Integrated Hepatitis C-Opioid Use Disorder Care Through Facilitated Telemedicine: A Randomized Trial.

Importance: Facilitated telemedicine may promote hepatitis C virus elimination by mitigating geographic and temporal barriers. Objective: To compare sustained virologic responses for hepatitis C virus among persons with opioid use disorder treated through facilitated telemedicine integrated into opioid treatment programs compared with off-site hepatitis specialist referral. Design, Setting, and Participants: Prospective, cluster randomized clinical trial using a stepped wedge design. Twelve programs throughout New York State included hepatitis C-infected participants (n = 602) enrolled between March 1, 2017, and February 29, 2020. Data were analyzed from December 1, 2022, through September 1, 2023. Intervention: Hepatitis C treatment with direct-acting antivirals through comanagement with a hepatitis specialist either through facilitated telemedicine integrated into opioid treatment programs (n = 290) or standard-of-care off-site referral (n = 312). Main Outcomes and Measures: The primary outcome was hepatitis C virus cure. Twelve programs began with off-site referral, and every 9 months, 4 randomly selected sites transitioned to facilitated telemedicine during 3 steps without participant crossover. Participants completed 2-year follow-up for reinfection assessment. Inclusion criteria required 6-month enrollment in opioid treatment and insurance coverage of hepatitis C medications. Generalized linear mixed-effects models were used to test for the intervention effect, adjusted for time, clustering, and effect modification in individual-based intention-to-treat analysis. Results: Among 602 participants, 369 were male (61.3%); 296 (49.2%) were American Indian or Alaska Native, Asian, Black or African American, multiracial, or other (ie, no race category was selected, with race data collected according to the 5 standard National Institutes of Health categories); and 306 (50.8%) were White. The mean (SD) age of the enrolled participants in the telemedicine group was 47.1 (13.1) years; that of the referral group was 48.9 (12.8) years. In telemedicine, 268 of 290 participants (92.4%) initiated treatment compared with 126 of 312 participants (40.4%) in referral. Intention-to-treat cure percentages were 90.3% (262 of 290) in telemedicine and 39.4% (123 of 312) in referral, with an estimated logarithmic odds ratio of the study group effect of 2.9 (95% CI, 2.0-3.5; P < .001) with no effect modification. Observed cure percentages were 246 of 290 participants (84.8%) in telemedicine vs 106 of 312 participants (34.0%) in referral. Subgroup effects were not significant, including fibrosis stage, urban or rural participant residence location, or mental health (anxiety or depression) comorbid conditions. Illicit drug use decreased significantly (referral: 95% CI, 1.2-4.8; P = .001; telemedicine: 95% CI, 0.3-1.0; P < .001) among cured participants. Minimal reinfections (n = 13) occurred, with hepatitis C virus reinfection incidence of 2.5 per 100 person-years. Participants in both groups rated health care delivery satisfaction as high or very high. Conclusions and Relevance: Opioid treatment program-integrated facilitated telemedicine resulted in significantly higher hepatitis C virus cure rates compared with off-site referral, with high participant satisfaction. Illicit drug use declined significantly among cured participants with minimal reinfections. Trial Registration: ClinicalTrials.gov Identifier: NCT02933970.

Telehealth and delivery of alcohol use disorder treatment in the Veterans Health Administration.

BACKGROUND: The use of telehealth treatment of alcohol use disorder (AUD) has increased since the start of the COVID-19 pandemic. However, it is unclear which patients are using telehealth and how telehealth visits are associated with treatment duration. This study examined characteristics associated with telehealth use among Veterans Health Administration patients receiving AUD treatment. METHODS: Using a national retrospective cohort study, we examined data from March 01, 2020 to February 28, 2021 to: First, identify patient characteristics associated with (a) any telehealth versus only in-person care for AUD treatment, and (b) video (≥1 video visit) versus only telephone visits for AUD treatment (≥1 telephone visit, no video) among any telehealth users. This analysis used mixed-effects logistic regression models to adjust for potential correlation across patients treated at the same facility. Second, we assessed whether visit modality was associated with the amount of AUD treatment received (number of AUD psychotherapy visits or medication coverage days). This analysis used mixed-effects negative binomial regression models. RESULTS: Among 138,619 patients who received AUD treatment, 52.8% had ≥1 video visit, 38.1% had ≥1 telephone but no video visits, and 9.1% had only in-person visits. In the regression analyses, patients who were male or had an opioid or stimulant use disorder (compared to having no non-AUD substance use disorder) were less likely to receive any telehealth-delivered AUD treatment compared to only in-person AUD treatment. Among patients who received any telehealth-delivered AUD treatment, those who were ≥45 years old (compared to 18-29 years old), Black (compared to White), diagnosed with a cannabis or stimulant use disorder, or diagnosed with a serious mental illness were less likely to receive a video visit than only telephone visits. Receiving any AUD telehealth was associated with receiving more psychotherapy visits and medication coverage days than only in-person care. CONCLUSIONS: Telehealth, a common modality for AUD treatment, supported a greater number of psychotherapy visits and a longer duration of medication treatment for AUD. However, some groups were less likely to receive any video telehealth than telephone visits, suggesting that multiple treatment modalities should remain available to ensure treatment access.

Reexamining "psychosocial clearance": A procedural framework for psychosocial evaluation in liver transplantation.

Psychosocial and "nonmedical" phenomena are commonly encountered in liver transplantation (LT) evaluations. They are simultaneously crucial decision-making factors and some of the most difficult and controversial clinical matters clinicians confront. Epidemiology, societal trends, and the preponderance of psychological and behavioral factors underpinning common end-stage liver diseases ensure that LT teams will continue to encounter highly complex psychosocial patient presentations. Psychosocial policies, practices, and opinions vary widely among clinicians and LT centers. Liver clinicians already report insufficient psychosocial expertise, which creates a large gap between the stark need for psychosocial expansion, improvement, and innovation in LT and the lack of accompanying guidance on how to achieve it. While the clinical domains of an LT psychosocial evaluation have been well-described, few articles analyze the procedures by which teams determine candidates' "psychosocial clearance" and no conceptual frameworks exist. This article proposes a framework of core domains of psychosocial evaluation procedures, common pitfalls, and practical improvement strategies.

"But I didn't drink!": What to do with discordant phosphatidylethanol results.

Liver transplantation (LT) teams must be adept at detecting, evaluating, and treating patients' alcohol use, given its prominence among psychological and behavioral phenomena which cause and contribute to liver diseases. Phosphatidylethanol (PEth) is a highly useful alcohol biomarker increasingly recommended for routine use in hepatology and LT. PEth is unique among alcohol biomarkers because of its wide detection window, high sensitivity and specificity, and the correlation of its numerical value with different patterns of alcohol use. Alongside myriad clinical opportunities in hepatology and LT, PEth also confers numerous challenges: little guidance exists about its clinical use; fearing loss of LT access and the reactions of their clinicians and families, candidates and recipients are incentivized to conceal their alcohol use; and liver clinicians report lack of expertise diagnosing and treating substance-related challenges. Discordance between patient self-reported alcohol use and toxicology is yet another common and particularly difficult circumstance. This article discusses the general toxicological properties of PEth; explores possible scenarios of concordance and discordance among PEth results, patient history, and self-reported drinking; and provides detailed clinical communication strategies to explore discordance with liver patients, a key aspect of its use.

Engaging people who use drugs in clinical research: integrating facilitated telemedicine for HCV into substance use treatment.

BACKGROUND: People who use drugs (PWUD) have difficulty participating in clinical research. We evaluated approaches to engage PWUD in clinical research, using facilitated telemedicine for hepatitis C virus (HCV) care as an example. METHODS: We analyzed stakeholder interview transcripts and study-related data (i.e., progress reports, meeting minutes) from interrelated studies to understand engagement experiences at the patient, site, and organizational levels. Stakeholders include patient-participants, opioid treatment program (OTP) staff and administrators, and research team members involved in HCV management through facilitated telemedicine integrated into OTPs. RESULTS: Three themes emerged. Initially, the research team sought understanding of the unique culture and community of each OTP (Theme 1). The team built trusting relationships through education, communication, and feedback (Theme 2). Finally, the research team enhanced collaborative care and incorporated the patients' voice to improve health outcomes (Theme 3). Patient-participants and OTP staff endorsed the integrated HCV care approach. Engagement practices are summarized as the CREATE framework (C = culture, R = respect, E = educate, A = advantage, T = trust, E = endorse). CONCLUSIONS: PWUD engagement in clinical research is maximized by building trusting relationships with open communication channels. Understanding the community, demonstrating respect, and augmenting knowledge are foundational for engaging PWUD in clinical research. These practices are transferable to engagement of PWUD in clinical research broadly.

People who use drugs rarely join clinical research studies for many reasons including mistrust of researchers and lack of access to healthcare. Their joining, however, is critical to understand how to address issues affecting their communities. For ten years, we have studied telemedicine (doctor visit through a computer) to increase healthcare access for people who use drugs with hepatitis C virus (HCV). HCV infection occurs commonly in people who use drugs and is curable in almost everyone who takes treatment. We place HCV treatment through facilitated telemedicine into drug treatment programs. A case manager who is familiar to patients oversees the telemedicine encounter with the doctor. We developed themes from interviews with patients, staff, and other involved people as well as from study documents. As a first step, researchers need to understand the culture and community of the drug treatment program. Knowing the culture permits researchers to connect the goals of the study with those of the drug treatment program. It also helps researchers build trust with the program staff. We have seen that trust between the researchers and the staff in the drug treatment program permits individuals with different jobs to work together to deliver HCV treatment resulting in a cure. During the entire process, a patient advisory committee made sure the patients were partners in the research. Based upon these results, we have developed a new approach, CREATE (C = Culture, R = respect, E = educate, A = advantage, T = trust, E = endorse), that explains each step in the process.

Modification of the diabetes prevention program for the treatment of nonalcoholic fatty liver disease: A pilot study.

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.

HBV screening among West Africans living in the US: Influences of stigma, health literacy, and self-efficacy.

BACKGROUND: Applying theoretically informed constructs using an adaptation of the "Theory of Planned Behavior," this study assessed social-cognitive and sociocultural determinants of HBV screening among West Africans living in the US to inform solutions to testing gaps. METHODS: We developed and administered a theory-based survey in both English (41%) and French (59%) from September 2021 to April 2022 to a sample of West African-born individuals (n = 162). Predictors of HBV screening included: attitudes, perceived behavioral control or self-efficacy, and subjective norms along with health literacy (HL), language proficiency, and stigma of HBV infection. We hypothesized that these constructs would predict HBV testing. We also conducted path analytic modeling to better understand both direct and indirect effects of key factors on HBV screening status. RESULTS: West Africans who completed the survey in English were younger with less education and lower income, whereas those who completed the survey in French reported higher HBV-related stigma. In a bivariate analysis of factors associated with HBV screening by language, less education was associated with lower HBV screening in English speakers. Adequate HL, higher self-efficacy, and higher English language proficiency were independently associated with HBV screening. Path analysis to better understand the interplay between social-cognitive and sociocultural factors revealed HL and stigma both had indirect effects on screening, mediated by differences in self-efficacy. CONCLUSIONS: This study identified HL and stigma as key indirect factors that influence HBV screening by way of self-efficacy in West Africans in the US. This work is a first step to identifying barriers that can lead to the development of an evidence-based intervention aimed at increasing HBV screening of West Africans to address health disparities.

Hepatocellular carcinoma in patients cured of chronic hepatitis C: Minimal steatosis.

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 × 103 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.

The impact of COVID-19 on trends in alcohol use disorder treatment in Veterans Health Administration.

BACKGROUND AND AIMS: The COVID-19 pandemic disrupted health-care provision in the United States and prompted increases in telehealth-delivery of care. This study measured alcohol use disorder (AUD) treatment trends across visit modalities before and during COVID-19. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We conducted a national, retrospective cohort study with interrupted time-series models to estimate the impact of COVID-19 on AUD treatment in the Veterans Health Administration (VHA) in the United States during pre-COVID-19 (March 2019 to February 2020) and COVID-19 (March 2020 to February 2021) periods. We analyzed monthly trends in telephone, video and in-person visits for AUD treatment and compared patient and treatment characteristics of patients receiving AUD treatment between the pre-COVID-19 and COVID-19 periods. AUD was defined using International Classification of Diseases, 10th revision (ICD-10) codes for alcohol abuse (F10.1) and alcohol dependence (F10.2), which have previously been used to study AUD in VHA. FINDINGS: The predicted percentage of VHA patients with an AUD diagnosis receiving any AUD treatment at the beginning of the pre-COVID period was 13.8% (n = 49 494). The predicted percentage decreased by 4.3% (P = 0.001) immediately at the start of the COVID-19 period due to a decline in AUD psychotherapy. Despite an increase of 0.3% per month (P = 0.026) following the start of COVID-19, the predicted percentage of VHA patients with an AUD diagnosis receiving any AUD treatment at the end of the study period remained below the pre-COVID-19 period. In February 2021, AUD psychotherapy visits were primarily delivered by video (50%, 58 748), followed by in-person (36.6%, 43 251) and telephone (13.8%, 16 299), while AUD pharmacotherapy visits were delivered by telephone (38.9%, 3623) followed by in-person (34.3%, 3193) and video (26.8%, 2498) modalities. Characteristics of VHA patients receiving AUD treatment were largely similar between pre-COVID-19 and COVID-19 periods. CONCLUSIONS: Despite increased telehealth use, the percentage of United States Veterans Health Administration patients with an alcohol use disorder (AUD) diagnosis receiving AUD treatment declined during COVID-19 (March 2020 to February 2021) mainly due to a decrease in psychotherapy.

Hepatocellular carcinoma surveillance, incidence, and tumor doubling times in patients cured of hepatitis C.

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.

A Digital Case-Finding Algorithm for Diagnosed but Untreated Hepatitis C: A Tool for Increasing Linkage to Treatment and Cure.

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.

Facilitating engagement of persons with opioid use disorder in treatment for hepatitis C virus infection via telemedicine: Stories of onsite case managers.

Although hepatitis C virus (HCV) infection has high prevalence and incidence in persons with opioid use disorder (PWOUD), their engagement in HCV care has been limited due to a variety of factors. In an ongoing multisite study at 12 opioid treatment programs (OTPs) throughout New York State (NYS), we have been evaluating telemedicine accompanied by onsite administration of direct acting antiviral (DAA) medications compared with usual care including offsite referral to a liver specialist for HCV management. Each site has a case manager (CM) who is responsible for all study-related activities including participant recruitment, facilitating telemedicine interactions, retention in care, and data collection. Our overall objective is to analyze CM experiences of clients' stories and events to understand how the telemedicine model facilitates HCV treatment. Hermeneutic phenomenology was used to interpret and to explicate common meanings and shared practices of the phenomena of case management, and a focus group with CMs was conducted to reinforce and expand on key themes identified from the CMs' stories. We identified three themes: (1) building trust, (2) identification of multiple competing priorities, and (3) development of personalized care approaches. Our results illustrate that trust is a fundamental pillar on which the telemedicine system can be based. Participants' experiences at the OTP can reinforce trust. Understanding the specific competing priorities and routinizing dedicated personalized approaches to overcome them are key to increasing participation in HCV care among PWOUD.

Innovations in Hepatitis C Screening and Treatment.

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.

Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study.

BACKGROUND & AIMS: Chronic liver disease (CLD) and cirrhosis are associated with immune dysregulation, leading to concerns that affected patients may be at risk of adverse outcomes following SARS-CoV-2 infection. We aimed to determine the impact of COVID-19 on patients with pre-existing liver disease, which currently remains ill-defined. METHODS: Between 25th March and 8th July 2020, data on 745 patients with CLD and SARS-CoV-2 (including 386 with and 359 without cirrhosis) were collected by 2 international registries and compared to data on non-CLD patients with SARS-CoV-2 from a UK hospital network. RESULTS: Mortality was 32% in patients with cirrhosis compared to 8% in those without (p <0.001). Mortality in patients with cirrhosis increased according to Child-Pugh class (A [19%], B [35%], C [51%]) and the main cause of death was from respiratory failure (71%). After adjusting for baseline characteristics, factors associated with death in the total CLD cohort were age (odds ratio [OR] 1.02; 1.01-1.04), Child-Pugh A (OR 1.90; 1.03-3.52), B (OR 4.14; 2.4-7.65), or C (OR 9.32; 4.80-18.08) cirrhosis and alcohol-related liver disease (OR 1.79; 1.03-3.13). Compared to patients without CLD (n = 620), propensity-score-matched analysis revealed significant increases in mortality in those with Child-Pugh B (+20.0% [8.8%-31.3%]) and C (+38.1% [27.1%-49.2%]) cirrhosis. Acute hepatic decompensation occurred in 46% of patients with cirrhosis, of whom 21% had no respiratory symptoms. Half of those with hepatic decompensation had acute-on-chronic liver failure. CONCLUSIONS: In the largest such cohort to date, we demonstrate that baseline liver disease stage and alcohol-related liver disease are independent risk factors for death from COVID-19. These data have important implications for the risk stratification of patients with CLD across the globe during the COVID-19 pandemic. LAY SUMMARY: This international registry study demonstrates that patients with cirrhosis are at increased risk of death from COVID-19. Mortality from COVID-19 was particularly high among patients with more advanced cirrhosis and those with alcohol-related liver disease.

Liver Injury in Patients Hospitalized with Coronavirus Disease 2019 Correlates with Hyperinflammatory Response and Elevated Interleukin-6.

Liver injury is commonly seen in coronavirus disease 2019 (COVID-19); however, the mechanism behind liver injury, particularly in patients with severe and critical COVID-19, remains unclear, and the clinical course is poorly described. We conducted a single-center retrospective cohort study of consecutive patients hospitalized with severe and critical COVID-19 with or without liver injury and who underwent immunologic testing (interleukin [IL]-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-1ß). Liver injury was defined as peak aminotransferases ≥3 times the upper limit of normal (40 U/L) or ≥120 U/L. Patients with liver injury were compared to those who had normal aminotransferases throughout the hospital course. We studied 176 patients: 109 with liver injury and 67 controls. Patients with liver injury were more likely to be men (71.6% vs. 37.3%, P < 0.001). Peak inflammatory markers and IL-6 were higher in the liver injury group: C-reactive protein (CRP), 247 vs. 168 mg/L, P < 0.001; lactate dehydrogenase (LDH), 706 vs. 421 U/L; ferritin, 2,973 vs. 751 ng/mL, P < 0.001; IL-6, 121.0 vs. 71.8 pg/mL, P < 0.001. There was no difference in the levels of IL-8, TNF-α, and IL-1ß. The liver injury group had a longer length of stay in the hospital and more severe COVID-19 despite having less diabetes and chronic kidney disease. Conclusion: An exaggerated hyperinflammatory response (cytokine storm) characterized by significantly elevated CRP, LDH, ferritin, and IL-6 levels and increasing severity of COVID-19 appears to be associated with the occurrence of liver injury in patients with severe/critical COVID-19.

Liver Injury in Liver Transplant Recipients With Coronavirus Disease 2019 (COVID-19): U.S. Multicenter Experience.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplantation (LT) recipients with COVID-19 are open for study. APPROACH AND RESULTS: We conducted a multicenter study in the United States of 112 adult LT recipients with COVID-19. Median age was 61 years (interquartile range, 20), 54.5% (n = 61) were male, and 39.3% (n = 44) Hispanic. Mortality rate was 22.3% (n = 25); 72.3% (n = 81) were hospitalized and 26.8% (n = 30) admitted to the intensive care unit (ICU). Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5× upper limit of normal [ULN]) in 22.2% (n = 18) and severe liver injury (ALT > 5× ULN) in 12.3% (n = 10). Compared to age- and sex-matched nontransplant patients with chronic liver disease and COVID-19 (n = 375), incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; P = 0.037). Variables associated with liver injury in LT recipients were younger age (P = 0.009; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), Hispanic ethnicity (P = 0.011; OR, 6.01; 95% CI, 1.51-23.9), metabolic syndrome (P = 0.016; OR, 5.87; 95% CI, 1.38-24.99), vasopressor use (P = 0.018; OR, 7.34; 95% CI, 1.39-38.52), and antibiotic use (P = 0.046; OR, 6.93; 95% CI, 1.04-46.26). Reduction in immunosuppression (49.4%) was not associated with liver injury (P = 0.156) or mortality (P = 0.084). Liver injury during COVID-19 was significantly associated with mortality (P = 0.007; OR, 6.91; 95% CI, 1.68-28.48) and ICU admission (P = 0.007; OR, 7.93; 95% CI, 1.75-35.69) in LT recipients. CONCLUSIONS: Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.

Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.

BACKGROUND: Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients. METHODS: In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death. FINDINGS: Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47-66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44-84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p<0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI -7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients. INTERPRETATION: Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic. FUNDING: European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

Response to 'hepatitis C cure improved patient-reported outcomes in patients with and without liver fibrosis in a prospective study at a large urban medical center'.

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.