Liver transplant allocation policies and outcomes in United States: A comprehensive review.

Liver transplant allocation policies in the United States has evolved over 3 decades. The donor liver organs are matched, allocated and procured by the Organ Procurement and Transplantation Network which is administered by the United Network of Organ Sharing (UNOS), a not-for-profit organization governed by the United States human health services. We reviewed the evolution of liver transplant allocation policies. Prior to 2002, UNOS used Child-Turcotte-Pugh score to list and stratify patients for liver transplantation (LT). After 2002, UNOS changed its allocation policy based on model for end-stage liver disease (MELD) score. The serum sodium is the independent indicator of mortality risk in patients with chronic liver disease. The priority assignment of MELD-sodium score resulted in LT and prevented mortality on waitlist. MELD-Sodium score was implemented for liver allocation policy in 2016. Prior to the current and most recent policy, livers from adult donors were matched first to the status 1A/1B patients located within the boundaries of the UNOS regions and donor-service areas (DSA). We reviewed the disadvantages of the DSA-based allocation policies and the advantages of the newest acuity circle allocation model. We then reviewed the standard and non-standard indications for MELD exceptions and the decision-making process of the National Review Liver Review Board. Finally, we reviewed the liver transplant waitlist, donation and survival outcomes in the United States.

Provider Attitudes Toward Risk-Based Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis in the United States.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers' opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patient's HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patient's HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001). CONCLUSIONS: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients' estimated HCC risk, instead of our current "one-size-fits all" strategy.

Expanding indications for liver transplantation in the era of liver transplant oncology.

Despite numerous advances and emerging data, liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications. In an era of persistent organ shortage and increasing organ demand, allocation of liver grafts must be considered carefully. While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation, tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes. As more studies seeking to expand the oncologic indications for liver transplantation are emerging, it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes. In addition, time from diagnosis to transplantation appears to correlate with survival, as stable disease over time portends better outcomes post-operatively. Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques. While tumor size and stage are important prognostic predictors for most malignancies, patient and tumor selection protocols are necessary. As the fields of medical and surgical oncology continue to evolve, it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively. Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms. Current data evaluating liver transplantation for expanded oncologic indications such as: expanded criteria hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed tumors, and liver limited metastatic colorectal carcinomas, incorporate multi-modal therapies and evaluation of tumor treatment response. While further investigation is necessary, initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.

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.

Current Management of Alcohol-Associated Liver Disease.

Alcohol consumption is a major risk factor for various diseases worldwide and is one of the most common causes of chronic liver disease. Alcohol use has risen over the past 30 years and is forecast to continue to rise. Concurrently, there has been an increased incidence of alcohol-associated liver disease (ALD). Alcohol use, regardless of the amount, leads to years of health loss across populations when considering the strong association between alcohol consumption and overall disease burden. Given the rising incidence of ALD and associated mortality, it is imperative to study the underlying factors driving these trends. This article summarizes the diagnosis and management of ALD, with a focus on various screening and prognostic tools and treatments for alcohol-associated hepatitis.

Risk of Hepatitis B Virus Reactivation Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection.

BACKGROUND: Direct acting antiviral (DAA) agents are the standard of care for treatment of hepatitis C virus (HCV)-infected individuals. Hepatitis B virus (HBV) reactivation during HCV treatment has been reported, the incidence and clinical outcome remains unclear. The aim of our study is to examine the risk of HBV reactivation in actively infected or previously exposed patients during or after HCV treatment with DAAs. METHODS: Adults with chronic HCV infection previously exposed or actively infected with HBV and treated with DAAs between December 2015 to 2016 were included. Electronic medical records were reviewed for HCV treatment dates, HCV treatment response, DAA used, HBV status, and concurrent HBV treatment. Primary end-point was to determine the risk of HBV reactivation during or up to 3 months after DAA treatment. RESULTS: We identified 283 patients, and 100% of patients completed HCV treatment with ledipasvir-sofosbuvir. 93% had HCV genotype-1 of whom 91% achieved sustained viral response at 12 weeks posttreatment (SVR-12). In total, 7% had HCV genotype-4 who achieved SVR-12 of 84%. Mean (±SD) age was 59.7 (±7) years, and 58% were male. A total of 45% of patients had hepatitis B core antibody (HBcAb) positive and hepatitis B surface antigen (HBsAg) negative. In total, 55% of patients had a positive HBsAg before HCV DAA treatment. No HBV reactivation was encountered in the (HBcAb) positive HBsAg-negative cohort nor in the (HBsAg) positive group with 95% confidence interval (0-0.023) and (0-0.019), respectively. CONCLUSION: In our study of patients with HCV and isolated hepatitis B core or HBsAg positivity, no HCV patients treated with DAA experienced HBV reactivation.

Update on the Management of Hepatitis C Virus Infection in the Setting of Chronic Kidney Disease and Kidney Transplantation.

Hepatitis C virus (HCV) infection is one of the major global health burdens. Chronic HCV infection can increase the risks of proteinuria and chronic kidney disease (CKD), as well as cause various types of glomerulonephritides. This article provides an update on the management of patients with HCV infection with CKD and a kidney transplantation. Newer direct-acting antiviral (DAA) agents are safe and effective in eliminating HCV infection in patients with CKD and in kidney transplant recipients. Society guidelines recommend elbasvir/grazoprevir and glecaprevir/pibrentasvir for HCV-infected patients with CKD stage 4 or 5, including patients on hemodialysis. Patients with CKD stages 1 to 3 with HCV infection can be treated with various sofosbuvir-based regimens. Major clinical trials have demonstrated the safety, efficacy, and feasibility of the use of DAA agents in treating HCVuninfected kidney transplant recipients of HCV-infected donors. The utilization of HCV-infected kidney donors may decrease kidney transplant waiting list mortality and reduce the donated kidney discard rate.

Eight-week ledipasvir/sofosbuvir in non-cirrhotic, treatment-naïve hepatitis C genotype-1 patients with hepatitis C virus-RNA < 6 million: Single center, real world effectiveness and safety.

AIM: To evaluate sustained viral response (SVR) of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 hepatitis C virus (HCV) patients with RNA < 6 million IU/mL. METHODS: We performed a retrospective cohort study to examine SVR rates, predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir (LDV/SOF) therapy among non-cirrhotic, genotype 1 HCV patients with viral load < 6 million IU/mL. Primary outcome was an achievement of SVR at 12 wk after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment. RESULTS: Total 736 patients: 55% males, 51% Caucasians and 65% were genotype 1a. Non-cirrhotic state of 53% was determined by clinical judgment (imaging, AST, platelet count) and 47% had documented liver fibrosis testing (biopsy, vibration-controlled transient elastography, serum biomarkers). Overall SVR12 was 96%. No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests were not associated with lower SVR [OR = 1.02, 95%CI: 0.48-2.17, P = 0.962]. The AUROC for hepatitis C RNA viral load was 0.734 (P < 0.001, 95%CI: 0.66-0.82). HCV RNA 2.2 million IU/mL was identified as the cutoff value with sensitivity 73% and specificity 64%. HCV RNA < 2.2 million IU/mL was associated with significantly higher SVR 98% with OR = 0.22 (95%CI: 0.1-0.49, P < 0.001) compared to SVR 92% in HCV RNA ≥ 2.2 million IU/mL. No death or morbidities were reported. CONCLUSION: Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic, untreated HCV genotype 1 patients with HCV RNA < 6 million IU/mL.

Real-World Experiences With a Direct-Acting Antiviral Agent for Patients With Hepatitis C Virus Infection.

CONTEXT: Traditional hepatitis C virus treatment was limited by low cure rates, side effects, and stringent monitoring requirements. Sofosbuvir, a direct-acting antiviral agent with a cure rate of 96%, was introduced in 2013. However, trials frequently excluded patients with advanced liver disease and prior treatment experience. This study aims to elucidate the real-world cure rates and sofosbuvir safety profile. METHODS: A retrospective cohort study was conducted at Kaiser Permanente Southern California involving patients with hepatitis C virus who received sofosbuvir treatment. Patients age 18 years and older were included, and pregnant patients were excluded. The primary end point was sustained virologic response at 12 weeks posttreatment. Secondary end points were safety and medication adherence. Multiple logistic regression analysis was used to compare patients with genotypes 1 and 2 infections. RESULTS: Of the 213 study patients, 42.3% had cirrhosis, and 38% were treatment-experienced. Most patients (69.5%) received dual therapy (sofosbuvir + ribavirin), whereas the remainder (30.5%) received triple therapy (sofosbuvir + ribavirin + interferon). The overall rate of sustained virologic response at 12 weeks posttreatment rate was 72.9% for genotype 1 infection, 64.7% in the treatment-experienced subgroup, and 66.7% in the cirrhosis subgroup. Rates of sustained virologic response at 12 weeks posttreatment for genotypes 2 and 3 were 90.8% and 55%, respectively. Most patients experienced anemia and fatigue. Women and patients with a lower baseline viral load were statistically more likely to be cured. CONCLUSION: Real-world cure rates were similar to rates seen in clinical trials for genotype 2 infection and lower for genotype 1 infection. Patients with genotype 1 and 3 infection did better with triple therapy compared with dual therapy. Patients tolerated therapy well with side effects, serious adverse events, and discontinuation rates similar to clinical trials. Women and patients with lower baseline hepatitis C viral load were more likely to achieve sustained virological response at 12 weeks posttreatment.

Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection.

Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus-infected patients who are treatment-naive, do not have cirrhosis, and have a pretreatment viral load <6,000,000 IU/mL. The effectiveness of this regimen, however, has not been fully confirmed by real-world experience. Using data from real-world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we used individual patient data from the IFI (Institut für Interdisziplinäre Medizin), Burman's Pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography, or serum biomarkers. We also performed a systematic review and meta-analysis of six additional real-world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of whom all had outcomes of cure or relapse without loss to follow-up. Per protocol rates of sustained virologic response at 12 weeks were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment-eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta-analysis of six additional real-world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (relative risk = 0.99, 95% confidence interval 0.98-1.00). CONCLUSION: An 8-week duration of treatment with LDV/SOF is highly effective in properly selected patients; greater use of this regimen is recommended. (Hepatology 2017;65:1094-1103).

Diagnosing hepatitis C virus and improved outcomes in overall and kidney graft survival among simultaneous liver-kidney transplant recipients in the post-MELD era.

OBJECTIVES: We compared survival outcomes among simultaneous liver-kidney transplants after model for end-stage liver disease (MELD) according to their specific diagnosis and hepatitis C virus versus nonhepatitis C virus. MATERIALS AND METHODS: Clinical data review was performed for all patients who underwent combined liver-kidney transplants at Johns Hopkins Hospital from January 31, 1995, to October 31, 2012. Differences in demographics and characteristics among 2 groups were compared using independent samples t test. Survival analysis and distributions were calculated using Kaplan-Meier and Mantel-Cox log-rank test. RESULTS: Of 48 combined liver-kidney transplants, 31 simultaneous liver-kidney transplants cases were included; nonsimultaneous liver-kidney transplants and patients with prior transplants were excluded. Proportions of age, sex, ethnicity, pre-MELD score, pretransplant renal replacement therapy requirement, hypertension, diabetes mellitus, and follow-up were similar in both groups. Median follow-up was 30 months. Overall and graft survival rates among simultaneous liver-kidney transplants recipients in the pre-MELD era were significantly superior to simultaneous liver-kidney transplants patients in the post-MELD era (P = .0473). However, overall and graft survival rates among simultaneous liver-kidney transplants recipients who had hepatitis C virus and non-hepatitis C virus causes were not statistically different. CONCLUSIONS: We demonstrated a statistically significant difference in overall and kidney graft survival between the post-MELD era and the pre-MELD era. Subgroup analyses of this group showed no statistically significant difference in overall and kidney-graft survival when compared with their specific diagnosis of hepatitis C virus. This must be further studied and verified in a larger cohort of patients to fully identify the effect of hepatitis C virus infection in this group of patients because it can affect both liver and kidney grafts after transplant.

Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma.

Esophageal cancer ranks sixth in cancer death. To explore its genetic origins, we conducted exomic sequencing on 11 esophageal adenocarcinomas (EAC) and 12 esophageal squamous cell carcinomas (ESCC) from the United States. Interestingly, inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs. There was a substantial disparity in the spectrum of mutations, with more indels in ESCCs, A:T>C:G transversions in EACs, and C:G>G:C transversions in ESCCs (P < 0.0001). Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53 cases) than in ESCCs from China (1 of 48 cases). A parallel analysis found that most mutations in EACs were already present in matched Barrett esophagus. These discoveries highlight key genetic differences between EACs and ESCCs and between American and Chinese ESCCs, and suggest that NOTCH1 is a tumor suppressor gene in the esophagus. Finally, we provide a genetic basis for the evolution of EACs from Barrett esophagus.