Faculty Bibliography

BACKGROUND:Since immunoprophylaxis failure can occur if maternal serum hepatitis B virus (HBV) DNA levels are >200,000 IU/ml, tenofovir disoproxil fumarate (TDF) therapy has been investigated for preventing mother to child transmission (PMTCT). METHODS:A literature search for maternal TDF therapy for PMTCT between 1/1/2015 and 7/1/21 on PUBMED, EMBASE, Cochrane, CNKI, and Wanfang databases was performed. Data from RCTs in English or Chinese were extracted and reviewed. The outcomes of interest included the efficacy and safety of TDF versus placebo for PMTCT. RESULTS:Among 11 RCTs identified from the databases, the risk-of-bias was low. All studies demonstrated that maternal TDF therapy initiated from the second or third trimester for highly viremic chronic hepatitis B mothers is highly effective and safe in the PMTCT of HBV, except one RCT performed in Thailand which showed no therapeutic advantage on TDF treatment versus placebo for PMTCT (0% vs 3% transmission). Recent emerging data suggest that maternal TDF therapy initiated at the 2nd or early 3rd trimester in mothers with HBV DNA >200,000 IU/ml achieved viremic control before delivery. In the 4-year long follow-up study for maternal TDF therapy, there were no impacts on infants' physical growth, psychological or mental development, and bone mineral density after fetal exposure to TDF. In the light of updated efficacy and safety data from RCTs, an algorithm was proposed. The approaches in resource-limit areas were discussed. CONCLUSIONS:TDF is safe for both mothers and infants as the preferred therapy for PMTCT in highly viremic mothers. TDF should be initiated at the second or early third trimester in the combination of the appropriate infants' immunoprophylaxis.

Real-world data are limited on tenofovir alafenamide (TAF). We aimed to study TAF real-world outcomes with other first-line regimens for chronic hepatitis B (CHB). We enrolled patients with CHB from 10 centers retrospectively and followed them for 36 months prospectively. We analyzed switching patterns of antiviral therapy and treatment outcomes of TAF, tenofovir disoproxil fumarate (TDF), and entecavir therapy. For efficacy and safety, we analyzed a subset of patients with complete data at 24 months after switching to TAF or remaining on TDF or entecavir. Among 1037 enrollees, 889 patients were analyzed. The mean age was 52%, and 72% were hepatitis B e antigen-negative. After enrollment, shifts in therapies were mostly in reduced use of TDF from 63% to 30% due to switching to TAF. Clinical parameters were compared at enrollment or initiation to measures at 24 months for patients remaining on TAF (187), TDF (229), or entecavir (181). At 24 months, a significantly higher portion of patients on TAF achieved hepatitis B virus (HBV) DNA ≤ 20 IU/ml (93% vs. 86%; p = 0.012) and normalized alanine aminotransferase (ALT) (66% vs. 56%; p = 0.031) with stable estimated glomerular filtration rates (eGFRs). However, a higher percentage of the patient with eGFR < 60 ml/mi/1.7 m² was observed in the TDF-treated group (9% vs. 4%; p = 0.010). In patients who remained on entecavir or TDF for 24 months, ALT and HBV-DNA results did not differ significantly from baseline. Treatment of CHB in the United States has significantly shifted from TDF to TAF. Our data suggest that switching from TDF or entecavir to TAF may result in increased frequency of ALT normalization and potential clearance of viremia at the 24-month time point.

Current therapeutic interventions can only suppress hepatitis B virus (HBV) replication or reduce complications without a cure. Therefore, further development of new treatment methods is critical for the global eradication of HBV. Accumulating evidence suggests that the liver and gut share an interconnected relationship referred to as the 'Gut-Liver Axis', where exchanges happen bi-directionally. The gut itself is the host to a unique microbiota profile which has metabolic, immunological, neurological and nutritional functions. Gut microbiota is not only constantly intersecting with the liver but also associated with hepatic injury when dysbiosis occurs. In recent years, there has been increased interest in gut microbiota and its implications on liver disease treatment. Progress has been made in understanding the complex relationship between chronic hepatitis B (CHB) and gut microbiota. New investigative techniques such as colony-free sequencing enabled new perspectives into this field. Mouse models and human studies revealed that HBV infection is associated with significant alteration of gut microbiota, which differ depending on the stage of CHB disease progression. Different mechanisms of the hepatic injury from gut microbiota dysbiosis have also been proposed based on findings of increased intestinal permeability to toxins, disruption of normal bacterial metabolism, and colonization of the gut by oral microbiota. New treatment methods targeting gut microbiota in CHB, such as probiotics and faecal microbiota transplant, have also gained promising results in recent years. The current review recapitulated the most recent investigations into the relationship between gut microbiota and CHB to provide research directions towards the new therapeutic target of CHB.

OBJECTIVE:The physical and neuromental development of infants remains uncertain after fetal exposure to tenofovir disoproxil fumarate (TDF) for the prevention of mother-to-child transmission of HBV. We aimed to investigate the safety of TDF therapy during the third trimester of pregnancy. DESIGN/METHODS:Infants from a previous randomised controlled trial were recruited for our long-term follow-up (LTFU) study. Mothers with chronic hepatitis B were randomised to receive TDF therapy or no treatment during the third trimester. Infants' physical growth or malformation, bone mineral density (BMD) and neurodevelopment, as assessed using Bayley-III assessment, were examined at 192 weeks of age. RESULTS:Of 180 eligible infants, 176/180 (98%) were enrolled and 145/176 (82%) completed the LTFU (control group: 75; TDF-treated group: 70). In the TDF-treated group, the mean duration of fetal exposure to TDF was 8.57±0.53 weeks. Congenital malformation rates were similar between the two groups at week 192. The mean body weight of boys in the control and TDF-treated groups was significantly higher (19.84±3.46 kg vs. 18.47±2.34 kg; p=0.03) and within the normal range (18.48±2.35 kg vs. 17.80±2.50 kg; p=0.07), respectively, when compared with the national standard. Other prespecified outcomes (head circumference, height, BMD, and cognitive, motor, social-emotional, and adaptive behaviour measurements) were all comparable between the groups. CONCLUSION/CONCLUSIONS:Infants with fetal exposure to TDF had normal physical growth, BMD and neurodevelopment at week 192. Our findings provide evidence on the long-term safety of infants after fetal exposure to maternal TDF therapy for preventing hepatitis B transmission. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT01488526.

To investigate whether IL-21 levels predict treatment outcomes of salvage therapy among patients with suboptimal response (SOR) to nucleos(t)ide analogues (NAs), serum IL-21 levels were measured in a prospective cohort of hepatitis B e antigen (HBeAg)-positive patients with SOR to antiviral therapy. The patients switched therapy to entecavir (ETV) with or without adefovir (ADV) for 104 weeks. IL-21 levels at treatment week 12 in patients who achieved HBeAg loss with undetectable levels of hepatitis B virus (HBV)-DNA at week 104 were the primary endpoint and the results were compared with those of corresponding patients without such an endpoint. Furthermore, IL-21 levels at treatment week 12 in patients who achieved an HBeAg-level decline at week 104 were assessed as the secondary endpoint. Among 24 enrolled patients with SOR to ADV (n=21), telbivudine (n=2) or ETV (n=1), the median (10-90th percentile) levels of HBeAg, HBV-DNA and ALT at baseline were 2.7 (0.2-3.1) log₁₀ S/CO, 5.2 (3.5-7.5) log₁₀ IU/ml and 0.9 (0.5-3.1) upper limit of normal, respectively. Comparison of the patients with and without HBeAg loss at week 104 indicated that their mean IL-21 levels did not significantly differ at week 12 (63.0±14.4 vs. 55.9±10.5 pg/ml; P=0.26). In the secondary endpoint analyses of patients with and without HBeAg level decline, the elevated levels of IL-21 at the first 12 weeks were significantly higher in the decline group (15.6±8.3 vs. 3.1±13.2 pg/ml; P=0.03). Following adjustment for confounding factors, the elevated levels of IL-21 from baseline to week 12 independently predicted an HBeAg level decline at week 104 (odds ratio=1.137, R²=0.23; P=0.047). In conclusion, the serum IL-21 levels at the first 12 weeks during the salvage therapy independently predicted HBeAg level decline at treatment week 104 in patients with SOR to NAs (ClinicalTrials.gov identifier: NCT01829685; date of registration, April 2013).

Accumulating evidence shows that the intestinal microbiota is closely related to the pathophysiology and the disease progression of chronic hepatitis B virus (HBV) infection. The intestinal microbiota acts on the host through its metabolites. This review aimed to discuss the effects of gut microbiota metabolites on the disease progression of chronic HBV infection. A literature search on PubMed database and Wiley Online Library with pre-specified criteria yielded 96 unique results. After consensus by all authors, the contents from 86 original publications were extracted and included in this review. In liver disease with HBV infection, the intestinal microbiota changed in different stages and affected the production of bacterial metabolites. The abundance of bacteria producing short-chain fatty acids such as butyrate reduced, which was associated with bacterial translocation and the progression of liver disease. The intestinal microbiota-bile acid-host axis was destroyed, affecting the progression of the disease. Under the control of intestinal microbiota, tryptophan affected the gut-liver axis through three main metabolic pathways, among which the kynurenine pathway was closely related to the immune response of hepatitis B. The level of trimethylamine-N-oxide decreased in liver cancer with HBV infection and were used as a potential biomarker of liver cancer. Vitamin deficiencies, including those of vitamin D and vitamin A related to microbiota, were common and associated with survival. Hydrogen sulfide regulated by the intestinal microbiota was also closely related to the gut-liver axis. In liver disease with hepatitis B infection, the intestinal microbiota is imbalanced, and a variety of intestinal microbiota metabolites participate in the occurrence and development of the disease.

Background Pivotal studies GS-US-320-0108 (HBeAg-negative) and GS-US-320-0110 (HBeAg-positive), demonstrated non-inferior antiviral efficacy of TAF vs. TDF with superior renal/ bone safety through 5-years, after up to 3 years of doubleblind (

BACKGROUND AND AIMS/OBJECTIVE:Non-Alcoholic Fatty Liver Disease (NAFLD) has become one of the most common causes of chronic liver disease in the pediatric population. Recent advances have been made in developing non-invasive measures for NAFLD assessment. This review presents an analysis of these latest developments and also proposes an algorithm for screening pediatric patients at risk for NAFLD. METHODS:A systematic literature search on PUBMED and EMBASE was conducted. Guidelines for clinical care of pediatric NAFLD were also reviewed. RESULTS:In imaging tests, transient elastography (TE) combined with controlled attenuation parameter (CAP) is a promising, relatively low-cost method offering an intermediate level of accuracy on accessing patient's fibrosis and steatosis in a singular package. Liver biopsy remains the gold standard for diagnosis and/or evaluation of NAFLD, but with our proposed algorithm on utilizing non-invasive testing, the number of liver biopsies required could decrease. The current evidence supports the implementation of TE and CAP in an evaluation algorithm for pediatric NAFLD. CONCLUSIONS:Current data support the use of TE and CAP as a first-line tool in the diagnosis and evaluation of adolescent NAFLD, to better stratify high-risk patients and cut down on the number of liver biopsies needed.