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Background and Aims: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. Methods: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. Results: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. Conclusions: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB. [ABSTRACT FROM AUTHOR]

Background Few safety and effectiveness results have been published regarding the administration of tenofovir alafenamide fumarate (TAF) during pregnancy for the prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV). Methods In this multicenter prospective observational study, pregnant women with HBV DNA levels higher than 200 000 IU/mL who received TAF or tenofovir disoproxil fumarate (TDF) from gestational weeks 24–35 to delivery were 1:1 enrolled and followed until postpartum month 6. Infants received immunoprophylaxis. The primary endpoint was the safety of mothers and infants. The secondary endpoint was the hepatitis B surface antigen (HBsAg)-positive rate at 7 months for infants. Results In total, 116 and 116 mothers were enrolled, and 117 and 116 infants were born, in the TAF and TDF groups, respectively. TAF was well tolerated during a mean treatment duration of 11.0 weeks. The most common maternal adverse event was nausea (19.0%). One (0.9%), 3 (2.6%), and 9 (7.8%) mothers had abnormal alanine aminotransferase levels at delivery and at postpartum months 3 and 6, respectively. The TDF group had safety profiles that were comparable to those of the TAF group. No infants had birth defects in either group. The infants' physical and neurological development at birth and at 7 months in the TAF group were comparable with those in the TDF group. The HBsAg positive rate was 0% at 7 months in all 233 infants. Conclusions Antiviral prophylaxis with TAF was determined to be generally safe for both mothers and infants and reduced the MTCT rate to 0%. [ABSTRACT FROM AUTHOR]

Background: Liver injuries have been reported in patients with coronavirus disease 2019 (COVID-19). This study aimed to investigate the clinical role played by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Methods: In this multicentre, retrospective study, the parameters of liver function tests in COVID-19 inpatients were compared between various time-points in reference to SARS-CoV-2 shedding, and 3 to 7 days before the first detection of viral shedding was regarded as the reference baseline.Results: In total, 70 COVID-19 inpatients were enrolled. Twenty-two (31.4%) patients had a self-medication history after illness. At baseline, 10 (14.3%), 7 (10%), 9 (12.9%), 2 (2.9%), 15 (21.4%), and 4 (5.7%) patients already had abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), albumin, and total bilirubin (TBIL) values, respectively. ALT and AST abnormal rates and levels did not show any significant dynamic changes during the full period of viral shedding (all p > 0.05). The GGT abnormal rate (p = 0.008) and level (p = 0.033) significantly increased on day 10 of viral shedding. Meanwhile, no simultaneous significant increases in abnormal ALP rates and levels were observed. TBIL abnormal rates and levels significantly increased on days 1 and 5 of viral shedding (all p < 0.05). Albumin abnormal decrease rates increased, and levels decreased consistently from baseline to SARS-CoV-2 clearance day (all p < 0.05). Thirteen (18.6%) patients had chronic liver disease, two of whom died. The ALT and AST abnormal rates and levels did not increase in patients with chronic liver disease during SARS-CoV-2 shedding.Conclusions: SARS-CoV-2 does not directly lead to elevations in ALT and AST but may result in elevations in GGT and TBIL; albumin decreased extraordinarily even when SARS-CoV-2 shedding ended. [ABSTRACT FROM AUTHOR]

Currently, COVID‐19 has been reported in nearly all countries globally. To date, little is known about the viral shedding duration, clinical course and treatment efficacy of COVID‐19 near Hubei Province, China. This multicentre, retrospective study was performed in 12 hospitals in Henan and Shaanxi Provinces from 20 January to 8 February 2020. Clinical outcomes were followed up until 26 March 2020. The viral shedding duration, full clinical course and treatment efficacy were analysed in different subgroups of patients. A total of 149 COVID‐19 patients were enrolled. The median age was 42 years, and 61.1% (91) were males. Of them, 133 (89.3%) had fever, 131 of 144 (91%) had pneumonia, 27 (18.1%) required intensive care unit (ICU) management, 3 (2%) were pregnant, and 3 (2%) died. Two premature newborns were negative for SARS‐CoV‐2. In total, the median SARS‐CoV‐2 shedding period and clinical course were 12 (IQR: 9–17; mean: 13.4, 95% CI: 12.5, 14.2) and 20 (IQR: 16–24; mean: 21.2, 95% CI: 20.1, 22.3) days, respectively, and ICU patients had longer median viral shedding periods (21 [17–24] versus 11 [9–15]) and clinical courses (30 [22–33] vs. 19 [15.8–22]) than non‐ICU patients (both p <.0001). SARS‐CoV‐2 clearances occurred at least 2 days before fatality in 3 non‐survivors. Current treatment with any anti‐viral agent or combination did not present the benefit of shortening viral shedding period and clinical course (all p >.05) in real‐life settings. In conclusion, the viral shedding duration and clinical course in Henan and Shaanxi Provinces were shorter than those in Hubei Province, and current anti‐viral therapies were ineffective for shortening viral shedding duration and clinical course in real‐world settings. These findings expand our knowledge of the SARS‐CoV‐2 infection and may be helpful for management of the epidemic outbreak of COVID‐19 worldwide. Further studies concerning effective anti‐viral agents and vaccines are urgently needed. [ABSTRACT FROM AUTHOR]

Currently, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been reported in almost all countries globally. No effective therapy has been documented for COVID-19, and the role of convalescent plasma therapy is unknown. In the current study, 6 patients with COVID-19 and respiratory failure received convalescent plasma a median of 21.5 days after viral shedding was first detected, all tested negative for SARS-CoV-2 RNA within 3 days after infusion, and 5 eventually died. In conclusion, convalescent plasma treatment can end SARS-CoV-2 shedding but cannot reduce the mortality rate in critically ill patients with end-stage COVID-19, and treatment should be initiated earlier. [ABSTRACT FROM AUTHOR]

Currently, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been reported in almost all countries globally. No effective therapy has been documented for COVID-19, and the role of convalescent plasma therapy is unknown. In the current study, 6 patients with COVID-19 and respiratory failure received convalescent plasma a median of 21.5 days after viral shedding was first detected, all tested negative for SARS-CoV-2 RNA within 3 days after infusion, and 5 eventually died. In conclusion, convalescent plasma treatment can end SARS-CoV-2 shedding but cannot reduce the mortality rate in critically ill patients with end-stage COVID-19, and treatment should be initiated earlier. [ABSTRACT FROM AUTHOR]

Background None of the current guidelines recommend antiviral therapy for inactive hepatitis B virus (HBV) carriers (IHCs). Methods In this real-world, multicenter, nonrandomized study, 32 participants meeting the inclusion criteria were enrolled 1:1 for treatment with peginterferon α-2b or monitoring without treatment based on participant preference. The expected treatment duration was 48 weeks. The primary end point was hepatitis B surface antigen (HBsAg) loss. The HBV vaccine could be injected after HBsAg loss. Results All patients had HBsAg levels of <20 IU/mL. The mean baseline HBsAg levels were 6.6 IU/mL and 5.8 IU/mL in the treated and untreated groups, respectively. Fifteen (93.8%) participants achieved HBsAg loss, 5 obtained HBsAg seroconversion after undergoing a mean of 19.7 weeks of therapy in the treated group, and no one in the follow-up group achieved HBsAg loss during a mean follow-up time of 12.6 months (P <.0001). Generally, the therapy was well tolerated. Nine of 11 individuals who exhibited HBsAg loss benefited from receiving the HBV vaccine. Conclusions This study provides justification for further studies of short-course peginterferon α-2b for the functional cure of IHCs with low HBsAg levels. Additionally, HBV vaccine injection is beneficial after interferon-induced HBsAg loss. [ABSTRACT FROM AUTHOR]

Background & Aims Few patients from developing countries can afford brand name direct-acting antiviral agents for treating hepatitis C virus (HCV) infection, and controversy regarding the bioequivalence of generics exists. This study aimed to observe the safety and efficacy of 8 or 12 weeks of generic ledipasvir-sofosbuvir with or without ribavirin for Chinese genotype 1b HCV-infected patients. Methods In this open-labelled observational study, 63 cirrhotic (group 1) and 65 non-cirrhotic (group 2) patients were administered generic ledipasvir-sofosbuvir plus 1000–1200 mg of ribavirin daily for 12 and 8 weeks, respectively; and 64 non-cirrhotic patients (group 3) received ledipasvir-sofosbuvir for 8 weeks. The primary efficacy endpoint was undetectable HCV RNA at week 12 (SVR12) after cessation of therapy. Safety and pharmacokinetic data were collected. Results One hundred and eighty-seven patients completed treatment, and the latest undetectable HCV RNA was observed in three patients with cirrhosis at week 5 during treatment. Intention-to-treat analysis revealed 96.8% (61/63), 96.9% (63/65), and 96.9% (62/64) of SVR12 rates in groups 1, 2, and 3, respectively. One patient in group 3 relapsed at post-treatment week 4. The regimens were generally well-tolerated. The most common adverse events were fatigue (17.8%), diarrhea (10.9%), and headache (9.9%). Four patients discontinued therapy due to diarrhea and vomiting. One patient from group 2 discontinued treatment on day 29 because of drug-unaffordability; fortunately, she achieved SVR12. Conclusion This study demonstrated that 8 or 12 weeks of generic ledipasvir-sofosbuvir with or without ribavirin are safe and effective for patients with genotype 1b HCV infection. Lay summary The price of Harvoni® has led to restrictions and access limitations in many developing and even developed countries with limited healthcare budgets. Gilead approved generic ledipasvir-sofosbuvir costs far less than Harvoni® and presents a similar cure rate for patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

There are increasing reports of neurological manifestation in children with coronavirus disease 2019 (COVID-19). However, the frequency and clinical outcomes of in hospitalized children infected with the Omicron variant are unknown. The aim of this study was to describe the clinical characteristics, neurological manifestations, and risk factor associated with poor prognosis of hospitalized children suffering from COVID-19 due to the Omicron variant. Participants included children older than 28 days and younger than 18 years. Patients were recruited from December 10, 2022 through January 5, 2023. They were followed up for 30 days. A total of 509 pediatric patients hospitalized with the Omicron variant infection were recruited into the study. Among them, 167 (32.81%) patients had neurological manifestations. The most common manifestations were febrile convulsions (n = 90, 53.89%), viral encephalitis (n = 34, 20.36%), epilepsy (n = 23, 13.77%), hypoxic-ischemic encephalopathy (n = 9, 5.39%), and acute necrotizing encephalopathy (n = 6, 3.59%). At discharge, 92.81% of patients had a good prognosis according to the Glasgow Outcome Scale (scores ≥ 4). However, 7.19% had a poor prognosis. Eight patients died during the follow-up period with a cumulative 30-day mortality rate of 4.8% (95% confidence interval (CI) 1.5–8.1). Multivariate analysis revealed that albumin (odds ratio 0.711, 95% CI 0.556–0.910) and creatine kinase MB (CK-MB) levels (odds ratio 1.033, 95% CI 1.004–1.063) were independent risk factors of poor prognosis due to neurological manifestations. The area under the curve for the prediction of poor prognosis with albumin and CK-MB was 0.915 (95%CI 0.799–1.000), indicating that these factors can accurately predict a poor prognosis. Conclusion: In this study, 32.8% of hospitalized children suffering from COVID-19 due to the Omicron variant infection experienced neurological manifestations. Baseline albumin and CK-MB levels could accurately predict poor prognosis in this patient population. What is Known: • Neurological injury has been reported in SARS-CoV-2 infection; compared with other strains, the Omicron strain is more likely to cause neurological manifestations in adults. • Neurologic injury in adults such as cerebral hemorrhage and epilepsy has been reported in patients with Omicron variant infection. What is New: • One-third hospitalized children with Omicron infection experience neurological manifestations, including central nervous system manifestations and peripheral nervous system manifestations. • Albumin and CK-MB combined can accurately predict poor prognosis (AUC 0.915), and the 30-day mortality rate of children with Omicron variant infection and neurological manifestations was 4.8%. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to articles "Unexpected early tumor recurrence in patients with hepatitis C virus -related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution," by M. Reig, Z. Marino, and C. Perello in the 2016 issue and "Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with SVR following IFN-free DAA treatment," by K. Kozbial, S. Moser, and R. Schwarzer in the 2016 issue.

Background: CCL22 played critical roles in Tregs recruitment. The upstream regulators modulating CCL22 in hepatocellular carcinoma (HCC) were not clearly understood. Methods: MiR‐23a, p‐p65, p65, CCL22, and Foxp3 levels were monitored by RT‐qPCR and western blotting. Immunofluorescence assay was used to perform the costaining of Foxp3 and CD4 on liver tissues. Transwell assay was applied to evaluate the migration ability of Tregs. Dual‐luciferase assay was performed to determine relationship of miR‐23a/CCL22 and p65/miR‐23a. Chromatin immunoprecipitation (ChIP) was applied to detect the direct binding of p65 to miR‐23a promoter. Xenograft tumor models were developed to investigate the functions of p65 and miR‐23a in vivo. Results: HBV infection was associated with reduced survival and increased Tregs recruitment in HCC patients. MiR‐23a was decreased, whereas p65, CCL22, and Foxp3 were increased in HBV+ tumors. MiR‐23a was inversely correlated with CCL22 and Foxp3 expression in HCC. MiR‐23a directly targeted CCL22 3'UTR, leading to CCL22 reduction and attenuated Tregs recruitment. Meanwhile, p65 functioned as a transcription repressor of miR‐23a by directly binding to its promoter. Inhibition of p65 induced miR‐23 expression, leading to less CCL22 expression and Tregs recruitment in vitro. CCL22 was the indispensable effector underlying p65/miR‐23a axis and Tregs recruitment. MiR‐23a inhibitor promoted xenografted tumor growth accompanying with upregulation of CCL22, whereas p65 inhibition exerted opposite effects. Conclusion: Blockage of p65 disinhibited miR‐23a expression, leading to CCL22 reduction and repress Tregs recruitment. Targeting p65/miR‐23a/CCL22 axis was a novel approach for HBV+ HCC treatment. [ABSTRACT FROM AUTHOR]

Background and aim Acute liver failure (ALF) is an uncommon but serious disease still carrying a high mortality. This study aimed to investigate the mechanism of AMPK on D-GalN/LPS-induced ALF. Methods In this study, we utilized intraperitoneal injection of D-GalN/LPS to induce ALF model, and analyzed the expression of AMPK, inflammatory cytokines (TNF-α, IL-1β and IL-6), Foxo3A and autophagy-related genes (Atg-5, Beclin-1, Atg-7) by real-time quantitative polymerase chain reaction (RT-PCR) in liver tissue. We also examined the level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of ALF mice. AMPK activation and inhibition of autophagy were induced by AICAR and 3-MA, respectively. Silence and overexpression of Foxo3A were performed by si-Foxo3A and pcDNA-Foxo3A, respectively. Lastly, the BMDM-conditioned medium (BMDM-CM) derived from BMDMs treated with AICAR and LPS were used to explore the effect of AMPK and Foxo3A on hepatocytes. Result The expression of AMPK was decreased in liver tissue and the level of ALT and AST were increased in serum of D-GalN/LPS-induced ALF mice. AMPK activation ameliorated ALF by inhibiting inflammation (downregulated TNF-α, IL-1β and IL-6 expression), activating autophagy (increased Atg-5, Beclin-1 and Atg-7 expression) and upregulating Foxo3A expression. Silence of Foxo3A decreased AMPK-activated autophagy, but overexpressing Foxo3A attenuated liver failure by activating autophagy. In addition, AMPK activation alleviated liver failure in vitro. Conclusion Thus, AMPK/Foxo3A/autophagy pathway may be an effective treatment approach to ameliorate ALF. [ABSTRACT FROM AUTHOR]

Aim Interleukin-21 ( IL-21) is involved in effective primary hepatic immune response against hepatitis B virus ( HBV) and profibrotic function. However, the role of IL-21 in HBV-associated liver cirrhosis is poorly understood. This study aimed to investigate the role of IL-21 in HBV-associated liver cirrhosis and possible mechanisms. Methods The study subjects included 10 healthy controls and 30 patients with HBV-associated liver cirrhosis that categorized into three subgroups based on Child- Pugh score ( A, 13; B, 10; C, 7). The frequencies of IL-21+ CD4+ T cells were detected by flow cytometry, and the level of IL-21 in plasma was measured by enzyme-linked immunoassay. The distribution of IL-21+ cells in situ in liver was observed by immunohistochemistry. In addition, the in vitro expression of α-smooth muscle actin (α- SMA), apoptosis and proliferation markers of LX-2 cells were examined by flow cytometry and Cell Counting Kit-8 kit. Finally, the collagen levels in the supernatant were measured by chemiluminescence. Results Increased peripheral number of IL-21+ CD4+ cells, elevated plasma level of IL-21 and IL-21+ cell accumulation in liver were observed in patients with HBV-associated liver cirrhosis. In vitro administration of IL-21 was accompanied with increased expression of α- SMA, inhibited LX-2 cells apoptosis and upregulated collagen production by LX-2 cells. Conclusion IL-21 may contribute to the fibrogenesis of HBV-associated liver cirrhosis by activating the hepatic stellate cells. Therefore, neutralization of IL-21 could be a favorable new therapeutic strategy for liver cirrhosis treatment. [ABSTRACT FROM AUTHOR]

Interleukin-21 (IL-21)+CD4+ T cells are involved in the immune response against hepatitis B virus (HBV) by secreting IL-21. However, the role of IL-21+CD4+ T cells in the immune response against chronic hepatitis C (CHC) virus infection is poorly understood. This study aimed to investigate the role of IL-21+CD4+ T cells in CHC patients and the potential mechanisms. The study subjects included nineteen CHC patients who were grouped by viral load (low, < 10 RNA copies/ml, n = 8; high, > 10 RNA copies/ml, n = 11). The peripheral frequency of HCV-specific IL-21+CD4+ T cells was higher in the low viral load group and was negatively correlated with the serum HCV RNA viral load in all CHC patients. Meanwhile, IL-21+ cells accumulated in the liver in the low viral load group. In vitro, IL-21 treatment increased the expression of proliferation markers and cytolytic molecules on HCV-specific CD8+ T cells. In summary, these findings suggest that HCV-specific IL-21+CD4+ T cells might contribute to HCV control by rescuing HCV-specific CD8+ T cells in CHC patients. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐17A is pro‐inflammatory cytokine which has been identified as a noninvasive marker of the pathogenesis of non‐alcoholic steatohepatitis (NASH). However, the underlying role of IL‐17A in NASH progression remains unclear. This study was designed to investigate the biological function and molecular mechanism of IL‐17A in the induction of NASH. The results showed that IL‐17A was highly expressed in high‐fat diet (HFD)‐induced NASH mouse model. Intravenous injection of IL‐17A exacerbated steatohepatitis process via promoting hepatocyte apoptosis. Furthermore, IL‐17A‐induced apoptosis was mediated by ERK1/2/p65 signaling pathway. In conclusion, we demonstrated that IL‐17A‐mediated ERK1/2/p65 signaling pathway was a promising target for the treatment of NASH. © 2018 IUBMB Life, 71(3):302–309, 2019 [ABSTRACT FROM AUTHOR]