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Background: Transarterial chemoembolization (TACE) is the most common procedure for the treatment of hepatocellular carcinoma (HCC). However, HCC is generally considered chemoresistant and data demonstrating the superiority of TACE over bland embolization (TAE) are lacking., Materials and Methods: A nationwide, retrospective cohort study of HCC patients treated with first-line TACE or TAE within the Veterans Affairs health care system (2005-2012) was performed. The primary outcome was overall survival. Risk of death by treatment type (TACE or TAE) was evaluated using multivariate (adjusted for age, presence of cirrhosis, Barcelona Clinic Liver Cancer stage, and Charlson comorbidity score) and propensity score-adjusted Cox regression., Results: The cohort included 405 patients treated with first-line transarterial embolization. Among these patients, 32 (7.9%) underwent TAE. Most of the patients (76.8%) had intermediate or advanced stage at presentation. Similar proportions of patients (TACE 53.3% versus TAE 43.7%; P = 0.30) received more than one embolization procedure. There was no difference in median survival (20.1 versus 23.1 mo, respectively; log-rank P = 0.84). Compared to TACE, there was no difference in risk of death associated with TAE after multivariate (hazard ratio [HR] 0.92; 95% CI, 0.61-1.37) and propensity score adjustment (HR = 0.86; 95% CI = 0.58-1.29)., Conclusions: There is no clear benefit associated with chemotherapy infusion over bland embolization for HCC treatment. Given the rising incidence of HCC in the United States and considering the added costs associated with TACE compared to TAE, future work comparing these competing management strategies is needed., (Published by Elsevier Inc.)

Background & Aims: Hepatocellular carcinoma (HCC) can develop in individuals without cirrhosis. We investigated risk factors for development of HCC in the absence of cirrhosis in a U.S., Methods: We identified a national cohort of 1500 patients with verified HCC during 2005 to 2010 in the U.S. Veterans Administration (VA) and reviewed their full VA medical records for evidence of cirrhosis and risk factors for HCC. Patients without cirrhosis were assigned to categories of level 1 evidence for no cirrhosis (very high probability) or level 2 evidence for no cirrhosis (high probability), which were based on findings from histologic analyses, laboratory test results, markers of fibrosis from noninvasive tests, and imaging features., Results: A total of 43 of the 1500 patients with HCC (2.9%) had level 1 evidence for no cirrhosis, and 151 (10.1%) had level 2 evidence for no cirrhosis; the remaining 1203 patients (80.1%) had confirmed cirrhosis. Compared with patients with HCC in presence of cirrhosis, greater proportions of patients with HCC without evidence of cirrhosis had metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), or no identifiable risk factors. Patients with HCC without evidence of cirrhosis were less likely to have abused alcohol or have hepatitis C virus infection than patients with cirrhosis. Patients with HCC and NAFLD (unadjusted odds ratio, 5.4; 95% confidence interval, 3.4-8.5) or metabolic syndrome (unadjusted odds ratio, 5.0; 95% confidence interval, 3.1-7.8) had more than 5-fold risk of having HCC in the absence of cirrhosis, compared with patients with HCV-related HCC., Conclusions: Approximately 13% of patients with HCC in the VA system do not appear to have cirrhosis. NAFLD and metabolic syndrome are the main risk factors for HCC in the absence of cirrhosis., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: HIV increases the risk of progression to hepatic fibrosis and cirrhosis among individuals coinfected with hepatitis C virus (HCV). However, the impact of HIV-related immune suppression on the risk of hepatocellular carcinoma (HCC) is currently unknown., Methods: We used the Veterans Affairs HIV Clinical Case Registry to identify patients with HIV infection between 1985 and 2010 and HCV coinfection (positive HCV RNA or genotype test) between 1995 and 2010. The outcome was incident HCC as indicated by International Classification of Diseases, 9th revision, Clinical Modification code (87% positive predictive value). Patients with HCV monoinfection were included as a comparison group for HCC incidence. Age-adjusted HCC incidence rates were calculated for the coinfected cohort and HCV monoinfected cohort. Cox proportional hazard models were used to determine hazard ratios (HRs) and 95% confidence intervals (CIs) for each risk factor on the time to HCC diagnosis in the coinfected cohort., Results: There were 66,991 veterans with HIV; 8563 had at least 1 positive HCV RNA test, and 234 of these developed HCC. The overall age-adjusted incidence rate of HCC in monoinfected patients was 2.99/1000 person-years vs. 4.44/1000 person-years in coinfected patients. In patients with coinfection, presence of cirrhosis (HR = 4.88; 95% CI: 3.30 to 7.21), HIV diagnosis >2002 (HR = 4.65; 95% CI: 2.70 to 8.02), and a recent low CD4 cell count <200 (HR = 1.71; 95% CI: 1.20 to 2.45) were associated with an increased risk for HCC., Conclusions: The risk of HCC in HCV- and HIV-coinfected veteran men was higher than HCV monoinfection. Diagnosis of cirrhosis and low recent CD4 cell count were the most important predictors of developing HCC in this group.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, no systemic studies from the United States have examined temporal trends, HCC surveillance practices, and outcomes of NAFLD-related HCC., Methods: We identified a national cohort of 1500 patients who developed HCC from 2005 through 2010 from Veterans Administration (VA) hospitals. We reviewed patients' full VA medical records; NAFLD was diagnosed based on histologic evidence for, or the presence of, the metabolic syndrome in the absence of hepatitis C virus (HCV) infection, hepatitis B, or alcoholic liver disease. We compared annual prevalence values for the main risk factors (NAFLD, alcohol abuse, and HCV), as well a HCC surveillance and outcomes, among HCC patients., Results: NAFLD was the underlying risk factor for HCC in 120 patients (8.0%); the annual proportion of NAFLD-related HCC remained relatively stable (7.5%-12.0%). In contrast, the proportion of HCC cases associated with HCV increased from 61.0% in 2005 (95% confidence interval, 53.1%-68.9%) to 74.9% in 2010 (95% confidence interval, 69.0%-80.7%). The proportion of HCC cases associated with only alcohol abuse decreased from 21.9% in 2005 to 15.7% in 2010, and the annual proportion of HCC cases associated with hepatitis B remained relatively stable (1.4%-3.5%). A significantly lower proportion of patients with NAFLD-related HCC had cirrhosis (58.3%) compared with patients with alcohol- or HCV-related HCC (72.4% and 85.6%, respectively; P < .05). A significantly higher percentage of patients with NAFLD-related HCC did not receive HCC surveillance in the 3 years before their HCC diagnosis, compared with patients with alcohol- or HCV-associated HCC. A lower proportion of patients with NAFLD-related HCC received HCC-specific treatment (61.5%) than patients with HCV-related HCC (77.5%; P < .01). However, the 1-year survival rate did not differ among patients with HCC related to different risk factors., Conclusions: NAFLD is the third most common risk factor for HCC in the VA population. The proportion of NAFLD-related HCC was relatively stable from 2005 through 2010. Although patients with NAFLD-related HCC received less HCC surveillance and treatment, a similar proportion survive for 1 year, compared with patients with alcohol-related or HCV-related HCC., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The effect of hepatitis B virus (HBV) coinfection in patients with hepatitis C virus (HCV) remains unclear. We used the National Veterans Affairs HCV Clinical Case Registry to identify patients with confirmed HCV viremia during 1997-2005. We defined HBV coinfection as a positive test for hepatitis B surface antigen, HBV DNA, or hepatitis B e antigen. We defined cirrhosis and hepatocellular carcinoma (HCC) based on the validated ICD-9 codes and determined mortality through the end of 2009. We performed Cox proportional hazard regression analyses to examine the effect of HBV coinfection stratified by HBV DNA status (positive or negative) on the risk of cirrhosis, HCC, and death adjusting for patients' age, gender, race, human immunodeficiency virus (HIV) infection, alcohol or drug use, Deyo Score, and antiviral treatment. Among 99,548 patients with HCV infection, 1,370 patients (1.4%) had HBV coinfection. Of the coinfected patients, 677 (49.4%) patients had at least one HBV DNA test done and 303 patients (44.7%) tested positive for HBV DNA. The incidence rates of cirrhosis, HCC, and death were significantly higher in patients with HBV coinfection and detectable HBV DNA compared to HCV monoinfection (36.8, 6.9, and 41.7 versus 17.4, 3.6, and 31.4 per 1,000 person-years, respectively; P < 0.05 for all comparisons). After adjustment for demographic, clinical, and treatment factors, patients with detectable HBV DNA had a significantly higher risk for cirrhosis (hazard ratio [HR] = 1.89 95% confidence interval [CI] = 1.46-2.45), HCC (HR = 2.12, 95% CI = 1.26-3.60), and death (HR = 1.62, 95% CI = 1.33-1.99) compared to HCV monoinfected patients. There were no differences in the risk of cirrhosis, HCC, or overall mortality between coinfected patients with undetectable HBV DNA and those with HCV monoinfection (HR = 1.18, 95% CI = 0.90-1.55; 1.54, 95% CI = 0.93-2.56; 1.08, 95% CI = 0.88-1.33, respectively)., Conclusion: We found that while only a small number of HCV patients were coinfected with HBV, patients with documented HBV viremia were at a significantly higher risk for cirrhosis, HCC, and overall death than HCV monoinfected patients. Absence of HBV replication was associated with a clinical course similar to that of HCV monoinfected patients., (© 2014 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objectives: The race of patients infected with hepatitis C virus (HCV) in the United States may be associated with the risk for cirrhosis and hepatocellular carcinoma (HCC). However, previous studies are too small to provide convincing data regarding the effect of race on cirrhosis and HCC risk after accounting for demographic, clinical, and virological factors., Methods: We used the Veterans Administration (VA) HCV Clinical Case Registry to identify patients with confirmed viremia between 2000 and 2009 and with at least 1 year of follow-up in the VA. We identified cirrhosis and HCC cases through early 2010. Cox proportional hazard regression models were performed to examine the effect of race on the risk for cirrhosis and HCC while adjusting for patients' age, gender, period of service (World War I/II, Vietnam era, post-Vietnam era), HIV coinfection, HBV coinfection, alcohol abuse, diabetes, body mass index, and antiviral treatment receipt and response., Results: There were 149,407 patients with active HCV viremia. Of them, 56.3% were non-Hispanic White (NHW), 36.1% were African American (AA), 6.0% were Hispanic, and 1.6% belonged to other racial groups. After an average follow-up of 5.2 years, 13,099 patients were seen to have a recorded diagnosis of cirrhosis and 3,551 had HCC. Hispanics had the highest annual incidence rates of cirrhosis and HCC (28.8 and 7.8%, respectively), whereas AAs had the lowest rates (13.3% and 3.9%, respectively) compared with NHWs (21.6 and 4.7%, respectively). There were differences among NHW, AA, and Hispanic patients in the rates of HIV infection (2.1, 2.5, and 6.0%, respectively), HCV genotype 1 (50.0, 50.6, and 64.2%, respectively), obesity (28.0, 25.4, and 30.9%, respectively), diabetes (8.7, 16.1, and 16.1%, respectively), and absence of antiviral treatment (81.1, 89.6, and 82.1%, respectively). However, adjusting for differences in demographic and clinical factors did not change the magnitude or direction of the race effect. Compared with NHWs, Hispanic patients had a higher risk of having cirrhosis recorded (adjusted hazard ratio (HR)=1.28, 95% confidence interval (CI)=1.21-1.37) and HCC (1.61, 95% CI=1.44-1.80). In contrast, AAs had a lower risk of cirrhosis (HR=0.58, 95% CI=0.55-0.60) and HCC (0.77, 95% CI=0.71-0.83) compared with NHWs., Conclusions: Hispanics with HCV are at a significantly higher risk, whereas AAs are at a considerably lower risk of developing cirrhosis and HCC than are NHWs. These associations persisted even after adjusting for a range of factors including HCV genotype, HCV treatment, diabetes, and body mass index.

Unlabelled: The delivery of treatment for hepatocellular carcinoma (HCC) could be influenced by the place of HCC diagnosis (hospitalization versus outpatient), subspecialty referral following diagnosis, as well as physician and facility factors. We conducted a study to examine the effect of patient and nonpatient factors on the place of HCC diagnosis, referral, and treatment in Veterans Administration (VA) hospitals in the United States. Using the VA Hepatitis C Clinical Case Registry, we identified hepatitis C virus (HCV)-infected patients who developed HCC during 1998-2006. All cases were verified and staged according to Barcelona Clinic Liver Cancer (BCLC) criteria. The main outcomes were place of HCC diagnosis, being seen by a surgeon or oncologist, and treatment. We examined factors related to these outcomes using hierarchical logistic regression. These factors included HCC stage, HCC surveillance, physician specialty, and facility factors, in addition to risk factors, comorbidity, and liver disease indicators. Approximately 37.2% of the 1,296 patients with HCC were diagnosed during hospitalization, 31.0% were seen by a surgeon or oncologist, and 34.3% received treatment. Being seen by a surgeon or oncologist was associated with surveillance (adjusted odds ratio [aOR] = 1.47; 95% CI: 1.20-1.80) and varied by geography (1.74;1.09-2.77). Seeing a surgeon or oncologist was predictive of treatment (aOR = 1.43; 95% CI: 1.24-1.66). There was a significant increase in treatment among patients who received surveillance (aOR = 1.37; 95% CI: 1.02-1.71), were seen by gastroenterology (1.65;1.21-2.24), or were diagnosed at a transplant facility (1.48;1.15-1.90)., Conclusion: Approximately 40% of patients were diagnosed during hospitalization. Most patients were not seen by a surgeon or oncologist for treatment evaluation and only 34% received treatment. Only receipt of HCC surveillance was associated with increased likelihood of outpatient diagnosis, being seen by a surgeon or oncologist, and treatment., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Goals: To evaluate the utilization and determinants of receiving palliative treatment for hepatocellular carcinoma (HCC), and its effect on survival., Background: Palliative treatment for HCC, including transarterial chemoembolization (TACE) and systemic chemotherapy, is available for patients who do not receive potentially curative therapy. The utilization and outcomes of these therapies in clinical practice are unknown., Study: We conducted a population-based cohort study using the Surveillance, Epidemiology, and End-Results Registry data linked to Medicare claims of HCC patients aged above 65 years diagnosed during 2000 to 2005 who did not receive liver transplant, resection, or ablation. The proportions of patients who received TACE or systemic chemotherapy were calculated by tumor stage, liver disease status, and non-HCC comorbidity. Determinants of receiving palliative therapy were examined in logistic regression models and propensity scores were calculated. Cox proportional hazards models were used to evaluate mortality risk., Results: We identified 3163 HCC patients (median age, 75 y; 67% men) who did not receive potentially curative treatment. Approximately 12.5% of patients received TACE and 11.0% received chemotherapy. In patients with early or intermediate stage HCC, no liver decompensation, and little or no comorbidity, only 22.8% received TACE and 13.8% received chemotherapy. Median survival was significantly higher among patients who received TACE (14.0 mo) compared with who received chemotherapy (5.0 mo) or no therapy (2.0 mo). A significant reduction in overall mortality was observed for TACE (54%) and chemotherapy (33%)., Conclusions: Utilization of palliative treatment for HCC is low, which could not be explained by clinical features. However, misclassification could have occurred due to the data source. Receipt of TACE or systemic chemotherapy was associated with a reduction in mortality.

Background & Aims: Hepatocellular carcinoma (HCC) can result from hepatitis C virus (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. α-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC., Methods: In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998, to January 1, 2007 (n = 1480 patients). The mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as less than 10 ng/mL (18%), 10 to less than 100 ng/mL (30%), 100 to less than 1000 ng/mL (22%), or 1000 ng/mL or more (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment., Results: The median survival times were significantly lower among patients with higher levels of AFP: 709 days for patients with less than 10 ng/mL, 422 days for patients with 10 to less than 100 ng/mL, 208 days for patients with 100 to less than 1000 ng/mL, and 68 days for patients with 1000 ng/mL or more. In the multivariate analysis, increased levels of AFP (10 to <100, 100 to <1000, and ≥1000) were associated significantly with increased mortality, compared with a serum AFP level of less than 10; hazard ratios were 1.50, 2.23, and 4.35, respectively., Conclusions: Serum AFP level at the time of diagnosis with HCV-related HCC is an independent predictor of mortality., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in the USA is largely unknown. The objective of this study was to evaluate the effectiveness of HCC surveillance in a national Veterans Administration (VA) practice setting, using the national VA hepatitis C virus (HCV) Clinical Case Registry., Method: The cohort consisted of 1480 HCV-infected patients who developed HCC during 1998-2007. The timing and intensity of receiving α-fetoprotein (AFP) and abdominal ultrasound (US) for HCC surveillance were evaluated. Overall mortality risk was examined using Cox proportional hazards regression models adjusting for demographics, clinical features and receipt of HCC-specific treatment., Results: The mean survival was 1.8 years following the HCC diagnosis date. Surveillance AFP or US were recorded in 77.8% of patients within 2 years prior to HCC diagnosis. Annual surveillance with both AFP and US was observed in only 2% of patients. The presence of either AFP or US surveillance during both 0-6 month and 7-24 month periods before HCC diagnosis was associated with a lower mortality risk (HR 0.71, 95% CI 0.62 to 0.82) compared with no surveillance. Receipt of two or more surveillance tests in the 0-6 months (HR 0.76 95% CI 0.66 to 0.88) and to a lesser extent in the 7-12 months (HR 0.81 95% CI 0.1 to 0.99) prior to HCC diagnosis was also associated with reduced mortality risk., Conclusions: Most patients with HCV-related cirrhosis do not receive regular imaging-based surveillance. The effectiveness of HCC surveillance tests in current clinical practice is rather modest in reducing HCC-related mortality.

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with hepatitis C virus (HCV) infection and cirrhosis. However, whether surveillance is being done as recommended is unknown., Objective: To examine the prevalence and determinants of HCC surveillance among HCV-infected patients with cirrhosis in Veterans Affairs (VA) health care facilities in the United States., Design: Retrospective cohort study of HCV-infected patients using data obtained from the national VA Hepatitis C Clinical Case Registry., Setting: 128 VA medical centers., Patients: HCV-infected patients with cirrhosis diagnosed between fiscal years 1998 and 2005., Measurements: Abdominal ultrasonography and measurement of α-fetoprotein for HCC surveillance were identified from administrative data by using a previously validated algorithm. Patients were categorized as having routine (tests done during at least 2 consecutive years in the 4 years after cirrhosis diagnosis), inconsistent (at least 1 test, but not routine), or no surveillance in the 4 years after cirrhosis diagnosis. Predictors of surveillance were identified by using hierarchical random-effects regression., Results: 126 670 patients with HCV were identified; 13 002 (10.1%) had cirrhosis. Approximately 42.0% of patients with cirrhosis received 1 or more HCC surveillance tests within the first year after the cirrhosis index date; however, a decline in receipt of surveillance was observed in the following 2 to 4 years. Among patients with cirrhosis and at least 2 years of follow-up, routine surveillance occurred in 12.0%, inconsistent surveillance in 58.5%, and no surveillance in 29.5%. Lower medical and psychological comorbid conditions, presence of varices, and the absence of decompensated liver disease were associated with a higher likelihood of receiving routine surveillance., Limitations: Hepatocellular carcinoma surveillance tests were indirectly identified from registry data. Physician recommendations could not be captured., Conclusion: Few HCV-infected veterans with cirrhosis received routine HCC surveillance. New strategies are needed to improve the implementation of HCC surveillance in clinical practice., Primary Funding Source: Houston Veterans Affairs Health Services Research and Development Center of Excellence and the National Cancer Institute.