Antiviral Therapy Utilization and 10-Year Outcomes in Resected Hepatitis B Virus- and Hepatitis C Virus-Related Hepatocellular Carcinoma.

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.

Racial and ethnic disparities in untreated patients with hepatitis C virus-related hepatocellular carcinoma but not in those with sustained virologic response.

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.

Bilateral Knee Lyme Arthritis in Children: A Report of 3 Cases.

CASES: Three patients presented with bilateral knee pain, effusion, decreased range of motion, and difficulty ambulating. Synovial analysis demonstrated leukocytosis in bilateral knees with positive serum enzyme-linked immunosorbent assay. All cases were managed with antibiotics and anti-inflammatories. One patient developed chronic Lyme arthritis and underwent arthroscopic synovectomy. CONCLUSION: Bilateral knee arthritis is a possible presentation of Lyme disease in children. Accurate diagnosis and treatment with antibiotics and anti-inflammatories can lead to satisfactory outcomes. Arthroscopic synovectomy may be indicated if conservative treatment fails.

Characteristics and Survival Outcomes of Hepatocellular Carcinoma Developed after HCV SVR.

The clinical presentation and survival of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication as compared to HCC in viremic patients are not well characterized. We aimed to investigate the characteristics and survival between HCV patients with and without viremia at HCC diagnosis.: We retrospectively analyzed overall survival outcomes in 1389 HCV-related HCC patients, including 301 with HCC developed after HCV eradication (post-SVR HCC) and 1088 with HCV viremia at HCC diagnosis (viremic HCC). We also evaluated overall survival in the two groups using propensity score-matching methods.: At HCC diagnosis, post-SVR HCC patients were older, less obese, less likely cirrhotic, with better liver function, lower alfa-fetoprotein levels, earlier BCLC stages, and higher rate of treatment with surgery. Overall, post-SVR HCC patients had higher median survival than viremic patients (153.3 vs. 55.6 months, p < 0.01), but post-SVR HCC was not independently associated with survival on multivariate analysis (adjusted HR: 1.05, 95% CI: 0.76-1.47). However, on sub-analysis, viremic HCC patients who subsequently received anti-viral treatment and achieved SVR had higher median survival than post-SVR HCC patients (p < 0.01). Viremic HCC with subsequent SVR was also significantly associated with lower mortality as compared to post-SVR HCC (adjusted HR: 0.18, 95% CI: 0.11-0.29). In addition, we observed similar findings in our analysis of the propensity score-matched cohorts.: The advantages in clinical and tumor characters at HCC diagnosis determined the better overall survival of post-SVR HCC patients; however, HCV eradication after HCC development was also associated with improved survival.

Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice.

BACKGROUND AND AIMS: Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. APPROACH AND RESULTS: We analyzed 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA < 20 IU/mL), biochemical (alanine aminotransferase [ALT] < 35/25 U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96 weeks after switch. Viral suppression (P < 0.001) and ALT normalization (P = 0.003) rates increased significantly after switch, with a trend for increasing complete response (Ptrend = 0.004), while the eGFR trend (Ptrend  > 0.44) or mean eGFR (P > 0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR < 90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P = 0.029) but not after TAF switch (P = 0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1. CONCLUSIONS: Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.

Differential characteristics and outcomes of Asian and non-Asian patients with HBV-related hepatocellular carcinoma.

BACKGROUND & AIMS: The epidemiology of hepatitis B virus (HBV) infection differs between Asians and non-Asians, but little is known regarding the effect of ethnicity on outcomes of HBV-related hepatocellular carcinoma (HCC). We aim to characterize the presentation and survival outcomes in Asian and non-Asian patients with HBV-related HCC. METHODS: We analyzed the baseline characteristics and long-term survival of 613 Asian and 410 non-Asian patients with HBV-related HCC from three US and one Spanish centre. RESULTS: Overall, non-Asian patients were more likely to have HIV or hepatitis C co-infection, cirrhosis, decompensated liver disease and advanced BCLC stage (all P ≤ .04). Compared with Asians, non-Asians were more likely to be listed for transplantation (P < .0001) and undergo HCC treatment with curative intent (P = .003). Propensity-score matching on HCC diagnosis year, gender and age was performed to balance the two groups for survival analysis and yielded 370 pairs of patients. There was no significant difference in survival overall (P = .43) and among patients with cirrhosis (P = .57). Among patients without cirrhosis, non-Asians had poorer 5-year survival compared with Asians (37.6% vs 53.7%, P = .01), and was associated with poorer survival after adjusting for age, gender, diabetes, alcohol, co-infections, diagnosis date, antiviral therapy, BCLC stage and HCC treatment (adjusted HR 2.01 [95% CI 1.07-3.74], P = .03). CONCLUSION: Among HBV-related HCC patients, non-Asians presented with more advanced BCLC stage compared to Asians. Non-Asian ethnicity was independently associated with twice the risk of mortality among patients without cirrhosis, but not among those with cirrhosis. Additional studies are needed to clarify this disparity.

Effects of Cirrhosis and Diagnosis Scenario in Metabolic-Associated Fatty Liver Disease-Related Hepatocellular Carcinoma.

Metabolic-associated fatty liver disease (MAFLD) is a major cause of liver-related complications, including hepatocellular carcinoma (HCC). While MAFLD-related HCC is known to occur in the absence of cirrhosis, our understanding of MAFLD-related HCC in this setting is limited. Here, we characterize MAFLD-related HCC and the impact of cirrhosis and screening on survival. This was a multicenter, retrospective, cohort study of MAFLD-related HCC. MAFLD was defined based on the presence of race-adjusted overweight, diabetes, or both hypertension and dyslipidemia in the absence of excess alcohol use or other underlying cause of liver disease. The primary outcome of interest was overall survival, and the primary dependent variables were cirrhosis status and prior HCC screening. We used Kaplan-Meier methods to estimate overall survival and Cox proportional hazards models and random forest machine learning to determine factors associated with prognosis. This study included 1,382 patients from 11 centers in the United States and East/Southeast Asia. Cirrhosis was present in 62% of patients, but under half of these patients had undergone imaging within 12 months of HCC diagnosis. Patients with cirrhosis were more likely to have early stage disease but less often received curative therapy. After adjustment, cirrhosis was not associated with prognosis, but the presence of cancer-related symptoms at diagnosis was associated with poorer prognosis. Conclusion: Cirrhosis was not associated with overall survival in this cohort of MAFLD-related HCC, while diagnosis in the presence of symptoms was associated with poorer prognosis. The HCC surveillance rate in patients with MAFLD-related HCC was disappointingly low in a multicenter cohort.

Clinical Features Associated with Survival Outcome in African-American Patients with Hepatocellular Carcinoma.

BACKGROUND: African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades. METHODS: HCC patients from three US medical centers were matched by year of diagnosis (1991-2016): AA (n = 578)/Caucasian (n = 578) and placed in one of two groups-HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted. RESULTS: Prior to 2010, there was no difference in survival between Caucasians and AA (p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26-2.43, p = 0.001) and child's class C (aHR 2.05, 95% CI: 1.23-3.41, p = 0.006) were the strongest predictors of mortality, while race was not. CONCLUSIONS: African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.

Real-world cure rates for hepatitis C virus treatments that include simeprevir and/or sofosbuvir are comparable to clinical trial results.

AIM: To assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection. METHODS: The real-world performance of patients treated with SMV/SOF ± ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer's perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression. RESULTS: SVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF ± RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: ± $18588) for SMV/SOF ± RBV; $223003 (± $77946) for SOF/RBV; and $126496 (± $31052) for SOF/PEG/RBV. Among patients on SMV/SOF ± RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score ≥ 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV. CONCLUSION: SVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs.

Hepatitis B surface antigen escape mutations: Indications for initiation of antiviral therapy revisited.

Approximately 240 million people are chronically infected with hepatitis B. The implementation of rigorous vaccination programs has led to an overall decrease in the prevalence of this disease worldwide but this may also have led to emergence of viral mutations that can escape the protection of hepatitis B surface antibody. As this phenomenon is increasingly recognized, concern for transmission to vaccinated individuals has also been raised. Herein, we describe two cases where the suspected presence of a hepatitis B surface antigen escape mutation impacted the decision to initiate early antiviral therapy, as well as provide a brief review of these mutations. Our findings described here suggest that a lower threshold for initiating therapy in these individuals should be considered in order to reduce the risk of transmission, as vaccination does not provide protection.

Hepatic decompensation/serious adverse events in post-liver transplantation recipients on sofosbuvir for recurrent hepatitis C virus.

AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection. METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome. RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m(2), 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases. CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.

Lamivudine resistance leading to de novo hepatitis B infection in recipients of hepatitis B core antibody positive liver allografts.

Most studies have shown that lamivudine (LAM) prophylaxis is sufficient to prevent hepatitis B virus (HBV) transmission in recipients of hepatitis B core antibody positive (HBcAb(+) ) allografts. However, de novo hepatitis B (DNHB) is known to occur in this patient population. Herein, we report a case series of four liver transplant recipients who developed DNHB after receiving HBcAb(+) allografts due to acquisition of LAM resistance mutations, suggesting that LAM prophylaxis may be suboptimal. A retrospective chart review was performed of all adult liver transplants performed at Mount Sinai from 2001 to 2010. A total of 79 patients received HBcAb(+) allografts for non-hepatitis B-related liver disease. Of these 79 recipients, four patients developed DNHB and were found to have documented LAM resistance. With the increasing use of HBcAb(+) donor livers, we suspect that there will also be a growing number of cases of DNHB due to acquisition of LAM resistance. We suggest that other agents, such as entecavir or tenofovir, be considered for use as prophylaxis in this patient population to decrease this risk.

Evaluation and selection of the patient with alcoholic liver disease for liver transplant.

Alcoholic liver cirrhosis is the second most common indication for liver transplantation in the United States. Studies have shown that these patients do as well as those transplanted for nonalcoholic liver disease. Recently, transplantation of patients with alcoholic liver disease has come under closer scrutiny following an article in the New England Journal of Medicine demonstrating comparable outcomes and survival in patients transplanted for acute alcoholic hepatitis. This article reviews the literature and data on the evaluation and selection of patients with alcoholic cirrhosis for liver transplant, and discusses the most recent indication (once a contraindication), acute alcoholic hepatitis.

Accelerated apoptosis contributes to aging-related hyperinflammation in endotoxemia.

Sepsis is associated with an increase in circulating levels of bacterial endotoxin. Sepsis is a particularly serious problem in the geriatric population due to the associated high mortality rate. However, it remains unknown whether this phenomenon is related to an increase in apoptosis in splenic cells. To investigate this issue, male Fischer-344 rats (young, 3 months old; aged, 24 months old) were subjected to endotoxemia by injection of LPS. Splenic samples were collected 4 h thereafter. Apoptosis was determined by cleaved caspase-3 levels and TUNEL staining. The levels of proinflammatory mediators, TNF-alpha, IL-6 and high mobility group box-1 (HMGB-1), were also measured. Our results showed that, while splenic cell apoptosis increased in the young and aged rats with endotoxemia, the aged animals had much higher levels of apoptotic cell death. The elevated expression of cell cycle inhibitory protein P21 was also observed in the aged animals after treatment with LPS. Moreover, endotoxemia significantly increased TNF-alpha, IL-6 and HMGB-1. The accelerated apoptosis in the aged animals was correlated with significantly higher levels of TNF-alpha, IL-6 and HMGB-1. It is suggested that this accelerated rate of apoptosis contributes to age-related hyperinflammation in endotoxemia. To investigate the factors involving accelerated apoptosis in aged animals, we analyzed the Fas/Fas ligand (Fas-L) pathway. Our results showed that Fas and Fas-L gene expression was markedly higher in the spleen in the aged animals after LPS. Similarly, cleaved caspase-8 expression, a downstream element of Fas and Fas-L, was also significantly higher in the aged rats after LPS. Fas-L neutralizing antibodies markedly decreased apoptosis and proinflammatory cytokines in the aged animals after endotoxemia. Thus, there is substantial evidence that the Fas/Fas-L pathway may play an important role in LPS-induced accelerated apoptosis and hyperinflammation in aged animals.

Aging-related hyperinflammation in endotoxemia is mediated by the alpha2A-adrenoceptor and CD14/TLR4 pathways.

AIMS: Sepsis is a major cause of morbidity and mortality in the elderly population. In prior studies, we have shown that in vivo, the inflammatory response in aged animals is exaggerated as compared to young animals and that this response likely accounts for the increased morbidity and mortality. Part of this uncontrolled inflammatory response in sepsis is due to the innate immune response. However, recent studies have shown that the pathogenesis of sepsis is much more complex. The adrenergic autonomic nervous system is now thought to play a key role in modulating the inflammatory response in sepsis. In this study, we hypothesize that not only is the innate immune response enhanced in response to lipopolysaccharide (LPS) in aged animals, but that the adrenergic nervous system also plays a role in the release of excess inflammatory cytokines. MAIN METHODS: Male Fischer-344 rats (young: 3 months; aged: 24 months) were used. Endotoxemia was induced by intravenous injection of lipopolysaccharide (LPS, 15 mg/kg BW). Splenic tissues were harvested and mRNA and protein were extracted. The protein expression of CD14 and TLR4, key mediators of LPS in the innate response, as well as alpha-2A adrenergic receptor (alpha(2A)-AR) and phosphodiesterase 4D (PDE4D), as the means by which the autonomic nervous system exerts its effects were analyzed. KEY FINDINGS: Splenic tissue concentrations of alpha(2A)-AR, PDE4D, CD14, and TLR4 were significantly increased in septic aged rats as compared to aged sham rats and septic young rats. The increased expression of alpha(2A)-AR in septic aged rats was further confirmed by immunohistochemical staining of splenic tissues. SIGNIFICANCE: These data support the hypothesis that not only is the innate immune response increased in aged animals during sepsis, but that there is also an upregulated response of the adrenergic autonomic nervous system that contributes to excess proinflammatory cytokine release.