The Effects And Predictors Of ?-interferon Based Antiviral Therapy Optimization On The Long-term Outcome Of HCC And Clinical Cure In CHB Patients

Aims:The effects and predictors of?-interferon(?-IFN)based antiviral therapy optimization on the long-term outcome of HCC and clinical cure in chronic hepatitis B(CHB)remains to be further investigated.We assessed whether antiviral strategy affected HCC development in CHB patients at different HCC risks,and evaluated the effect and predictors of different strategies with?-IFN on clinical cure for CHB patients with viral response by NAs treatment.Methods:In the study 1,the CHB patients who received standard antiviral therapy and regular follow-up at the Department of Infectious Disease of Ruijin Hospital from April2003 to January 2017 were included.Patients treated with NAs only were classified into the NAs group while those received IFN treatment?24 weeks with or without NAs were defined as the IFN group.Kaplan-meier curves,Cox regression,propensity score matching(PSM)and receiver operating characteristic(ROC)curves were used to evaluate the effect of antiviral strategies on the long-term outcome of HCC in CHB patients at different HCC risks.In the study 2,HBeAg negative and noncirrhotic CHB patients with virological response by NAs continued to achieve add-on or switch-to therapy with pegylataed interferon(PEG-IFN)for?24 weeks in the Department of Infectious Diseases of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and the Second Affiliated Hospital of Chongqing Medical University from January 2012 to June 2017 were included.The above-mentioned methods were used to analyze the effect and predictors of different strategies with PEG-IFN on clinical cure.Results:1.In the study 1,1112 patients were included,of which 31 patients developed HCC,and the median follow-up period was 5.41 years.The 10-year cumulative incidence of HCC between the IFN and NAs group in the entire(n=1112)and na(?)ve(n=755)cohorts was 2.7%vs 8.0%,p<0.001;0.0%vs 8.9%,p<0.001;respectively.After PSM,the 10-year cumulative incidence of HCC between the IFN and NAs group in the entire and na(?)ve population was 0.5%vs 6.8%,p=0.019;0.0%vs 9.8%,p=0.041;respectively.2.Multivariate Cox analysis showed that age(Hazard ratio[95%CI],2.87[1.09-7.55],p=0.032),gender(5.67[1.72-18.70],p=0.004),cirrhosis(5.46[2.49-11.97],p<0.001),antiviral strategy(0.15[0.04-0.66],p=0.012)were independent risk factors for HCC development.3.For the CHB patients at low HCC risk(CU-HCC<5,GAG-HCC<82,REACH-B<8,PAGE-B<10),there were no significant differences in the 10-year cumulative incidence of HCC between the IFN and NAs group(all p values>0.05).For the CHB patients at high HCC risk(CU-HCC?5,GAG-HCC?82,REACH-B?8,PAGE-B?10),the 10-year cumulative incidence of HCC between the IFN and NAs group were 5.3%vs 12.3%,p<0.001;11.1%vs 13.3%,p=0.031;2.6%vs 9.3%,p<0.001;3.1%vs11.1%,p<0.001;respectively.4.In the study 2,250 patients were included,of which 50 cases obtained HBsAg clearance,and the median follow-up period was 48 weeks.The overall cumulative incidence of HBsAg clearance in the add-on group(n=120)and switch-to(n=130)group was 31.29%vs 28.01%,p=0.20.After PSM,the overall cumulative rate of HBsAg clearance in the two groups(n=91 pairs)was 21.99%vs 38.11%,p=0.14.5.Multivariate Cox analysis showed that baseline HBsAg levels(0.21[0.15-0.31],p<0.001),and HBsAg reduction at 24 weeks during treatment(3.47[2.56-4.70],p<0.001)were independent factors for HBsAg clearance.6.ROC curve suggests that the area under the ROC curve of the baseline HBsAg level and HBsAg reduction at 24 weeks during treatment predicting HBsAg clearance through PEG-IFN therapy is 0.869,0.932;the cut-off values were 500 IU/mL,0.75 log₁₀ IU/mL;respectively.7.The entire cohort was divided into four subgroups based on the cutoff values of 500IU/mL for HBsAg level at baseline and 0.75 log₁₀ IU/mL for HBsAg reduction at 24weeks during treatment.The overall cumulative incidence of HBsAg clearance during treatment for the subgroup with HBsAg at baseline<500 IU/mL and HBsAg reduction at24 weeks>0.75 log₁₀ IU/mL was 85.87%,significantly higher than the other three groups(all p values<0.05).Conclusion:1.Reduction of HCC development was more significant in CHB patients at higher HCC risk with IFN-based therapy than NAs treatment.2.Age,gender,cirrhosis and antiviral strategy were independent factors for CHB related HCC development.3.For HBeAg negative and noncirrhotic CHB patients with virological response by NAs,there was no significant difference in the cumulative incidence of HBsAg clearance between the add-on and switch-to therapy with PEG-IFN.Baseline HBsAg level and HBsAg reduction at 24 weeks during treatment were indepedent factors of HBsAg clearance through PEG-IFN therapy.Among these patients,those with baseline HBsAg level<500 IU/mL and HBsAg reduction at 24 weeks during treatment>0.75 log₁₀IU/mL were the benefit population who could obtain HBsAg clearance.