 x 10 3 /μL were the strongest predictor of SVR by classification and regression tree. Relapse occurred in 25% (27/104) of patients with an end-of-treatment response and was associated with non-FVR (OR = 4.77, 95%CI: 1.68-13.56), HCV sub-genotype 1a (OR = 5.20; 95%CI: 1.40-18.97), and FIB-4 ≥ 3.25 (OR = 2.77; 95%CI: 1.07-7.22)., Conclusion: The SVR rate was 42% with telaprevir- or boceprevir-based triple therapy in real-world practice. Low platelets and advanced fibrosis were associated with treatment failure and relapse., Competing Interests: Conflict-of-interest statement: Kian Bichoupan is a paid consultant for Gilead Sciences and Janssen Pharmaceuticals, Inc. Dr. Andrea D Branch is a paid consultant for Gilead Sciences and Janssen Pharmaceuticals, Inc. Dr. Douglas T Dieterich serves as a paid lecturer, consultant and is a member on scientific advisory boards of companies which either develop or assess medicines used for the treatment of viral hepatitis. These companies include Gilead Sciences, Abbvie, Achillion, Bristol-Myers Squibb, Merck, and Janssen Pharmaceuticals, Inc. Dr. Thomas D Schiano is a paid consultant for Salix, Merck, Gilead, BMS, Novartis and Janssen and received research support from Mass biologics, Gilead, Merck, Biotest and Genentech. Michel Ng is a paid member of AbbVie’s Speakers bureau. Viktoriya Khaitova is a paid member of a scientific advisory board for Abbvie, and Johnson & Johnson. Dr. Valerie Martel-Lafferiere, Dr. Emily A Schonfeld, Dr. James Crismale, Alicia Stivala, Donald Gardenier, Dr. David Sachs, Dr. Joseph A. Odin, Dr. Lawrence Liu, Dr. Neal M Patel, and Dr. Ponni V Perumalswami do not have any disclosures.

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., (© 2016 John Wiley & Sons Ltd.)

Background and Aim: To investigate the impact of a sustained virological response (SVR) to hepatitis C virus (HCV) treatment on liver stiffness (LS)., Methods: LS, measured by transient elastography (FibroScan), demographic and laboratory data of patients treated with interferon (IFN)-containing or IFN-free regimens who had an SVR24 (undetectable HCV viral load 24 weeks after the end of treatment) were analyzed using two-tailed paired t-tests, Mann-Whitney Wilcoxon Signed-rank tests and linear regression. Two time intervals were investigated: pre-treatment to SVR24 and SVR24 to the end of follow-up. LS scores ≥ 12.5 kPa indicated LS-defined cirrhosis. A p-value below 0.05 was considered statistically significant., Results: The median age of the patients (n = 100) was 60 years [IQR (interquartile range) 54-64); 72% were male; 60% were Caucasian; and 42% had cirrhosis pre-treatment according to the FibroScan measurement. The median LS score dropped from 10.40 kPa (IQR: 7.25-18.60) pre-treatment to 7.60 kPa (IQR: 5.60-12.38) at SVR24, p <0.01. Among the 42 patients with LS-defined cirrhosis pre-treatment, 25 (60%) of patients still had LS scores ≥ 12.5 kPa at SVR24, indicating the persistence of cirrhosis. The median change in LS was similar in patients receiving IFN-containing and IFN-free regimens: -1.95 kPa (IQR: -5.75 --0.38) versus -2.40 kPa (IQR: -7.70 --0.23), p = 0.74. Among 56 patients with a post-SVR24 LS measurement, the LS score changed by an additional -0.90 kPa (IQR: -2.98-0.5) during a median follow-up time of 1.17 (IQR: 0.88-1.63) years, which was not a statistically significant decrease (p = 0.99)., Conclusions: LS decreased from pre-treatment to SVR24, but did not decrease significantly during additional follow-up. Earlier treatment may be needed to reduce the burden of liver disease.

Background: Patients with hepatitis C virus (HCV) with or without human immunodeficiency virus (HIV) achieve high sustained virological response (SVR) rates on sofosbuvir (SOF)-containing regimens in clinical trials. Real world data on patients coinfected with HCV and HIV treated with SOF-based regimens are lacking., Methods: This observational cohort study included HIV/HCV-coinfected adults with genotype 1 HCV who initiated treatment with a SOF-containing regimen between December 2013 and December 2014 (n = 89) at the Mount Sinai Hospital or the Brooklyn Hospital Center. The primary outcome was SVR at 12 weeks after the end of treatment. The secondary outcomes were risk factors for treatment failure, serious adverse events, and side effects. A post hoc per protocol analysis of SVR was performed on patients who completed treatment and follow-up., Results: In an intention-to-treat analysis, SVR rates were 76% (31/41) for simeprevir (SMV)/SOF, 94% (16/17) for SMV/SOF/ribavirin (RBV), and 52% (16/31) for SOF/RBV. The SVR rates of SMV/SOF/RBV and SMV/SOF did not differ significantly in this small study (P = .15). However the SVR rate of SMV/SOF/RBV was higher than that of SOF/RBV (P < .01). In a per protocol analysis, SMV/SOF/RBV had a higher SVR rate than SOF/RBV: 100% (16/16) vs 57% (16/28) (P < .01). The most commonly reported adverse effects were rash, pruritus, fatigue, and insomnia. One patient who had decompensated cirrhosis prior to treatment initiation died after receiving SMV/SOF., Conclusions: SMV/SOF ± RBV is an effective option with minimal adverse effects for most HIV-positive patients with genotype 1 HCV. SMV should be used with caution in patients with decompensated cirrhosis., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Mutations at positions 70 and/or 91 in the core protein of genotype-1b, hepatitis C virus (HCV) are associated with hepatocellular carcinoma (HCC) risk in Asian patients. To evaluate this in a US population, the relationship between the percentage of 70 and/or 91 mutant HCV quasispecies in baseline serum samples of chronic HCV patients from the HALT-C trial and the incidence of HCC was determined by deep sequencing. Quasispecies percentage cut-points, ≥42% of non-arginine at 70 (non-R(70)) or ≥98.5% of non-leucine at 91 (non-L(91)) had optimal sensitivity at discerning higher or lower HCC risk. In baseline samples, 88.5% of chronic HCV patients who later developed HCC and 68.8% of matched HCC-free control patients had ≥42% non-R(70) quasispecies (P = 0.06). Furthermore, 30.8% of patients who developed HCC and 54.7% of matched HCC-free patients had quasispecies with ≥98.5% non-L(91) (P = 0.06). By Kaplan-Meier analysis, HCC incidence was higher, but not statistically significant, among patients with quasispecies ≥42% non-R(70) (P = 0.08), while HCC incidence was significantly reduced among patients with quasispecies ≥98.5% non-L(91) (P = 0.01). In a Cox regression model, non-R(70) ≥42% was associated with increased HCC risk. This study of US patients indicates the potential utility of HCV quasispecies analysis as a non-invasive biomarker of HCC risk.

Background: Sub-Saharan African nations have among the highest rates of chronic hepatitis B virus (HBV) infection worldwide, but little is known about HBV infection in African-born persons in the United States., Methods: From October 2011 to July 2013, community-based HBV screenings were conducted targeting persons originating from Africa in New York City. Persons were identified as currently HBV infected (HBsAg positive) or exposed (HBcAb positive)., Results: Overall, 955 persons were screened for HBV; the median age was 45 years (interquartile range, 35-54 years) and 75.5% were men. Of these, 919 persons had no history of liver disease, of whom 9.6% (n = 88) had current HBV infection and 73.9% (n = 679) had exposure. In logistic regression, older age (odds ratio [OR], 0.97; 95% confidence interval [CI], .94-.99; P < .01) and female sex (OR, 0.35; 95% CI, .14-.75; P < .01) were less likely to be associated with HBV infection, whereas having a mother with hepatitis was associated with infection (OR, 18.8; 95% CI, 2.72-164.65; P < .01). HBV exposure was associated with older age (OR, 1.03; 95% CI, 1.01-1.04; P < .01), whereas female sex (OR, 0.46; 95% CI, .33-.66; P < .01) and history of blood transfusion (OR, 0.43; 95% CI, .22-.83; P = .01) were negatively associated. A patient navigator linked 97% of infected persons to care. Eleven persons were recommended for treatment, of whom 9 (82%) started therapy. Three persons were diagnosed with hepatocellular carcinoma on the first screening ultrasound., Conclusions: The high burden of HBV infection among African immigrants in the United States underscores a need for continued screening and linkage to care in this at-risk population., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: In the era of combination therapy for human immunodeficiency virus (HIV), liver disease, and hepatocellular carcinoma (HCC) are major causes of death for patients coinfected with HIV and hepatitis B virus (HBV). This study compared HIV provider and hepatologist awareness of and adherence to the American Association for the Study of Liver Diseases (AASLD) practice guidelines for chronic HBV management. The primary endpoint of HIV provider adherence to HCC screening recommendations was compared to that of hepatologists at a large metropolitan academic medical center., Methods: Medical record database searches by ICD-9 codes were used to identify HIV/HBV coinfected (n = 144) and HBV monoinfected (n = 225) patients who were seen at least twice over a 2-year period in outpatient clinics. Adherence to AASLD guidelines was assessed by chart review. Provider awareness was evaluated through a voluntary anonymous survey with knowledge-based questions., Results: Over a 2-year period, only 36.0% of HIV/HBV coinfected patients seen in HIV practices completed HCC screening compared to 81.8% of HBV monoinfected patients in hepatology practices (P < .00001). Similarly, HIV providers less frequently monitored HBV viral load (P < .0001), HBeAg/anti-HBe (P < .00001), HBsAg/anti-HBs (P < .00001) than hepatologists but screened more often for hepatitis A immunity (P = .028). Self-reported adherence and knowledge scores were similar among 19 HIV providers and 16 hepatologists., Conclusions: HIV providers ordered significantly fewer HCC screening and HBV monitoring tests than hepatologists within a single academic medical center. In the setting of increased reliance on quality indicators for care, both patients and providers will benefit from greater adherence to established guidelines., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Although patients infected by genotype 1b hepatitis C virus (HCV) with Q(70) and/or M(91)core gene mutations have an almost five-fold increased risk of developing hepatocellular carcinoma (HCC) and increased insulin resistance, the absence of a suitable experimental system has precluded direct experimentation on the effects of these mutations on cellular gene expression., Methods: HuH7 cells were treated long-term with human serum to induce differentiation and to produce a model system for testing high-risk and control HCV. For clinical validation, profiles of infected cells were compared to each other and to those of liver biopsies of patients with early-stage HCV-related cirrhosis followed prospectively for up to 23 years (n=216)., Results: Long-term culture in human serum produced growth-arrested, hepatocyte-like cells whose gene profile overlapped significantly with that of primary human hepatocytes. High-risk (Q(70)/M(91)) and control (R(70)/L(91)) viruses had dramatically different effects on gene expression of these cells. The high-risk virus enhanced expression of pathways associated with cancer and type II diabetes, while the control virus enhanced pathways associated with oxidative phosphorylation. Of special clinical relevance, the transcriptome of cells replicating the high-risk virus correlated significantly with an HCC high-risk profile in patients (Bonferroni-corrected p=0.03), whereas no such association was observed for non-HCC-related clinical outcomes., Conclusions: The cell-based system allowed direct head-to-head comparison of HCV variants, and provided experimental support for previous clinical data indicating an oncogenic effect of core gene mutations. This simple experimental system distinguished HCV variants and will enable future mechanistic analysis and exploration of interventional approaches., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aim: To determine risk factors associated with hepatitis C virus (HCV) treatment failure after direct acting antivirals in patients with complex treatment histories., Methods: All HCV mono-infected patients who received treatment at our institution were queried. Analysis was restricted to patients who previously failed treatment with boceprevir (BOC) or telaprevir (TVR) and started simeprevir (SMV) and sofosbuvir (SOF) ± ribavirin (RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus (HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December, 31(st) 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics, HCV infection, and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/SOF., Results: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon (PEG) and RBV who failed this triple therapy were subsequently re-treated with an off-label all-oral regimen of SMV and SOF for 12 wk, with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response, but later relapsed. Eight (100%) patients were male. Mean age was 56 (range, 49-64). Eight (100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6 (mean 3.8). Eight (100%) patients were male had liver cirrhosis as determined by Fibroscan or MRI. Seven (87.5%) patients had genotype 1a HCV. Seven (87.5%) patients had over 1 million IU/mL HCV RNA at the time of re-treatment., Conclusion: This study identifies factors associated with SMV/SOF treatment failure and provides evidence that twleve weeks of SMV/SOF/RBV is insufficient in cirrhotics with high-titer genotype 1a HCV.

New and relatively well-tolerated medications to treat hepatitis C virus (HCV) infection have presented an opportunity for hepatologists to eliminate HCV in liver transplant (LT) candidates prior to transplantation. While concern for causing decompensated liver disease in the sickest subset of pre-transplant patients makes some clinicians reluctant to offer treatment, we believe that several advantages of early HCV eradication appear to shift the debate in favor of using anti-HCV agents before LT. There are encouraging safety data for new HCV medications in cirrhotic patients, and given the limited supply of donor livers available, delaying or possibly preventing the need for LT by treating HCV can offer significant benefit. Post-LT, making immunosuppression management easier as well as avoiding both extrahepatic manifestations of HCV (e.g., diabetes mellitus and kidney disease) and the dilemma of distinguishing post-transplant viral recurrence from allograft rejection makes earlier treatment of HCV especially appealing to clinicians. Furthermore, retrospective data have demonstrated a mortality benefit among HCV patients who are free of the virus at the time of LT. This article explores arguments for and against treating HCV in patients on the transplant list., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)