Novel index for the prediction of significant liver fibrosis and cirrhosis in chronic hepatitis B patients in China

BACKGROUND Noninvasive,practical,and convenient means of detection for the prediction of liver fibrosis and cirrhosis in China are greatly needed.AIM To develop a precise noninvasive test to stage liver fibrosis and cirrhosis.METHODS With liver biopsy as the gold standard,we established a new index,[alkaline phosphatase(U/L)+gamma-glutamyl transpeptidase(U/L)/platelet(109/L)(AGPR)],to predict liver fibrosis and cirrhosis.In addition,we compared the area under the receiver operating characteristic curve(AUROC)of AGPR,gammaglutamyl transpeptidase to platelet ratio,aspartate transaminase to platelet ratio index,and FIB-4 and evaluated the accuracy of these routine laboratory indices in predicting liver fibrosis and cirrhosis.RESULTS Correlation analysis revealed a significant positive correlation between AGPR and liver fibrosis stage(P<0.001).In the training cohort,the AUROC of AGPR was 0.83(95%CI:0.78-0.87)for predicting fibrosis(≥F2),0.84(95%CI:0.79-0.88)for predicting extensive fibrosis(≥F3),and 0.87(95%CI:0.83-0.91)for predicting cirrhosis(F4).In the validation cohort,the AUROCs of AGPR to predict≥F2,≥F3 and F4 were 0.83(95%CI:0.77-0.88),0.83(95%CI:0.77-0.89),and 0.84(95%CI:0.78-0.89),respectively.CONCLUSION The AGPR index should become a new,simple,accurate,and noninvasive marker to predict liver fibrosis and cirrhosis in chronic hepatitis B patients.

Distribution and changes in hepatitis C virus genotype in China from 2010 to 2020

BACKGROUND Hepatitis C virus(HCV)causes a large number of infections worldwide.New infections seem to be increasing according to a report of the World Health Organization in 2015.Although direct-acting antivirals are quite effective for most genotypes of the HCV,some genotypes fail to respond.Therefore,the trend of genotype distribution is vital to better control the development of this infection.AIM To analyze the distribution and trends of the HCV genotype before and after the emergence of direct-acting antivirals in China.METHODS We searched all literature published in five electronic databases-China National Knowledge Infrastructure,Wan Fang Data,VIP Chinese Journal Database,Chinese Biomedical Literature Service System,and PubMed-from January 1,2010 to December 31,2020.The search strategy combined medical subject headings and free-text terms,including“hepatitis C virus”or“HCV”and“genotype”or“subtype”and“China”or“Chinese”.Additional relevant articles were searched by manual selection.Data were extracted to build a database.All of the data were totaled according to regions,periods,routes of transmission,and sexes.The percentages in various stratifications were calculated.RESULTS There were 76110 samples from 30 provinces included in the study.Genotype 1(G1)accounted for 58.2%of cases nationwide,followed by G2,G6,G3b,G3a,unclassified and mixed infections(17.5%,7.8%,6.4%,4.9%,1.8%,and 1.2%,respectively).The constitution of genotype varied among different regions,with G6 and G3b being more common in the south and southwest,respectively(28.1%,15.4%).The past ten years have witnessed a decrease in G1 and G2 and an increase in G3 and G6 in almost all regions.The drug-use population had the most abundant genotypes,with G6 ranking first(33.3%),followed by G1 and G3b(23.4%,18.5%).CONCLUSION G3 and G6 pose a new challenge for HCV infection.This study revealed the distribution of HCV genotypes in China over the past 10 years,providing information for HCV management strategies.

Emerging antivirals for the treatment of hepatitis B

Chronic infection with hepatitis B virus(HBV)constitutes a major global public health threat,causing substantial disease burdens such as liver cirrhosis and hepatocellular carcinoma,thus representing high unmet medical needs.Currently available therapies are safe,well tolerated,and highly effective in decreasing viremia and improving measured clinical outcomes with low rates of antiviral resistance.However,long-term management remains a clinical challenge,mainly due to the slow kinetics of HBV surface antigen clearance.In this article,we review emerging antivirals directed at novel targets derived from mechanisms of viral cellular entry,viral replication,viral assembly,and the host immune response,leading to preclinical and clinical trials for possible future therapeutic intervention.The recent therapeutic advances in the development of all categories of HBV inhibitors may pave the way for regimens of finite duration that result in long-lasting control of chronic hepatitis B infection.

Histopathology and the predominantly progressive,indeterminate and predominately regressive score in hepatitis C virus patients after direct-acting antivirals therapy

BACKGROUND Histological changes after direct-acting antivirals(DAAs)therapy in hepatitis C virus(HCV)patients has not been elucidated.Whether the predominantly progressive,indeterminate and predominately regressive(P-I-R)score,evaluating fibrosis activity in hepatitis B virus patients has predictive value in HCV patients has not been investigated.AIM To identify histological changes after DAAs therapy and to evaluate the predictive value of the P-I-R score in HCV patients.METHODS Chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included.Sustained virologic response(SVR)was defined as an undetectable serum HCV RNA level at 24 wk after treatment cessation.The Ishak system and P-I-R score were assessed.Inflammation improvement and fibrosis regression were defined as a≥2-points decrease in the histology activity index(HAI)score and a≥1-point decrease in the Ishak fibrosis score,respectively.Fibrosis progression was defined as a≥1-point increase in the Ishak fibrosis score.Histologic improvement was defined as a≥2-points decrease in the HAI score without worsening of the Ishak fibrosis score after DAAs therapy.The P-I-R score was also assessed.“absolutely reversing or advancing”was defined as the same directionality implied by both change in the Ishak score and posttreatment P-I-R score;and“probably reversing or advancing”was defined as only one parameter showing directionality.RESULTS Thirty-eight chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included.The mean age of these patients was 40.9±14.6 years and there were 53%(20/38)males.Thirty-four percent(13/38)of patients were cirrhotic.Eighty-two percent(31/38)of patients achieved inflammation improvement.The median HAI score decreased significantly after SVR(pretreatment 7.0 vs posttreatment 2.0,Z=-5.146,P=0.000).Thirty-seven percent(14/38)of patients achieved fibrosis improvement.The median Ishak score decreased significantly after SVR(pretreatment 4.0 vs posttreatment 3.0,Z=-2.354,P=0.019).Eighty-two percent(31/38)of patients showed histological improvement.The P-I-R score was evaluated in 61%(23/38)of patients.The progressive group showed lower platelet(P=0.024)and higher HAI scores(P=0.070)before treatment.In patients with stable Ishak stage after treatment:Progressive injury was seen in 22%(4/18)of patients,33%(6/18)were classified as indeterminate and regressive changes were seen in 44%(8/18)of patients who were judged as probably reversing by the Ishak and P-I-R systems.CONCLUSION Significant improvement of necroinflammation and partial remission of fibrosis in HCV patients occurred shortly after DAAs therapy.The P-I-R score has potential in predicting fibrosis in HCV patients.

Effect of spleen operation on antiviral treatment in hepatitis Cvirus-related cirrhotic patients

AIM:To investigate the impact of spleen operation(SO) on interferon-α(IFN-α)-based antiviral treatment in patients with hepatitis C virus(HCV)-related cirrhosis.METHODS:Studies were systematically identified by searching electronic databases including MEDLINE,Cochrane Library,Elsevier,and Embase up to September 30,2013,and relevant clinical studies were reviewed.Sustained virological response(SVR) rate and adherence to therapy were taken as the endpoints of interest.RESULTS:A total of 603 patients from 16 studies were included in the systematic review.Of 372 patients who underwent SO followed by antiviral treatment,the total SVR rate was 39.5%.SVR was associated with HCV genotypes 2/3(OR = 10.84; 95%CI:5.47-21.47; P < 0.00001).IFN-α dose needed to be reduced in 29.4%,and IFN-α-based therapy was discontinued in 11.5% of patients.Analysis of controlled studies showed that SVRs were achieved in 34.1% of patients with SO and 31.1% of patients without SO.SO had no effect on the SVR rate in cirrhotic patients with genotype 1 HCV infection(OR = 1.28; 95%CI:0.51-3.22; P = 0.60),but improved the SVR rate in patients with genotypes 2/3 infection,though the difference was not significant(OR = 0.36; 95%CI:0.13-1.02; P = 0.05).CONCLUSION:SO combined with IFN-α-based antiviral therapy may be suitable in cirrhotic patients with genotypes 2/3 HCV infection,but not in those with genotype 1 infection.

HBsAg stimulates NKG2D receptor expression on natural killer cellsand inhibits hepatitis C virus replication

Background： Higher hepatitis B surface antigen （HBsAg） facilitates hepatitis C virus （HCV） clearance inpatients with hepatitis B virus （HBV）/HCV co-infection. We investigated the effect of exogenous HBsAgon the inhibition of HCV replication mediated by natural killer （NK） cells.

Recovery of natural killer cells is mainly in post-treatment period in chronic hepatitis C patients treated with sofosbuvir plus ledipasvir

AIM To investigate how natural killer(NK) cells are affected in the elimination of hepatitis C virus(HCV) by sofosbuvir/ledipasvir, two highly effective direct-acting antivirals(DAAs). METHODS Thirteen treatment-na?ve and treatment-experienced chronic hepatitis C(CHC) patients were treated with sofosbuvir/ledipasvir, and NK cells were detected at baseline, weeks 2, 4, 8 and 12 during therapy, and week post of treatment(Pt)-12 and 24 after the end of therapy by multicolor flow cytometry and compared with those from 13 healthy controls. RESULTS All patients achieved sustained virological response. There was a significant decline in CD56^(bright) NK cell frequencies at week 8(P = 0.002) and week 12(P = 0.003), which were altered to the level comparable to healthy controls at week Pt-12, but no difference was observed in the frequency of CD56^(dim) NK cells. Compared with healthy controls, the expression levels of NKG2A, NKp30 and CD94 on NK cells from CHC patients at baseline were higher. NKG2A, NKp30 and CD94 started to recover at week 12 and reached the levels similar to those of healthy controls at week Pt-12 or Pt-24. Before treatment, patients have higher interferon(IFN)-γ and perforin levels than healthy controls, and IFN-γ started to recover at week 8 and reached the normalized level at week Pt-12. CONCLUSION NK cells of CHC patients can be affected by DAAs, and phenotypes and function of NK cells recover not at early stage but mainly after the end of sofosbuvir/ledipasvir treatment.

Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acidenhanced magnetic resonance imaging for evaluating fibrosis regression in chronic hepatitis C patients after direct-acting antiviral

BACKGROUND Direct acting antiviral(DAA)therapy has enabled hepatitis C virus infection to become curable,while histological changes remain uncontained.Few valid noninvasive methods can be confirmed for use in surveillance.Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid(Gd-EOB-DTPA)is a liver-specific magnetic resonance imaging(MRI)contrast,related to liver function in the hepatobiliary phase(HBP).Whether Gd-EOB-DTPA-enhanced MRI can be used in the diagnosis and follow up of hepatic fibrosis in patients with chronic hepatitis C(CHC)has not been investigated.AIM To investigate the diagnostic and follow-up values of Gd-EOB-DTPA-enhanced MRI for hepatic histology in patients with CHC.METHODS Patients with CHC were invited to undergo Gd-EOB-DTPA-enhanced MRI and liver biopsy before treatment,and those with paired qualified MRI and liver biopsy specimens were included.Transient elastography(TE)and blood tests were also arranged.Patients treated with DAAs who achieved 24-wk sustained virological response(SVR)underwent Gd-EOB-DTPA-enhanced MRI and liver biopsy again.The signal intensity(SI)of the liver and muscle were measured in the unenhanced phase(UEP)(SI_(UEP-liver),SI_(UEP-muscle))and HBP(SI_(HBP-liver),SI_(HBP-muscle))via MRI.The contrast enhancement index(CEI)was calculated as[(SI_(HBP-liver)/SI_(HBP-muscle))]/[(SI_(UEP-liver)/SI_(UEP-muscle))].Liver stiffness measurement(LSM)was confirmed with TE.Serologic markers,aspartate aminotransferase-to-platelet ratio index(APRI)and Fibrosis-4(FIB-4),were also calculated according to blood tests.The grade of inflammation and stage of fibrosis were evaluated with the modified histology activity index(mHAI)and Ishak fibrosis score,respectively.Fibrosis regression was defined as a≥1-point decrease in the Ishak fibrosis score.The correlation between the CEI and liver pathology was evaluated.The diagnostic and follow-up values of the CEI,LSM,and serologic markers were compared.RESULTS Thirty-nine patients with CHC were enrolled[average age,42.3±14.4 years;20/39(51.3%)male].Twenty-one enrolled patients had eligible paired Gd-EOB-DTPA-enhanced MRI and liver tissues after achieving SVR.The mHAI median significantly decreased after SVR[baseline 6.0(4.5-13.5)vs SVR 2.0(1.5-5.5),Z=3.322,P=0.017],but the median stage of fibrosis did not notably change(P>0.05).Sixty pairs of qualified MRI and liver tissue samples were available for use to analyze the relationship between the CEI and hepatic pathology.The CEI was negatively correlated with the mHAI(r=-0.56,P<0.001)and Ishak score(r=-0.69,P<0.001).Further stratified analysis showed that the value of the CEI decreased with the progression of the stage of fibrosis rather than with the grade of necroinflammation.For patients with Ishak score≥5,the areas under receiver operating characteristics curve of the CEI,LSM,APRI,and FIB-4 were approximately at baseline,0.87–0.93,and after achieving SVR,0.83–0.91.The CEI cut-off value was stable(baseline 1.58 and SVR 1.59),but those of the APRI(from 1.05 to 0.24),FIB-4(from 1.78 to 1.28),and LSM(from 10.8 kpa to 7.1 kpa)decreased dramatically.The APRI and FIB-4 cannot be used as diagnostic means for SVR in patients with Ishak score≥3(P>0.05).Seven patients achieved fibrosis regression after achieving SVR.In these patients,the CEI median increased(from 1.71 to 1.83,Z=-1.981,P=0.048)and those of the APRI(from 1.71 to 1.83,Z=-2.878,P=0.004)and LSM(from 6.6 to 4.8,Z=-2.366,P=0.018)decreased.However,in patients without fibrosis regression,the medians of the APRI,FIB-4,and LSM also changed significantly(P<0.05).CONCLUSION Gd-EOB-DTPA-enhanced MRI has good diagnostic value for staging fibrosis in patients with CHC.It can be used for fibrotic-change monitoring post SVR in patients with CHC treated with DAAs.

Neoantigen vaccine:An emerging immunotherapy for hepatocellular carcinoma

Tumor-specific neoantigens,which are expressed on tumor cells,can induce an effective antitumor cytotoxic T-cell response and mediate tumor regression.Among tumor immunotherapies,neoantigen vaccines are in early human clinical trials and have demonstrated substantial efficiency.Compared with more neoantigens in melanoma,the paucity and inefficient identification of effective neoantigens in hepatocellular carcinoma(HCC)remain enormous challenges in effectively treating this malignancy.In this review,we highlight the current development of HCC neoantigens in its generation,screening,and identification.We also discuss the possibility that there are more effective neoantigens in hepatitis B virus(HBV)-related HCC than in non-HBV-related HCC.In addition,since HCC is an immunosuppressive tumor,strategies that reverse immunosuppression and enhance the immune response should be considered for the practical exploitation of HCC neoantigens.In summary,this review offers some strategies to solve existing problems in HCC neoantigen research and provide further insights for immunotherapy.

Association of FOXP3 Gene Polymorphism with Chronic Hepatitis B in Chinese Population

Objective The forkhead transcription factor FOXP3 is a key molecular which can mediate regulatory T cells immune-related inhibitory functions. Increased levels of FOXP3-positive Tregs in peripheral blood have been proved to be associated with a less favorable prognosis in various inflammatory diseases. It is of great interest to investigate the correlation between single nucleotide polymorphism(SNP) of FOXP3 gene and the susceptibility of chronic hepatitis B(CHB). Methods Two SNPs rs2280883 and rs3761549 of FOXP3 gene in 285 patients with CHB and 295 matched controls were analyzed by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry(MALDI-TOF). Results At rs2280883, there were no significant differences in the distribution of C and T alleles between CHB donors and healthy donors, but at rs3761549, C allele was associated with CHB(P = 0.001). Compared with healthy controls, patients with CHB had high frequencies of TT genotype(73.7%) at rs2280883 or CC genotype(73.6%) at rs3761549 of FOXP3 gene. Patients who carried rs2280883 CC genotype [OR 1.744(95% CI 1.068- 2.848), P = 0.011] or rs3761549 CC genotype [OR 1.633(95% CI 1.146- 2.327), P = 0.0001] had higher risk of suffering from CHB. Stratified analysis showed that rs3761549 CC genotype was significantly associated with high incidence of HBeAg(P = 0.019). Conclusions These results suggested that FOXP3 gene polymorphism at rs2280883 and rs3761549 might be associated with the increased susceptibility to CHB.

CD4^+CXCR5^+ T cells activate CD27^+IgG^+ B cells via IL-21 in patients with hepatitis C virus infection

BACKGROUND： Chronic hepatitis C virus （HCV） infection causes the skewing and activation of B cell subsets, but the characteristics of IgG＋ B cells in patients with chronic hepa- titis C （CHC） infection have not been thoroughly elucidated. CD4＋CXCR5＋ follicular helper T （Tfh） cells, via interleukin （IL）-21 secretion, activate B cells. However, the role of CD4＋CXCR5＋ T cells in the activation ofIgG＋ B cells in CHC patients is not clear. METHODS： The frequency of IgG＋ B cells, including CD27-IgG＋ B and CD27＋IgG＋ B cells, the expression of the activation markers （CD86 and CD95） in IgG＋ B cells, and the percentage of circu- lating CD4＋CXCR5＋ T cells were detected by flow cytometry in CHC patients （n=70） and healthy controls （n=25）. The con- centrations of serum IL-21 were analyzed using ELISA. The role of CD4＋CXCR5＋ T cells in the activation of IgG＋ B cells was investigated using a co-culture system. RESULTS： A significantly lower proportion of CD27＋IgG＋ B cells with increased expression of CD86 and CD95 was observed in CHC patients. The expression of CD95 was negatively correlated with the percentage of CD27＋IgG＋ B cells, and it contributed to CD27＋IgG＋ B cell apoptosis. Circulating CD4＋CXCR5＋ T cells and serum IL-21 were significantly increased in CHC patients. Moreover, circulating CD4＋CXCR5＋ T cells from CHC patients induced higher expressions of CD86 and CD95 in CD27＋IgG＋ B cells in a co-culture system; the blockade of the IL-21 decreased the expression levels of CD86 and CD95 in CD27＋IgG＋ B cells.CONCLUSIONS： HCV infection increased the frequency of CD4＋CXCR5＋ T cells and decreased the frequency of CD27＋IgG＋ B cells. CD4＋CXCR5＋ T cells activated CD27＋IgG＋ B cells via the secretion of IL-21.

Radiomics model based on contrast-enhanced computed tomography to predict early recurrence in patients with hepatocellular carcinoma after radical resection

BACKGROUND Radical resection remains an effective strategy for patients with hepatocellular carcinoma(HCC).Unfortunately,the postoperative early recurrence(recurrence within 2 years)rate is still high.AIM To develop a radiomics model based on preoperative contrast-enhanced computed tomography(CECT)to evaluate early recurrence in HCC patients with a single tumour.METHODS We enrolled a total of 402 HCC patients from two centres who were diagnosed with a single tumour and underwent radical resection.First,the features from the portal venous and arterial phases of CECT were extracted based on the region of interest,and the early recurrence-related radiomics features were selected via the least absolute shrinkage and selection operator proportional hazards model(LASSO Cox)to determine radiomics scores for each patient.Then,the clinicopathologic data were combined to develop a model to predict early recurrence by Cox regression.Finally,we evaluated the prediction performance of this model by multiple methods.RESULTS A total of 1915 radiomics features were extracted from CECT images,and 31 of them were used to determine the radiomics scores,which showed a significant difference between the early recurrence and nonearly recurrence groups.Univariate and multivariate Cox regression analyses showed that radiomics scores and serum alphafetoprotein were independent indicators,and they were used to develop a combined model to predict early recurrence.The area under the receiver operating characteristic curve values for the training and validation cohorts were 0.77 and 0.74,respectively,while the C-indices were 0.712 and 0.674,respectively.The calibration curves and decision curve analysis showed satisfactory accuracy and clinical utilities.Kaplan-Meier curves based on recurrence-free survival and overall survival showed significant differences.CONCLUSION The preoperative radiomics model was shown to be effective for predicting early recurrence among HCC patients with a single tumour.

An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients:High-sensitivity Quantitative HBsAg Loss

In the era of antiviral therapy,the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus(HBV)replication to the pursuit of serological clearance of HBs surface antigen(HBsAg).Based on the life cycle of HBV,HBsAg originates from covalently closed circular DNA(cccDNA)and integrated HBV DNA,thus reflecting their transcriptional activity.Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA.HBsAg loss improves the recovery of abnormal immune function,which in turn,may further promote the clearance of residual viruses.Combined with functional cure and the great improvement of clinical outcomes,the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B(CHB).For many other risk factors besides HBV itself,patients with HBsAg loss still need regular monitoring.In this review,we summarized the evolution of CHB treatment,the origin of serum HBsAg,the pattern of HBsAg seroclearance,and the effect of HBsAg loss on immune function and disease outcomes.In addition,we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.

Trends of Mortality in End-Stage Liver Disease—China,2008–2020

Introduction:Liver cancer and cirrhosis represent the most prevalent forms of end-stage liver diseases(ESLDs).Notably,in China,deaths attributed to ESLDs contribute significantly to the global mortality rate of these disorders.Enhanced comprehension of the mortality profile associated with ESLDs in China could provide crucial insights into intervention prioritization,which could in turn help reduce the overall global burden of these diseases.Methods:Data were obtained from China’s Disease Surveillance Points system.The presentation includes both crude and age-standardized mortality rates,stratified by sex,residential location,and region.Using Joinpoint Regression,trends in annual mortality rates were estimated from the period of 2008 to 2020 and expressed as the average annual percentage change(AAPC).Results:In 2020,the gross mortality rate of ESLD stood at 30.08 cases per 100,000 individuals.A higher age-standardized ESLD mortality rate was observed in males and rural populations in comparison to their female and urban counterparts,respectively.Noticeably,the highest mortality rates associated with liver cancer and cirrhosis were reported in South and Southwest China,respectively.A positive correlation was noticed between age-specific ESLD mortality rates and advancing age.Interestingly,an annual decrease in the ESLD mortality rate was observed from 2008 to 2020.In urban contexts,the AAPC of cirrhosis was noted to be higher than that of liver cancer.Conclusions:The mortality rate associated with ESLDs in China decreased between 2008 and 2020.Nevertheless,the death burden attributable to ESLD continues to be alarmingly high.Future initiatives should prioritize the reduction of ESLD mortality in particular populations:males,elderly individuals,and those residing in rural regions of South and Southwest China.The emphasis of future interventions should beplaced on antiviral therapy for adults diagnosed with viral hepatitis,and on the prevention of hepatitis B virus(HBV)infection across all demographics.

Impact of hepatitis C virus genotype 3 on liver disease progression in a Chinese national cohort

Background:Hepatitis C virus(HCV)genotype 3,particularly subtype 3b,is increasing in prevalence and distribution in China.This study evaluated the prevalence,regional distribution,clinical characteristics,host factors,treatment outcomes,and disease progression of patients with HCV genotype 3 in China.Methods:A 5-year follow-up was preceded by a cross-sectional study.Treatment choices were at the discretion of treating physicians.Estimated infection time to overall-disease-progression(defined by≥1 of:newly diagnosed cirrhosis;cirrhosis at baseline,Child-Turcotte-Pugh score increased 2 points or more;progression from compensated cirrhosis to decompensated cirrhosis;hepatocellular carcinoma;liver transplantation;or death)was calculated using the Kaplan-Meier method.Cox regression analyses were conducted to evaluate the risk factors for disease progression.Results:The cross-sectional study enrolled 997 patients,including 91 with HCV genotype 3 infection.Among them,subtype 3b(57.1%)was more dominant than subtype 3a(38.5%).Five hundred and twelve patients were included into the follow-up phase.Among patients analyzed for estimated infection time to overall-disease-progression,52/304(17.1%)patients with HCV genotype 1 and 4/41(9.8%)with HCV genotype 3(4/26 with genotype 3b,0/13 with genotype 3a,and 0/2 with undefined subtype of genotype 3)experienced overall-disease-progression.Patients with HCV genotype 3 were younger than those with genotype 1(mean age:39.5±8.7 vs.46.9±13.6 years)and demonstrated more rapid disease progression(mean estimated infection time to overall-disease-progression 27.1 vs.35.6 years).Conclusions:HCV genotype 3,specifically subtype 3b,is associated with more rapid progression of liver disease.Further analysis to compare HCV subtype 3a and 3b is needed in high prevalence regions.

Association between CISH polymorphisms and spontaneous clearance of hepatitis B virus in hepatitis B extracellular antigen-positive patients during immune active phase

Background Some hepatitis B extracellular antigen （HBeAg）-positive chronic hepatitis B （CHB） patients in their immune active phase can clear the virus spontaneously and enter into an inactive hepatitis B virus （HBV） carrier state,indicating a benign prognosis.In this study,the association between cytokine-inducibie SRC homology 2 domain protein （C/SH） gene polymorphisms at-292 （rs414171） and the spontaneous clearance of HBV in HBeAg-positive CHB patients in immune the active phase was investigated.Methods Seventy HBeAg-positive CHB patients in the immune active phase were followed up for 76 weeks without antiviral therapy.The alanine transaminase,aspartate transaminase,HBV DNA,HBeAg and hepatitis B extracellular antibody levels were tested regularly.At week 76,27 patients were classified into group A （HBV DNA level below 2 104 IU/ml and the value of HBeAg declined below 10％ of the baseline at week 76）,and 43 patients were classified into group B （HBV DNA level higher than 2×104 IU/ml or the value of HBeAg did not decline substantially at week 76）.CISH （rs414171） polymorphisms were also tested using the iPLEX system.Results The HBV DNA levels at week 12 were significantly greater in group B compared with group A （group A：（6.87±1.40） log10IU/ml; group B：（7.61±1.38） log10IU/ml,P=0.034） and the HBeAg values were greater in group B at week 28 compared with group A （P=0.001）.The differences in HBV DNA and HBeAg values increased between the groups over time.Sixteen patients in group A and 11 in group B were genotype AA.Those with genotype AT or TT included 11 in group A and 31 in group B （AA vs.AT and TT,odds ratio 4.10 （95％ confidence interval：1.462-11.491）,P=0.006）.Conclusion CISH gene polymorphisms at-292 （rs414171） are associated with HBV clearance in HBeAg-positive CHB patients in the immune active phase,and AA is a favorable genotype for this effect.

Efficacy and Safety of 12-week Interferon-based Danoprevir Regimen in Patients with Genotype 1 Chronic Hepatitis C

Background and Aims:Genotype(GT)1 remains the predominant hepatitis c virus(HCV)GT in Chinese patients.Over 80%of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860,which is favorable for interferon-based treatment regimens.This phaseⅢclinical trial aimed to evaluate the efficacy and safety of the ritonavirboosted danoprevir plus pegylated-interferonα-2a and ribavirin regimen for 12 weeks in treatment-na(i)ve mainland Chinese patients infected with HCV GT1 without cirrhosis.Methods:One hundred and forty-one treatment-na(i)ve,non-cirrhotic HCV GT1 Chinese patients(age≥18 years)were enrolled for this single-arm,multicenter,phaseⅢMANASA study(NCT03020082).Patients received a combination of ritonavir-boosted danoprevir(100 mg/100 mg)twice a day plus subcutaneous injection of weekly pegylated-interferonα-2a(180μg)and oral ribavirin(1000/1200 mg/day body weight<75/≥75 kg)for 12 weeks.The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment.The secondary end-points were safety outcomes,tolerability,virologic response over time and relapse rate.Results:All enrolled patients were HCV GT1-infected,and most among them(97.9%,123/141)had the HCV GT1b subtype.Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype(87.2%,123/141).Overall,140 patients completed the 12-week treatment,and 97.1%(136/140)patients achieved sustained virologic response at 12 weeks(per protocol population group,95%confidence interval:92.9-99.2%).Only drug-related serious adverse event occurred.Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction.One patient discontinued treatment because of severe head injury in a car accident.Conclusions:The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferonα-2a and ribavirin produced a sustained virologic response rate of 97.1%after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients,and was safe and well tolerated.

Patient Education Improves Patient Knowledge and Acceptance on Antiviral Therapy of Hepatitis C in Rural China

It is estimated that 130-150 million people are chronically infected with hepatitis C virus （HCV） worldwide. During the late 1980s and early 1990s, illegal commercial plasma or blood donation practices were common in selected rural areas of China, which caused a rapid spread of HCV infection. Cross-sectional studies have showed that the prevalence rates of HCV infection in former paid plasma or blood donors varied from 9.6% to 72.8%. Chronic HCV infection can cause cirrhosis, liver failure, and hepatocellular carcinoma （HCC）, and is a major global health problem.

Expert Consensus on Diagnosis and Treatment of End-Stage Liver Disease Complicated with Infections

End-stage liver disease(ESLD)is a life-threatening clinical syndrome that markedly increases mortality in patients with infections.In patients with ESLD,infections can induce or aggravate the occurrence of liver decompensation.Consequently,infections are among the most common complications of disease progression.There is a lack of working procedure for early diagnosis and appropriate management for patients with ESLD complicated by infections as well as local and international guidelines or consensus.This consensus assembled up-to-date knowledge and experience across Chinese colleagues,providing data on principles as well as working procedures for the diagnosis and treatment of patients with ESLD complicated by infections.

Efficacy of Real-world Entecavir Therapy in Treatment-naive Chronic Hepatitis B Patients

Background：Entecavir （ETV） has been shown to be effective in randomized controlled trials in highly selected patients with hepatitis B virus （HBV） infection.This study aimed to evaluate the efficacy of ETV in chronic hepatitis B （CHB） patients in the real-world setting.Methods：A total of 233 treatment-na（i）ve,CHB patients who received at least 12 months of ETV treatment were included in this retrospective study.Rates of virological response （VR）,hepatitis B s antigen （HBsAg） loss,hepatitis B e antigen （HBeAg） clearance/seroconversion,virological breakthrough,cirrhosis,and hepatocellular carcinoma were evaluated.Results：Of 233 patients,175 patients were male,with mean age of 43 years old,and 135 patients were HBeAg positive.The mean baseline levels of serum alanine aminotransferase and HBV DNA in all patients were 230 U/L and 6.6 log 10 IU/ml,respectively.The mean follow-up period was 28 months.The cumulative rates of achieving VR increased from 3.4% at 3 months to 94.4% at 60 months.Primary nonresponse occurred in 3 （1.3%） patients.Partial VR （PVR） occurred in 61 （26.2%） patients at 12 months.The baseline serum HBV DNA level （hazard ratio [HR],2.054;P 〈 0.001） was an independent risk factor for PVR.HBsAg loss did not occur.The cumulative rates of HBeAg clearance increased from 2.2% at 3 months to 28.2% at 60 months.PVR was the significant determinant of HBeAg clearance （HR,0.341;P =0.026）.Age （HR,1.072;P =0.013） and PVR （HR,5.131;P =0.017） were the significant determinants of cirrhosis.Conclusions：ETV treatment was effective for HBV DNA suppression in this study,but HBsAg loss and HBeAg clearance/seroconversion rates were lower compared with previous clinical trials.PVR was associated with HBeAg clearance and cirrhosis.