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Summary Background Alcohol-related liver disease is the leading indication for liver transplantation in the USA. After remaining stable for over three decades, the number of deaths due to alcohol-related liver disease has been increasing as a result of increased high-risk drinking. We aimed to project trends in alcohol-related cirrhosis and deaths in the USA up to 2040 and assess the effect of potential changes in alcohol consumption on those trends. Methods In this modelling study, we developed a multicohort state-transition (Markov) model of high-risk alcohol drinking patterns and alcohol-related liver disease in high-risk drinking populations born in 1900–2016 in the USA projected up to 2040. We used data from the National Epidemiologic Survey on Alcohol and Related Conditions, National Institute of Alcohol Abuse and Alcoholism, US National Death Index, National Vital Statistics System, and published studies. We modelled trends in alcohol-related liver disease under three projected scenarios: the status quo scenario, in which current trends continued; a moderate intervention scenario, in which trends in high-risk drinking reduced to 2001 levels under some hypothetical moderate intervention; and a strong intervention, in which trends in high-risk drinking decreased by 3·5% per year under some hypothetical strong intervention. The primary outcome was to project deaths associated with alcohol-related liver disease from 2019 to 2040 for each pattern of alcohol consumption under the different scenarios. Findings Our model closely reproduced the observed trends in deaths due to alcohol-related liver disease from 2005 to 2018. Under the status quo scenario, age-standardised deaths due to alcohol-related liver disease are expected to increase from 8·23 (95% uncertainty interval [UI] 7·92–9·29) per 100 000 person-years in 2019 to 15·20 (13·93–16·19) per 100 000 person-years in 2040, and from 2019 to 2040, 1 003 400 (95% CI 896 800–1 036 200) people are projected to die from alcohol-related liver disease, resulting in 1 128 400 (1 113 200–1 308 400) DALYs by 2040. Under the moderate intervention scenario, age-standardised deaths due to alcohol-related liver disease would increase to 14·49 (95% UI 12·55–14·57) per 100 000 person-years by 2040, with 968 100 (95% UI 845 600–975 900) individuals projected to die between 2019 and 2040—35 300 fewer deaths than under the status quo scenario (a 3·5% decrease). Whereas, under the strong intervention scenario, age-standardised deaths due to alcohol-related liver disease would peak at 8·65 (95% UI 8·12–9·51) per 100 000 person-years in 2024 and decrease to 7·60 (6·96–8·10) per 100 000 person-years in 2040, with 704 300 (95% CI 632 700–731 500) individuals projected to die from alcohol-related liver disease in the USA between 2019 and 2040—299 100 fewer deaths than under the status quo scenario (a 29·8% decrease). Interpretation Without substantial changes in drinking culture or interventions to address high-risk drinking, the disease burden and deaths due to alcohol-related liver disease will worsen in the USA. Additional interventions are urgently needed to reduce mortality and morbidity associated with alcohol-related liver disease. Funding American Cancer Society and the Robert Wood Johnson Health Policy Research Fellowship.

The practice of transplanting hepatitis C (HCV)-infected livers into HCV-uninfected recipients has not previously been recommended in transplant guidelines, in part because of concerns over uncontrolled HCV infection of the allograft. Direct-acting antivirals (DAAs) provide an opportunity to treat donor derived HCV-infection, and should be administered early in the post-transplant period. However, evidence on the safety and efficacy of an immediate DAA treatment approach, including how to manage logistical barriers surrounding timely DAA procurement, are required prior to broader use of HCV-positive donor organs. We report the results of a trial in which fourteen HCV-negative patients underwent successful liver transplantation from HCV-positive donors. Nine patients received viremic (nucleic acid testing (NAT)-positive) livers, and started a 12-week course of oral glecaprevir-pibrentasvir (GP) within 5 days of transplant. Five patients received livers from HCV antibody-positive non-viremic donors and were followed using a reactive approach. Survival in NAT-positive recipients is 100% at a median follow-up of 46 weeks. An immediate treatment approach for HCV NAT-positive liver transplantation into uninfected recipients is safe and efficacious. Securing payer approval for DAAs early in the post-transplant course could enable need-based allocation of HCV-positive donor organs irrespective of candidate HCV status, while averting chronic HCV allograft infection.

Accurate prediction of outcomes for alcohol-associated hepatitis (AH) is critical, as prognosis determines treatment eligibility. Computed tomography (CT) features may provide prognostic information beyond traditional models. Our aim was to identify CT features that predict outcomes in AH. We studied 108 patients retrospectively with definite or probable AH, who underwent admission abdominal CT. A radiologist blinded to outcome evaluated eight CT features. The primary outcome was 90-day mortality. Twenty-five (23.2%) patients died within 90 days. While traditional prognostic tools, including Maddrey discriminant function (DF), predicted 90-day mortality (OR 1.01 [1.00, 1.03], P = 0.02), abdominal CT findings were also accurate predictors. On abdominal CT, patients with severe AH had larger volume of ascites (moderate/large volume: 34.0 vs. 8.2%, P

PURPOSE OF REVIEW: Because of long waitlist times and high waitlist morbidity and mortality, strategies to increase utilization of Hepatitis C viremic deceased donor organs are under investigation in kidney, liver, heart and lung transplantation. RECENT FINDINGS: Direct-acting antiviral medications for Hepatitis C virus infection have high cure rates and are well tolerated. Small, single-center trials in kidney and heart transplant recipients have demonstrated that with early post-transplant direct-acting antiviral therapy, 100% of uninfected recipients of Hepatitis C viremic organs have been cured of infection after transplantation. SUMMARY: In this manuscript, we review the risks and rewards of utilizing Hepatitis C viremic organs for transplantation.

Background The hepatitis C virus (HCV) care cascade has changed dramatically following the introduction of direct-acting anti-virals (DAAs). Up-to-date estimates of the cascade are needed to monitor progress, identify key gaps and inform policy. Aim To estimate the current and future HCV care cascade in the United States, nationally and in select subpopulations of interest. Methods We used a previously validated mathematical model to simulate the landscape of HCV in the United States from 2011 onwards, accounting for HCV screening policy updates, newer HCV treatments and rising HCV incidence. Results By the end of 2018, of 4.29 million HCV persons alive, 2.71 million (63%) were actively viremic, 2.24 million (52%) aware and 1.58 million (37%) cured. By 2030, under the status quo, of 3.65 million HCV persons alive, 1.88 million (51%) would be viremic, 2.25 million (62%) aware and 1.77 million (49%) cured. The HCV care cascade in 2018 differed substantially by subpopulation: of 1.34 million incarcerated HCV persons, 96% were viremic, 36% aware and 4% cured; of 0.87 million HCV persons in Medicare, 31% were viremic, 72% aware and 69% cured; and of 0.37 million HCV persons in Medicaid, 49% were viremic, 54% aware and 51% cured. Implementing universal screening, providing unrestricted treatment and controlling HCV incidence were factors found to have the largest effect on improving the HCV care cascade. Conclusions Since the launch of DAAs, the HCV care cascade has shifted towards higher awareness and treatment rates; however, additional interventions are needed to move towards HCV elimination.

Under current guidelines, hepatitis C virus (HCV)-positive livers are not transplanted into HCV-negative recipients because of adverse posttransplant outcomes associated with allograft HCV infection. However, HCV can now be cured post-LT (liver transplant) using direct-acting antivirals (DAAs) with >90% success; therefore, HCV-negative patients on the LT waiting list may benefit from accepting HCV-positive organs with preemptive treatment. Our objective was to evaluate whether and in which HCV-negative patients the potential benefit of accepting an HCV-positive (i.e., viremic) organ outweighed the risks associated with HCV allograft infection. We developed a Markov-based mathematical model that simulated a virtual trial of HCV-negative patients on the LT waiting list to compare long-term outcomes in patients: (1) willing to accept any (HCV-negative or HCV-positive) liver versus (2) those willing to accept only HCV-negative livers. Patients receiving HCV-positive livers were treated preemptively with 12 weeks of DAA therapy and had a higher risk of graft failure than those receiving HCV-negative livers. The model incorporated data from published studies and the United Network for Organ Sharing (UNOS). We found that accepting any liver regardless of HCV status versus accepting only HCV-negative livers resulted in an increase in life expectancy when Model for End-Stage Liver Disease (MELD) was ≥20, and the benefit was highest at MELD 28 (0.172 additional life-years). The magnitude of clinical benefit was greater in UNOS regions with higher HCV-positive donor organ rates, that is, Regions 1, 2, 3, 10, and 11. Sensitivity analysis demonstrated that model outcomes were robust. CONCLUSION Transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy could improve patient survival on the LT waiting list. Our analysis can help inform clinical trials and minimize patient harm. (Hepatology 2018;67:2085-2095).

Introduction. Hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement remains a leading adverse event. Controversy remains regarding the optimal stent diameter given that smaller stents may decrease the amount of shunted blood and decrease the risk of HE, but stent patency and/or clinical adequacy of portal decompression may also be affected. We aim to provide meta-analysis-based evidence regarding the safety and efficacy of 8 mm vs. 10 mm stents during TIPS placement. Methods. PubMed, Embase, Cochrane Library, and Web of Science were searched for studies comparing 8 mm and 10 mm stents during TIPS placement for portal hypertension decompression in cirrhotic patients. Randomized controlled trials and cohort studies were prioritized for inclusion. Overall evaluation of quality and bias for each study was performed. The outcomes assessed were the prevalence of HE, rebleeding or failure to control refractory ascites, and overall survival. Subgroup analysis based on TIPS indication was conducted. Results. Five studies with a total number of 489 cirrhotic patients were identified. The pooled hazard ratio (HR) of post-TIPS HE was significantly lower in patients in the 8 mm stent group than in the 10 mm stent group (HR: 0.68, 95% CI: 0.51~0.92, p value < 0.0001). The combined HR of post-TIPS rebleeding/the need for paracentesis was significantly higher in patients in the 8 mm stent group than in the 10 mm stent group (HR: 1.76, 95% CI: 1.22~2.55, p value < 0.0001). There was no statistically significant difference in the overall survival between the 8 mm and 10 mm stent groups. The combined risk of HE in the variceal bleeding subgroup was statistically lower (HR: 0.52, CI: 0.34-0.80) with an 8 mm stent compared with a 10 mm stent. The combined risk of both rebleeding/paracentesis and survival was not statistically significant between 8 mm and 10 mm stent use in subgroup analysis. Conclusion. 8 mm stents during TIPS placement are associated with a significant lower risk of HE compared to 10 mm stents (32% decreased risk), as well as a 76% increased risk of rebleeding/paracentesis. Meta-analysis results suggest that there is not one superior stent choice for all clinical scenarios and that the TIPS indication of variceal bleeding or refractory ascites might have different appropriate selection of the shunt diameter.

Summary Background Low donor heart availability underscores the need to identify all potentially transplantable organs. We sought to determine whether pre-emptive administration of pangenotypic direct-acting antiviral therapy can safely prevent the development of chronic hepatitis C virus (HCV) infection in uninfected recipients of HCV-infected donor hearts. Methods Patients were recruited for this an open-label, single-centre, proof-of-concept study from Nov 1, 2017, to Nov 30, 2018. Following enrolment, the recipient's status on the heart transplantation waiting list was updated to reflect a willingness to accept either an HCV-positive or HCV-negative heart donor. Patients who underwent transplantation with a viraemic donor heart, as determined by nucleic acid testing (NAT), received pre-emptive oral glecaprevir-pibrentasvir before transport to the operating room followed by an 8-week course of glecaprevir-pibrentasvir after transplantation. Patients receiving HCV antibody-positive donor hearts without detectable circulating HCV RNA were followed using a reactive approach and started glecaprevir-pibrentasvir only if they developed viraemia. The primary outcome was achievement of sustained virological response 12 weeks after completion of glecaprevir-pibrentasvir therapy (SVR12). Patients were followed from study enrolment to 1 year after transplantation. This is an interim analysis, initiated after all enrolled patients reached the primary outcome. Results reflect data from Nov 1, 2017, to May 30, 2019. This trial is registered with ClinicalTrials.gov , number NCT03208244 . Findings 55 patients were assessed for eligibility and 52 consented to enrolment. 25 patients underwent heart transplantation with HCV-positive donor hearts (20 NAT-positive, five NAT-negative), three of whom underwent simultaneous heart–kidney transplantation. All 20 recipients of NAT-positive hearts tolerated glecaprevir-pibrentasvir and showed rapid viral suppression (median time to clearance 3·5 days, IQR 0·0–8·3), with the subsequent achievement of SVR12 by all 20. The five recipients of NAT-negative grafts did not become viraemic. Median pre-transplant waiting time for patients following enrolment in the HCV protocol was 20 days (IQR 8–57). Patient and allograft survival were 100% at a median follow-up of 10·7 months (range 6·5–18·0). Interpretation Pre-emptive administration of glecaprevir-pibrentasvir therapy results in expedited organ transplantation, rapid HCV suppression, prevention of chronic HCV infection, and excellent early allograft function in patients receiving HCV-infected donor hearts. Long-term outcomes are not yet known. Funding American Association for the Study of Liver Diseases, National Institutes of Health, and the Massachusetts General Hospital.

BACKGROUND The AIMS65 score and the Glasgow-Blatchford risk score (GBRS) are validated preendoscopic risk scores for upper gastrointestinal hemorrhage (UGIH). GOALS To compare the 2 scores' performance in predicting important outcomes in UGIH. STUDY A prospective cohort study in 2 tertiary referral centers and 1 community teaching hospital. Adults with UGIH were included. The AIMS65 score and GBRS were calculated for each patient. The primary outcome was inpatient mortality. Secondary outcomes were 30-day mortality, in-hospital rebleeding, 30-day rebleeding, length of stay, and a composite endpoint of in-hospital mortality, transfusions, or need for intervention (endoscopic, radiologic, or surgical treatment). The area under the receiver operating characteristic curve (AUROC) was calculated for each score and outcome. RESULTS A total of 298 patients were enrolled. The AIMS65 score was superior to the GBRS in predicting in-hospital mortality (AUROC, 0.85 vs. 0.66; P

Budd Chiari syndrome (BCS) results from hepatic outflow obstruction. Endovascular management to restore venous patency, including inferior vena cava (IVC) angioplasty with stenting, and transjugular intrahepatic shunt (TIPS) placement to decompress liver congestion, have become standard of care. Herein, we describe a patient with BCS requiring liver transplantation and the surgical technique of suprahepatic IVC anastomosis including thoracic extension of an IVC stent with a review of the relevant literature. A 29-year-old female with BCS due to polycythemia vera, who had been previously managed with TIPS and IVC stent placement, was taken for liver transplantation. Preoperative imaging confirmed stent extension into the thoracic IVC and the stent was unable to be removed intraoperatively. The thoracic IVC was clamped through the diaphragm at the level of the right atrium and the stent was left in place and incorporated within the suprahepatic anastomosis with good vascular outcome at one year follow up. Diligent preoperative preparation is essential with adequate imaging and cardiac surgical consultation in patients with malpositioned stents. Review of the literature shows four cases in which performing the suprahepatic anastomosis including an embedded stent is a viable alternative that allows for avoidance of a thoracotomy.

Background & Aims Guidelines do not recommend transplanting hepatitis C virus (HCV)-infected livers into HCV-uninfected recipients. Direct-acting antivirals (DAAs) can be used to treat donor-derived HCV infection. However, the added cost of DAA therapy is a barrier. We evaluated the cost effectiveness of transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy. Methods A previously validated Markov-based mathematical model was adapted to simulate a virtual trial of HCV-negative patients on the liver transplant waitlist. The model compared long-term clinical and economic outcomes in patients willing to accept only HCV-negative livers vs those willing to accept any liver (HCV negative or HCV positive). Recipients of HCV-positive livers received 12 weeks of preemptive DAA therapy. The model incorporated data from the United Network for Organ Sharing and published sources. Results For patients with a model for end-stage liver disease (MELD) score ≥ 22, accepting any liver vs waiting for only HCV-negative livers was cost effective, with incremental cost-effectiveness ratios ranging from $56,100 to $91,700/quality-adjusted life-year. For patients with a MELD score of 28 (the median MELD score of patients undergoing transplantation in the United States), accepting any liver was cost effective at an incremental cost-effectiveness ratio of $62,600/quality-adjusted life year. In patients with low MELD scores, which may not accurately reflect disease severity, accepting any liver was cost effective, irrespective of MELD score. Conclusions Using a Markov-based mathematical model, we found transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy to be a cost-effective strategy that could improve health outcomes.

Purpose Donor availability has continued to be a major issue limiting the number of cardiac transplantations in the United States. Given this shortage, it is necessary to consider strategies aimed at increasing the donor pool. We sought to evaluate the expanded use of hepatitis C virus (HCV) donor hearts, and characterize early allograft function in HCV-negative patients receiving pre-emptive anti-viral therapy following receipt of an HCV-infected donor heart. Methods Patients who underwent heart transplantation with HCV-positive donors at our institution between November 2017 and October 2018 were studied. Invasive hemodynamic and echocardiographic data were collected from routine scheduled post-transplant procedures. Intensive care unit (ICU) time, time on inotropes and time until discharge were evaluated from the index hospitalization for heart transplantation and compared to data from our center in patients receiving non-HCV hearts between January 2016 and June 2018. Results In total, there have been 23 recipients of donor HCV-positive heart transplants. Cardiac allograft and patient survival has been 100% at a median of 114 (IQR 81-190) days post-transplant. The average time on inotropes was 4.7±3.3 days in recipients of donor HCV-positive heart transplants, average time spent in the ICU was 7.2±4 days in the study group compared with 7.8±7.8 days in patients receiving non-HCV hearts and the average time to discharge was 19 ± 9 days in the study group compared with 21±22 days in patients receiving non-HCV hearts (both p>0.05). Among 80 echocardiograms done on or after post-operative day 2 in recipients of HCV-positive donor hearts, the ejection fraction (EF) was 65±9% with a single value falling below 50% (45%) that normalized 6 days later. One and 8-week hemodynamic values, respectively, were as follows: right atrial pressure of 7±5 and 5±3 mmHg, mean pulmonary arterial pressure of 20±7 and 20±6 mmHg, mean pulmonary capillary wedge pressure of 14±6 and 11±5 mmHg, and cardiac index of 2.8±0.8 and 2.9±0.4 L/min/m2. Conclusion In this single-center prospective study, patients who received preemptive direct-acting antiviral therapy following receipt of an HCV-positive donor heart demonstrated preserved early allograft function post-transplant.

Purpose Due to the shortage of donor hearts in the United States, it is essential we continuously evaluate strategies aimed at increasing donor organ availability. Our institution sought to expand the cardiac donor pool by utilizing hepatitis C virus (HCV) positive donor hearts. In a single center retrospective study, we examined the quality of HCV-positive donor hearts as compared to HCV-negative donor hearts. Methods Between October 2015 and October 2018, 111 cardiac transplants occurred at our center. 23 of these organs came from HCV-positive donors. Baseline donor characteristics were examined for all cardiac transplants and donor quality between HCV-positive and HCV-negative donors compared. Results Twenty-three (20%) of patients received HCV-positive hearts. On average the HCV-positive donors were accepted by our program at lower match sequence numbers than HCV-negative donors (sequence 12±17 versus 64±103, p 0.05 for all comparisons) was seen between HCV-positive and HCV-negative donor hearts. Acceptance of HCV-positive donor hearts facilitated dual-organ transplantation with 3 (13%) patients receiving dual organs as compared to only 4 (4%) in the HCV-negative recipient group. All patients who received HCV-positive donor hearts were alive at the time of this analysis compared to 89% in the HCV-negative group. Conclusion In this single-center study, patients who underwent HCV-positive donor heart transplantation received hearts at lower sequence numbers with a trend toward lower donor age. Short-term outcomes with HCV-positive donor hearts are favorable. Acceptance of HCV-positive donor hearts represents a potential approach to safely expand the available donor pool.

BACKGROUND: The introduction of oral direct-acting antivirals (DAAs) has dramatically changed the landscape of HCV treatment. However, a small percentage of patients fail to achieve sustained virologic response (SVR). Understanding the number of people who fail on DAAs and require re-treatment is important for budget impact and disease burden projections. AIM: To quantify the number of HCV patients who fail to achieve SVR on oral DAAs (NS5A vs. non-NS5A) and require re-treatment. METHODS: We used a mathematical model to simulate clinical management of HCV in the United States, which included the implementation of HCV screening, treatment, and disease progression. We simulated different waves of DAA treatment and used real-world data to extract SVR rates and market shares of available therapies. RESULTS: Our model projected that the number of people living without viremia (i.e., cured) would increase from 0.70 million in 2014 to 1.78 million by 2020. Between 2014 and 2020, 1.50 million people would receive treatment with DAAs, of whom 124,000 (8.3%) are projected to fail to achieve SVR. Among those treatment failures, 66,600 (53.7%) patients would fail treatment with NS5A inhibitors and 69,600 (56.1%) would have cirrhosis. During the same period 34,200 people would progress to decompensated cirrhosis and 27,300 would develop hepatocellular carcinoma after failing to achieve SVR. CONCLUSIONS: Even in the era of highly-effective DAAs, a significant number of patients will fail to achieve SVR and will require re-treatment options. Timely and effective re-treatment is essential to prevent the long-term sequelae of HCV.

It is not standard practice to treat patients with acute hepatitis C virus (HCV) infection. However, as the incidence of HCV in the United States continues to rise, it may be time to re-evaluate acute HCV management in the era of direct-acting antiviral agents (DAAs). In this study a microsimulation model was developed to analyze the tradeoffs between initiating HCV therapy in the acute versus chronic phase of infection. By simulating the lifetime clinical course of patients with acute HCV infection, we were able to project long-term outcomes such as quality-adjusted life years (QALYs) and costs. We found that treating acute HCV versus deferring treatment until the chronic phase increased QALYs by 0.02 and increased costs by $483 in patients not at risk of transmitting HCV. The resulting incremental cost effectiveness ratio (ICER) was $19,991 per QALY, demonstrating that treatment of acute HCV was cost-effective using a willingness-to-pay threshold of $100,000 per QALY. In patients at risk of transmitting HCV, treating acute HCV became cost-saving, increasing QALYs by 0.03 and decreasing costs by $3655. Conclusion: Immediate treatment of acute HCV with DAAs can improve clinical outcomes and be highly cost-effective or cost-saving compared with deferring treatment until the chronic phase of infection. If future studies continue to demonstrate effective HCV cure with shorter 6 week treatment duration, then it may be time to revisit current HCV guidelines to incorporate recommendations that account for the clinical and economic benefits of treating acute HCV in the era of DAAs. This article is protected by copyright. All rights reserved.

ObjectivesOral direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have dramatically changed the treatment paradigm. Our aim was to project temporal trends in HCV diagnosis, treatment and disease burden in France, Germany, Italy, Spain and the UK.DesignA mathematical simulation model of natural history of HCV infection.ParticipantsHCV-infected patients defined based on country-specific age, fibrosis and genotype distributions.InterventionsHCV screening practice and availability of different waves of DAA treatment in each country.Outcome measuresTemporal trends in the number of patients who achieve sustained virological response (SVR), fail treatment (by drug regimen) and develop advanced sequelae from 2014 to 2030 in each country.ResultsWe projected that 1 324 000 individuals would receive treatment from 2014 to 2030 in the five European countries and 12 000–37 000 of them would fail to achieve SVR. By 2021, the number of individuals cured of HCV would supersede the number of actively infected individuals in France, Germany, Spain and the UK. Under status quo, the diagnosis rate would reach between 65% and 75% and treatment coverage between 65% and 74% by 2030 in these countries. The number of patients who fail treatment would decrease over time, with the majority of those who fail treatment having been exposed to non-structural protein 5A inhibitors.ConclusionsIn the era of DAAs, the number of people with HCV who achieved a cure will exceed the number of viraemic patients, but many patients will remain undiagnosed, untreated, fail multiple treatments and develop advanced sequelae. Scaling-up screening and treatment capacity, and timely and effective retreatment are needed to avail the full benefits of DAAs and to meet HCV elimination targets set by WHO.