Faculty Bibliography

BACKGROUND:Data on tenofovir alafenamide fumarate (TAF) therapy for preventing mother to child transmission of hepatitis B virus (HBV) are lacking. AIMS/OBJECTIVE:To investigate the efficacy and safety of TAF therapy for preventing hepatitis B mother to child transmission. METHODS:Mothers with chronic HBV infection, positive for hepatitis B e-antigen and with HBV DNA >200 000 IU/mL received TAF for preventing mother to child transmission were enrolled retrospectively from multiple centres with data collection on mother-infant dyads up to postpartum week 24-28. Primary measurements were the mother to child transmission rate and infants' malformation rate. Secondary assessments included maternal HBV DNA reduction at delivery, and maternal or infant adverse events during follow up. RESULTS:Among 71 mothers enrolled, the mean (±SD) age was 30.3 (±2.2) years. TAF therapy was initiated during the second or third trimester and continued to delivery with a mean (±SD) duration of 12.8 (±4.0) weeks. At delivery, 85.9% (61/71) of the mothers achieved HBV DNA <200 000 IU/L. Seventy-three infants (two sets of twins) were born from mothers treated with TAF and none had congenital defects or malformations. All infants received HBV immunoglobulin and vaccine at birth with additional HBV vaccinations at one and six months. At age 24-28 weeks, all infants had negative hepatitis B surface antigen and undetectable levels of HBV DNA (<100 IU/mL). Body weight, height, and head circumferences were comparable to national standards for physical development. No severe adverse effects were reported in either mothers or infants. CONCLUSIONS:TAF for highly viraemic mothers effectively prevented mother to child transmission of hepatitis B. There were no safety concerns for either mothers or infants with 24-28 weeks of follow up.

Little data exists on basal core promoter/precore (BCP/PC) mutations in chronic hepatitis B (CHB) patients at the immune-tolerance (IT) phase. We studied consecutive treatment-naïve, CHBe-antigen (HBeAg) positive patients who had undergone liver biopsy and genotyping. Those in the IT phase or immune-clearance (IC) phase were enrolled for comparison of the frequency of BCP/PC mutations and their clinical presentations. Subgroup analyses for the IT group were also performed between patients with and without mutations, and IC patients between fibrosis stages≤2 vs fibrosis>2.Among 301 patients enrolled, 88/301 (29.24%) and 213/301 (70.76%) were at the IT and IC phase, respectively. The frequency of BCP/PC mutations in IT phase was significantly lower than those in IC phase (15.91% vs 64.79 %, P<0.001). The BCP mutation only was significantly more frequent than the PC mutation in both groups and also in all IC subgroups. IT patients with BCP/PC mutations had significantly higher quantitative anti-HBc levels compared with those of patients with wild-type virus (P<0.05). They also had significantly lower mean levels of alanine transaminase, aspartate transaminase, total bilirubin, and qAnti-HBc compared with those of IC patients (all P<0.05). Additionally, they were significantly younger in mean age; had higher platelet count, higher levels of HBV DNA and surface antigen, as well as higher frequency of genotype B than those of IC patients with fibrosis>2 (all P<0.05). BCP/PC mutations were found in IT patients with CHB. They had distinct clinical characteristics when compared with patients with wild-type or at IC phase. Further studies are needed to understand their natural history and treatment outcomes.

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

OBJECTIVES/OBJECTIVE:Minority patients are under-screened for chronic hepatitis C (CHC) in the USA, and limited data exist for minority patients with advanced fibrosis. METHODS:In this cross-sectional study, CHC patients who were prescribed direct-acting antiviral agents were divided into White patients and minority patient groups. Primary measurements were the mean fibrosis scores and percentages of patients with stage III-IV fibrosis (late presenters) for the two groups. RESULTS:Among the 1421 patients with self-reported ethnicity, 697 were White patients, and 724 were minority patients (484 Hispanic, 175 Black, 65 Asians). Compared to the White, minority patients had significantly higher mean fibrosis score (p < 0.001) and a higher percentage of late presenters (p < 0.001). In subgroup analyses, the mean fibrosis scores for Hispanic, Black and Asian patients were 2.58 ± 1.38, 2.28 ± 1.41 and 2.28 ± 1.40, respectively. CONCLUSIONS:Minority populations with CHC in the USA experience disparities in access to treatment in the early stages of liver fibrosis. Public health strategies are necessitated to address the inequality, as late presenters are at risk of hepatocellular carcinoma.

BACKGROUND:A critical aspect of liver transplantation in hepatitis B patients is to prevent graft reinfection with hepatitis B virus. The use of hepatitis B immune globulin after transplant was a significant milestone, which allowed prolonged graft and patient survival by controlling hepatitis B reinfection in liver grafts. The development of anti-viral treatments with oral nucleos(t)ide analogues, led to a further reduction in graft reinfection and improvement in patient survival. The combination of the aforementioned two therapies has been widely used in hepatitis B-associated liver transplants. AIM/OBJECTIVE:To address the post-transplant management of hepatitis B and provide updates on preventing graft reinfection. METHODS:We performed a literature search on Ovid and PubMed for RCTs or cohort studies in English, which investigated the effectiveness of hepatitis B immune globulin and anti-viral therapy on hepatitis B-associated transplants (1/2000-1/2020). Studies that met pre-established criteria were reviewed. RESULTS:Based on currently available evidence, an algorithm for post-transplant management with anti-viral therapy is proposed. Also, the management of recipients who received grafts from hepatitis B core antibody-positive donors is discussed. CONCLUSIONS:The development of hepatitis B immune globulin and anti-viral treatments led to substantial improvement in graft and patient survival. The prevention of hepatitis B graft reinfection is complex and involves a broad interdisciplinary team.

Background and Aims: Recent studies demonstrate that the population with CHB is aging. Tenofovir alafenamide (TAF) is a first-line treatment for chronic hepatitis B virus infection (CHB), particularly in those at risk for TDF-associated bone and renal effects, including patients with advanced age. We reviewed our experience in the subset of geriatric CHB patients participating in ongoing TAF clinical trials.
Method(s): Included were patients age >=65 y treated with TAF in 3 large Phase 3 trials (pooled analysis of viremic patients naive to TAF in Studies 108 and 110, and suppressed patients switched from TDF to TAF [vs continued TDF] in Study 4018), and data from a single arm Phase 2 study in virally suppressed patients with renal and/or hepatic impairment switched to TAF from TDF and/or other antivirals (Study 4035). Efficacy (HBV DNA >9 or >0 IU/mL) and safety (adverse events [AEs], serious AEs, changes in hip and spine bone mineral density [BMD] and changes in creatinine clearance [eGFRCG]) were assessed for older (>=65 y) vs younger (>5 y) patients. In Studies 108, 110, and 4018, results for TDF in patients >=65 y were also determined for comparison.
Result(s): A total of 124 patients >=65 y were included, representing 6.5% of all enrolled patients. Other than age, decreases in renal/bone parameters, and increased comorbidities, the older and younger groups were generally similar. Efficacy and safety results are summarized in the Table. Rates of virologic suppression was comparable in geriatric vs non-geriatric patients treated with TAF. Overall, AEs and SAEs were similar between older vs younger patients; there were no Grade 3/4 AEs related to study drug in patients >=65 y. Compared with younger patients, declines in eGFRCGand hip/spine BMD were greater in viremic older patients; however, the decreases were less than in older patients on TDF. In suppressed patients, eGFRCGincreases were greater in younger vs older patients receiving TAF, while changes in hip and spine BMD were similar; TDF treatment resulted in declines in BMD and eGFRCG.
Conclusion(s): The efficacy and safety of TAF in geriatric CHB patients were generally similar to younger patients. Small improvements in renal and bone parameters can be seen in older patients switched from TDF to TAF.
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