BACKGROUND & AIMS:Direct-acting antiviral agents (DAA)-mediated HCV cure correlates with better outcomes, but there are insufficient data on detailed mortality-related risk factors after cure. This study sought to clarify mortality and associated risk factors post-HCV cure. METHODS:The study included HCV patients with sustained virological response following DAA (DAA-SVR) from 39 REAL-C centres in North America, Europe and Asia-Pacific. The primary outcome was all-cause mortality in DAA-SVR patients. Mortality rate per 1000 patient-years (PY) was calculated as the number of deaths divided by total PY multiplied by 1000. RESULTS:A total of 10 034 DAA-SVR patients (stratified by cirrhosis status: 5611 non-cirrhosis, 4153 compensated, 270 decompensated) were included. With a median follow-up of 4.76 PY, 4.9% (491) died. The all-cause mortality rates were 6.2, 13.1, 60.0 and 10.4 per 1000 PY for patients without cirrhosis, compensated and decompensated cirrhosis, and overall patients, respectively. The 5-year cumulative survival was 95.1% (94.5%-95.6%) overall, with the lowest rate of 73.9% (67.0%-79.5%) in decompensated cirrhosis. Non-liver-related death was the main cause in non-cirrhosis (non-liver-related vs. liver: 5.2 vs. 0.8 per 1000 PY)/compensated cirrhosis (8.2 vs. 4.8 per 1000 PY), while liver-related death was dominant in decompensated cirrhosis (24.7 vs. 33.8 per 1000 PY). Risk factors for higher mortality included age > 65 (3.2-fold), male (1.5-fold), cirrhosis (decompensated 7.6-fold) and baseline DM (1.5-fold). CONCLUSION:This study showed significant age, sex, fibrosis stage and DM differences in mortality and causes among DAA-SVR patients. It provided granular subgroup data for precision medicine to support individualised care, future modelling studies and public health planning.

INTRODUCTION:Direct-acting antiviral agents effectively cure chronic hepatitis C (CHC), whereas curative therapy for chronic hepatitis B (CHB) is rare. We aimed to compare hepatocellular carcinoma (HCC) incidence between suppressed CHB vs cured CHC patients with cirrhosis. METHODS:We analyzed 5,773 cirrhosis patients from 43 centers in 9 countries: 1,877 with treated and suppressed CHB and 3,896 with direct-acting antiviral agents-cured CHC using inverse probability treatment weight and competing risk analysis through Fine and Gray method. RESULTS:After inverse probability treatment weight (on age, sex, ethnicity, study location, albumin, total bilirubin, creatinine, platelet, tobacco use, alcohol use, diabetes mellitus, hypertension, hyperlipidemia, cardiovascular disease, steatotic liver disease, obesity, and follow-up years), 2 study groups became similar in relevant characteristics. The 5-year cumulative HCC incidence was significantly higher in suppressed CHB compared with cured CHC (18.1% vs 7.4%, P < 0.001) with consistent findings in subgroups by sex and Model for End-Stage Liver Disease (all P < 0.021), fast CHB responders (time from treatment to viral suppression <1 year) ( P < 0.001), and CHB suppressed for <2 years ( P < 0.001), but not among CHB suppressed for ≥2 years whose HCC incidence was similar to those of cured CHC ( P = 0.954). On multivariable analysis, CHB suppression <2 years as compared with cured CHC (subdistribution hazard ratio 20.92, P < 0.001) and total bilirubin (subdistribution hazard ratio 0.71, P = 0.04) were associated with higher HCC risk. DISCUSSION:HCC risk remains high in both treated and suppressed CHB cirrhosis and cured CHC cirrhosis. However, with prolonged CHB suppression, risk of HCC can be reduced, highlighting benefits of early treatment and viral suppression in patients with CHB.

INTRODUCTION:This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis. METHODS:Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS:Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. DISCUSSION:Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).

BACKGROUND & AIMS:Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS:A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS:During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION:Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS:One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

PURPOSE There are limited data on antiviral treatment utilization and its impact on long-term outcomes of hepatitis B virus (HBV)– and hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC) after hepatic resection. We aimed to determine the utilization and impact of antivirals in HBV- and HCV-related HCC. METHODS This cohort study included 1,906 participants (1,054 HBV-related HCC and 852 HCV-related HCC) from 12 international sites. All participants had HBV- or HCV-related HCC and underwent curative surgical resection. The primary outcome was the utilization of antiviral therapy, and the secondary outcome was long-term overall survival (OS). RESULTS The mean (±standard deviation [SD]) age was 62.1 (±11.3) years, 74% were male, and 84% were Asian. A total of 47% of the total cohort received antiviral therapy during a mean (±SD) follow-up of 5.0 (±4.3) years. The overall antiviral utilization for participants with HBV-related HCC was 57% and declined over time, from 65% before 2010, to 60% from 2010 to 2015, to 47% beyond 2015, P < .0001. The overall utilization of antivirals for HCV-related HCC was 35% and increased over time, from 24% before 2015 to 74% from 2015 and beyond, P < .0001. The 10-year OS was lower in untreated participants for both HBV (58% v 61%) and HCV participants (38% v 82%; both P < .0001). On multivariable Cox regression analysis adjusted for relevant confounders, antiviral therapy initiated before or within 6 months of HCC diagnosis was independently associated with lower mortality in both HBV- (adjusted hazard ratio [aHR], 0.60 [95% CI, 0.43 to 0.83]; P = .002) and HCV-related HCC (aHR, 0.18 [95% CI, 0.11 to 0.31]; P < .0001). CONCLUSION Antiviral therapy is associated with long-term survival in people with HBV- or HCV-related HCC who undergo curative resection but is severely underutilized.

Background and Aims: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. Methods: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. Results: The mean age was 62 +/- 13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but >= 97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. Conclusions: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

Summary Background Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. Aim To evaluate the impact of HCV treatment on such disparities. Methods In a retrospective cohort study, we analysed 6069 patients with HCV‐related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. Results The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%–15%, 20% vs. 10%–17% and 10% vs. 5%–7%, respectively; all p < 0.0001). Treatment rate with direct‐acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients ( p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10‐year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients ( p < 0.0001). There were no statistically significant differences among those with SVR ( p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non‐U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). Conclusion DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Tenofovir disoproxil fumarate (TDF) is associated with a higher risk of nephrotoxicity compared with entecavir (ETV) or tenofovir alafenamide (TAF).1,2 One-fifth of transplant recipients develop chronic kidney disease (CKD) within 5 years after transplantation, contributed by the use of nephrotoxic immunosuppressive medications.3 Prior studies conducted in the nontransplant setting reported superior renal safety in TAF compared with TDF but data in liver transplant (LT) recipients have so far been limited to small case series.1,4-6 Therefore, the goals of this study were to examine changes in renal function in a large multicenter cohort of LT recipients with chronic hepatitis B who were treated with TAF, TDF, or ETV for the prevention of hepatitis B virus (HBV) reinfection or reactivation from receipt of a positive HBV core antibody graft.

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child–Turcotte–Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3–4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated.

Background:: Remdesivir is recommended for certain hospitalized patients with COVID-19. However, these recommendations are based on evidence from small randomized trials, early observational studies, or expert opinion. Further investigation is needed to better inform treatment guidelines with regard to the effectiveness of remdesivir among these patients.Methods: We emulated a randomized target trial using chargemaster data from 333 US hospitals from 1 May 2020 to 31 December 2021. We compared three treatment protocols: remdesivir within 2 days of hospital admission, no remdesivir within the first 2 days of admission, and no remdesivir ever. We used baseline comorbidities recorded from encounters up to 12 months before admission and identified the use of in-hospital medications, procedures, and oxygen supplementation from charges. We estimated the cumulative incidence of mortality or mechanical ventilation/extracorporeal membrane oxygenation with an inverse probability of censoring weighted estimator. We conducted analyses in the total population as well as in subgroups stratified by level of oxygen supplementation.Results:: A total of 274,319 adult patients met the eligibility criteria for the study. Thirty-day in-hospital mortality risk differences for patients adhering to the early remdesivir protocol were -3.1% (95% confidence interval = -3.5%, -2.7%) compared to no early remdesivir and -3.7% (95% confidence interval -4.2%, -3.2%) compared to never remdesivir, with the strongest effect in patients needing high-flow oxygen. For mechanical ventilation/extracorporeal membrane oxygenation, risk differences were minimal.Conclusions:: We estimate that, among hospitalized patients with COVID-19, remdesivir treatment within 2 days of admission reduced 30-day in-hospital mortality, particularly for patients receiving supplemental oxygen on the day of admission.

IMPORTANCE A high proportion of underserved patients with cirrhosis receive care at safety-net hospitals (SNHs). While liver transplant (LT) can be a life-saving treatment for cirrhosis, data on referral patterns from SNHs to LT centers are lacking. OBJECTIVE To identify factors associated with LT referral within the SNH context. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 521 adult patients with cirrhosis and model for end-stage liver disease-sodium (MELD-Na) scores of 15 or greater. Participants received outpatient hepatology care at 3 SNHs between January 1, 2016, and December 31, 2017, with end of follow-up on May 1, 2022. EXPOSURES Patient demographic characteristics, socioeconomic status, and liver disease factors. MAIN OUTCOMES AND MEASURES Primary outcome was referral for LT. Descriptive statistics were used to describe patient characteristics. Multivariable logistic regression was performed to evaluate factors associated with LT referral. Multiple chained imputation was used to address missing values. RESULTS Of 521 patients, 365 (70.1%) were men, the median age was 60 (IQR, 52-66) years, most (311 [59.7%]) were Hispanic or Latinx, 338 (64.9%) had Medicaid insurance, and 427 (82.0%) had a history of alcohol use (127 [24.4%] current vs 300 [57.6%] prior). The most common liver disease etiology was alcohol associated liver disease (280 [53.7%]), followed by hepatitis C virus infection (141 [27.1%]). Median MELD-Na score was 19 (IQR, 16-22). One hundred forty-five patients (27.8%) were referred for LT. Of these, 51 (35.2%) were wait-listed, and 28 (19.3%) underwent LT. In a multivariable model, male sex (adjusted odds ratio [AOR], 0.50 [95% CI, 0.31-0.81]), Black race vs Hispanic or Latinx ethnicity (AOR, 0.19 [95% CI, 0.04-0.89]), uninsured status (AOR, 0.40 [95% CI, 0.18-0.89]), and hospital site (AOR, 0.40 [95% CI, 0.18-0.87]) were associated with lower odds of being referred. Reasons for not being referred (n = 376) included active alcohol use and/or limited sobriety (123 [32.7%]), insurance issues (80 [21.3%]), lack of social support (15 [4.0%]), undocumented status (7 [1.9%]), and unstable housing (6 [1.6%]). CONCLUSIONS In this cohort study of SNHs, less than one-third of patients with cirrhosis and MELD-Na scores of 15 or greater were referred for LT. The identified sociodemographic factors negatively associated with LT referral highlight potential intervention targets and opportunities to standardize LT referral practices to increase access to life-saving transplant among underserved patients.

Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population. We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment. From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42

The demand for orthotopic liver transplantation (OLT) is projected to increase, which indicates a need to expand the liver donor pool. We aimed to investigate the use of hepatitis B virus (HBV)–positive grafts and the outcomes of recipients undergoing OLT with HBV‐positive grafts. We conducted a retrospective cohort study analyzing all deceased donors and OLT recipients in the Organ Procurement and Transplantation Network database from January 1999 through March 2021. Donor HBV status was positive if hepatitis B surface antigen was positive or HBV nucleic acid testing was detectable. Recipients of HBV‐positive allografts were matched 1:5 to recipients of HBV‐negative allografts based on recipient and donor age, transplant year, recipient sex, donation after circulatory death, recipient location, and Model for End‐Stage Liver Disease score at transplant. Among the 185,212 potential donors, 422 (0.2%) were HBV positive, and 265 (63%) of the HBV‐positive grafts were transplanted (14 of 265 [5.3%] in HBV‐positive recipients). The overall discard rate for HBV‐positive donors of 37.2% (157/422) remained significantly higher than the discard rate for HBV‐negative donors of 26.5% (49,026/185,212) during the study period (p < 0.001). Recipients of HBV‐positive (n = 209) grafts had similar mortality (log‐rank, p = 0.47) and graft loss (log‐rank, p = 0.72) rates to the matched recipients of HBV‐negative allografts (n = 1045). The 3‐year graft survival rate was 77.9% for the HBV‐positive group and 79.7% in the matched HBV‐negative group. Based on this analysis, transplant recipients of HBV‐positive liver allografts do not experience increased rates of mortality or graft loss. One strategy that may help expand the donor pool and lower the waitlist mortality rate is using HBV‐positive allografts.