Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated with a multitude of adverse outcomes. We aimed to estimate the pooled incidence of NAFLD-related adverse events. METHODS: We performed a systematic review and meta-analysis of cohort studies of adults with NAFLD to evaluate the pooled incidence of adverse events. RESULTS: 19,406 articles were screened, 409 full-text articles reviewed, and 79 eligible studies (1,377,466 persons) were included. Mean age was 51.47 years and body mass index 28.90 kg/m2. Baseline comorbidities included metabolic syndrome (41.73%), cardiovascular disease (CVD) (16.83%), cirrhosis (21.97%), and nonalcoholic steatohepatitis (NASH) (58.85%). Incidence rate per 1,000 person-years for mortality included: all-cause (14.6), CVD-related (4.53), non-liver cancer-related (4.53), and liver-related (3.10). Incidence for liver-related events included overall (24.3), fibrosis progression (49.0), cirrhosis (10.9), liver transplant (12.0), and hepatocellular carcinoma (HCC) (3.39). Incidence for non-liver events included metabolic syndrome (25.4), hypertension (25.8), dyslipidemia (26.4), diabetes (19.0), CVD (24.77), renal impairment (30.3), depression/anxiety (29.1), and non-liver cancer (10.5). Biopsy-proven NASH had higher incidence of HCC (P=0.043) compared to non-NASH. Higher rates of CVD and mortality were observed in North America and Europe, hypertension and non-liver cancer in North America, and HCC in Western Pacific/Southeast Asia (P<0.05). No significant differences were observed by sex. Time-period analyses showed decreasing rates of cardiovascular and non-liver cancer mortality and increasing rates of decompensated cirrhosis (P<0.05). CONCLUSION: People with NAFLD have high incidence of liver and non-liver adverse clinical events, varying by NASH, geographic region, and time-period, but not sex.

Outcomes of Sequential Therapy With Tenofovir Alafenamide After Long-term Entecavir.

INTRODUCTION: Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch. METHODS: ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL). RESULTS: We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR. DISCUSSION: After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.

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.

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.

HCC risk post-SVR with DAAs in East Asians: findings from the REAL-C cohort.

BACKGROUND: Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients. METHODS: To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups. RESULTS: In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p < 0.001). Achieving SVR was independently associated with decreased HCC risk (adjusted HR [aHR]: 0.41, p = 0.002). Next, we stratified the SVR cohort of 5646 patients to cirrhotic and noncirrhotic subgroups. Among cirrhotic SVR patients, aged ≥ 60, having an albumin bilirubin grade (ALBI) of 2 or 3 (aHR: 2.5, p < 0.001), and baseline AFP ≥ 10 ng/mL (aHR: 1.6, p = 0.001) were associated with higher HCC risk, while among the non-cirrhotic SVR group, only baseline AFP ≥ 10 ng/mL was significant (aHR: 4.26, p = 0.005). CONCLUSIONS: Achieving SVR decreases HCC risk; however, among East Asians, patients with elevated pretreatment AFP remained at risk. Pretreatment AFP, an easily obtained serum marker, may provide both prognostic and surveillance value for HCC in East Asian patients who obtained SVR.

Cure With Interferon-Free Direct-Acting Antiviral Is Associated With Increased Survival in Patients With Hepatitis C Virus-Related Hepatocellular Carcinoma From Both East and West.

BACKGROUND AND AIMS: Survival data among patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after achieving sustained virologic response (SVR) with interferon-free direct-acting antivirals (DAAs) in both Asian and western countries are limited. Survival rates were compared between patients with HCV-related HCC who were untreated for HCV and those who achieved SVR. APPROACH AND RESULTS: Using data from two U.S. and six Asian centers from 2005 to 2017, we categorized 1,676 patients who were mono-infected with HCV-related HCC into patients untreated for HCV (untreated group) and DAA-treated patients with SVR (SVR group) and matched by propensity score matching (PSM); multivariable Cox regression with HCV treatment status as a time-varying covariate was used to determine mortality risk and landmark analysis to avoid immortal time bias. There were 1,239 untreated patients and 437 patients with SVR. After PSM, background risks of the 321 pairs of matched patients were balanced (all P > 0.05). After time-varying adjustment for HCV treatment initiation compared with untreated patients, patients with SVR had significantly higher 5-year overall survival (87.78% vs. 66.05%, P < 0.001). Multivariable Cox regression showed that SVR was independently associated with a 63% lower risk of 5-year all-cause mortality (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16-0.83; P = 0.016) and 66% lower risk of 5-year liver-related mortality (HR, 0.34; 95% CI, 0.13-0.88; P = 0.026) with similar trends after removing patients with liver transplants. Landmark analysis at 90, 180, and 360 days showed consistent results (HRs ranged 0.22 to 0.44, all P < 0.05). CONCLUSION: In this multinational consortium, patients with HCV-related HCC who obtained SVR achieved a 60%-70% improvement in 5-year survival (both all-cause and liver related) compared with patients untreated for HCV. Patients eligible for HCC therapy should also be considered for DAA therapy.

Higher risk of hepatocellular carcinoma in Hispanic patients with hepatitis C cirrhosis and metabolic risk factors.

The effect of metabolic syndrome on chronic liver diseases other than non-alcoholic fatty liver disease has not been fully elucidated. Our goal was to evaluate if metabolic syndrome increased the risk of liver-related complications, specifically hepatocellular carcinoma (HCC) and decompensation, in cirrhotic chronic hepatitis C (CHC) patients. We conducted a retrospective cohort study of 3503 consecutive cirrhotic CHC patients seen at Stanford University from 1997-2015. HCC developed in 238 patients (8-year incidence 21%) and hepatic decompensation in 448 patients (8-year incidence 61%). The incidence of HCC and decompensation increased with Hispanic ethnicity, diabetes, and number of metabolic risk factors. Multivariate Cox regression analysis demonstrated that, independent of HCV therapy and cure and other background risks, Hispanic ethnicity with ≥2 metabolic risk factors significantly increased the risk of HCC and hepatic decompensation. There was no interaction between Hispanic ethnicity and metabolic risk factors. All in all, metabolic risk factors significantly increase the risk of liver-related complications in cirrhotic CHC patients, especially HCC among Hispanics. As the prevalence of metabolic syndrome increases globally, targeted health interventions are needed to help curb the effects of metabolic syndrome in CHC patients.

Temporal trends in disease presentation and survival of patients with hepatocellular carcinoma: A real-world experience from 1998 to 2015.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the few cancers whose incidence continues to increase. The goal of the current study was to investigate the presentation and survival trends of patients with HCC presenting to a university hospital between 1998 and 2015. METHODS: Study data were ascertained by individual chart review with survival data also supplemented by National Death Index query up to December 31, 2015. Patients were divided into three 6-year groups by diagnosis date (1998-2003, 2004-2009, and 2010-2015). RESULTS: A total of 2106 consecutive patients with HCC were included. The majority of patients had either hepatitis C (56.7%) or hepatitis B (22.1%), but cases of nonalcoholic steatohepatitis HCC increased by 68% over the most recent time period. Screening/surveillance identified 61% of HCC cases, but only 31% of these patients underwent curative treatment, which did not increase significantly over time. The overall median survival was 29.8 months (2.48 years) and without improvement over time. On multivariable analysis, Asian or Hispanic ethnicity, meeting Milan criteria, and receiving any of the standard HCC treatments were found to be significantly associated with improved survival, but diagnosis time period and liver disease etiology were not. CONCLUSIONS: Over the last 18 years, the percentage of cases of nonalcoholic steatohepatitis HCC has increased but not overall survival. It is interesting to note that only 31% of patients with HCC identified via screening/surveillance received any curative treatment. Further research is needed to better understand the barriers to curative care for patients with HCC and the causes of the lack of improvement in survival in the more recent patient cohort. Cancer 2018;124:2588-98. © 2018 American Cancer Society.