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In patients with chronic hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) is considered a functional cure. However, HBsAg loss is uncommon with existing therapies, and predictive factors associated with HBsAg seroreversion are unknown. Using pooled data from three phase 3 clinical trials of patients with CHB treated with nucleos(t)ide analogue (NUC) monotherapy or peginterferon (Peg‐IFN) ± NUC combination therapy, we conducted a retrospective analysis to characterize patients who achieved sustained HBsAg loss, the predictors of HBsAg seroreversion, and the impact of hepatitis B surface antibody (anti‐HBs) seroconversion on durability of HBsAg loss. In these three international trials, 1,381 adults with CHB received either NUC monotherapy for up to 10 years or Peg‐IFN‐containing regimens for up to 1 year. A total of 55 patients had confirmed HBsAg loss, defined as two or more consecutive negative‐qualitative HBsAg results, with a minimum of one repeat result after the end of treatment. Throughout a median of 96 (quartile [Q]1, Q3, 46, 135) weeks follow‐up after HBsAg loss, HBsAg loss was durable in 82% (n = 45) of patients, with 10 patients experiencing HBsAg seroreversion. Anti‐HBs seroconversion was observed during follow‐up in 78% of patients who lost HBsAg and in 60% of those who subsequently seroreverted. In analyzing predictors of HBsAg seroreversion, study treatment was significant, yet anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not. Risk of HBsAg seroreversion was observed to be lower if HBsAg loss was sustained through the off‐treatment week 24 visit (8/10 seroreversions occurred by posttreatment week 24). Conclusion: HBsAg loss after NUC or Peg‐IFN‐containing regimens was durable in 82% of patients with CHB. Anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not significantly associated with durability of HBsAg loss.

Human plasma contains RNA transcripts released by multiple cell types within the body. Single-cell transcriptomic analysis allows the cellular origin of circulating RNA molecules to be elucidated at high resolution and has been successfully utilized in the pregnancy context. We explored the application of a similar approach to develop plasma RNA markers for cancer detection. Single-cell RNA sequencing was performed to decipher transcriptomic profiles of single cells from hepatocellular carcinoma (HCC) samples. Cell-type-specific transcripts were identified and used for deducing the cell-type-specific gene signature (CELSIG) scores of plasma RNA from patients with and without HCC. Six major cell clusters were identified, including hepatocyte-like, cholangiocyte-like, myofibroblast, endothelial, lymphoid, and myeloid cell clusters based on 4 HCC tumor tissues as well as their paired adjacent nontumoral tissues. The CELSIG score of hepatocyte-like cells was significantly increased in preoperative plasma RNA samples of patients with HCC (n = 14) compared with non-HCC participants (n = 49). The CELSIG score of hepatocyte-like cells declined in plasma RNA samples of patients with HCC within 3 days after tumor resection. Compared with the discriminating power between patients with and without HCC using the abundance of ALB transcript in plasma [area under curve (AUC) 0.72)], an improved performance (AUC: 0.84) was observed using the CELSIG score. The hepatocyte-specific transcript markers in plasma RNA were further validated by ddPCR assays. The CELSIG scores of hepatocyte-like cell and cholangiocyte trended with patients' survival. The combination of single-cell transcriptomic analysis and plasma RNA sequencing represents an approach for the development of new noninvasive cancer markers.

In this phase 3 study involving patients with HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis, treatment with 12 weeks of sofosbuvir and velpatasvir resulted in a sustained virologic response in 99% of patients. The hepatitis C virus (HCV), a single-stranded RNA virus of the family Flaviviridae with six major genotypes, infects up to 150 million people worldwide. 1 , 2 Chronic HCV infection causes progressive liver fibrosis, which can lead to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. 3 , 4 As many as half a million people die annually from liver disease associated with chronic HCV infection. 5 In recent years, the development of drugs that directly interfere with HCV replication has revolutionized HCV treatment. There are now effective combinations of direct-acting antiviral agents for most patients, but in choosing an appropriate regimen, clinicians must take into account . . .

Aspirin at low doses and other nonsteroidal antiinflammatory drugs (NSAIDs) are major causes of upper gastrointestinal bleeding worldwide. Low-dose aspirin is increasingly used for cardiovascular prophylaxis, but it doubles the risk of bleeding ulcers, even at doses as low as 75 mg daily. 1 Other NSAIDs are commonly taken for musculoskeletal pain. Epidemiologic studies have shown that the use of NSAIDs increases the risk of ulcer complications by a factor of 4. 2 A history of upper gastrointestinal bleeding is a significant risk factor for recurrent bleeding in those taking low-dose aspirin 3 or other NSAIDs. 3 , 4 To date, there are few strategies . . .

Background: Most noninvasive predictive models of liver fibrosis are complicated and have suboptimal sensitivity. This study was designed to identify serum proteomic signatures associated with liver fibrosis and to develop a proteome-based fingerprinting model for prediction of liver fibrosis. Methods: Serum proteins from 46 patients with chronic hepatitis B (CHB) were profiled quantitatively on surface-enhanced laser desorption/ionization (SELDI) ProteinChip arrays. The identified liver fibrosis-associated proteomic fingerprint was used to construct an artificial neural network (ANN) model that produced a fibrosis index with a range of 0–6. The clinical value of this index was evaluated by leave-one-out cross-validation. Results: Thirty SELDI proteomic features were significantly associated with the degree of fibrosis. Cross-validation showed that the ANN fibrosis indices derived from the proteomic fingerprint strongly correlated with Ishak scores (r = 0.831) and were significantly different among stages of fibrosis. ROC curve areas in predicting significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) were 0.906 and 0.921, respectively. At 89% specificity, the sensitivity of the ANN fibrosis index in predicting fibrosis was 89%. The sensitivity for prediction increased with degree of fibrosis, achieving 100% for patients with Ishak scores >4. The accuracy for prediction of cirrhosis was also 89%. Inclusion of International Normalized Ratio, total protein, bilirubin, alanine transaminase, and hemoglobin in the ANN model improved the predictive power, giving accuracies >90% for the prediction of fibrosis and cirrhosis. Conclusions: A unique serum proteomic fingerprint is present in the sera of patients with fibrosis. An ANN fibrosis index derived from this fingerprint could differentiate between different stages of fibrosis and predict fibrosis and cirrhosis in CHB infection.

Hepatitis B virus infection is a major public health problem worldwide; roughly 30% of the world's population show serological evidence of current or past infection. Hepatitis B virus is a partly double-stranded DNA virus with several serological markers: HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG. It is transmitted through contact with infected blood and semen. A safe and effective vaccine has been available since 1981, and, although variable, the implementation of universal vaccination in infants has resulted in a sharp decline in prevalence. Hepatitis B virus is not cytopathic; both liver damage and viral control—and therefore clinical outcome—depend on the complex interplay between virus replication and host immune response. Overall, as much as 40% of men and 15% of women with perinatally acquired hepatitis B virus infection will die of liver cirrhosis or hepatocellular carcinoma. In addition to decreasing hepatic inflammation, long-term antiviral treatment can reverse cirrhosis and reduce hepatocellular carcinoma. Development of new therapies that can improve HBsAg clearance and virological cure is warranted.

Background: Variations in the hepatitis B virus (HBV) genome may develop spontaneously or under selective pressure from antiviral therapy. Such variations may confer drug resistance or affect virus replication capacity, resulting in failure of antiviral therapy. Methods: A duplex PCR was used to amplify the region of the reverse transcriptase gene, the precore promoter, and the basal core promoter of the HBV genome. Four multiplex primer-extension reactions were used to interrogate 60 frequently observed HBV variants during antiviral therapy. Automated MALDI-TOF mass spectrometry (MS) was used for mutation detection. Capillary sequencing was used to confirm the MS results. Results: The limit of quantification was 1000 HBV copies/mL for multiplex detection of HBV variants. Fifty-three variants (88.3%) were analyzed successfully in at least 90% of the sera from 88 treatment-naive patients and 80 patients with virologic breakthrough. MS was able to detect twice as many minor variants as direct sequencing while achieving close to full automation. MS and direct sequencing showed only 0.1% discordance in variant calls. Conclusions: This platform based on multiplex primer extension and MALDI-TOF MS was able to detect 60 HBV variants in 4 multiplex reactions with accuracy and low detection limits.

Significance We used massively parallel sequencing to study the size profiles of plasma DNA samples at single-base resolution and in a genome-wide manner. We used chromosome arm-level z -score analysis (CAZA) to identify tumor-derived plasma DNA for studying their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These findings have shed light on fundamental biological characteristics of plasma DNA and related diagnostic applications for cancer. The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z -score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.

This Review presents current epidemiological trends of the most common liver diseases in Asia–Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia–Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care.

Background: The use of MALDI-TOF mass spectrometry (MS) in quantitative glycan profiling has not been reported. In this study, we attempted to establish a high-throughput quantitative assay for profiling serum N-glycome, and we applied the new assay to identifying serum N-glycans for diagnosis of liver fibrosis and cirrhosis. Methods: N-glycans from whole serum proteins in 2 μL serum were released by enzymatic digestion, cleaned up by hydrophilic chromatography, and subsequently quantitatively profiled with a linear MALDI-TOF MS system, which was originally designed for quantitative proteomic profiling. Serum N-glycome profiles from 46 patients with chronic hepatitis B infection and with different degrees of liver fibrosis were examined. Results: The intra- and interassay CVs of peak intensities of the standard N-glycans were <8% and <17%, respectively. When the assay was applied to the analysis of serum N-glycome profiles, 17 peaks were found to be potential biomarkers for detection of liver fibrosis/cirrhosis. Linear regression analysis revealed that 4 peaks of 1341.5, 1829.7, 1933.3, and 2130.3 m/z (all P <0.005) had complementary value in detecting liver fibrosis and included them, but not any serological markers, in the diagnostic model. Leave-one-out cross-validation showed the diagnostic model could identify significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5), both at 85% accuracy. Conclusion: This is the first study to illustrate the quantitative aspect of MALDI-TOF MS in N-glycome profiling and the first study to reveal the potential value of the serum N-glycan profile for identifying liver fibrosis.