On-treatment monitoring of liver fibrosis with serum hepatitis B core-related antigen in chronic hepatitis B

BACKGROUND Non-invasive evaluation for liver fibrosis is clinically important,especially in patients with undetectable hepatitis B virus(HBV)DNA treated with nucleoside analogs.AIM To clarify the monitoring power of hepatitis B core-related antigen(HBcrAg)for hepatic histologic changes in patients with chronic hepatitis B(CHB)treated with entecavir.METHODS This prospective multicenter study used multiple ordinal and multivariate logistics regression analysis to assess variables associated with Ishak fibrosis score and regression for fibrosis regression,respectively,in 403 CHB patients,including 374 with entecavir for 72 weeks(291 underwent paired liver biopsy)and 29 as controls.RESULTS Level of HBcrAg correlated negatively with liver fibrosis staging(γ=-0.357,P<0.001)in hepatitis B e antigen(HBeAg)-positive patients,and positively with liver fibrosis staging in HBeAg-negative patients.Higher HBcrAg concentration was associated with younger age,HBeAg positive status,high HBV DNA loads,high level of hepatitis B surface antigen(HBsAg)and higher necroinflammation,but not with HBV genotype.Serum concentration of HBcrAg,basal core promoter/precore(BCP/PC)mutant,quantitation of HBsAg(qHBsAg)and platelet counts were independently associated with Ishak fibrosis score on multiple ordinal regression.HBV DNA was undetectable in 88.37%of patients treated with entecavir at week 72,while their level of HBcrAg was still detectable.A greater reduction in post-treatment HBcrAg concentration was associated with the regression of hepatic fibrosis and histological improvement.HBcrAg concentration>6.33 log IU/mL at baseline and logarithmic reduction>1.03 log IU/mL at week 72 were associated with a higher chance of regression of liver fibrosis and histological improvement,respectively.CONCLUSION HBcrAg level is associated with liver fibrosis progression.HBcrAg is an excellent monitor of hepatic histological changes,especially in CHB patients treated with nucleoside analogs.

Influence of weight management on the prognosis of steatohepatitis in chronic hepatitis B patients during antiviral treatment

Background:Although concomitant nonalcoholic steatohepatitis(NASH)is common in chronic hepatitis B(CHB),the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear.We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment.Methods:In the post-hoc analysis of a multicenter trial,na?ve CHB patients receiving 72-week entecavir treatment were enrolled.We evaluated the biochemical,viral and histopathological responses of these patients.The histopathological features of NASH were also evaluated,using paired liver biopsies at baseline and week 72.Results:A total of 1000 CHB patients were finally enrolled for analysis,with 18.2%of whom fulfilling the criteria of NASH.A total of 727 patients completed entecavir antiviral treatment and received the second biopsy.Serum HBe Ag loss,HBe Ag seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH(P>0.05).Among patients with NASH,the hepatic steatosis,ballooning,lobular inflammation scores and fibrosis stages all improved during follow-up(all P<0.001),46%(63/136)achieved NASH resolution.Patients with baseline body mass index(BMI)≥23 kg/m2(Asian criteria)[odds ratio(OR):0.414;95%confidence interval(95%CI):0.190-0.899;P=0.012]and weight gain(OR:0.187;95%CI:0.050-0.693;P=0.026)were less likely to have NASH resolution.Among patients without NASH at baseline,22(3.7%)developed NASH.Baseline BMI≥23 kg/m2(OR:12.506;95%CI:2.813-55.606;P=0.001)and weight gain(OR:5.126;95%CI:1.674-15.694;P=0.005)were predictors of incident NASH.Conclusions:Lower BMI and weight reduction but not virologic factors determine NASH resolution in CHB.The value of weight management in CHB patients during antiviral treatment deserves further evaluation.

Recent progress in pulsed electric field ablation for liver cancer

The number of liver cancer patients is likely to continue to increase in the coming decades due to the aging of the population and changing risk factors.Traditional treatments cannot meet the needs of all patients.New treatment methods evolved from pulsed electric field ablation are expected to lead to breakthroughs in the treatment of liver cancer.This paper reviews the safety and efficacy of irreversible electroporation in clinical studies,the methods to detect and evaluate its ablation effect,the improvements in equipment and its antitumor effect,and animal and clinical trials on electrochemotherapy.We also summarize studies on the most novel nanosecond pulsed electric field ablation techniques in vitro and in vivo.These research results are certain to promote the progress of pulsed electric field in the treatment of liver cancer.

Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications:Molecular mechanisms and therapeutic inventions

Hepatitis B virus(HBV)has posed a threat to public health,mainly resulting in liver damage.With long-term accumulation of extracellular matrix,patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma.The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality.With deeper understanding of the bidirectional interaction between the liver and the gut(gut-liver axis),there is a growing consensus that the human health closely relates to the gut microbiota.Supported by animal and human studies,the gut microbiota alters as the HBV-related liver fibrosis initials and progresses,characterized as the decrease of the ratio between“good”and“potentially pathogenic”microbes.When the primary disease is controlled via antiviral treatment,the gut microbiota dysfunction tends to be improved.Conversely,the recovery of gut microbiota can promote the regression of liver fibrosis.Therapeutic strategies targeted on gut microbiota(rifaximin,probiotics,engineered probiotics and fecal microbiota transplantation)have been applied to animal models and patients,obtaining satisfactory results.

A Diagnostic Tool for Identification of Etiologies of Fever of Unknown Origin in Adult Patients

The diagnosis and treatment of fever of unknown origin (FUO) are huge challenges to clinicians.Separating the etiologies of FUO into infectious and non-infectious disease is conducive to clinical physicians not only on making decisions rapidly concerning the prescription of suitable antibiotics but also on further analysis of the final diagnosis.In order to develop and validate a diagnostic tool to efficiently distinguish the etiologies of adult FUO patients as infectious or non-infectious disease,FUO patients from the departments of infectious disease and internal medicine in three Chinese tertiary hospitals were enrolled retrospectively and prospectively.By using polynomial logistic regression analysis,the diagnostic formula and the associated scoring system were developed.The variables included in this diagnostic formula were from clinical evaluations and common laboratory examinations.The proposed tool could discriminate infectious and noninfectious causes of FUO with an area under receiver operating characteristic curve (AUC) of 0.83,sensitivity of 0.80 and specificity of 0.75.This diagnosis tool could predict the infectious and non-infectious causes of FUO in the validation cohort with an AUC of 0.79,sensitivity of 0.79 and specificity of 0.70.The results suggested that this diagnostic tool could be a reliable tool to discriminate between infectious and non-infectious causes of FUO.

Human microbiome is a diagnostic biomarker in hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.

The latest research progress on minimally invasive treatments for hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related death worldwide.Due to the high prevalence of hepatitis B virus(HBV)infection in China,the incidence of HCC in China is high,and liver cirrhosis caused by chronic hepatitis also brings great challenges to treatment.This paper reviewed the latest research progress on minimally invasive treatments for HCC,including percutaneous thermal ablation and new nonthermal ablation techniques,and introduced the principles,advantages,and clinical applications of various therapeutic methods in detail.Data sources:The data of treatments for HCC were systematically collected from the Pub Med,Science Direct,American Chemical Society and Web of Science databases published in English,using“minimally invasive”and“hepatocellular carcinoma”or“liver cancer”as the keywords.Results:Percutaneous thermal ablation is still a first-line strategy for the minimally invasive treatment of HCC.The effect of microwave ablation(MWA)on downgrading treatment before liver transplantation is better than that of radiofrequency ablation(RFA),while RFA is more widely used in the clinical practice.High-intensity focused ultrasound(HIFU)is mainly used for the palliative treatment of advanced liver cancer.Electrochemotherapy(ECT)delivers chemotherapeutic drugs to the target cells while reducing the blood supply around HCC.Irreversible electroporation(IRE)uses a microsecond-pulsed electric field that induces apoptosis and necrosis and triggers a systemic immune response.The nanosecond pulsed electric field(ns PEF)has achieved a good response in the ablation of mice with HCC,but it has not been reported in China for the treatment of human HCC.Conclusions:A variety of minimally invasive treatments provide a sufficient survival advantage for HCC patients.Nonthermal ablation will lead to a new wave with its unique advantage of antitumor recurrence and metastasis.

Irreversible electroporation plus chemotherapy versus chemotherapy alone as treatments for patients with locally advanced pancreatic cancer

Pancreatic cancer is a major health problem worldwide,with a high incidence and mortality rate.It is estimated that it has become the sixth leading cause of cancer-related death in China and the fourth leading cause of cancer-related death globally[1].For patients with locally advanced pancreatic cancer(LAPC),there are no standard treatment options.

Fecal microbiota transplantation has therapeutic effects on chronic hepatits B patients via altering composition of gut microbiota

Chronic hepatits B(CHB)is an increasingly disturbing public health issue worldwide.Currently,interferon and oral antiviral drugs such as entecavir(ETV)or tenofovir disoproxil fumarate(TDF)are two internationally recognized drugs for the treatment of CHB.However,the HBeAg clearance or seroconversion rate is low even in patients with long-term antiviral therapy.Many patients have to increase the dosage of antiviral therapy drugs[1].Intestinal microorganisms are confirmed to play an important role in the pathogenesis of different chronic liver diseases including CHB,and fecal microbiota transplantation(FMT)may be a novel treatment strategy for CHB.

Tenofovir disoproxil fumarate in Chinese chronic hepatitis B patients:Results of a multicenter,double-blind,double-dummy,clinical trial at 96 weeks

BACKGROUND Tenofovir disoproxil fumarate(TDF)is a prodrug of a nucleotide analogue.As an antiviral drug,TDF has been proposed in the first-line treatment of chronic hepatitis B(CHB).Qingzhong,a brand name of TDF,commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd.,and Viread,another brand name of TDF,commercialized by GlaxoSmithKline,have both been approved by the State Food and Drug Administration,China.AIM To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients.METHODS This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857.A total of 330 Chinese CHB patients,among which 232 were hepatitis B e antigen(HBeAg)-positive,were included in this 5-year-long,multicenter,double-blinded,double-dummy,randomized-controlled,noninferiority phase III trial.The participants were initially randomized into two groups:Group A(n=161),in which the participants received 300 mg Qingzhong once a day for 48 wk;and Group B,in which the participants received 300 mg Viread once a day for 48 wk.Starting from week 49,all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week.In this study,the primary endpoint was the decrease in plasma level of hepatitis B virus(HBV)DNA at the 96th week,while the secondary endpoints were suppression of HBV replication,alanine aminotransferase(ALT)normalization,HBeAg loss,and HBeAg seroconversion rates.RESULTS For the participants with HBeAg-positive CHB,the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B(5.77 vs 5.73 log10 IU/mL,P>0.05)at the 96th week.In addition,similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA,HBeAg loss,and HBeAg seroconversion(71.05%vs 77.97%,31.00%vs 27.27%,and 20.22%vs 15.79%,respectively,in Group A vs Group B;P>0.05).For the participants with HBeAg-negative CHB,the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B(4.46 vs 4.70 log10 IU/mL,P>0.05)at the 96th week.In addition,similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA(87.23%vs 94.12%in Group A vs Group B,respectively;P>0.05).Finally,similar percentages of CHB patients(HBeAg-positive or HBeAg-negative)in the two groups exhibited normalization of ALT(80.14%vs 84.57%in Group A vs Group B,respectively;P>0.05),and similar incidences of adverse events were observed(106 vs 104 in Group A vs Group B,respectively;P>0.05).CONCLUSION Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

Characterization of oral and gut microbiome and plasma metabolomics in COVID-19 patients after 1-year follow-up

Background:Due to the outbreak and rapid spread of coronavirus disease 2019(COVID-19),more than 160 million patients have become convalescents worldwide to date.Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19.However,it is unknown whether their characteristics return to normal after the 1-year recovery.Methods:We recruited 35 confirmed patients to provide specimens at discharge and 1 year later,as well as 160healthy controls.A total of 497 samples were prospectively collected,including 219 tongue-coating,129 stool and 149 plasma samples.Tongue-coating and stool samples were subjected to 16S rRNA sequencing,and plasma samples were subjected to untargeted metabolomics testing.Results:The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal.In the recovery process,the microbial diversity gradually increased.Butyric acid-producing microbes and Bifidobacterium gradually increased,whereas lipopolysaccharideproducing microbes gradually decreased.In addition,sphingosine-1-phosphate,which is closely related to the inflammatory factor storm of COVID-19,increased significantly during the recovery process.Moreover,the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later.Conclusions:This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19.The key microbiome and metabolites in the process of recovery were identified,and provided new treatment ideas for accelerating recovery.And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.

Alterations in the human oral microbiome in cholangiocarcinoma

Dear Editor,Alterations in the human microbiome are closely related to various hepatobiliary diseases.Gut microbial dysbiosis has been found in patients with cholangiocarcinoma(CCA)[1].However,the characteristics of oral microbiome in patients with CCA have not been studied.

Complete Human Immunodeficiency Virus-1 Specific T Lymphocyte Response to Chinese Human Immunodeficiency Virus-1 B/C Chronic Infectors

Objective To characterize the human immunodeficiency virus （HIV） -specific T lymphocyte responses and identify the immunodominant regions in Chinese HIV-1 recombinant subtype B/C chronic infectors at complete genome level. Methods Twenty-five HIV-I B/C recombinant chronic infectors were screened for their specific T lymphocyte responses to a panel of peptides corresponding to the complete HIV-1 subtype B genome by gamma interferon ELISPOT assay. Kruskal-Wallis nonparametric analysis of variance was used to test significant differences across gene regions, and Tukey pairwise analysis was used to identify differences between gene regions. Spearman rank correlation was used to assess the relation between responses. Results The order of recognized frequencies of specific T lymphocyte responses to HIV proteins was Nef〉Vpr〉Gag〉Pol〉Vpu〉Env〉Rev〉Vif〉Tat. When adjusted for protein length, Nef, Vpr, Gag, and Pol were the most intensely targeted proteins and the central region of Nef, Gag p24, Pol RT, and Vpr was most frequently recognized. No significant correlation was observed between the magnitude of IFN-γ production of HIV-l-specific T lymphocyte responses and plasma viremia, breadth of response and CD4 counts. Conclusion The central region of Nef, Gag p24, Pol RT, and Vpr is most frequently targeted in HIV-1 B/C recombinants chronic infectors. HIV-1-specific T lymphocyte responses and plasma viremia or CD4 counts play no protective role at complete genome level in these infectors.

The correlation between gut microbiome and atrial fibrillation: pathophysiology and therapeutic perspectives

Regulation of gut microbiota and its impact on human health is the theme of intensive research.The incidence and prevalence of atrial fibrillation(AF)are continuously escalating as the global population ages and chronic disease survival rates increase;however,the mechanisms are not entirely clarified.It is gaining awareness that alterations in the assembly,structure,and dynamics of gut microbiota are intimately engaged in the AF progression.Owing to advancements in next-generation sequencing technologies and computational strategies,researchers can explore novel linkages with the genomes,transcriptomes,proteomes,and metabolomes through parallel meta-omics approaches,rendering a panoramic view of the culture-independent microbial investigation.In this review,we summarized the evidence for a bidirectional correlation between AF and the gut microbiome.Furthermore,we proposed the concept of“gut-immune-heart”axis and addressed the direct and indirect causal roots between the gut microbiome and AF.The intricate relationship was unveiled to generate innovative microbiota-based preventive and therapeutic interventions,which shed light on a definite direction for future experiments.

HBsAg Loss Due to Tenofovir Treatment for HBV Reactivation Following DAAs Therapy in One Patient with HBV-HCV Coinfection

Hepatitis B virus(HBV)reactivation induced by administration of direct-acting antiviral agents(DAAs)to treat hepatitis C virus(HCV)infection has been reported in previous studies,the subsequent clinical outcomes varied from no symptom to liver failure or death,however,the timing of anti-HBV treatment is controversial.We report the clinical HBV reactivation in a 51 years old female fibrotic patient with chronic HBV-HCV infection during the paritaprevir/ritonavir/ombitasvir and dasabuvir(PrOD)therapy.Her baseline HCV RNA,HBV DNA,alanine aminotransferase(ALT),and liver stiffness measurement levels were 5,560,000IU/mL,<15IU/mL,48U/L,and 11.8 kPa,respectively.At 8weeks of PrOD treatment,her HCV RNA,HBV DNA,and ALT levels were<15IU/mL,2,880,000 IU/mL,and 837U/L,respectively,and clinical reactivation was diagnosed.Meanwhile,tenofovir was immediately used for anti-HBV treatment.Fortunately,HBV DNA and ALT were undetectable and normalized after 16weeks of anti-HBV therapy,and unexpectedly,hepatitis B surface antigen loss occurred at 80weeks of anti-HBV treatment.This study may extend our understanding of the timing of anti-HBV therapy to prevent potential HBV reactivation during DAAs treatment in HBVHCV coinfected patients,and proper initiation timing may lead to functional cure of chronic HBV infection.