Association of vitamin D with functional cure in chronic hepatitis B: Insights from a retrospective cohort study and an intervention study.

BACKGROUND & AIM: Functional cure for chronic hepatitis B (CHB) patients can be achieved using nucleos(t)ide analogues (NAs) and pegylated interferon alpha (Peg-IFNα) combination treatment. However, the role of vitamin D in functional cure remains unclear. We aimed to investigate the association between vitamin D levels and functional cure in CHB patients. METHODS: A retrospective study was conducted to detect changes in serum 25-hydroxyvitamin D (25(OH)D) levels in 526 CHB patients. Furthermore, an intervention study was conducted on 90 CHB patients with baseline vitamin D insufficiency, and 45 patients were randomly assigned to the control group receiving NAs/Peg-IFNα treatment, whereas the remaining patients were categorized into the vitamin D group (VD group) receiving NAs/Peg-IFNα treatment combined with vitamin D supplementation at 800 IU/day. RESULTS: A retrospective study revealed a progressive elevation in serum 25(OH)D levels throughout the duration of treatment. The cured group displayed significantly higher serum 25(OH)D levels than the uncured group (P = 0.046) at the end of treatment, and the changes in serum 25(OH)D (Δ25(OH)D) levels between the two groups were found to be significantly different (P < 0.0001). In the intervention study, the VD group tended to have an increased functional cure rate (48.0 %) compared with the control group (34.3 %) in the binary logistic regression equation analysis (P = 0.09). Notably, a linear mixed-effects model in the longitudinal analysis indicated a significant impact of serum 25(OH)D levels on treatment outcomes (P = 0.017). CONCLUSIONS: Serum 25(OH)D and Δ25(OH)D were both positively associated with functional cure in this retrospective study, and vitamin D supplementation may be helpful for functional cure in CHB patients. REGISTRATION NUMBER OF CLINICAL TRIAL: ChiCTR1800020108.

Real-world efficacy and safety of dolutegravir plus lamivudine versus tenofovir plus lamivudine and efavirenz in ART-naïve HIV-1-infected adults.

Limited real-world data on dolutegravir (DTG) plus lamivudine (3TC) for HIV-1-infected individuals have been reported. This study aimed to evaluated the real-world efficacy and safety of DTG + 3TC in ART-naïve HIV-1-infected adults in China. This real-world prospective observational cohort study enrolled HIV-1-infected adults receiving ART initiation with DTG + 3TC (D3 group) or tenofovir plus lamivudine and efavirenz (TDF + 3TC + EFV, TLE group) with subgroups of low viral load (LVL, ≤500,000 copies/mL) and high viral load (HVL, >500,000 copies/mL) according to baseline HIV-1 RNA. Efficacy were assessed by proportion of virologic suppression, changes of CD4+ cell count and CD4/CD8 ratio, HIV-1 DNA decay, and safety by symptoms and changes of laboratory indicators at week 4, 12, 24, 36, and 48. Totally 45 participants in D3 group and 95 in TLE group were enrolled. The proportion of HIV RNA < 50 copies/mL were 48.7% (19/39), 84.6% (33/39), 100% (39/39), 100% (39/39) in D3-LVL subgroup at week 4, 12, 24, 48, compared with 1.3% (1/75), 14.7% (11/75), 86.7% (65/75), 96.0% (72/75) in TLE-LVL subgroup, with P < .05 at week 4, 12, and 36. The proportion were 0.0% (0/6), 66.7% (4/6), 83.3% (5/6), 100% (6/6) in D3-HVL subgroup compared with 0.0% (0/20), 5.0% (1/20), 85.0% (17/20), 100% (20/20) in TLE-HVL subgroup, with P < .05 at week 12. No virologic rebound was observed in D3 group. Mean change of CD4/CD8 ratio were higher in D3-LVL versus TLE-LVL subgroup at each scheduled visit (P < .05), while CD4+ cell counts increased significantly in D3-HVL versus TLE-HVL subgroup at week 4 and 12 (P < .05). Less complaint of dizziness, insomnia, dreaminess and amnesia, lower elevated level of triglyceride and higher elevated level of creatinine from baseline to week 48 were documented in D3 group (P < .05). Total HIV-1 DNA decayed along with HIV-1 RNA after DTG + 3TC initiation in both D3-LVL and D3-HVL subgroups. DTG + 3TC achieved virological suppression more rapidly and stably versus TDF + 3TC + EFV in ART-naïve HIV-1-infected adults, with better immunological response and less adverse drug effect, and reduced total HIV-1 DNA effectively. DTG + 3TC is a potent regimen for ART-naïve individuals with HIV-1 infection.

Long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure: a retrospective study.

BACKGROUND: The long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is not well characterised. We assessed long-term outcomes and the associated risk factors of HBV-ACLF patients in southern China. METHODS: We retrospectively analysed clinical data, adverse events, and clinical endpoint events of HBV-ACLF patients treated at our department between January 2014 and December 2018. RESULTS: A total of 616 (52.3%) patients with cirrhosis and 561 (47.7%) patients without cirrhosis were included. In 973 (83%) patients, the disease was associated only with HBV, while 204 (17%) patients had two or more aetiological factors. The proportion of patients receiving antiviral treatment for HBV was low (20.3%). Further analyses indicated that patients without cirrhosis had a significantly lower 90-day liver transplantation-free mortality and higher 5-year survival rate than those with cirrhosis (59.5% vs. 27.6%; 62% vs. 36%; P < 0.05). Remarkably, self-withdrawal of nucleos(t)ide analog (NA) was an independent risk factor for short-term prognosis. Age, cirrhosis at admission, and platelet level were closely related to long-term prognosis of HBV-ACLF patients. CONCLUSION: The proportion of HBV-ACLF patients receiving antiviral treatment is very low in south China. Cirrhosis at admission has a significant effect on both short-term and long-term prognosis. No significant improvement in the short-term prognosis of HBV-ACLF patients was observed compared with previous studies. More comprehensive access to antiviral treatment and long-term surveillance of HBV patients are key imperatives to reduce the incidence of HBV-ACLF and improve the prognosis. Trial Registration The trial was registered at ClinicalTrials.gov (CT.gov identifier: NCT04231565) on May 13, 2020: https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S0009OZY&selectaction=Edit&uid=U00036P1&ts=2&cx=27seqt.

Serum IL-5 levels predict HBsAg seroclearance in patients treated with Nucleos(t)ide analogues combined with pegylated interferon.

Background: Knowing about cytokine profile contributes to clarify the underling immune mechanism of HBsAg seroclearance rate increase. This study aims to investigate cytokine changes during nucleos(t)ide analogues (NAs) and peginterferon-α (Peg-IFNα) therapy and their impact on the HBsAg serologic response. Methods: A total of 78 HBV DNA-negative chronic Hepatitis B (CHB) patients were studied after a lead-in phase of NAs with complete serum cytokines. Serum cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17 and TNF-α) were quantified by flow cytometry (FCM) every 24 weeks, before, during and at the end of NAs and Peg-IFNα treatment. Clinical and laboratory data were also taken at the same time. Analysis was performed between cured and uncured groups characterized by HBsAg seroclearance. PBMCs samples from five patients (two in cured group and three in uncured group) were analyzed by FCM. Results: HBsAg seroclearance was achieved in 30 (38,5%) patients defined as the cured group. In comparison to uncured individuals, cured patients showed similar expressions of serum IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17 and TNF-α during the treatment of NAs and Peg-IFNα. Compared with the uncured groups, IL-5 was remarkably increased in cured patients. IL-5 at weeks 24 and 48 were associated with HBsAg seroconversion (p=0.033 and 0.027, respectively). PBMCs sample analysis confirmed the predicted value of IL-5 in response to NAs and Peg-IFNα treatment. Conclusions: IL-5 at weeks 24 and 48 might be used as a biomarker for HBsAg seroclearance in NAs-experienced CHB patients treated with NAs combined with Peg-IFNα. More importantly, exploiting the expression of this cytokine may help to develop a better understanding of the immune pathogenesis of chronic HBV infection.

Association between the nasopharyngeal microbiome and metabolome in patients with COVID-19.

SARS-CoV-2, the causative agent for COVID-19, infect human mainly via respiratory tract, which is heavily inhabited by local microbiota. However, the interaction between SARS-CoV-2 and nasopharyngeal microbiota, and the association with metabolome has not been well characterized. Here, metabolomic analysis of blood, urine, and nasopharyngeal swabs from a group of COVID-19 and non-COVID-19 patients, and metagenomic analysis of pharyngeal samples were used to identify the key features of COVID-19. Results showed lactic acid, l-proline, and chlorogenic acid methyl ester (CME) were significantly reduced in the sera of COVID-19 patients compared with non-COVID-19 ones. Nasopharyngeal commensal bacteria including Gemella morbillorum, Gemella haemolysans and Leptotrichia hofstadii were notably depleted in the pharynges of COVID-19 patients, while Prevotella histicola, Streptococcus sanguinis, and Veillonella dispar were relatively increased. The abundance of G. haemolysans and L. hofstadii were significantly positively associated with serum CME, which might be an anti-SARS-CoV-2 bacterial metabolite. This study provides important information to explore the linkage between nasopharyngeal microbiota and disease susceptibility. The findings were based on a very limited number of patients enrolled in this study; a larger size of cohort will be appreciated for further investigation.

The relationship between the clearance of HBsAg and the remodeling of B cell subsets in CHB patients treated with Peg-IFN-α.

BACKGROUND: The seroconversion of the hepatitis B antigen is the ideal outcome for long-acting interferon-pegylated interferon-α (Peg-IFN-α) treatment among patients with chronic hepatitis B (CHB). B-cell response plays an important role in the process of hepatitis B antigen clearance, but the specific mechanism by which B-cell improve hepatitis B virus (HBV) is still unclear. METHODS: A total of 103 CHB patients participated in this study. The patients received 24 weeks of Peg-IFN-α treatment. Flow cytometry was used to detect B-cell surface markers' cluster of differentiation cluster of differentiation CD19, CD24, and CD27 in the peripheral blood mononuclear cells (PBMCs) of CHB patients before and after 24 weeks of Peg-IFN-α treatment. RESULTS: After 24 weeks of Peg-IFN-α treatment, the content of memory B cells (CD19+CD27+) and effector B cells (CD19+CD38+) increased significantly. Further analysis showed that the clearance of the hepatitis B antigen was correlated with the change value, ΔT, of plasma cells before and after treatment. The B-cell subsets (CD19+CD24+; CD19+CD40+; CD19+CD40+; CD19+CD80+), was also tested and the results showed that CD19+CD24+ and CD19+CD80+ content also increased significantly after treatment. CONCLUSIONS: After Peg-IFN-α treatment, the B-cell subsets of CHB patients are remodeled. Thus, Peg-IFN-α treatment appears to play an important role in the remodeling of B cell subsets and the clearance of HBV antigens. The results of this study provide a theoretical basis and guidance for the clinical treatment of CHB.

Association between effective hepatic blood flow and the severity and prognosis of hepatitis B virus-related acute on chronic liver failure.

BACKGROUND: Hepatic inflammation resulted in hepatocyte necrosis and microcirculatory dysfunction in acute on chronic liver failure (ACLF) with cirrhosis or not. The influence of effective hepatic blood flow (EHBF) on the severity of liver failure has not been fully elucidated. AIM: The aim of this study was to assess the correlation between the EHBF and the severity and the prediction of 90-day mortality rate of hepatitis B virus-related ACLF (HBV-ACLF). METHODS: In this retrospective study, patients hospitalized for HBV-ACLF or decompensated cirrhosis and who underwent an indocyanine green (ICG) clearance test between June 2016 and July 2018 were enrolled. EHBF was measured by the ICG clearance test and patients were categorized into the ACLF without cirrhosis (HBV-ACLF-no-Cir), ACLF with cirrhosis (HBV-ACLF-Cir) and decompensated cirrhosis (HBV-De-Cir). RESULTS: A total of 522 patients (HBV-ACLF-no-Cir: 84, HBV-ACLF-Cir: 111 and HBV-De-Cir: 327) were enrolled. The mean EHBF in the HBV-De-Cir was significantly higher than that in the HBV-ACLF-no-Cir and HBV-ACLF-Cir (0.36 vs. 0.21 vs. 0.20 L/min, P < 0.001). EHBF was significantly correlated with the total bilirubin, prothrombin activity and model for end-stage liver disease (MELD) in the HBV-ACLF-no-Cir. The predicted 90-day mortality rate using the MELD, EHBF, ICG-retention rate at 15 min (R15%) and EHBF-R15% scores were similar. The sensitivity and specificity of the EHBF varied between 68.5-80.2% and 45.8-73.7%, respectively. The EHBF-MELD score had the highest specificity. CONCLUSION: EHBF was significantly lower in the patients with ACLF compared to decompensated cirrhosis. The EHBF were closely related to the severity of HBV-ACLF and can be used for predicting the 90-day mortality rate of HBV-ACLF.

SARS-CoV-2 can be detected in urine, blood, anal swabs, and oropharyngeal swabs specimens.

PURPOSE: The purpose of this study was to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA) in urine and blood specimens, and anal and oropharyngeal swabs from patients with confirmed SARS-CoV-2 infection, and correlated positive results with clinical findings. METHODS: Patients with confirmed SARS-CoV-2 infections were included in this study. Patients' demographic and clinical data were recorded. Quantitative real-time polymerase chain reaction was used to detect SARS-CoV-2 RNA in urine and blood specimens, and anal and oropharyngeal swabs. The study is registered at ClinicalTrials.gov (No. NCT04279782, 19 February, 2020). RESULTS: SARS-CoV-2 RNA was present in all four specimen types, though not all specimen types were positive simultaneously. The presence of viral RNA was not necessarily predictive of clinical symptoms, for example, the presence of viral RNA in the urine did not necessarily predict urinary tract symptoms. CONCLUSIONS: SARS-CoV-2 can infect multiple systems, including the urinary tract. Testing different specimen types may be useful for monitoring disease changes and progression, and for establishing a prognosis.

A cross-sectional comparison of epidemiological and clinical features of patients with coronavirus disease (COVID-19) in Wuhan and outside Wuhan, China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread outside the initial epicenter of Wuhan. We compared cases in Guangzhou and Wuhan to illustrate potential changes in pathogenicity and epidemiological characteristics as the epidemic has progressed. METHODS: We studied 20 patients admitted to the Third Affiliated Hospital of Sun Yat-Sen University in Guangzhou, China from January 22 to February 12, 2020. Data were extracted from medical records. These cases were compared with the 99 cases, previously published in Lancet, from Wuhan Jinyintan Hospital from January 1 to January 20, 2020. RESULTS: Guangzhou patients were younger and had better prognosis than Wuhan patients. The Wuhan patients were more likely to be admitted to the ICU (23% vs 5%) and had a higher mortality rate (11% vs 0%). Cases in Guangzhou tended to be more community clustered. Diarrhea and vomiting were more common among Guangzhou patients and SARS-CoV-2 RNA was found in feces. Fecal SARA-CoV-2 RNA remained positive when nasopharyngeal swabs turned negative in some patients. CONCLUSIONS: This study indicates possible diminishing virulence of the virus in the process of transmission. Yet persistent positive RNA in feces after negative nasopharyngeal swabs suggests a possible prolonged transmission period that challenges current quarantine practices.

Recurrence of positive SARS-CoV-2 RNA in COVID-19: A case report.

The ongoing outbreak of COVID-19 that began in Wuhan, China, has constituted a Public Health Emergency of International Concern, with cases confirmed in multiple countries. Currently, patients are the primary source of infection. We report a confirmed case of COVID-19 whose oropharyngeal swab test of SARS-CoV-2 RNA turned positive in convalescence. This case highlights the importance of active surveillance of SARS-CoV-2 RNA for infectivity assessment.

Effects of Antiviral Therapy on HBV Reactivation and Survival in Hepatocellular Carcinoma Patients Undergoing Hepatic Artery Infusion Chemotherapy.

BACKGROUND: This study aimed to investigate the influence of hepatic artery infusion chemotherapy (HAIC) on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) positive patients with primary hepatocellular carcinoma (HCC) as well as evaluate the role of antiviral prophylaxis in these patients. METHODS: We enrolled 170 HBsAg-positive advanced HCC patients receiving HAIC using mFOLFOX regimen, of which 137 patients received antiviral prophylaxis. Risk factors for HBV reactivation were analyzed. The overall survival (OS) from the first application of HAIC were compared between antiviral and non-antiviral groups. RESULTS: A total of 25 patients (14.7%) developed HBV reactivation after HAIC, of which 16 patients received antiviral treatment and nine patients did not. The incidence of HBV reactivation was 11.7% (16/137) in antiviral group and 27.3% (9/33) in non-antiviral group respectively. No antiviral prophylactic was the only significant risk factor for HBV reactivation (OR=12.35, 95% confidence interval (CI) 4.35-33.33, p<0.001). Patients in antiviral group received more cycles of HAIC compared with non-antiviral group (3.11 ± 1.69 vs 1.75 ± 1.18, p<0.05) at the time of HBV reactivated. Seven of the 25 HBV reactivation patients developed hepatitis. OS in antiviral group was significantly longer than that of non-antiviral group (median 16.46 vs 10.68 months; HR=0.57; 95% CI, 0.36-0.91; p<0.05). CONCLUSIONS: HBV reactivation is more prone to occur in the HBsAg-positive HCC patients undergoing HAIC without antiviral prophylaxis. Regular monitoring of HBV DNA and antiviral prophylaxis are suggested to prevent HBV reactivation as well as prolong the OS of these patients. NAME OF THE TRIAL REGISTER: HAIC Using Oxaliplatin Plus Fluorouracil/Leucovorin for Patients with Locally Advanced HCC. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/, identifier NCT02436044.

Evaluation of Ficus tikoua leaves extract as an eco-friendly corrosion inhibitor for carbon steel in HCl media.

An effective and biodegradable Ficus tikoua leaves extract was studied as a corrosion inhibitor for carbon steel in hydrochloric acid. Systematic electrochemical experiments and morphological characterization were carried out to investigate the properties of the corrosion inhibitor. Meanwhile, quantum chemical calculations were performed to aid further understanding of the electrochemical mechanism. The electrochemical results reveal that the extract inhibitors act as a mixed-type with an inhibition efficiency up to 95.8% at 298 K. Moreover, this extract shows good inhibory activity at a wide range of temperatures and the corresponding results were further confirmed by morphological analysis. The chemical formulae of these major components are fully optimized in the DFT with B3LYP in the gas phase and the base set is 6-311++G (d, p).

MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/ß-Catenin Signaling.

BACKGROUND/AIMS: MicroRNA-197 (miR-197) has been shown to play roles in epithelialmesenchymal transition (EMT) and metastasis. The Wnt/ß-catenin pathway is associated with EMT, but whether miR-197 regulatesWnt/ß-catenin remains unclear. This study was to demonstrate the role of miR-197 on the Wnt/ß-catenin pathway in hepatocellular carcinoma (HCC). METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-197 in 105 HCC specimens and 15 HCC cell lines. We tested the predicted target gene of miR-197 using a genetic report system. The role of miR-197 in HCC cell invasion and migration (wound healingand cell invasion and migrationby Transwell assays) and in an HCC xenograft modelwas analyzed. RESULTS: Using a miRNA microarray analysis of HCC specimens and compared with non-metastatic HCC, miR-197 was identified as one of the most upregulated miRNAs in metastatic HCC. miR-197 expression was positively associated with the invasiveness of HCC cell lines. Metastatic HCC cells with high miR-197 expression had Wnt/ß-catenin signaling activation. High levels of miR-197 expression also promoted EMT and invasionHCC cells in vitro and in vivo. miR-197 directly targeted Axin-2, Naked cuticle 1 (NKD1), and Dickkopf-related protein 2 (DKK2), leading to inhibition of Wnt/ß-catenin signaling. High miR-197 expression was found in HCC specimens from patients with portal vein metastasis;high miR-197 expression correlated to the expression of Axin2, NKD1, and DKK2. CONCLUSION: miR-197 promotes HCC invasion and metastasis by activating Wnt/ß-catenin signaling. miR-197 could possibly be used as a prognostic marker and therapeutic target for HCC.

miR-214/199a/199a* cluster levels predict poor survival in hepatocellular carcinoma through interference with cell-cycle regulators.

AIMS: To identify the clinical and functional association of miR-214/199a/199a* cluster in human hepatocellular carcinoma (HCC) and to clarify the mechanism of miR-214. METHODS: Kaplan-Meier and Cox proportional regression analyses were used to determine the association of miR-214/199a/199a* cluster levels with the survival of HCC patients. The role of miR-214 in regulating HCC cell proliferation was studied with miR-214 mimics/inhibitor-treated cells. Furthermore, the inhibition effect of miR-214 on E2F2, cyclin-dependent kinase (CDK) 3 and CDK6 expression was assessed in HCC cell lines with miR-214 mimics/inhibitors to increase/decrease miR-214 expression. Direct binding of miR-214 to the 3'-untranslated regions of E2F2, CDK3, and CDK6 was verified by dual-luciferase reporter assay. RESULTS: In analyzing HCC clinical specimens and cell lines, we discovered a uniform decrease in miR-214/199a/199a* expression in comparison with noncancerous tissue or normal liver epithelial cell lines. Higher miR-214 levels were related with improved patient survival. Overexpression of miR-214 in HCC cells inhibited proliferation by inducing G1-S checkpoint arrest. Conversely, RNA interference-mediated silencing of miR-214 promoted cell-cycle progression and accelerated the proliferation of HCC cells. E2F2, CDK3 and CDK6 were each directly targeted for inhibition by miR-214, and restoring their expression reversed miR-214 inhibition of cell-cycle progression. The relationship between expression of miR-214 and its targets was confirmed in HCC tumor xenografts and clinical specimens. CONCLUSIONS: Our results demonstrate that miR-214 has tumor-suppressive activity in HCC through inhibition of E2F2, CDK3 and CDK6.

Durability of efficacy after telbivudine off-treatment in chronic hepatitis B patients.

BACKGROUND/AIMS: Current international guidelines indicate that finite therapy with nucleos(t)ide analogues (NAs) is possible in chronic hepatitis B (CHB) patients. Here we evaluate the durability of efficacy after telbivudine (LdT) off-treatment. METHODS: 39 CHB patients with normalized ALT, undetectable HBV-DNA and HBeAg seroconversion for at least 48 weeks were observed after telbivudine discontinuation. We analyzed the follow-up clinical condition of off-treatment, calculated the cumulative clinical relapse rate, and explored the predictive factors for clinical relapse. RESULTS: Totally 8 patients encountered clinical relapse in the first 60 weeks after telbivudine discontinuation. The cumulative clinical relapse rates at week 24, 48, 60 and 204 were respectively 2.6%, 7.7%, 16.3% and 23.3%. No significant difference was found between cumulative clinical relapse rates of HBeAg(+) and HBeAg(-). No significant baseline or on-treatment factors for clinical relapse were found. CONCLUSION: The present study demonstrated that most CHB patients maintained sustained response and HBeAg seroconversion following telbivudine off-treatment. Clinical relapses may often occur in the early period, with low clinical relapse rate. More follow-up data will be on-going and complemented in the further studies.