Expert perspectives for the pharmacist on facilitating and improving the use of albumin in cirrhosis.

PURPOSE: Albumin, the most abundant and arguably most important protein in the human body, plays a unique role in decompensated cirrhosis because its structure and function are quantitatively and qualitatively affected. A literature review was performed to provide insights into albumin use. The manuscript was developed using a multidisciplinary approach; 2 hepatologists, a nephrologist, a hospitalist, and a pharmacist, who are all members of or work closely with the Chronic Liver Disease Foundation, collaborated to write this expert perspective review. SUMMARY: Cirrhosis represents the potential end in the spectrum of all chronic liver diseases. Decompensated cirrhosis, defined by the overt manifestation of liver failure (eg, ascites, hepatic encephalopathy, variceal bleeding), is the inflection point associated with increased mortality. Human serum albumin (HSA) infusion serves an important role in the treatment of advanced liver disease. The benefits of HSA administration in patients with cirrhosis are widely accepted, and its use has been advocated by several professional societies. However, inappropriate HSA use can lead to significant adverse patient events. This paper discusses the rationale for the administration of HSA in the treatment of complications of cirrhosis, analyzes the data on the use of HSA in cirrhosis, and streamlines practical recommendations set forth in published guidance. CONCLUSION: Use of HSA in clinical practice needs to be improved. The objective of this paper is to empower pharmacists to facilitate and improve the use of HSA in patients with cirrhosis at their practice sites.

Ursodeoxycholic acid is associated with a reduction in SARS-CoV-2 infection and reduced severity of COVID-19 in patients with cirrhosis.

BACKGROUND AND AIMS: Studies have demonstrated that reducing farnesoid X receptor activity with ursodeoxycholic acid (UDCA) downregulates angiotensin-converting enzyme in human lung, intestinal and cholangiocytes organoids in vitro, in human lungs and livers perfused ex situ, reducing internalization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell. This offers a potential novel target against coronavirus disease 2019 (COVID-19). The objective of our study was to compare the association between UDCA exposure and SARS-CoV-2 infection, as well as varying severities of COVID-19, in a large national cohort of participants with cirrhosis. METHODS: In this retrospective cohort study among participants with cirrhosis in the Veterans Outcomes and Costs Associated with Liver cohort, we compared participants with exposure to UDCA, with a propensity score (PS) matched group of participants without UDCA exposure, matched for clinical characteristics, and vaccination status. The outcomes included SARS-CoV-2 infection, symptomatic, at least moderate, severe, or critical COVID-19, and COVID-19-related death. RESULTS: We compared 1607 participants with cirrhosis who were on UDCA, with 1607 PS-matched controls. On multivariable logistic regression, UDCA exposure was associated with reduced odds of developing SARS-CoV-2 infection (adjusted odds ratio [aOR] 0.54, 95% confidence interval [CI] 0.41-0.71, p < 0.0001). Among patients who developed COVID-19, UDCA use was associated with reduced disease severity, including symptomatic COVID-19 (aOR 0.54, 95% CI 0.39-0.73, p < 0.0001), at least moderate COVID-19 (aOR 0.51, 95% CI 0.32-0.81, p = 0.005), and severe or critical COVID-19 (aOR 0.48, 95% CI 0.25-0.94, p = 0.03). CONCLUSIONS: In participants with cirrhosis, UDCA exposure was associated with both a decrease in SARS-CoV-2 infection, and reduction in symptomatic, at least moderate, and severe/critical COVID-19.

The multi-drug resistant organisms infections decrease during the antimicrobial stewardship era in cirrhotic patients: An Italian cohort study.

BACKGROUND AND PURPOSE: Bacterial infections represent a major cause of morbidity and mortality in cirrhotic patients. Our aim was to assess the incidence of bacterial infections, in particular due to multidrug-resistant organisms (MDROs) before and after the introduction of the antimicrobial stewardship program, "Stewardship Antimicrobial in VErona" (SAVE). In addition, we also analysed the liver complications and the crude mortality during the whole follow up. METHODS: We analysed 229 cirrhotic subjects without previous hospitalization for infections enrolled at the University Verona Hospital from 2017 to 2019 and followed up until December 2021 (mean follow-up 42.7 months). RESULTS: 101 infections were recorded and 31.7% were recurrent. The most frequent were sepsis (24.7%), pneumonia (19.8%), spontaneous bacterial peritonitis (17.8%). 14.9% of infections were sustained by MDROs. Liver complications occurred more frequently in infected patients, and in case of MDROs infections with a significantly higher MELD and Child-Pugh score. In Cox regression analysis, mortality was associated with age, diabetes and bacterial infections episodes (OR 3.30, CI 95%: (1.63-6.70). Despite an increase in total infections over the past three years, a decrease in the incidence rate in MDROs infections was documented concurrently with the introduction of SAVE (IRD 28.6; 95% CI: 4.6-52.5, p = 0.02). CONCLUSIONS: Our study confirms the burden of bacterial infections in cirrhotic patients, especially MDROs, and the strong interconnection with liver complications. The introduction of SAVE decreased MDROs infections. Cirrhotic patients require a closer clinical surveillance to identify colonized patients and avoid the horizontal spread of MDROs in this setting.

Ivermectin Attenuates CCl4-Induced Liver Fibrosis in Mice by Suppressing Hepatic Stellate Cell Activation.

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl4)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis.

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid.

BACKGROUND & AIMS: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. METHODS: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. CONCLUSIONS: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Projected Long-Term Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Hepatitis C Outcomes in the United States: A Modeling Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic disrupted access to and uptake of hepatitis C virus (HCV) care services in the United States. It is unknown how substantially the pandemic will impact long-term HCV-related outcomes. METHODS: We used a microsimulation to estimate the 10-year impact of COVID-19 disruptions in healthcare delivery on HCV outcomes including identified infections, linkage to care, treatment initiation and completion, cirrhosis, and liver-related death. We modeled hypothetical scenarios consisting of an 18-month pandemic-related disruption in HCV care starting in March 2020 followed by varying returns to pre-pandemic rates of screening, linkage, and treatment through March 2030 and compared them to a counterfactual scenario in which there was no COVID-19 pandemic or disruptions in care. We also performed alternate scenario analyses in which the pandemic disruption lasted for 12 and 24 months. RESULTS: Compared to the "no pandemic" scenario, in the scenario in which there is no return to pre-pandemic levels of HCV care delivery, we estimate 1060 fewer identified cases, 21 additional cases of cirrhosis, and 16 additional liver-related deaths per 100 000 people. Only 3% of identified cases initiate treatment and <1% achieve sustained virologic response (SVR). Compared to "no pandemic," the best-case scenario in which an 18-month care disruption is followed by a return to pre-pandemic levels, we estimated a smaller proportion of infections identified and achieving SVR. CONCLUSIONS: A recommitment to the HCV epidemic in the United States that involves additional resources coupled with aggressive efforts to screen, link, and treat people with HCV is needed to overcome the COVID-19-related disruptions.

COVID-19 After Treatment With Direct-acting Antivirals for HCV Infection and Decompensated Cirrhosis: A Case Report.

BACKGROUND: Eradication of hepatitis C virus (HCV) from chronic HCV-infected patients could improve liver function and prevent hepatocarcinogenesis in the long term. Eradication of HCV by direct-acting antivirals (DAAs) also leads to dynamic immunological changes. We report a case of recurrent coronavirus disease 2019 (COVID-19) that developed immediately after combination treatment with DAAs for HCV infection and decompensated cirrhosis. CASE REPORT: A 55-year-old male was started on a 12-week treatment with combination of HCV NS5A inhibitor velpatasvir and HCV NS5B polymerase inhibitor sofosbuvir. HCV RNA became undetectable after six weeks of treatment and was undetectable at the end of the treatment (EOT). Twelve days after the EOT, we diagnosed the patient with COVID-19 pneumonia, admitted him to our hospital and he was discharged two weeks later. One week after his discharge, he visited our hospital again, was diagnosed with recurrent COVID-19 pneumonia readmitted for a second time. Four days after second admission, cardiac arrest occurred, however, he recovered from severe COVID-19 and achieved sustained virological response and his liver function improved. CONCLUSION: In the COVID-19 era, while attention should be paid to the occurrence or exacerbation of infection, including COVID-19, interferon-free DAA combination therapy should be performed for HCV-infected individuals.

L-ornithine L-aspartate in acute treatment of severe hepatic encephalopathy: A double-blind randomized controlled trial.

BACKGROUND AND AIMS: Data on the use of intravenous L-ornithine L-aspartate (LOLA) in the treatment of overt HE (OHE) is limited. We evaluated the role of intravenous LOLA in patients of cirrhosis with OHE grade III-IV. APPROACH AND RESULTS: In a double-blind randomized placebo-controlled trial, 140 patients were randomized to a combination of LOLA, lactulose, and rifaximin (n = 70) or placebo, lactulose, and rifaximin (n = 70). LOLA was given as continuous intravenous infusion at a dose of 30 g over 24 h for 5 days. Ammonia levels, TNF-α, ILs, and endotoxins were measured on days 0 and 5. The primary outcome was the improvement in the grade of HE at day 5. Higher rates of improvement in grade of HE (92.5% vs. 66%, p < 0.001), lower time to recovery (2.70 ± 0.46 vs. 3.00 ± 0.87 days, p = 0.03), and lower 28-day mortality (16.4% vs. 41.8%, p = 0.001) were seen in the LOLA group as compared with placebo. Levels of inflammatory markers were reduced in both groups. Significantly higher reductions in levels of blood ammonia, IL-6, and TNF-α were seen in the LOLA group. CONCLUSIONS: Combination of LOLA with lactulose and rifaximin was more effective than only lactulose and rifaximin in improving grades of HE, recovery time from encephalopathy, with lower 28-day mortality.

Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial.

BACKGROUND: Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. METHODS: The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. DISCUSSION: The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. TRIAL REGISTRATION: EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). CLINICALTRIALS: gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).

Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.

Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo (n = 21) or efruxifermin 28 mg (n = 19), efruxifermin 50 mg (n = 20) or efruxifermin 70 mg (n = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint-absolute change from baseline in HFF measured as magnetic resonance imaging-proton density fat fraction at week 12-was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were -12.3% (-infinity (-inf), -10.3), -13.4% (-inf, -11.4) and -14.1% (-inf, -12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (-inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo (P < 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1-2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1-2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1-F3 stage NASH, with an acceptable safety profile.

Survival and outcomes for co-infection of chronic hepatitis C with and without cirrhosis and COVID-19: A multicenter retrospective study.

BACKGROUND: Chronic liver disease, particularly cirrhosis, is associated with worse outcomes in patients infected with coronavirus disease 2019 (COVID-19). AIM: To assess outcomes of COVID-19 infection among patients with pre-existing hepatitis C with or without liver cirrhosis. METHODS: This multicenter, retrospective cohort study included all cases of confirmed co-infection of severe acute respiratory syndrome coronavirus 2 and chronic hepatitis C with or without liver cirrhosis who were admitted to six hospitals (Al-Sahel Hospital, Al-Matareya Hospital, Al-Ahrar Hospital, Ahmed Maher Teaching Hospital, Al-Gomhoreya Hospital, and the National Hepatology and Tropical Medicine Research Institute) affiliated with the General Organization for Teaching Hospitals and Institutes in Egypt. Patients were recruited from May 1, 2020, to July 31, 2020. Demographic, laboratory, imaging features, and outcomes were collected. Multivariate regression analysis was performed to detect factors affecting mortality. RESULTS: This retrospective cohort study included 125 patients with chronic hepatitis C and COVID-19 co-infection, of which 64 (51.20%) had liver cirrhosis and 40 (32.00%) died. Fever, cough, dyspnea, and fatigue were the most frequent symptoms in patients with liver cirrhosis. Cough, sore throat, fatigue, myalgia, and diarrhea were significantly more common in patients with liver cirrhosis than in non-cirrhotic patients. There was no difference between patients with and without cirrhosis regarding comorbidities. Fifteen patients (23.40%) with liver cirrhosis presented with hepatic encephalopathy. Patients with liver cirrhosis were more likely than non-cirrhotic patients to have combined ground-glass opacities and consolidations in CT chest scans: 28 (43.75%) vs 4 (6.55%), respectively (P value < 0.001). These patients also were more likely to have severe COVID-19 infection, compared to patients without liver cirrhosis: 29 (45.31%) vs 11 (18.04%), respectively (P value < 0.003). Mortality was higher in patients with liver cirrhosis, compared to those with no cirrhosis: 33 (51.56%) vs 9 (14.75%), respectively (P value < 0.001). All patients in Child-Pugh class A recovered and were discharged. Cirrhotic mortality occurred among decompensated patients only. A multivariate regression analysis revealed the following independent factors affecting mortality: Male gender (OR 7.17, 95%CI: 2.19-23.51; P value = 0.001), diabetes mellitus (OR 4.03, 95%CI: 1.49-10.91; P value = 0.006), and liver cirrhosis (OR 1.103, 95%CI: 1.037-1.282; P value < 0.0001). We found no differences in liver function, COVID-19 disease severity, or outcomes between patients who previously received direct-acting antiviral therapy (and achieved sustained virological response) and patients who did not receive this therapy. CONCLUSION: Patients with liver cirrhosis are susceptible to higher severity and mortality if infected with COVID-19. Male gender, diabetes mellitus, and liver cirrhosis are independent factors associated with increased mortality risk.

COVID-19 Mid-term Impact on Hepatocellular Carcinoma in Patients With Hepatitis C Chronic Infection.

BACKGROUND/AIM: Liver injury has been frequently reported in association with SARS-CoV-2 infection, but data are still lacking regarding the impact of pre-existing liver damage and neoplasia on SARS-CoV-2 infection outcome and vice-versa. This study aimed to assess the effects of SARS-CoV-2 infection on hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infected patients, both in therapeutic-naïve and patients treated with direct acting antivirals. PATIENTS AND METHODS: We conducted a retrospective cohort study on 21 patients with a personal history of HCV infection, that have been diagnosed with different forms of HCC and who were subsequently infected with SARS-CoV-2. Patients were monitored by liver function tests, tumoral markers, blood cell count, and coagulation profile periodically. RESULTS: Solitary HCC nodules were predominant among the subjects who achieved sustained virologic response, while multinodular and infiltrative patterns were mostly prevalent among the treatment-naïve group. Most patients had mild and moderate COVID-19 infections. CONCLUSION: Within the current global pandemic crisis, cancer patients are highly vulnerable and in need of constant monitoring. Among patients with HCC, the ones with cured HCV infection may be at a lower risk of fatality than those with active HCV infection, when diagnosed with SARS-CoV-2 infection.

Review of galectin-3 inhibitors in the treatment of nonalcoholic steatohepatitis.

INTRODUCTION: Galectin-3 (Gal-3) is a ß-galactoside binding protein associated with many disease pathologies, including chronic inflammation and fibrogenesis. It has been implicated in the disease severity of NASH, although its precise role is unknown. Inhibition of Gal-3 has shown to improve and prevent fibrosis progression and has now reached phase III clinical trial in NASH patients. AREAS COVERED: This discusses the role of Gal-3 in NASH. It brings together the current findings of Gal-3 in NASH and hepatic fibrosis by analyzing recent data from animal model studies and clinical trials. EXPERT OPINION: Gal-3 inhibitors, in particular, Belapectin (GR-MD-02), have shown promising results for NASH with advanced fibrosis. In a phase 2 trial, Belapectin did not meet the primary endpoint. However, a sub-analysis of Belapectin among a separate group of patients without esophageal varices showed 2 mg/kg of GR-MD-02 reduced HVPG and the development of new varices. A subsequent study is under way, aiming to replicate the positive findings in phase 2 and demonstrate greater efficacy. If Belapectin is shown to be effective, it will be coupled with other drugs that target steatohepatitis to maximize efficacy and disease reversal.

Australia could miss the WHO hepatitis C virus elimination targets due to declining treatment uptake and ongoing burden of advanced liver disease complications.

Australia was one of the first countries to introduce government-funded unrestricted access to direct-acting antiviral (DAA) therapy, with 88,790 treated since March 2016. However, treatment uptake is declining which could potentially undermine Australia's progress towards the WHO HCV elimination targets. Using mathematical modelling, we updated estimates for those living with chronic HCV in Australia, new cases of decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality among the HCV-cured and viraemic populations from 2015 to 2030. We considered various DAA treatment scenarios incorporating annual treatment numbers to 2020, and subsequent uptake per year of 6,790 (pessimistic), 8,100 (intermediate), and 11,310 (optimistic). We incorporated the effects of excess alcohol consumption and reduction in progression to DC and HCC among cirrhosis-cured versus viraemic individuals. At the end of 2020, we estimated 117,810 Australians were living with chronic HCV. New cases per year of DC, HCC, and liver-related mortality among the HCV viraemic population decreased rapidly from 2015 (almost eliminated by 2030). In contrast, the growing population size of those cured with advanced liver disease meant DC, HCC, and liver-related mortality declined slowly. The estimated reduction in liver-related mortality from 2015 to 2030 in the combined HCV viraemic and cured population is 25% in the intermediate scenario. With declining HCV treatment uptake and ongoing individual-level risk of advanced liver disease complications, including among cirrhosis-cured individuals, Australia is unlikely to achieve all WHO HCV elimination targets by 2030.