Publications by authors named "Mindie H Nguyen"

245 Publications

Initial Evaluation, Long-Term Monitoring, and Hepatocellular Carcinoma Surveillance of Chronic Hepatitis B in Routine Practice: A Nationwide US Study.

Am J Gastroenterol 2021 Apr 29. Epub 2021 Apr 29.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA; Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.

Introduction: Previous studies, mostly small and single center, have shown gaps in the evaluation and monitoring of patients with chronic hepatitis B (CHB) virus infection. We aimed to examine the rates and predictors of adherence to guidelines for CHB care in a large nationwide cohort.

Methods: We identified adult patients with CHB infection from the Truven MarketScan databases of commercially insured and Medicare patients with private insurance supplement (2007-2014) using International Classification of Diseases, Ninth Revision, Clinical Modification codes. The initial evaluation cohort had at least 6 months follow-up, whereas at least 12 months was required for the long-term monitoring cohort.

Results: We analyzed 55,317 eligible patients with CHB infection: mean age 46 ± 12 years, 58% men, and 14.8% with cirrhosis. Over a mean follow-up of 3.2 ± 2.3 years, 55.8% had specialist (gastroenterology or infectious diseases) visits. For initial evaluation, 59% of patients received both alanine aminotransferase (ALT) and hepatitis B virus (HBV) DNA tests, whereas only 33% had ALT, HBV DNA, and hepatitis B e antigen tests, with higher frequencies among patients with specialist visits. For long-term monitoring, only 25% had both ALT and HBV DNA tests performed annually. Among patients at higher risk of developing hepatocellular carcinoma (patients with cirrhosis, male patients without cirrhosis older than 40 years, and female patients without cirrhosis older than 50), less than 40% underwent annual hepatocellular carcinoma surveillance, with 25% never receiving surveillance during the study period. Predictors of optimal initial evaluation and long-term monitoring were compensated cirrhosis (odds ratio: 1.60 and 1.47, respectively) and specialist visits (odds ratio: 1.86 and 1.31, respectively) (both P < 0.001).

Discussion: In this large cohort of patients with CHB infection with private insurance or Medicare with private insurance supplement, we observed poor adherence to the recommended initial evaluation and long-term monitoring. Among the predictors of adherence were specialist visits. Further efforts are needed to identify barriers and improve access to care.
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http://dx.doi.org/10.14309/ajg.0000000000001271DOI Listing
April 2021

A population-based US study of hepatitis C diagnosis rate.

Eur J Gastroenterol Hepatol 2021 Apr 16. Epub 2021 Apr 16.

Division of Gastroenterology and Hepatology, Stanford University Medical Center Division of General Internal Medicine, Cedars-Sinai Medical Center, Los Angeles Department of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.

Background: Underdiagnosis of HCV infection may hinder the obtainment of 2030 elimination goal.

Objective: To estimate the pre-DAA HCV diagnosis rate to inform future public health effort.

Methods: Data were obtained from three nationwide databases (Truven Health MarketScan Research Database 2007-2014, US Census Bureau 2012-2016 and NHANES 2007-2014). HCV diagnosis was defined with either one inpatient or two outpatient HCV International Classification of Disease 9 codes, providing the number of patients with diagnosed HCV (Truven). US Census Bureau data were used for age- and sex-standardization. We derived the total (diagnosed and undiagnosed) HCV infection using the NHANES database. To determine the rate and number of undiagnosed HCV, we subtracted diagnosed HCV burden (Truven) from the total HCV burden (NHANES).

Results: Of the 198 073 302 privately insured Americans, 1.49% (2 951 490 persons) had HCV infection. However, only 362 672 (12.29%) persons were diagnosed with HCV, leaving 2 588 818 (87.71%) undiagnosed. About two-third (68.04%) and one-third (33.04%) of diagnosed HCV patients had HCV RNA or genotype tests overall, with even lower rates for the ≥65 age group, respectively.

Conclusion: In the pre-DAA era, only 12% of insured Americans with HCV were diagnosed. While this grim statistic is expected to rise, much more effort is needed to enhance the HCV care cascade.
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http://dx.doi.org/10.1097/MEG.0000000000002149DOI Listing
April 2021

Fatty Liver Index and Development of Cardiovascular Disease: Findings from the UK Biobank.

Dig Dis Sci 2021 Mar 29. Epub 2021 Mar 29.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA, 94304, USA.

Background: Nonalcoholic fatty liver disease is common and is associated with rising morbidity and mortality in the UK. Cardiovascular disease is the main cause of death in people with nonalcoholic fatty liver disease.

Aims: To determine the association between baseline cardiovascular risk factors with fatty liver index, and to investigate the association between fatty liver index and the incidence of cardiovascular disease in the UK.

Methods: This study is a population-based retrospective cohort study using the UK Biobank database.

Results: The mean fatty liver index in the study cohort was 44.9, and 33.7% met the criteria for nonalcoholic fatty liver disease. Fatty liver index was significantly associated with a wide range of cardiovascular risk factors at baseline. During a mean follow-up of 7.86 years, the combined incidence of cardiovascular disease was 6.92 per 1000-person years at risk. We found significant association between fatty liver index and incident cardiovascular disease in the fully adjusted model. We found significant association between fatty liver index and incident cardiovascular disease in subgroups stratified by BMI as well as subgroups with fatty liver index < 30, < 60, and ≥ 60.

Conclusions: Fatty liver index not only predicts NAFLD diagnosis, but also indicates baseline and future development of cardiovascular disease on long-term follow-up across weight categories and fatty liver index spectrum. These findings can inform clinicians and other stakeholders on cardiovascular disease management and preventive efforts. Patients with high fatty liver index should be counseled on the increased future risk of developing cardiovascular disease.
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http://dx.doi.org/10.1007/s10620-021-06954-yDOI Listing
March 2021

Characteristics and healthcare costs in the aging hepatitis B population of Japan: A nationwide real-world analysis.

Dig Dis 2021 Mar 15. Epub 2021 Mar 15.

Introduction: Advancing age, comorbidity, and financial burden have been observed in chronic hepatitis B (CHB) patients globally. As Japan is leading the world in aging demographics, similar real-world data are urgently needed for its CHB population to inform all stakeholders.

Methods: This cross-sectional study characterized the demographics, comorbidities, and healthcare costs of a large Japanese real-world adult (≥18 years) CHB patient (ICD-10: B18.1) population from the Medical Data Vision database from 01/01/2012 to 31/12/2016. Comorbidities were identified by ICD-10 codes and the annual point-prevalence and Charlson Comorbidity Index (CCI) score were calculated. Annual mean and median all-cause healthcare utilization and costs per-patient were calculated. Comparison tests were conducted for CCI scores, prevalence of comorbidities and healthcare resource utilization and costs.

Results: We identified 11,125 CHB patients. Between 2012 and 2016, the mean age increased from 62.0±13.3 to 65.2±13.2 years, and the percentage of those aged ≥65 years increased from 45.6% to 60.7%. The prevalence of cirrhosis remained similar (5.8% in 2012 and 5.6% in 2016, p=0.69) while hepatocellular carcinoma decreased from 6.3% to 4.5% (p<0.01). The prevalence of non-liver comorbidities increased (40.9% to 52.0% for cancer (p<0.01), 12.1% to 17.7% for osteoporosis (p<0.01), and 10.7% to 15.0% for renal impairment (p<0.01). Healthcare resource utilization and costs also increased, with a 119.3% increase in the median total healthcare costs from ¥229,143 in 2012 to ¥502,467 in 2016 (p<0.01).

Conclusions: The CHB population of Japan is predominantly elderly and carry a high non-liver comorbidity burden, while incurring increasing healthcare costs.
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http://dx.doi.org/10.1159/000515854DOI Listing
March 2021

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

Liver Int 2021 Mar 13. Epub 2021 Mar 13.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.

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.
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http://dx.doi.org/10.1111/liv.14877DOI Listing
March 2021

Treatment and renal outcomes up to 96 weeks after tenofovir alafenamide switch from tenofovir disoproxil fumarate in routine practice.

Hepatology 2021 Mar 11. Epub 2021 Mar 11.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.

Background: Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer pro-drug, tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population.

Approach & Results: We analyzed 834 CHB patients previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 U.S. and Asia centers for changes in viral (HBV DNA <20 IU/mL), biochemical (ALT <35/25 U/L for male/ female) and complete (viral+biochemical) response; as well as estimated glomerular filtration rate (eGFR, mL/min/1.73 m ) up to 96-weeks after switch. Viral suppression (P<0.001) and ALT normalization (P=0.003) rates increased significantly after switch, as well as trend for increasing complete response (P =0.004) while eGFR trend (P >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 (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, 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1.

Conclusion: Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.
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http://dx.doi.org/10.1002/hep.31793DOI Listing
March 2021

Predictors of Outcomes of Patients Referred to a Transplant Center for Urgent Liver Transplantation Evaluation.

Hepatol Commun 2021 Mar 27;5(3):516-525. Epub 2020 Dec 27.

Division of Gastroenterology and Hepatology Stanford University Medical Center Stanford CA USA.

Liver transplantation (LT) is definitive treatment for end-stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty-two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol-associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait-listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89;  = 0.003), Asian race (OR, 1.52 = 0.02), non-Hispanic ethnicity (OR, 1.49 = 0.04), hyponatremia (OR, 1.38;  = 0.04), serum albumin (OR, 1.13 = 0.01), and Model for End-Stage Liver Disease (MELD)-Na (OR, 1.02 = 0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77 = 0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF-C) score >51.5 (OR, 1.26 = 0.03), acute-on-chronic liver failure (ACLF) grade 3 (OR, 1.41 = 0.01), hepatorenal syndrome (HRS) (OR, 1.38 = 0.01), and respiratory failure (OR, 1.51 = 0.01). Predictors of 3-month mortality included CLIF-C score >51.5 (hazard ratio [HR], 2.52;  = 0.04) and intensive care unit (HR, 8.25 < 0.001). MELD-Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non-Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF-C score predicted being declined for LT and mortality.
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http://dx.doi.org/10.1002/hep4.1644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917272PMC
March 2021

Epidemiology, pathogenesis, diagnosis, surveillance, and management of hepatocellular carcinoma associated with vascular liver disease.

Kaohsiung J Med Sci 2021 Mar 2. Epub 2021 Mar 2.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA.

Vascular liver disease (VLD) presents special challenges in the diagnosis, surveillance, and treatment of hepatocellular carcinoma (HCC). HCC arising in the setting of vascular liver disease is often thought to be due to elevated hepatic arterial blood flow, rather than progressive fibrosis from chronic inflammation as with other chronic liver conditions such as viral hepatitis, autoimmune, and metabolic liver diseases. Vascular alteration inherent in VLD often impedes HCC non-invasive diagnosis and loco-regional treatment that depend on vascular properties found in typical liver environment. Benign and pre-malignant liver nodules such as focal nodular hyperplasia and hepatocellular adenoma are also more common in certain VLDs, further adding to surveillance and diagnostic challenges. In this synopsis, we aimed to review available literature on the epidemiology, surveillance, diagnosis, and management of HCC in patients with VLD and specifically Budd-Chiari syndrome, congenital porto-systemic shunts, Fontan-associated liver disease, hereditary hemorrhagic telangiectasia.
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http://dx.doi.org/10.1002/kjm2.12368DOI Listing
March 2021

Defining Age-Related Thresholds for ALT and the Risk of Confounders.

Clin Gastroenterol Hepatol 2021 Feb 19. Epub 2021 Feb 19.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Department of Epidemiology and Population Health, Stanford University, Palo Alto, California.

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http://dx.doi.org/10.1016/j.cgh.2021.02.029DOI Listing
February 2021

Letter to the Editor: HCC surveillance in cirrhosis patients: Is the real-world situation even worse than reported?

Hepatology 2021 Feb 22. Epub 2021 Feb 22.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, United States.

We read with interest the recent systematic review and meta-analysis by Wolf and colleagues, which reported a pooled estimate for hepatocellular carcinoma (HCC) surveillance of 24.0% for patients with cirrhosis (1). We applaud the authors for performing this comprehensive study on a topic that is not only relevant clinically but also timely, especially with the increasing burden of cirrhosis in recent decades.
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http://dx.doi.org/10.1002/hep.31760DOI Listing
February 2021

Chronic hepatitis, osteoporosis, and men: under-recognised and underdiagnosed.

Lancet Diabetes Endocrinol 2021 03;9(3):141

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(21)00020-6DOI Listing
March 2021

Treatment eligibility in hepatitis B: a call for better linkage to optimal care.

Lancet Gastroenterol Hepatol 2021 03;6(3):160

Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA; Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA 94304, USA. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(20)30391-5DOI Listing
March 2021

The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040.

Hepatol Int 2021 Feb 12. Epub 2021 Feb 12.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 780 Welch Road, CJ250K, Palo Alto, CA, 94304, USA.

Background: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD.

Methods: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD-8 studies) patients.

Results: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983-2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD.

Conclusion: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.
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http://dx.doi.org/10.1007/s12072-021-10143-4DOI Listing
February 2021

Sarcopenic Obesity in Non-Alcoholic Fatty Liver Disease-The Union of Two Culprits.

Life (Basel) 2021 Feb 4;11(2). Epub 2021 Feb 4.

Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA 94304, USA.

Non-alcoholic fatty liver disease (NAFLD) continues to rise and has become the most common cause of chronic liver disease among all ages and ethnicities. Metabolic disorders, such as obesity and insulin resistance, are closely associated with sarcopenia and NAFLD. Sarcopenic obesity is a clinical disorder characterized by the simultaneous loss of skeletal muscle and gain of adipose tissue. It is associated with worse outcomes in individuals with NAFLD. It is projected that NAFLD and sarcopenia will rise as the prevalence of obesity continues to increase at an unparallel rate. Recently, sarcopenia and sarcopenic obesity have gained considerable interest, but we still lack a well-defined definition and a management approach. Therefore, it is imperative to continue shining the light on this topic and better understand the underlying mechanism as well as treatment options. In this review article, we aimed to address the pathophysiology, impact, and outcomes of sarcopenic obesity on NAFLD.
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http://dx.doi.org/10.3390/life11020119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914533PMC
February 2021

Twelve-month post-treatment parameters are superior in predicting hepatocellular carcinoma in patients with chronic hepatitis B.

Liver Int 2021 Feb 7. Epub 2021 Feb 7.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.

Background & Aims: There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre-treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre- and post-treatment parameters in this population.

Methods: We included two treatment-naïve CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n = 1480, Korea prospective SAINT cohort) and the validation cohort (n = 426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine and random forest algorithms to develop the HCC prediction model and selected the most optimal method.

Results: We evaluated both pre-treatment and the 12-month clinical parameters on-treatment and found the 12-month on-treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha-foetoprotein and platelet at 12 months showed the best performance (AUROC = 0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC = 0.844) and better than other existing prediction models including the APA, PAGE-B and GAG models (AUROC = 0.769 to 0.818).

Conclusions: We provided a simple-to-use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12 months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844) (Clinical trial number: KCT0003487).
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http://dx.doi.org/10.1111/liv.14820DOI Listing
February 2021

One-year Fibrosis-4 index helps identify minimal HCC risk in non-cirrhotic chronic hepatitis B patients with antiviral treatment.

Hepatol Int 2021 Feb 5;15(1):105-113. Epub 2021 Feb 5.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St, Taipei, 10002, Taiwan.

Background And Aims: Fibrosis-4 (FIB-4) index is a HCC predictor in chronic hepatitis B (CHB) patients. However, little is known about whether FIB-4 helps identify non-cirrhotic CHB patients with minimal HCC risk after prolonged nucleos(t)ide analogue (NA) therapy.

Methods: A total of 1936 ethnically diverse, non-cirrhotic CHB patients were enrolled in this retrospective multi-national study. All patients received prolonged NA treatment, including entecavir and tenofovir disoproxil fumarate. We explored whether FIB-4 cutoff of 1.30, a marker indicative of mild fibrosis severity, could stratify HCC risks in these patients.

Results: A total of 48 patients developed HCC after a mean follow-up of 6.98 years. FIB-4 level at 1 year after treatment (1-year FIB-4) was shown to be associated with HCC development and was superior to pre-treatment FIB-4 value. When patients were stratified by 1-year FIB-4 of 1.30, the high FIB-4 group was at an increased HCC risk compared to the low FIB-4 group, with a hazard ratio of 4.87 (95% confidence interval: 2.48-9.55). Multivariable analysis showed that sex and 1-year FIB-4 were independent predictors, with none of the 314 female patients with low 1-year FIB-4 developing HCC. Finally, 1-year FIB-4 of 1.30 consistently stratified HCC risks in patients with low PAGE-B score, a score composed of baseline age, sex and platelet count, and the annual incidence rate of HCC was 0.11% in those with PAGE-B < 10 + 1-year FIB-4 < 1.30.

Conclusions: In non-cirrhotic CHB patients receiving prolonged NA therapy, 1-year FIB-4 < 1.30 is useful for identifying those with minimal HCC risk by combining with female sex or low PAGE-B score.
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http://dx.doi.org/10.1007/s12072-020-10124-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863859PMC
February 2021

NASH/liver fibrosis prevalence and incidence of non-liver comorbidities among people with NAFLD and incidence of NAFLD by metabolic comorbidites: Lessons from South Korea.

Dig Dis 2021 Feb 3. Epub 2021 Feb 3.

Background: NAFLD incidence, NASH prevalence, NAFLD fibrosis prevalence, incidence of metabolic comorbidities, as well as mortality data in the NAFLD population remain limited.

Aims: We used a meta-analytic approach to "stage" NAFLD among the Korean population.

Methods: We searched PubMed, Embase, Cochrane Library, and KoreaMed from inception until June 29, 2019 and calculated pooled estimates via random-effects model.

Results: We screened 1,485 studies and analyzed 191 eligible studies: 179 (3,556,579 participants) for NAFLD prevalence and outcome analysis and 32 (1,089,785 participants) for NAFLD incidence analysis. NAFLD prevalence was 31.46% overall and 50-60% in those with metabolic risks. The incidence (per 1,000 person-years) of NAFLD was 42.8 overall and 70-77% in those with metabolic risk. The incidence (per 1,000 person-years) of new onset T2DM, hypertension, cardiovascular disease, and chronic kidney disease were found to be 16.9, 47.9, 100.6, and 13.9, respectively. From biopsy data, 30.21% of the NAFLD population had moderate-to-severe steatosis (9 studies, 2,461 participants) and 52.27% had NASH (7 studies, 1,168 participants); 85.41% had fibrosis < stage 2 (8 studies, 1,995 participants). All-cause mortality was 2.6 (1.3 if without malignancy) per 1,000 person-years.

Conclusions: The overall prevalence of NAFLD was 31.46% with an incidence rate of 42.8 per 1000 person-years. NASH prevalence was 52% but <15% had significant fibrosis. The prevalence and incidence of non-liver comorbidities was high especially for cardiovascular disease incidence. The burden of NAFLD is high in Korea. Health policy efforts need to be directed towards reversing the course of NAFLD disease.
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http://dx.doi.org/10.1159/000514953DOI Listing
February 2021

Natural History and Hepatocellular Carcinoma Risk in Untreated Chronic Hepatitis B Patients With Indeterminate Phase.

Clin Gastroenterol Hepatol 2021 Jan 16. Epub 2021 Jan 16.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California. Electronic address:

Background & Aims: Many patients with chronic hepatitis B (CHB) may not conform to any of the defined phases and hence are classified as indeterminate. We aimed to characterize the baseline prevalence of indeterminate patients and their natural history, phase transition, and hepatocellular carcinoma (HCC) risk.

Methods: This was a retrospective cohort study of 3366 adult untreated noncirrhotic CHB patients seen at 5 US clinics and 7 Taiwanese townships who had at least 1 year of serial laboratory data before enrollment with a mean follow-up period of 12.5 years. Patients' clinical phases were determined at baseline and through serial data during follow-up evaluation, based on the American Association for the Study of Liver Diseases 2018 guidance.

Results: At baseline, 1303 (38.7%) patients were in the indeterminate phase. By up to year 10 of follow-up evaluation, 686 patients (52.7%) remained indeterminate, while 283 patients (21.7%) became immune active. Compared with patients who remained inactive, patients who remained indeterminate had a higher 10-year cumulative HCC incidence (4.6% vs 0.5%; P < .0001) and adjusted hazard ratio for HCC of 14.1 (P = .03). Among patients who remained indeterminate, age 45 years and older (adjusted hazard ratio, 18.4; P = .005) was associated independently with HCC development.

Conclusions: Nearly 40% of patients had indeterminate CHB phase. Of these, half remained indeterminate and one-fifth transitioned to the immune active phase. HCC risk in persistently indeterminate CHB was 14 times higher than inactive CHB. Among persistently indeterminate CHB patients, age 45 years and older was associated with an 18 times higher risk for HCC development. Further studies are needed to evaluate the potential benefit of antiviral therapy for indeterminate patients, especially in the older subgroup.
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http://dx.doi.org/10.1016/j.cgh.2021.01.019DOI Listing
January 2021

Risk of hepatocellular carcinoma with tenofovir versus entecavir in chronic hepatitis B - Authors' reply.

Lancet Gastroenterol Hepatol 2021 02;6(2):87-88

Division of Gastroenterology and Hepatology, Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA 94304, USA. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(20)30395-2DOI Listing
February 2021

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

Hepatol Commun 2021 Jan 24;5(1):122-132. Epub 2020 Sep 24.

Division of Gastroenterology and Hepatology Stanford University Medical Center Stanford CA.

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. 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.
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http://dx.doi.org/10.1002/hep4.1606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789832PMC
January 2021

Transition rates to cirrhosis and liver cancer by age, gender, disease and treatment status in Asian chronic hepatitis B patients.

Hepatol Int 2021 Feb 4;15(1):71-81. Epub 2021 Jan 4.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Hepatitis Research Center, College of Medicine and Cohort Research Center and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.

Methods: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.

Results: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.

Conclusion: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.
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http://dx.doi.org/10.1007/s12072-020-10113-2DOI Listing
February 2021

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

Hepatol Int 2020 Dec 4;14(6):1023-1033. Epub 2020 Dec 4.

Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.

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.
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http://dx.doi.org/10.1007/s12072-020-10105-2DOI Listing
December 2020

Non-invasive diagnosis methods are needed in paediatric non-alcoholic fatty liver disease.

Liver Int 2021 May 9;41(5):1161. Epub 2020 Dec 9.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA.

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http://dx.doi.org/10.1111/liv.14748DOI Listing
May 2021

Association between fatty liver and cirrhosis, hepatocellular carcinoma, and HBsAg seroclearance in chronic hepatitis B.

J Infect Dis 2020 Nov 29. Epub 2020 Nov 29.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA.

Background: Chronic hepatitis B (CHB) and fatty liver (FL) are common, natural history data on concurrent FL and CHB (FL-CHB) are limited. This study aimed to evaluate the effect of FL on cirrhosis, hepatocellular carcinoma (HCC), and HBsAg seroclearance incidence in CHB patients.

Methods: In a retrospective cohort study of 6,786 adult CHB patients, we used propensity score matching (PSM) to balance the FL-CHB and non-FL CHB groups. Kaplan-Meier methods were used to compare cumulative cirrhosis, HCC, and HBsAg seroclearance rates between subgroups.

Results: Before PSM, compared to non-FL CHB, FL-CHB patients had lower 10-year cumulative rates of cirrhosis, HCC, and a higher HBsAg seroclearance rate. Similar results were found in the matched FL-CHB and non-FL CHB patients, as well as in antiviral treated PSM cohort. Cox proportional hazards model indicated FL to remain significantly and strongly associated with lower risk of cirrhosis and HCC (HR: 0.19, 95% CI: 0.12-0.33, P<0.001, 0.21, 95% CI: 0.09-0.51, P=0.001, respectively) in antiviral treated patients, but not in untreated patients.

Conclusions: FL was significantly associated with lower cirrhosis and HCC risk and higher HBsAg seroclearance. Further studies are needed to confirm our funding and investigate the mechanisms underlying the impact of FL on CHB.
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http://dx.doi.org/10.1093/infdis/jiaa739DOI Listing
November 2020

Provider Perspectives on HCC Surveillance in Patients With Cirrhosis: Community Provider Perspectives Matter.

Clin Gastroenterol Hepatol 2020 Nov 26. Epub 2020 Nov 26.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California.

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http://dx.doi.org/10.1016/j.cgh.2020.10.050DOI Listing
November 2020

Review article: current gaps and opportunities in HBV prevention, testing and linkage to care in the United States-a call for action.

Aliment Pharmacol Ther 2021 01 22;53(1):63-78. Epub 2020 Nov 22.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.

Background: The World Health Organization (WHO) has set an elimination goal for hepatitis B virus (HBV) by 2030, so a comprehensive review of current HBV testing and care gaps are needed to help formulate solutions and opportunities for action.

Aims: To summarise current gaps and barriers, and to propose solutions for HBV prevention, testing and linkage to care in the United States METHODS: Relevant guidelines and studies were reviewed including a systematic review of HCC surveillance adherence.

Results: A total of 64.5 million (95% CI, 61.3-67.5) high-risk US adults had no evidence of HBV immunity. Only 18.6% (95% CI, 13.5-29.9) of privately insured patients with HBV infection have been diagnosed. Among those with known HBV infection, linkage to care rate (33.3%-57%) was poor and the adherence to guidelines regarding anti-viral therapy (30.66% [95% CI, 30.28-31.03]) and HCC surveillance (8%-87%, from a systematic review) were poor with even more concerning data for care and treatment retention. The causes are complex and include lack of access to medical care, lack of physician knowledge, lack of patient health literacy and awareness, linguistic and cultural barriers and fear of stigma.

Conclusions: A 'scale-up' effort is needed to optimise the care continuum to achieve the WHO 2030 targets. As targeted screening policy has leftover 80% of patients undiagnosed, we advocate for universal screening which can help to remove barriers regarding stigma. More active and system level interventions are also needed to improve linkage to care for patients with HBV infection.
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http://dx.doi.org/10.1111/apt.16125DOI Listing
January 2021

Prevalence of Hepatitis B Vaccination Coverage and Serologic Evidence of Immunity Among US-Born Children and Adolescents From 1999 to 2016.

JAMA Netw Open 2020 11 2;3(11):e2022388. Epub 2020 Nov 2.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California.

Importance: The World Health Assembly has called for the elimination of hepatitis B and C by 2030. As hepatitis B has no cure, the US strategy to eliminate hepatitis B has focused on prevention through vaccination. However, there are limited data on the trend in vaccine-associated immunity since the US implementation of universal infant hepatitis B vaccination.

Objective: To compare self-reported hepatitis B vaccination coverage among children and adolescents with serologic evidence of immunity and infection in the US from 1999 to 2016.

Design, Setting, And Participants: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2016. US-born persons aged 2 to 18 years without missing hepatitis B serologic test results and with reported vaccination history were included. Data were analyzed from September 2017 to June 2018.

Main Outcomes And Measures: The proportion of participants who reported complete vaccination for hepatitis B and who had positive serologic test results indicating immunity.

Results: Of 21 873 children and adolescents, 51.2%% were male, and the mean (SD) age was 10.6 (4.6) years. The survey reported that hepatitis B vaccination coverage increased significantly from 1999 to 2016 (from 62.6% [95% CI, 58.6%-66.4%] to 86.3% [95% CI, 82.9%-89.2%]; P < .001). Vaccine-associated immunity also increased from 1999 to 2016 among children aged 2 to 5 years (from 60.7% [95% CI, 48.8%-71.4%] to 65.2% [95% CI, 57.4%-72.3%]; P = .001) but decreased among children aged 6 to 10 years (from 64.6% [95% CI, 57.7%-70.9%] to 46.5% [95% CI, 39.1%-54.0%]; P < .001), adolescents aged 11 to 13 years (from 68.8% [95% CI, 58.1%-77.8%] to 26.2% [95% CI, 18.6%-35.5%]; P < .001), and adolescents aged 14 to 18 years (from 68.5% [95% CI, 62.9%-73.6%] to 15.6% [95% CI, 12.2%-19.8%]; P < .001). By birth year, serologic evidence of vaccine-associated immunity significantly decreased in the 1994-2003 NHANES birth cohort but not among those born between 1988 and 1993. Non-US-born children and adolescents did not show the same decreasing trend in immunity.

Conclusions And Relevance: In this cross-sectional study, decreasing hepatitis B immunity was observed among US-born children and adolescents in the 1994-2003 NHANES birth cohort despite increasing rates of hepatitis B vaccination coverage. These findings suggest a possible need for surveillance and a booster vaccine dose for hepatitis B as those without serologic evidence of immunity become young adults and may engage in behaviors associated with an increased risk for infection.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.22388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658733PMC
November 2020

ALT Levels for Asians With Metabolic Diseases: A Meta-analysis of 86 Studies With Individual Patient Data Validation.

Hepatol Commun 2020 Nov 9;4(11):1624-1636. Epub 2020 Sep 9.

Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA.

The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta-analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound-detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random-effects mixed model and upper threshold (95th-percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper threshold of 32. The ALT upper threshold was 37 in males versus 31 in females, 39 in overweight versus 28 in normal-weight individuals, and 36 for diabetics versus 33 for nondiabetics. We validated our study level data with individual patient level data in 6,058 individuals from five study centers in Japan. Consistent with our study-level data, we found that the ALT upper threshold in our individual patient data analysis was indeed higher in overweight versus normal-weight individuals (39 vs. 32) and in diabetics versus nondiabetics (42 vs. 33). We provide validated reference ranges for ALT upper threshold derived from Asians without known liver disease, including individuals with ultrasound-detected nonalcoholic fatty liver disease who are normal weight, overweight, nondiabetic, and diabetic, to inform practice.
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http://dx.doi.org/10.1002/hep4.1593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603525PMC
November 2020

Genomic analysis of Vascular Invasion in Hepatocellular Carcinoma (HCC) Reveals Molecular Drivers and Predictive Biomarkers.

Hepatology 2020 Nov 3. Epub 2020 Nov 3.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, CA, United States.

Vascular invasion is a critical risk factor for hepatocellular carcinoma (HCC) recurrence and poor survival. The molecular drivers of vascular invasion in HCC are largely unknown. Deciphering the molecular landscape of invasive HCC will help identify novel therapeutic targets and noninvasive biomarkers. To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with vascular invasion using the multi-platform cancer genome atlas (TCGA) data (n=373). In the TCGA liver hepatocellular carcinoma (LIHC) cohort, macrovascular invasion was present in 5% (n=17) of tumors and microvascular invasion in 25% (n=94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA and proteomic changes in vascular invasion. We performed comparative proteomic analyses of invasive human HCC and MYC driven murine HCC and identified fibronectin to be proteomic biomarker of invasive HCC (mouse Fn1 p= 1.7 X 10 ; human FN1 p=1.5 X 10 ) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n=153; p<0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n=35, mean=307.7 μg/ml, SEM=35.9) when compared to cirrhosis (n=10, mean=41.8 μg/ml, SEM=13.3; p<0.0001). CONCLUSION: Our study evaluates the molecular landscape of tumors with vascular invasion, identifying distinct transcriptional, epigenetic and proteomic changes driven by the MYC oncogene. We show that MYC upregulates fibronectin expression which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising non-invasive proteomic biomarker of vascular invasion in HCC.
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http://dx.doi.org/10.1002/hep.31614DOI Listing
November 2020

Incidence, Factors, and Patient-Level Data for Spontaneous HBsAg Seroclearance: A Cohort Study of 11,264 Patients.

Clin Transl Gastroenterol 2020 09;11(9):e00196

Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA.

Introduction: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the functional cure of hepatitis B infection, occurs rarely. Prior original studies are limited by insufficient sample size and/or follow-up, and recent meta-analyses are limited by inclusion of only study-level data and lack of adjustment for confounders to investigate HBsAg seroclearance rates in most relevant subgroups. Using a cohort with detailed individual patient data, we estimated spontaneous HBsAg seroclearance rates through patient and virologic characteristics.

Methods: We analyzed 11,264 untreated patients with chronic hepatitis B with serial HBsAg data from 4 North American and 8 Asian Pacific centers, with 1,393 patients with HBsAg seroclearance (≥2 undetectable HBsAg ≥6 months apart) during 106,192 person-years. The annual seroclearance rate with detailed categorization by infection phase, further stratified by hepatitis B e antigen (HBeAg) status, sex, age, and quantitative HBsAg (qHBsAg), was performed.

Results: The annual seroclearance rate was 1.31% (95% confidence interval: 1.25-1.38) and over 7% in immune inactive patients aged ≥55 years and with qHBsAg <100 IU/mL. The 5-, 10-, 15-, and 20-year cumulative rates were 4.74%, 10.72%, 18.80%, and 24.79%, respectively. On multivariable analysis, male (adjusted hazard ratio [aHR] = 1.66), older age (41-55 years: aHR = 1.16; >55 years: aHR = 1.21), negative HBeAg (aHR = 6.34), and genotype C (aHR = 1.82) predicted higher seroclearance rates, as did lower hepatitis B virus DNA and lower qHBsAg (P < 0.05 for all), and inactive carrier state.

Discussion: The spontaneous annual HBsAg seroclearance rate was 1.31%, but varied from close to zero to about 5% among most chronic hepatitis B subgroups, with older, male, HBeAg-negative, and genotype C patients with lower alanine aminotransferase and hepatitis B virus DNA, and qHBsAg independently associated with higher rates (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A367).
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http://dx.doi.org/10.14309/ctg.0000000000000196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494149PMC
September 2020