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HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB.A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo.Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

Background. Over the last 20 years, the prevalence of hepatitis B virus (HBV) infection in China has decreased gradually due to the application of a national HBV vaccination program. In contrast, the prevalence of alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune liver disease, and drug-induced liver injury has markedly increased. Methods. We conducted a retrospective review of 82,562 hospitalized patients diagnosed with liver cirrhosis in Beijing 302 Hospital from 2002 to 2013. Results. The top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. The percentage of HBV cirrhosis decreased from 81.53% in 2002 to 66.0% in 2013, whereas the frequency of alcoholic cirrhosis increased from 3.34% in 2002 to 8.40% in 2013. Females (84.34%) accounted for the majority of cirrhotic patients with autoimmune liver diseases. Males accounted for 80.16% of HBV cirrhosis patients and 98.02% of alcoholic cirrhosis patients. Conclusion. In Beijing 302 Hospital, the top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. Over the last 12 years, the prevalence of HBV cirrhosis has decreased gradually, whereas that of alcoholic cirrhosis has increased significantly.

The implementation of a hepatitis B vaccination program in China has led to a significant decline in the prevalence and incidence of liver diseases secondary to hepatitis B virus over the past two decades. With recent changes in the economy and increases in average incomes in China during the same period, there has been a rapid rise in per capita alcohol consumption and an epidemic of obesity. We hypothesized that the burden of liver diseases in China has shifted from infectious to non-infectious etiologies. We retrospectively analyzed the data of 20,378 patients who were hospitalized in Beijing 302 hospital between 2002 and 2013. We found that the total admission rate secondary to alcoholic liver disease (ALD), non-alcoholic liver disease (NAFLD), autoimmune liver disease (AILD), and drug-induced liver injury (DILI) was 10.7%. ALD was the leading cause of inpatient hospitalization (3.9% of total admissions). The rate of inpatient admission for ALD, AILD, and DILI increased by 170%, 111%, and 107%, respectively during the study period. Chinese herbal medicine was the primary cause of DILI in our subjects. The burden of non-infectious liver diseases has increased over the last decade among hospitalized patients in a large tertiary hospital in China. The increase in the rate of admission for ALD and DILI from Chinese herbal medicine suggests that strategies to reduce harmful use of alcohol and increase awareness and education on the use of herbal medicine are needed.

Worldwide, hepatitis B virus (HBV) infection is one of the leading causes of chronic liver disease. Because HBV is not a cytopathogenic virus, host immune responses induced by viral persistence are generally thought to be responsible for the disease progression of chronic HBV infection.1 Generally, HBV-specific T cells were believed to play important roles in inducing hepatocellular damage during chronic HBV infection2,3; however, recent studies have shown that these cells often display functional impairment, such as T cell exhaustion by up-regulation of programmed death 1,4,5 T cell attrition through the B cell lymphoma 2 interacting mediator,6 and impaired T cell receptor signaling through the ζ-chain.7 T cell impairment is even more pronounced in the livers of patients with chronic hepatitis B (CHB) versus their blood.5 Furthermore, activated HBV-specific CD8 T cells are often found to be present in the livers of patients without evident liver immunopathology, whereas non–virus-specific lymphocytes have usually massively infiltrated the livers of patients with hepatocellular damage.8 A model of HBV-transgenic mice has further confirmed that non–virus-specific lymphocytes can exacerbate the liver inflammation initiated by virus-specific CD8 T cells.9,10 These findings suggest that non–virus-specific inflammatory cells infiltrating the liver may actively participate in HBV-associated liver pathogenesis. Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection.11 Recent studies have clearly suggested that NK cells may contribute to liver pathogenesis in rodent models12 and in patients with chronic hepatitis C virus (HCV) or HBV infection.13–16 Particularly during HCV infection, the viral infection results in an elevation of interferon-α (IFN-α) that subsequently polarizes NK cells toward cytolytic activity to induce liver injury.15 Emerging evidence indicates that during HBV infection, the early NK cell responses may lead to the initial control of the acute infection and allow the timely and efficient development of an adaptive immune response.17,18 However, if the virus persists, activated NK cells can mediate hepatocyte apoptosis by up-regulating tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in hepatitis B e antigen (HBeAg)–negative patients with hepatic flares14 and Fas ligand (FasL) in patients with HBV-associated acute-on-chronic liver failure.16 Although these studies have partially defined the role of NK cells in liver injury, NK cells may also use some other ligands to mediate liver injury in various disease progression phases of chronic HBV infection. In addition, recently available data about NK cells in CHB patients were primarily obtained from the peripheral compartments18,19; detailed information about the roles of NK cells in the liver pathogenesis of chronic HBV infection is scarce, especially for HBeAg-positive subjects. HBeAg-positive individuals with chronic HBV infection are generally divided into two groups: immune-tolerant (IT) carriers and immune-activated (IA) patients. The former group is characterized by minimal liver damage, normal alanine aminotransferase (ALT) levels, and active viral replication; the latter, generally after the IT phase, have increased liver injury and decreased viral replication.1,20 In this study, we comprehensively characterized the hepatic NK cells in these HBV-infected individuals and demonstrated that NK cell–mediated liver pathogenesis depended on an imbalanced cytokine milieu in the livers of these IA patients. Our findings may facilitate the rational development of immunotherapeutic strategies for enhancing viral control while limiting or blocking liver injury and inflammation.

Aims: This study attempts to characterize the feature of immunologically competent cells (ICCs) and evaluate its clinical implication in patients with acute-on-chronic liver failure (ACLF) in relation to chronic hepatitis B virus (HBV) infection. Methods: Circulating ICCs were examined in ACLF patients (n = 75), as well as in patients with hepatitis B (CHB, n = 31), CHB-related liver cirrhosis (LC, n = 36), and normal controls (NC, n = 30). Intrahepatic ICCs in some patients were further analyzed via immunohistochemical and flow cytometric assays. Results: Total lymphocytes, CD4+ T cells, CD8+ T cells, and NK cells in circulation were numerically lower in the ACLF and LC groups compared to the CHB and NC groups. Importantly, the number of these cells was significantly lower in non-surviving ACLF patients compared with surviving ACLF patients. In comparison to NC, ACLF patients displayed a significantly higher ratio of liver-infiltrating CD4+ T-cell frequency than its circulating counterpart, suggesting that the possiblility of the ICCs compartmentalization from the peripheral blood into the liver in ACLF. Immunohistochemical analysis showed that intrahepatic CD4+ cells, CD8+ cells, and CD56+ cells were significantly higher in the ACLF group compared with the other three groups, suggesting a stronger cellular immune response-mediated inflammation in ACLF group than other patient groups. Conclusions: The abnormal prevalence of circulating and intrahepatic ICCs possibly acts as an important factor that may drive the progression of HBV-related ACLF.

Background This study aimed to investigate the relationships of intrahepatic cccDNA with serum HBsAg and with HBV DNA in treatment-naive patients throughout acute and chronic HBV infection. Methods A total of 120 patients who had a liver biopsy were enrolled, including 19 with acute hepatitis B (AHB), and 101 patients with chronic HBV infection (CHB) of whom were 10 in immune-tolerant (IT) phase, 59 in immune-clearance (IC) phase, 8 in low-replicative (LR) phase, and 24 in HBeAg-negative hepatitis (ENH) phase. Intrahepatic cccDNA, serum HBsAg and serum HBV DNA levels were comparatively analyzed. Results The median intrahepatic cccDNA levels were 0.18 4.80, 3.81, 0.22 and 0.97 copies/cell for patients with AHB, CHB-IT, CHB-IC, CHB-LR, and CHB-ENH, respectively. In AHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg (r = 0.665, P = 0.003), as well as serum HBV DNA (r = 0.536, P = 0.022). In CHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg in the IC phase (r = 0.392, P = 0.005), and with serum HBV DNA in the IC phase (r = 0.301, P = 0.036) and ENH phase (r = 0.588, P = 0.013). HBV replicative efficiency, defined as the ratio of serum HBV DNA to intrahepatic cccDNA, was obviously lower in AHB and CHB-LR patients than in CHB-IT, CHB-IC and CHB-ENH patients (0.70 and 0.53 vs. 1.12, 1.09 and 0.99, P