Optimization of Mother-to-Child Hepatitis B Virus Prevention Program: Integration of Maternal Screening and Infant Post-vaccination Serologic Testing.

BACKGROUND: Evaluation of the impact on mother-to-child transmission (MTCT) of a HBV-prevention program that incorporates maternal antiviral prophylaxis is hindered by the limited availability of real-world data. METHODS: This study analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for HBsAg among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 01/01/2008-31/12/2022. Through linkage with the National Health Insurance Database, information of maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies. RESULTS: Totally, 2,460,218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and HBeAg seropositivity rates among native pregnant women aged 15-49 years decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (p for both trends < 0.0001). Among the 22,859 at-risk infants undergoing PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; p < 0.001). The MTCT rate was 1.72% (11/641) for infants born to HBeAg-positive mothers with antiviral prophylaxis. MTCT risk increased with maternal HBeAg-positivity (OR 9.29, 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR 0.28, 0.16-0.49). For infants with maternal HBeAg-positivity, MTCT risk was associated with mothers born in the immunization era (OR 1.40, 1.17-1.67). CONCLUSIONS: MTCT was related to maternal HBeAg-positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk.

CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection.

Background & Aim: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between CTLA-4 genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection. Methods: We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the CTLA-4 gene single nucleotide polymorphisms rs4553808 (-A1661G)/rs5742909 (-C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort. Results: CTLA-4 promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the CTLA-4 AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; p = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 vs. 0.03 log10 IU/ml/year, p = 0.02). The CTLA-4 AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (p = 0.01). Conclusions: Chronic HBV-infected patients with a CTLA-4 AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion. Impact and implications: The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that CTLA-4 haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.

Tenofovir alafenamide or tenofovir disoproxil fumarate in pregnancy to prevent HBV transmission: Maternal ALT trajectory and infant outcomes.

BACKGROUND: The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother-to-child HBV transmission is a key step towards hepatitis elimination. However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation. METHODS: The maternal and infant outcomes were compared in multi-centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow-ups. To explore the dynamic pre- and postpartum changes in ALT levels, we used a group-based trajectory model for analysing data of 332 women from three prospective studies. RESULTS: After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg-positive rates among 12-month-old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF-treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%). CONCLUSIONS: TAF effectively reduces mother-to-child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment. CLINICAL TRIAL NUMBER: NCT03695029 (ClinicalTrials.gov).

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

The magnetic resonance imaging and age-adjusted matrix metalloproteinase-7 assist the diagnosis of biliary atresia.

BACKGROUND: We investigated the utilities of the liver-to-psoas apparent diffusion coefficient ratios (LTPAR) yielded by diffusion-weighted magnetic resonance imaging (DWMRI) and the age-adjusted serum matrix metalloproteinase-7 (MMP-7) for the diagnosis of biliary atresia (BA) in cholestatic infants. METHODS: In total, 170 cholestatic infants were recruited, of whom 50 (29.41%) were diagnosed with BA after cholestatic workups. The LTPAR and MMP7 levels were assessed. RESULTS: The LTPAR was significantly lower in BA infants, and the age-adjusted MMP7 ratio was significantly higher, compared to other cholestatic infants (both p < 0.001). Receiver operating characteristic curve analysis yielded a cutoff > 0.1 ng/mL.day for the age-adjusted MMP-7 ratio, and an LTPAR < 1.01 for the optimal prediction of BA (both p < 0.001). Univariate logistic regression analysis revealed that both an age-adjusted MMP-7 ratio > 0.1 ng/mL.day and an LTPAR < 1.01 were significant predictors of BA among cholestatic infants (odds ratio = 30.98 and 13.28; p < 0.001 and < 0.001, respectively). The significance of the age-adjusted MMP-7 ratio and the LTPAR persisted on multivariate logistic regression analysis after adjusting for sex and the serum gamma-glutamyl transferase level (p < 0.001 and < 0.001, respectively). The negative predictive values (NPVs) for BA were 91.49% and 94.17%, respectively, for the LTPAR and age-adjusted MMP-7 ratio. CONCLUSION: The age-adjusted MMP-7 ratio and the LTPAR are both significant non-invasive predictors of BA. The consideration of both serum and imaging parameters may enhance BA diagnostic performance in cholestatic infants.

Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B.

BACKGROUND & AIMS: A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB. METHODS: To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. RESULTS: Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination. CONCLUSIONS: R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.

Increasing Trend and Effects of Pediatric Palliative Care on Children With Noncancer Diagnoses.

OBJECTIVES: Pediatric palliative care (PPC), especially among noncancer pediatric patients, faces challenges including late referral, limited patient care, and insufficient data for Asian patients. METHODS: This retrospective cohort study used the integrative hospital medical database between 2014 and 2018 to analyze the clinical characteristics, diagnoses, and end-of-life care for patients aged less than 20 who had died in our children's hospital, a tertiary referral medical center implementing PPC shared-care. RESULTS: In our cohort of 323 children, 240 (74.3%) were noncancer patients who a younger median age at death (5 vs. 122 months, P < 0.001), lower rate of PPC involvement (16.7 vs. 66%, P < 0.001), and fewer survival days after PPC consult compared to cancer patients (3 vs. 11, P = 0.01). Patients not receiving PPC had more ventilator support (OR 9.9, P < 0.001), and less morphine use on their final day of life (OR 0.1, P < 0.001). Also, patients not receiving PPC had more cardiopulmonary resuscitation on the last day of life (OR 15.3, P < 0.001) and died in the ICU (OR 8.8, P < 0.001). There was an increasing trend of noncancer patients receiving PPC between 2014 and 2018 (P < 0.001). CONCLUSIONS: High disparities exist between children receiving PPC in cancer versus noncancer patients. The concept of PPC is gradually becoming accepted in noncancer children and is associated with more pain-relief medication and less suffering during end-of-life care.

The prognosis of citrin deficiency differs between early-identified newborn and later-onset symptomatic infants.

BACKGROUND: The prognosis for patients with citrin deficiency is not always benign. This study examined the differences between patients identified early by newborn screening and patients identified later with cholestasis/hepatitis. MATERIALS AND METHODS: This retrospective study included 42 patients with genetically confirmed SLC25A13 mutations who were born between May 1996 and August 2019. Fifteen patients were identified during newborn screening (NBS group) and 27 patients were identified through the onset of cholestasis/hepatitis in infancy (clinical group). RESULTS: Overall, 90% of the patients presented with cholestasis, among whom 86% (31/36) recovered at a median age of 174 days. Compared with patients in the clinical group, patients in the NBS group were significantly younger at diagnosis and at cholestasis-free achievement; they also had significantly lower levels of peak direct bilirubin and liver enzymes. At the median follow-up age of 11.8 years, 21% of the patients had dyslipidemia, whereas 36% of the patients had failure to thrive. The overall mortality rate was 2.4%. Variant c.851_854del was the most frequent, constituting 44% of the mutant alleles. CONCLUSION: Patients identified early by NBS had a better prognosis, demonstrating the importance of a timely diagnosis of NICCD and the need for careful follow-up. IMPACT: Some cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) are not benign. Compared with patients identified later based on the presence of cholestasis/hepatitis, patients identified early by newborn screening have less severe cholestasis and are cholestasis-free at a significantly younger age. A timely diagnosis is needed, along with follow-up examinations that assess metabolic profile and body weight, to improve the long-term prognosis of NICCD patients.

Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases.

OBJECTIVES: To determine how advanced genetic analysis methods may help in clinical diagnosis. STUDY DESIGN: We report a combined genetic diagnosis approach for patients with clinical suspicion of genetic liver diseases in a tertiary referral center, using tools either tier 1: Sanger sequencing on SLC2SA13, ATP8B1, ABCB11, ABCB4, and JAG1 genes, tier 2: panel-based next generation sequencing (NGS), or tier 3: whole-exome sequencing (WES) analysis. RESULTS: In a total of 374 patients undergoing genetic analysis, 175 patients received tier 1 Sanger sequencing based on phenotypic suspicion, and pathogenic variants were identified in 38 patients (21.7%). Tier 2 included 216 patients (39 of tier 1-negative patients) who received panel-based NGS, and pathogenic variants were identified in 60 (27.8%). In tier 3, 41 patients received WES analysis, and 20 (48.8%) obtained genetic diagnosis. Pathogenic variants were detected in 6 of 19 (31.6%) who tested negative in tier 2, and a greater detection rate in 14 of 22 (63.6%) patients with deteriorating/multiorgan disease receiving one-step WES (P = .041). The overall disease spectrum is comprised of 35 genetic defects; 90% of genes belong to the functional categories of small molecule metabolism, ciliopathy, bile duct development, and membrane transport. Only 13 (37%) genetic diseases were detected in more than 2 families. A hypothetical approach using a small panel-based NGS can serve as the first tier with diagnostic yield of 27.8% (98/352). CONCLUSIONS: NGS based genetic test using a combined panel-WES approach is efficient for the diagnosis of the highly diverse genetic liver diseases.

A Pilot Study of Biliary Atresia Newborn Screening Using Dried Blood Spot Matrix Metalloproteinase-7.

OBJECTIVES: Timely diagnosis is a critical challenge and is associated with improved survival of biliary atresia (BA) patients. We aimed to measure matrix metalloproteinase-7 (MMP-7) levels in BA patients within 3 days of birth using the dried blood spot (DBS) method and evaluate its potential as a screening tool. METHODS: The study enrolled 132 patients, including 25 patients diagnosed with BA and 107 non-BA patients with other congenital or perinatal conditions from the National Taiwan University Children Hospital. The stored DBS samples collected from 48 to 72 hours of life were retrieved from newborn screening centers. MMP-7 on the DBS was quantified using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The MMP-7 levels of BA patients on the DBS were significantly higher than those of non-BA patients (19.2 ± 10.4 vs 5.6 ± 2.7 ng/mL, P value < 0.0001). MMP-7 levels in non-BA patients, including 5 patients with hepatobiliary structural anomaly, 9 patients with intrahepatic cholestasis, and 93 patients with other perinatal diseases, were 11.6 ± 4.2 ng/mL, 6.9 ± 3.0 ng/mL, and 5.2 ± 2.1 ng/mL, respectively. The DBS MMP-7 level showed good accuracy for identifying BA, with an area under the curve of 93.7% [95% confidence interval (CI): 87.7%-99.7%]. The MMP-7 cutoff at 8.0 ng/mL showed a sensitivity of 92.0% (95% CI: 75.0%-98.6%) and specificity of 92.5% (95% CI: 85.9%-96.1%) for detecting BA from other congenital or perinatal diseases. CONCLUSIONS: MMP-7 DBS analysis can be used to distinguish BA from other conditions as early as 3 days of age.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

OBJECTIVE: aaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. METHODS: aaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. RESULTS: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. CONCLUSION: aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

SLCO1B1 and SLCO1B3 genetic mutations in Taiwanese patients with Rotor syndrome.

Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both SLCO1B1 and SLCO1B3 genes, causing defective OATP1B1 and OATP1B3 in the sinusoidal membrane and interrupted bilirubin uptake of the hepatocytes. We report five Taiwanese pediatric and adult patients aged 5-32 years presenting with conjugated hyperbilirubinemia, and were found to have genetic variants of SLCO1B1 and SLCO1B3. Two also had history of prolonged neonatal jaundice. Genetic analysis using panel-based next generation sequencing revealed three patients with homozygous mutations c.1738C>T (p.R580∗) in SLCO1B1 and a transposon LINE-1 insertion in SLCO1B3, one patient with homozygous mutations for another haplotype, c.757C>T (p.R253∗) in SLCO1B1 and c.1747+1G>A in SLCO1B3. Another patient had heterozygous c.1738C>T (p.R580∗) in SLCO1B1 linked with a LINE-1 insertion in SLCO1B3, and heterozygous c.757C>T (p.R253∗) in SLCO1B1 linked with c.1747+1G>A in SLCO1B3. In conclusion, we present the first time of genetic diagnosis of Rotor syndrome in Taiwan. Advanced genetic testing has enhanced the diagnosis of rare diseases with mild symptoms.

The Moderated Mediating Effects of Nutrition and Physical Activity Between Fatigue and Quality of Life in Childhood Cancer Survivors.

PURPOSE: The aim of this study was to investigate the associations between nutrition, physical activity, fatigue, and quality of life (QoL) among childhood cancer survivors. The specific purpose was to examine whether nutrition mediated and physical activity moderated the relationship between fatigue and QoL in this population. METHODS: A pooled sample of 120 childhood cancer survivors was recruited at pediatric oncology wards and ambulatory settings between August 2020 and May 2021. We collected data on participants' demographic characteristics, fatigue, nutritional status, physical activity, and QoL. We then adapted Hayes Process Macro to examine the mediating and moderating effects of nutrition and physical activity on the relationship between fatigue and QoL. RESULTS: In models adjusted for age and sex, (1) the simple mediation analysis identified the mediating effect of nutrition on the relationship between fatigue and QoL; and (2) the mediation and moderation analysis identified that the direct effect of nutrition between fatigue and QoL was significant when adding (a) physical activity and (b) fatigue × physical activity. There were significantly decreasing trends in physical activity at 1 standard deviation below the mean and at the mean, but not at 1 standard deviation above the mean. CONCLUSIONS: Our findings demonstrate that nutrition mediated and physical activity moderated the relationship between fatigue and QoL. This highlights an opportunity to enhance QoL among childhood cancer survivors through healthy lifestyle interventions. To ensure that future interventions address children's needs and promote the greatest impact, such interventions should include nutrition and physical activity components that involve nurses, pediatric oncology physicians, nutritionists, and physical therapists.

The effects of job characteristics on physicians' orientation toward lifelong learning.

With the rapidly growing body of medical knowledge, physicians must engage in lifelong learning. Physicians' orientation toward lifelong learning is of crucial importance. This study aimed to explore the effects of job characteristics on physicians' lifelong learning. A multicenter study collecting data from physicians from three medical centers in Taiwan was performed. A total of 321 physicians were surveyed with the Chinese version of the Job Content Questionnaire (C-JCQ) and the revised Jefferson Scale of Physician Lifelong Learning (JeffSPLL) to assess their job characteristics (i.e., job demands, job control, social support) and orientation toward lifelong learning. Exploratory factor analysis was employed to validate both questionnaires. Hierarchical regression was utilized to explore the relationship of job characteristics and predictors with physicians' lifelong learning. The results revealed that job demands (ß = 0.10), job control (ß = 0.19), social support from supervisors (ß = 0.16), the interaction of job demands × job control (ß = - 0.11) and the interaction of job demands × social support from colleagues (ß = 0.13) were significantly (p < .05, p < .001) related to lifelong learning. Moreover, physicians in the active group (high demand, high control) possessed a stronger orientation toward lifelong learning (mean = 3.57) than those in the low-strain group (mean = 3.42), high-strain group (mean = 3.39) and passive group (mean = 3.20). In conclusion, examining physicians' job demands, job control and social support helps us to understand their orientation toward lifelong learning and may provide insight to improve educational strategies.

Baseline Hepatitis B Virus Surface Antigen Titers in Childhood Predict the Risk of Advanced Liver Fibrosis in Adulthood.

BACKGROUND & AIMS: Hepatitis B virus (HBV) surface antigen (HBsAg) is a marker of both HBV covalently closed circular DNA and integrated HBV genome, whereas the HBV core-related antigen (HBcrAg) indicates the transcriptional activity of covalently closed circular DNA. This study examined the relationship between HBsAg and HBcrAg titers in childhood and advanced fibrosis in adulthood. METHODS: We recruited 214 initially hepatitis B e antigen-positive chronic HBV-infected patients who were followed for a total of 6371 person-years. None of the patients were co-infected with hepatitis C or D virus. Serum HBsAg and HBcrAg titers were assessed at 10 and 15 years of age. Transient elastography was performed at a mean final age of 38.21 years to identify advanced fibrosis. RESULTS: Patients with advanced fibrosis in adulthood had a higher rate of genotype C HBV infection and a higher HBsAg titer at 10 and 15 years of age (P = .003, P = .03, and P = .005, respectively). The HBcrAg titer was not correlated with advanced fibrosis (P > .05). Receiver operating characteristic curve analysis showed that HBsAg cutoffs of >4.23 and >4.44 log10 IU/mL at 10 and 15 years of age, respectively, best predicted advanced fibrosis in the fourth decade of life (P = .001 and P < .001, respectively). In a multivariate analysis, both an HBsAg titer >4.44 log10 IU/mL at 15 years of age and HBV genotype C were predictors of advanced fibrosis (odds ratios, 15.43 and 4.77; P = .01 and P = .02, respectively). CONCLUSIONS: HBsAg titers in childhood predict the progression to liver fibrosis in adulthood.

Characterization of Hepatitis B Virus in Tenofovir-Treated and Untreated Chronically Infected Mothers and Their Immunoprophylaxis Failure Infants.

BACKGROUND: Maternal tenofovir disoproxil fumarate (TDF) therapy during late pregnancy can reduce mother-to-infant transmission of hepatitis B virus (HBV). We investigated HBV mutations associated with maternal TDF therapy and their role in infant immunonophylaxis failure (IPF). METHODS: Serum samples from untreated (n = 89) and TDF-treated (n = 68), highly viremic, chronically infected mothers and their infants were analyzed for HBV DNA by nested polymerase chain reaction (PCR) and direct sequencing. RESULTS: At delivery, compared with untreated mothers, TDF-treated mothers had a lower HBV DNA titer and a higher frequency of basal core promoter (BCP) gene mutations, but they had similar frequencies in pre-S/S and pre-core/core mutations. The 14 mothers harboring surface "a" determinant mutants did not transmit the mutants to their immunized infants. Such mutants were found in 3 of 13 IPF infants; the 13 mothers had wild-type hepatitis B surface antigen (HBsAg). In univariable analysis, maternal HBV DNA titer (odds ratio [OR]: 1.54; 95% confidence intervals [CI]: 1.02-2.33; P = .039), genotype C (OR: 4.18; 95% CI: 1.28-13.62; P = .018) and pre-S1 wild-type sequence (OR: 6.33; 95% CI: 1.85-21.68; P = .003) at delivery were associated with infant IPF. Multivariable analyses showed that maternal genotype C (OR: 3.71; 95% CI: 1.11-12.36; P = .033) and pre-S1 wild-type (OR: 6.34; 95% CI: 1.79-22.44; P = .004) were associated with infant IPF independently of maternal viremia. CONCLUSIONS: Along with high maternal HBV DNA titer at delivery, maternal genotype C and pre-S1 wild-type sequence were potential risk factors for infant IPF, although BCP mutations were not. The offspring of pregnant women harboring "a" determinant mutants as major strains seemed to be protected by immunoprophylaxis. CLINICAL TRIALS REGISTRATION: NCT01312012.

Different clinical and genetic features of Alagille patients with progressive disease versus a jaundice-free course.

Background and Aim: Alagille syndrome (ALGS) is a multisystem disorder with variable clinical courses. This study investigated the clinical and genetic features of ALGS patients with different outcomes and analyzed the liver pathology at liver transplantation (LT) compared with that in biliary atresia (BA). Methods: We report the clinical characteristics, outcomes, and genetic mutations of 25 children with ALGS followed for a median of 7.3 years. Patients were classified into (i) jaundice-free (JF) group (resolving jaundice after 2 years of age); (ii) progressive disease (PD) group (persistent jaundice or progressive cholestasis). In addition, we analyzed the explant liver in 10 ALGS patients compared with 20 age-matched BA patients at the time of LT. Results: Nine patients (36%) in the JF group had a favorable outcome, with longer native liver survival than patients with PD (n = 16, P < 0.001). Fourteen of the PD group patients received LT or died. We identified 18 different JAG1 mutations in 22 patients. Three unrelated probands in the JF group had the same de novo mutation in JAG1, c.2122-2125delCAGT. Compared with BA children, ALGS patients had lower METAVIR scores in liver pathology, higher serum albumin levels, and lower weight-for-age z-scores when receiving LT. Conclusion: One-third of ALGS patients had JF and a favorable course. Children with ALGS presenting with persistent jaundice beyond 2 years of age should be cautioned for poor prognosis. ALGS patients tend to have a lesser extent of cirrhosis, and more growth problems than BA patients at the time of LT.