Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence

AIM: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection.

Long-term hepatic consequences of chemotherapy-related HBV reactivation in lymphoma patients

AIM: To investigate the long-term consequences of chemotherapy-related HBV reactivation in patients with lymphoma.METHODS: This study was based on the database of published prospective study evaluating HBV reactivation in HBV lymphoma patients during chemotherapy.Deteriorated liver reserve (DLR) was defined as development of either one of the following conditions during follow-up: (1) newly onset parenchyma liver disease, splenomegaly or ascites without evidence of lymphoma involvement; (2) decrease of the ratio (albumin/globulin ratio) to less than 0.8 or increase of the ratio of INR of prothrombin time to larger than 1.2 without evidence of malnutrition or infection. Liver cirrhosis was diagnosed by imaging studies.RESULTS: A total of 49 patients were included. The median follow-up was 6.2 years (range, 3.9-8.1 years).There were 31 patients with and 18 patients without HBV reactivation. Although there was no difference of overall survival (OS) and chemotherapy response rate between the two groups, DLR developed more frequently in patients with HBV reactivation (48.4% vs 16.7%; P= 0.0342). Among the HBV reactivators, HBV genotype C was associated with a higher risk of developing DLR (P = 0.0768) and liver cirrhosis (P = 0.003). Four of five patients with sustained high titer of HBV DNA and two of three patients with multiple HBV reactivation developed DLR. Further, patients with a sustained high titer of HBV DNA had the shortest OS among the HBV reactivators (P= 0.0000). No patients in the non-HBV reactivation group developed hepatic failure or liver cirrhosis.CONCLUSION: Chemotherapy-related HBV reactivation is associated with the long-term effect of deterioration of hepatic function.

Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection

Dual hepatitis C virus(HCV)/hepatitis B virus(HBV)infection is found in HBV or HCV endemic areas,and in specific populations exhibiting a high risk of parenteral viral transmission.Clinical observations have revealed that HCV/HBV dually infected patients demonstrate a higher risk of liver disease progression compared with HBV or HCV monoinfected patients.The viral activity responsible for liver disease progression can be determined by examining the viral loads of HCV and HBV and by conducting liver biopsy examinations.Recent trials have confirmed that the combination therapy of peginterferon alpha-2a or 2b and ribavirin for dual hepatitis patients with HCV dominance appears to be as effective and safe as it is in patients with HCV monoinfections.Strikingly,approximately 60% of dually infected patients with inactive hepatitis B before treatment develop HBV reactivation after the clearance of the HCV.The clinical significance of this HBV reactivation and the strategy to prevent and treat this event should be determined.Furthermore,approximately 30%of dually infected patients lost hepatitis B surface antigen(HBsAg)within 5 years after the start of peginterferonbased therapy,and 40%of them harbored occult HBV infection.The underlying mechanisms of their accelerating HBsAg seroclearance and the development of occult HBV await further investigations.Moreover,the optimal treatment strategies for dually infected patients who are seropositive for the hepatitis B e antigen must be explored.Finally,the advent of new direct-acting antiviral-based anti-HCV therapy may change the optimal therapies for patients with dual hepatitis in the near future,which warrants further clinical trials.

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Hepatitis B virus （HBV） reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor （TNF） blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-a blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-a blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-a blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose- and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-a blockage therapy occurred at early time points after HBV infection. In addition, TNF-a blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death （PD）- 1highCD127low exhausted T cells. Furthermore, TNF-a blockade abolished Toll-like receptor 9 （TLR9） ligand-induced facilitation of HBV viral clearance. Taken together, TNF-a blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-a blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during theraoy with TNF-a-blocking agents.

Asialo GM1-positive liver-resident CD8 T cells that express CD44 and LFA-1 are essential for immune clearance of hepatitis B virus

Persistent hepatitis B virus(HBV)infection results in chronic liver diseases that may progress to chronic hepatitis,liver cirrhosis,and subsequent hepatocellular carcinoma.Previous studies demonstrated that adaptive immunity,in particular CD8 T cells,is critical in HBV elimination.Recent studies have revealed a distinct tissue-localized T cell lineage,tissue-resident memory(TRM)cells,that is crucial for protective immunity in peripheral tissues.In this study,we showed that treatment with an anti-asialo GM1(ASGM1)antibody(Ab),which depletes NK cells,led to impairment of HBV clearance in a mouse animal model.Unexpectedly,the ability to clear HBV was not significantly impaired in NFIL3 KO mice,which are deficient in NK cells,implying that other non-NK ASGM1-positive immune cells mediate HBV clearance.We isolated intrahepatic ASGM1-positive cells from NFIL3 KO mice and analyzed the immune phenotype of these cells.Our results demonstrated a distinct population of CD44+LFA-1hi CD8 T cells that were the major intrahepatic ASGM1-positive immune cells in NFIL3 KO mice.Importantly,transcriptome analysis revealed that these ASGM1-positive CD8 T cells had distinct gene profiles and shared a similar core gene signature with TRM cells.In addition to both transcriptional and phenotypic liver residency characteristics,ASGM1-positive CD8 T cells were able to home to and be retained in the liver after adoptive transfer.Taken together,our study results indicate that these ASGM1-positive liver-resident CD8 T cells are the major effector immune cells mediating anti-HBV immunity.