Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer‐related deaths worldwide. Sarcomatoid HCC is a rare histological subtype of HCC with largely ...unclear clinical manifestations and outcomes. We evaluated the clinical manifestations and outcomes of patients with sarcomatoid HCC. We identified 5,047 patients with histologically proven HCC from the Cancer Registry Database (1996‐2016) of National Taiwan University Hospital. Among them, 40 patients with sarcomatoid HCC were identified from the pathology database of National Taiwan University Hospital. We included 160 patients with nonsarcomatoid HCC through propensity score matching according to sex, age, and Barcelona Clinic Liver Cancer stage. The majority of these patients with sarcomatoid HCC were men (75%); their median age was 58 years. Only 47.5% of the patients with sarcomatoid HCC presented with typical image patterns of HCC. The pathological grading of sarcomatoid HCC was more advanced compared with that of nonsarcomatoid HCC (42.5% vs. 23.8% in grade III and IV, P < 0.0001). The sarcomatoid group had significantly shorter median recurrence‐free (13.3 vs. 84.2 months, log‐rank P < 0.0001) and overall (8.3 vs. 69.3 months, log‐rank P < 0.0001) survival than did the nonsarcomatoid group. The results of the multivariable Cox proportional hazard model revealed histological sarcomatoid subtype as an independent factor for all‐cause mortality (hazard ratio HR, 6.47; 95% confidence interval CI, 3.12‐13.43; P < 0.0001) and tumor recurrence (HR, 4.08; 95% CI, 1.72‐9.66; P = 0.001). Conclusion: Compared with nonsarcomatoid HCC, sarcomatoid HCC was associated with more advanced histological grades and atypical image patterns. Histological sarcomatoid subtype is an independent predictor of tumor recurrence after curative treatment and all‐cause mortality in patients with HCC.
Background & Aims Patients with chronic hepatitis B virus (HBV) infection have a high risk for developing hepatocellular carcinoma (HCC). Patients with lower levels of hepatitis B surface antigen ...(HBsAg) have higher chances of losing HBsAg than those with high levels. However, little is known about whether higher levels of HBsAg increase risk for HCC. Methods We followed 2688 Taiwanese HBsAg-positive patients without evidence of cirrhosis for a mean time period of 14.7 years. In addition to the known risk factors of HCC, we investigated the association between levels of HBsAg and development of HCC. Results Of the patients followed, 191 developed HCC, with an average annual incidence rate of 0.5%. Baseline levels of HBsAg and HBV were associated with development of HCC, and risk increased with level. Compared to HBsAg level, by receiver operating characteristic curve analysis, HBV DNA level better predicted the development of HCC during 10-year and 15-year periods (both, P < .001). However, when we evaluated hepatitis B e antigen−negative patients with levels of HBV DNA <2000 IU/mL, factors that determined HCC risk included sex, age, and levels of alanine aminotransferase and HBsAg (≥1000 IU/mL), but not level of HBV DNA. Multivariate analysis showed that the adjusted hazard ratio for HCC in patients with levels of HBsAg ≥1000 IU/mL versus <1000 IU/mL was 13.7 (95% confidence interval: 4.8−39.3). Conclusions Among patients infected with HBV genotype B or C, determinants of HCC risk include their sex, age, hepatitis B e antigen status, HBV genotype, and levels of alanine aminotransferase and HBV DNA, but not level of HBsAg. Among hepatitis B e antigen−negative patients with low viral loads, HCC risk is determined by levels of HBsAg and alanine aminotransferase and age, but not HBV DNA.
Viral hepatitis and its sequelae are important health problems worldwide, including Taiwan. For the last 40 years, Taiwan's scientists and health care providers have worked hard to control these ...sequelae, and the results have been excellent. The author, Ding‐Shinn Chen, had a key role in planning and establishing the control program in Taiwan, and participated in the endeavors from the very beginning. In this perspective, he describes how he became interested in research as a medical student, his encounters with hepatitis B and C, how he and his colleagues started early detection of hepatocellular carcinoma (HCC), how he helped Taiwan's government create and implement the Viral Hepatitis Control Program, and how the effectiveness of the program in the decrease of hepatitis B carriage and HCC was monitored. He also discusses how he pioneered the use of interferon‐α plus ribavirin to treat chronic hepatitis C. Hepatitis B viral load as a risk factor for HCC and cirrhosis in hepatitis B surface antigen carriers is reviewed briefly, as is the prevention of sequelae by antiviral therapies. Finally, Dr. Chen discusses unresolved issues that must be addressed and predicts the changes of the patterns of liver disease in Taiwan beyond the mid‐21st century, which is in part affected by the fight against viral hepatitis that was initiated in the early 1980s. Conclusion: Dr. Chen's perspective illustrates Taiwan's fight against viral hepatitis over the last 40 years. This experience can be shared by other countries in which the disease is equally prevalent. (HEPATOLOGY 2011;)
The gender disparity of hepatocellular carcinoma (HCC) is most striking in hepatitis B virus (HBV)‐related cases. The majority of such HCC cases contain integrated HBV, and some hotspot integrations, ...such as those in the telomerase reverse transcriptase gene (TERT) promoter, activate gene expression to drive carcinogenesis. As the HBV genome contains both androgen‐responsive and estrogen‐responsive motifs, we hypothesized that the integrated HBV DNA renders a similar regulation for downstream gene expression and thus contributes to male susceptibility to HCC. To test this hypothesis, the HBV integration sites and the common mutations in the TERT promoter and tumor protein P53 (TP53) coding region were analyzed in 101 HBV‐related HCC cases using a capture‐next‐generation sequencing platform. The results showed that both HBV integration and –124G>A mutation in the TERT promoter region, occurring in a mutually exclusive manner, were more frequent in male than in female patients with HCC (integration: 22/58 male patients with HCC, 6/36 female patients with HCC, P = 0.0285; –124G>A: 17/62 male patients with HCC, 3/39 female patients with HCC, P = 0.0201; in combination, 39/62 male patients with HCC, 9/39 female patients with HCC, P < 0.0001). The effects of sex hormone pathways on the expression of TERT with both genetic changes were investigated using a reporter assay. HBV integration in the TERT promoter rendered the TERT transcription responsive to sex hormones, with enhancement by androgen receptor (AR) but suppression by estrogen receptor, both of which were dependent on hepatocyte nuclear factor 4 alpha. Besides, AR also increased TERT expression by targeting TERT promoter mutations in a GA binding protein transcription factor subunit alpha–dependent manner. Conclusion: TERT elevation by AR through integrated HBV and point mutation at the TERT promoter region was identified as a mechanism for the male dominance of HBV‐related HCCs; telomerase and AR thus may be targets for intervention of HCC.
Background & Aims Immunoprophylaxis reduces but does not completely eradicate hepatitis B virus (HBV) transmission. This prospective study aims at assessing the rate and risk factors of maternally ...transmitted HBV infection. Methods We enrolled 303 mother-infant pairs with positive maternal hepatitis B surface antigen (HBsAg) under current immunization program. Maternal viral load was determined by a real-time PCR-based assay. The children were tested for HBsAg at 4–8 months and/or 1–3 years of age. Rates of HBV infection were estimated using a multivariate logistic regression model. Results HBeAg-positive mothers (81/303, 26.7%) had higher viral loads than HBeAg-negative mothers (7.4 ± 1.9 vs. 2.7 ± 1.4 log10 copies/ml, p <0.0001). Ten children, born to HBeAg-positive mothers with high viral load (median, 8.4; range, 6.5–9.5 log10 copies/ml), were chronically infected. After adjustment for maternal age, birth type, factors related to maternal-fetal hemorrhage, gestational age, infant gender, birth weight, timeliness of vaccination, and feeding practice, maternal viral load was significantly associated with risk of infection (adjusted odds ratio for each log10 copy/ml increase, 3.49; 95% confidence interval (CI), 1.63–7.48; p = 0.001). The predictive rates of infection at maternal viral load levels of 7, 8, and 9 log10 copies/ml were 6.6% (95% CI, 0.5–12.6%; p = 0.033), 14.6% (95% CI, 5.6–23.6%; p = 0.001), and 27.7% (95% CI, 13.1–42.4%; p <0.001), respectively. Conclusions Additional strategies to further reduce transmission should be considered in mothers with a viral load above 7–8 log10 copies/ml.
Background and Aims
Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to ...implement salvage therapies appropriately. This study examined the feasibility of virus‐host chimera DNA (vh‐DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting.
Approach and Results
HBV integration in 50 patients with HBV‐related HCC was determined by the Hybridization capture‐based next‐generation sequencing (NGS) platform. For individual HCC, the vh‐DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV‐related HCC. Tumor‐specific ddPCR was developed to measure the corresponding vh‐DNA copy number in baseline plasma from each patient immediately before surgery. vh‐DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh‐DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh‐DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh‐DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh‐DNA, whereas 18.2% were from de novo HCC.
Conclusions
vh‐DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV‐related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.
Data regarding the nephrotoxicity of sofosbuvir (SOF) remain controversial. We compared the evolution of estimated glomerular filtration rate (eGFR) in patients with chronic HCV infection receiving ...SOF-based or SOF-free direct-acting antivirals (DAAs).
A total of 481 patients with compensated liver diseases and eGFR ≥30 ml/min/1.73m2, receiving SOF-based (n = 308) or SOF-free (n = 173) DAAs for 12 weeks, were prospectively enrolled. The eGFR was assessed from baseline to off-treatment week 24 using the chronic kidney disease (CKD)-epidemiology collaboration equation. Differences in the evolution of eGFR between regimens were compared by a generalized linear mixed-effects model. Multivariate analysis was performed for factors affecting eGFR evolution.
Patients receiving SOF-based DAAs experienced a significant on-treatment decline in eGFR (adjusted slope coefficient difference: −1.24 ml/min/1.73m2/month; 95% CI −1.35 to −1.13; p <0.001) and a significant off-treatment improvement (adjusted slope coefficient difference: 0.14 ml/min/1.73m2/month; 95% CI 0.08 to 0.21; p = 0.004) compared to patients receiving SOF-free DAAs. Multivariate analysis showed age per 1-year increase (adjusted slope coefficient difference: −0.05 ml/min/1.73m2/month; 95% CI −0.05 to −0.04; p <0.001), SOF-based DAAs (adjusted slope coefficient difference: −0.33 ml/min/1.73m2/month; 95% CI −0.49 to −0.17; p <0.001), and CKD stage (adjusted slope coefficient difference: −1.44 ml/min/1.73m2/month; 95% CI −1.58 to −1.30; p <0.001 for stage 3 vs. 1, and −3.59 ml/min/1.73m2/month; 95% CI −3.88 to −3.30; p <0.001 for stage 2 vs. 1) were independent factors affecting eGFR evolution from baseline to off-treatment week 24.
Patients receiving SOF-based DAAs exhibited a quadratic trend, with eGFR worsening on treatment and improving off treatment. Increasing age, SOF-based DAAs, and more advanced baseline CKD stage are independently associated with a decline in eGFR in patients with HCV receiving DAAs.
While the efficacy of sofosbuvir for the treatment of hepatitis C virus is clear, data regarding its possible nephrotoxicity are controversial. Herein, we showed that sofosbuvir worsened on-treatment kidney function but led to an off-treatment improvement. Our findings suggest that treating physicians should be alert to risk factors for kidney dysfunction before initiating direct-acting antiviral treatment for patients with hepatitis C virus infection.
NCT04047680
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•Patients receiving SOF-based DAAs exhibit a quadratic trend, with eGFR worsening on treatment and improving off treatment.•Patients receiving SOF-free DAAs have a linear trend with eGFR improving on and off treatment.•Increasing age, use of SOF-based DAAs, and more advanced baseline CKD stage are independent risk factors of eGFR decline.
Significance Ninety-five percent of adult-acquired infections lead to spontaneous clearance, whereas >90% of exposed neonates and ∼30% of children aged 1–5 y fail to resolve hepatitis B virus (HBV) ...and develop chronic infection. A strong, diverse, adaptive immune response is considered essential for HBV clearance, but the mechanisms to generate a favorable response remain elusive. Here, we show that, while 12-wk-old C3H/HeN mice cleared HBV within 6 wk postinjection (wpi), their 6-wk-old counterparts remained HBV-positive at 26 wpi. Sterilization of gut microbiota from 6 to 12 wk of age using antibiotics prevented mice from rapidly clearing HBV. This model is valuable to the study of liver tolerance and enables the investigation of the mechanisms involved in effective control of HBV.
A unique feature of hepatitis B virus (HBV) infection in humans is that viral clearance heavily depends on the age of exposure. However, the reason for this remains unclear. Here we show that gut microbiota contribute to the age dependence of HBV immunity in a hydrodynamic transfection mouse model. Although adult (12-wk-old) C3H/HeN mice cleared HBV within 6 wk postinjection (wpi), their young (6-wk-old) counterparts remained HBV-positive at 26 wpi. Sterilization of gut microbiota from 6 to 12 wk of age using antibiotics prevented adult mice from rapidly clearing HBV. Young mice with the Toll-like-receptor (TLR) 4 mutation (C3H/HeJ) exhibited rapid HBV clearance. The results suggest that an immuno-tolerating pathway to HBV prevailed in young mice, before the establishment of gut bacteria, through a TLR4-dependent pathway and that the maturation of gut microbiota in adult mice stimulated liver immunity, resulting in rapid HBV clearance.
Chronic hepatitis B patients with high viral loads are at increased risk of cirrhosis and hepatocellular carcinoma (HCC). In patients with low viral loads, higher hepatitis B surface antigen (HBsAg) ...levels have been shown to predict HCC development. However, little is known about the difference in risk for other hepatitis B virus (HBV)‐related adverse outcomes with varying HBsAg levels. A total of 1,068 Taiwanese hepatitis B e antigen (HBeAg)‐negative HBV carriers with serum HBV DNA level <2,000 IU/mL at baseline were followed for a mean duration of 13.0 years. Patients were categorized based on their HBsAg levels, and the relationships between HBsAg level and development of HBeAg‐negative hepatitis, hepatitis flare, and cirrhosis were investigated. Of the 1068 patients with low viral loads, 280 developed HBeAg‐negative hepatitis, with an annual incidence rate of 2.0%. HBsAg level, but not HBV DNA level, was found to be a risk factor for HBeAg‐negative hepatitis. Multivariate analysis showed that the adjusted hazard ratio in patients with an HBsAg level ≥1,000 versus <1000 IU/mL was 1.5 (95% confidence interval, 1.2–1.9). The positive correlation was present when evaluating other endpoints, including hepatitis flare and cirrhosis, and remained consistent when the study population was restricted to those with normal alanine aminotransferase (ALT) level at baseline. The annual incidence rate of HBeAg‐negative hepatitis was lowered to 1.1% in patients with low levels of HBV DNA, HBsAg, and ALT. Conclusion: In HBeAg‐negative patients with low viral loads and genotype B or C virus infection, a higher HBsAg level can predict disease progression. HBsAg <1,000 IU/mL in combination with low levels of HBV DNA and ALT help define minimal‐risk HBV carriers. (HEPATOLOGY 2013)
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