Faculty Bibliography

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 (

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.

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.

BACKGROUND:Appropriate passive-active immunoprophylaxis effectively reduces mother-to-child transmission (MTCT) of hepatitis B virus (HBV), but the immunoprophylaxis failure was still more than 5% under the current strategy. The study objective was to investigate the effects of high dose of HB vaccine on MTCT and immune response for infants born to hepatitis B surface antigen (HBsAg)-positive mothers. METHODS:This was a prospective, multicenter, large-sample cohort study in four sites of China, and 955 pairs of HBsAg-positive mothers and their infants were enrolled in our investigation. The infants were given 10 μg or 20 μg HB vaccine (at age 0, 1, and 6 months) plus HB immunoglobulin (at age 0 and 1 month). Serum HBsAg, antibody to HBsAg (anti-HBs), and/or HBV DNA levels in the infants were determined at age 12 months. The safety of 20 μg HB vaccine was evaluated by adverse events and observing the growth indexes of infants. RESULTS:IU/mL, 20 μg HB vaccine did not present these above response advantages. The 20 μg HB vaccine showed good safety for infants. CONCLUSIONS:IU/mL. TRIAL REGISTRATION/BACKGROUND:Chinese Clinical Trial Registry, ChiCTR-PRC-09000459.

BACKGROUND & AIMS/OBJECTIVE:Nucleotides with add-on interferon treatment (NUC-IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse. METHODS:Patients with CHB who achieved HBsAg loss and HBV DNA levels <20 IU/ml after IFN or NUC-IFN therapy were enrolled and followed up for 96 weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse. RESULTS:420 patients were included in intention-to-treat analysis with 290 and 130 in the IFN and NUC-IFN groups respectively. At week 96, the intention-to-treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P = .70), viremia (16.90% vs 13.08%, P = .32) and clinical relapse (11.38% vs 10.00%, P = .68); the per-protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC-IFN group (15.25%, 4.24% and 0.85%, P > .05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC-IFN-treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero-reversion and recurrence of viremia in IFN treated group. CONCLUSION/CONCLUSIONS:NUC-IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399).

ABSTRACT/UNASSIGNED:To compare the diagnostic utility of serum markers in nonalcoholic fatty liver disease (NAFLD) patients with chronic hepatitis B (CHB).This study enrolled 118 consecutive biopsy-proven NAFLD patients with or without CHB. Fibrosis scores of each marker were compared against histological fibrosis staging. Receiver operating characteristic curve (ROC) analysis helped assess the accuracy of each marker.In patients with both diseases, 12.96% (7/54) had advanced fibrosis on biopsy and aspartate aminotransferase (AST) to platelet ratio index was the best performing marker for predicting advanced fibrosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the ROC (95% confidence interval) for AST to platelet ratio index (APRI) were 0%, 93.62%, 0%, 86.27%, and 0.676 (0.524-0.828), respectively. The markers ranked as follows from highest to lowest with respect to their accuracy: APRI; BARD; fibrosis-4; and AST to ALT ratio. In patients without CHB, fibrosis-4 was the best performing marker for predicting advanced fibrosis. The sensitivity, specificity, PPV, NPV, and area under the ROC (95% confidence interval) for fibrosis-4 were 77.78%, 85.45%, 46.67%, 95.92%, and 0.862 (0.745-0.978), respectively.Serum markers are less reliable in predicting advanced fibrosis in NAFLD patients with CHB; APRI is the most accurate predictor of the absence of advanced fibrosis.

Background & Aims Fewer data exist on neuro-mental development after fetal exposure to telbivudine. We investigated the developmental consequences of infants from mothers that received telbivudine treatment for chronic hepatitis B (CHB). Methods CHB mothers with high viral load at gestational week 28 were assigned to receive either telbivudine (LdT) or usual care without antiviral therapy, based on the mothers' preference. Their infants were followed for 52 weeks to assess physical and neuro-metal development with Gesell Developmental Schedule tools. Developmental consequences were compared between the two groups. Results Among 258 mothers enrolled, 159 and 99 in the telbivudine-treated and the non-treated group, respectively. The mean duration of telbivudine therapy for the treatment group was 12.31 ± 1.02 weeks. When compared to the control group, infants at the treated-group at the age of 52 weeks had similar neuro-mental development outcomes regarding Gesell Developmental Schedule scores for gross motor (p = 0.55), fine motor (p = 0.31), adaptive (p = 0.10), linguistic (p = 0.97), and personal social (p = 0.52) domains; their physical parameters were also comparable, which included mean height (77.83±3.31 vs. 77.55±3.03 cm; p=0.51) and mean body weight (and 10.59±1.14 vs.10.57±1.19 kg; p=0.89). However, the vertical transmission rates were slightly higher in the control group (3.19% [3/94] vs. 0% [0/150]; p=0.056). Multivariate logistic regression suggested that telbivudine did not associated with negative developmental consequences. Conclusions The developmental consequences of prenatal telbivudine exposure were comparable to those without the exposure in one year observation. We now know that Telbivudine therapy is safe for hepatitis B mothers during pregnancy; ClincialTrials.gov number, NCT02301650.

We primarily quantified exposure patterns, transmission characteristics, and the clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among household contacts of individuals with severe coronavirus disease-2019 (COVID-19). We conducted a retrospective cohort study of 20 index patients hospitalized with severe COVID-19 and 79 of their household contacts. We determined the transmission frequency, range of manifestations of SARS-CoV-2 infection, and factors associated with infection in household settings. Of the 79 household contacts, 53 (67%) developed SARS-CoV-2 infection (49 [62%] symptomatic, 4 [5%] asymptomatic). Eight patients (10%) developed severe COVID-19, and one died of COVID-19 pneumonia (case-fatality rate: 1.9%). The probability of SARS-CoV-2 infection was similar in children and adults (55% vs. 72%, p = .14), with children being less likely to develop the symptomatic disease (46% vs. 68%, p = .06). Handwashing ≥ 5 times/day was associated with reduced infection risk (52.8% vs. 76.9%, p = .04). SARS-CoV-2 has a high frequency of transmission among household contacts. Nonhospitalized individuals with SARS-CoV-2 infection should be quarantined in patient care facilities rather than at home to minimize spread, if possible, and frequent handwashing should be practiced to prevent transmission.

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.