Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication

BACKGROUND Chronic hepatitis C virus(HCV)infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood.Clearance of HCV by antivirals results in host immune modification,which may interfere with immune-mediated cancer surveillance.Identifying HCV patients who remain at risk of hepatocellular carcinoma(HCC)following HCV eradication remains an unmet need.We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.AIM To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.METHODS One hundred treatment-naïve HCV patients with advanced fibrosis(F3/4)treated with direct-acting antivirals(DAAs)or peginterferon/ribavirin who achieved sustained virologic response[SVR,defined as undetectable HCV RNA throughout 12 wk(SVR12)for the DAA group or 24 wk(SVR24)for the interferon group after completion of antiviral therapy]were enrolled since 2003.The primary endpoint was the development of new-onset HCC.Standard HCC surveillance(abdominal ultrasound andα-fetoprotein)was performed every six months during the followup.Overall,64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.RESULTS HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication.In univariate analysis,the Fibrosis-4 index(FIB-4),hemoglobin A1c(HbA1c),the dynamics of tumor necrosis factor-α(TNF-α),and TNF-like weak inducer of apoptosis(TWEAK)after antiviral therapy were significant HCC predictors.The multivariate Cox regression model showed thatΔTNF-α(≤-5.7 pg/mL)was the most important risk factor for HCC(HR=11.54,95%CI:2.27-58.72,P=0.003 in overall cases;HR=9.98,95%CI:1.88-52.87,P=0.007 in the interferon group).An HCC predictive model comprising FIB-4,HbA1c,ΔTNF-α,andΔTWEAK had excellent performance,with 3-,5-,10-,and 13-year areas under the curve of 0.882,0.864,0.903,and 1.000,respectively.The 5-year accumulative risks of HCC were 0%,16.9%,and 40.0%in the low-,intermediate-,and high-risk groups,respectively.CONCLUSION Downregulation of serum TNF-αsignificantly increases the risk of HCC after HCV eradication.A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.

Outreach onsite treatment with a simplified pangenotypic directacting anti-viral regimen for hepatitis C virus micro-elimination in a prison

BACKGROUND Prisoners are at risk of hepatitis C virus(HCV)infection,especially among the people who inject drugs(PWID).We implemented an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic direct-acting antivirals(DAA)regimen,12 wk of sofosbuvir/velpatasvir,in a PWID-dominant prison in Taiwan.AIM To implement an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic DAA regimen in a PWID-dominant prison in Taiwan.METHODS HCV-viremic patients were recruited for onsite treatment program for HCV micro-elimination with a pangenotypic DAA regimen,12 wk of sofosbuvir/velpatasvir,from two cohorts in Penghu Prison,either identified by mass screen or in outpatient clinics,in September 2019.Another group of HCV-viremic patients identified sporadically in outpatient clinics before mass screening were enrolled as a control group.The primary endpoint was sustained virological response(SVR12,defined as undetectable HCV ribonucleic acid(RNA)12 wk after end-of-treatment).RESULTS A total of 212 HCV-viremic subjects were recruited for HCV micro-elimination campaign;91 patients treated with sofosbuvir/Ledipasvir or glecaprevir/pibrentasvir before mass screening were enrolled as a control.The HCV microelimination group had significantly lower proportion of diabetes,hypertension,hyperlipidemia,advanced fibrosis and chronic kidney diseases,but higher levels of HCV RNA.The SVR12 rate was comparable between the HCV microelimination and control groups,95.8%(203/212)vs 94.5%(86/91),respectively,in intent-to-treat analysis,and 100%(203/203)vs 98.9%(86/87),respectively,in perprotocol analysis.There was no virological failure,treatment discontinuation,and serious adverse event among sofosbuvir/velpatasvir-treated patients in the HCV micro-elimination group.CONCLUSION Outreach mass screening followed by immediate onsite treatment with a simplified pangenotypic DAA regimen,sofosbuvir/velpatasvir,provides successful strategies toward HCV micro-elimination among prisoners.

Real-world Effectiveness and Tolerability of Interferonfree Direct-acting Antiviral for 15,849 Patients with Chronic Hepatitis C:A Multinational Cohort Study

Background and Aims:As practice patterns and hepatitis C virus(HCV)genotypes(GT)vary geographically,a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal.This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs,focusing on GT3 and GT6.Methods:We analyzed the sustained virological response(SVR12)of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific,North America,and Europe between 07/01/2014–07/01/2021.Results:The mean age was 62±13 years,with 49.6%male.The demographic breakdown was 91.1%Asian(52.9%Japanese,25.7%Chinese/Taiwan residents,5.4%Korean,3.3%Malaysian,and 2.9%Vietnamese),6.4%White,1.3%Hispanic/Latino,and 1%Black/African-American.Additionally,34.8%had cirrhosis,8.6%had hepatocellular carcinoma(HCC),and 24.9%were treatment-experienced(20.7%with interferon,4.3%with direct-acting antivirals).The largest group was GT1(10,246[64.6%]),followed by GT2(3,686[23.2%]),GT3(1,151[7.2%]),GT6(457[2.8%]),GT4(47[0.3%]),GT5(1[0.006%]),and untyped GTs(261[1.6%]).The overall SVR12 was 96.9%,with rates over 95%for GT1/2/3/6 but 91.5%for GT4.SVR12 for GT3 was 95.1%overall,98.2%for GT3a,and 94.0%for GT3b.SVR12 was 98.3%overall for GT6,lower for patients with cirrhosis and treatment-experienced(TE)(93.8%)but≥97.5%for tretment-naive patients regardless of cirrhosis status.On multivariable analysis,advanced age,prior treatment failure,cirrhosis,active HCC,and GT3/4 were independent predictors of lower SVR12,while being Asian was a significant predictor of achieving SVR12.Conclusions:In this diverse multinational realworld cohort of patients with various GTs,the overall cure rate was 96.9%,despite large numbers of patients with cirrhosis,HCC,TE,and GT3/6.SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent(>91%).

Community-centered Disease Severity Assessment of Metabolic Dysfunction-associated Fatty Liver Disease

Background and Aims:Disease severity across the different diagnostic categories of metabolic dysfunction-associated fatty liver disease(MAFLD)remains elusive.This study assessed the fibrosis stages and features of MAFLD between different items.We also aimed to investigate the associations between advanced fibrosis and risk factors.Methods:This multicenter cross-sectional study enrolled adults participating in liver disease screening in the community.Patients were stratified following MAFLD diagnostic criteria,to group A(395 patients)for type 2 diabetes,group B(1,818 patients)for body mass index(BMI)>23 kg/m^(2),and group C(44 patients)for BMI≤23kg/m^(2) with at least two metabolic factors.Advanced fibrosis was defined as a fibrosis-4 index>2.67.Results:Between 2009 and 2020,1,948 MAFLD patients were recruited,including 478 with concomitant liver diseases.Advanced fibrosis was observed in 125 patients.A significantly larger proportion of patients in group C(25.0%)than in group A(7.6%)and group B(5.8%)had advanced fibrosis (p<0.01).Logistic regression analysis found that hepatitis B virus(HBV)/hepatitis C virus(HCV)coinfection(odds ratio[OR]:12.14,95%confidence interval[CI]:4.04-36.52;p<0.01),HCV infection(OR:7.87,95%CI:4.78-12.97;p<0.01),group C(OR:6.00,95%CI:2.53-14.22;p<0.01),and TC/LDL-C(OR:1.21,95%CI:1.06-1.38;p<0.01)were significant predictors of advanced fibrosis.Conclusions:A higher proportion of lean MAFLD patients with metabolic abnormalities had advanced fibrosis.HCV infection was significantly associated with advanced fibrosis.

Treatment efficacy for patients with chronic hepatitis C and preexisting hepatocellular carcinoma by directly acting antivirals

Aim:Despite the high cure rate of interferon-free directly acting antivirals(DAAs)for chronic hepatitis C(CHC)patients,the treatment efficacy for patients with preexisting hepatocellular carcinoma(HCC)remains undefined.We aimed in the present study to address the issue by using novel DAAs in treating CHC patients who were adherent to treatment in Taiwan.Methods:CHC patients with or without HCC were consecutively enrolled.The primary objective was sustained virological response(SVR)defined as undetectable HCV RNA throughout 12 weeks of a post-treatment follow-up period(SVR12).Only patients with available SVR12 were enrolled for final analysis.Results:A total of 1237 patients(1113 non-HCC,101 inactive HCC and 23 active HCC)were enrolled.The overall SVR12 rate was 98.9%,and was similar between HCV patients with and without pre-existing HCC(98.4%vs.98.9%,P=0.64).While HCC patients were classified as those who had active or inactive HCC,the SVR12 was also similar between patients with and without active HCC(95.7%vs.99.0%,P=0.34).Among the 101 patients without viable HCC at the time of DAA initiation,eighty-four patients exhibited curative therapy and the other 17 ;patients experienced HCC recurrence before DAAs.Among the 23 patients with viable HCC at the time of DAA treatment,10 patients had received curative therapy for HCC whereas the remaining 13 patients had HCC that was never cured.The SVR12 rates were also similar among the four subpopulations,being 98.8%(83/84),100%(17/17),90%(9/10)and 100%(13/13)respectively.Conclusion:CHC patients with HCC who were adherent to potent DAAs achieved similar SVR12 rate compared to those without HCC and could be effectively treated.