| Objective:1.This study aimed to analyze the clinical efficacy of entecavir(ETV)sequential combined with pegylated interferon(PEG-IFN)to week 72 in chronic hepatitis B e antigen(HBeAg)-positive with poor response to pegylated interferon monotherapy for 24 weeks.2.The study preliminary explored the evaluation indices of safe ETV cessation in the simultaneous and sequential combination therapy with PEG-IFN and ETV for chronic hepatitis B e antigen HBeAg-positive patients.3.To explore the impact of HBV DNA by different detection methods on judging the efficacy in the treatment of chronic hepatitis B e antigen HBeAg-positive with PEG-IFN.Methods:This clinical study was performed by using a retrospective method in the real world.Subjects were recruited from the outpatient and ward of Second People's Hospital of Tianjin between January 2012 and January 2017.1.A total of 252 patients submitted to PEG-IFNa-2b primarily antiviral therapy.The patients who had achieved HBV DNA ? 2000 IU/ml at week 24 with PEG-IFNa-2b monotherapy and continued to PEG-IFNa-2b monotherapy to 72 weeks were classified under the PEG-IFN monotherapy group.The patients who did not achieve HBV DNA ? 2000 IU/ml after 24 weeks of PEG-IFN monotherapy,adding ETV to ongoing peg-IFN therapy from 24 to 72 weeks were classified under ETV combination group.The patients from each treatment group were matched at a 1:1ratio according to the following criteria: age difference of ?10 years,gender and baseline difference in HBsAg levels of <0.15 lgIU/ml,HBeAg levels of <0.2 lgCOI and HBV DNA levels of <1.0 lgIU/ml.A total of 23 individuals were included in each group after the matched pairing was performed.The mean decline and downward trend of the HBeAg and hepatitis B surface antigen(HBsAg)levels,and the rates of HBV DNA-negative and HBeAg seroconversion of the two groups were compared.2.A total of 26 patients applied the simultaneous combination therapy withPEG-IFNa-2b and ETV,and 93 cases applied PEG-IFNa-2b monotherapy initial,adding ETV to ongoing PEG-IFN therapy in the later.3 of the former and 8 of the latter were chosen who were treated by combination therapy with different courses before ETV cessation,and continued peg-IFN monotherapy more than 24 weeks after the discontinuation of ETV.The HBeAg,HBsAg and HBV DNA changes of these 12 patients were shown when ETV combination,ETV cessation and 24 weeks of ETV cessation.The related indicators of stopping ETV safely in the patients who underwent simultaneous or sequential combination therapy were analyzed.3.In the 252 patients of applying PEG-IFNa-2b primarily antiviral therapy,104 cases were chosen who were detected HBV DNA-negative by low sensitive detection method(The minimum detection limit 500 copies/mL)within the 24 weeks.In the 36 weeks after HBV DNA-negative by low sensitive detection method of chronic hepatitis B with pegylated interferon,the patients HBV DNA-negative persistently by highly sensitive detection method(The minimum detection limit 20 IU/mL)were enrolled in the negative group.The patients HBV DNA-positive persistently by highly sensitive detection method were enrolled in the positive group.The decline of HBeAg and HBsAg,and the rate of HBe Ag serological conversion were observed in the 12,24 and 36 weeks after HBV DNA-negative by low sensitive detection method.Results:1.The HBe Ag and hepatitis B surface antigen(HBsAg)levels of the PEG-IFN monotherapy group significantly decreased but that of the ETV combination group slowly declined from week 0 to 24(1.20 lgCOI;0.34 lgIU/mL vs.0.51 lgCOI;0.09lgIU/m L).The rate of HBV DNA-negative(8/23,26.1% vs 0/23,0%;P=0.004),the decline of HBeAg(1.20 lgCOI vs.0.51 lgCOI;P = 0.005)and HBe Ag seroconversion levels(26.1% vs.0%;P = 0.022)were higher in the PEG-IFN monotherapy group than that in the ETV combination group.The HBeAg and HBsAg levels of the PEG-IFN monotherapy group slowly declined from week 24 to 48 but rapidly reduced in the ETV combination group(0.11 lgCOI;0.11 lgIU/mL vs.1.00lgCOI;0.30 lgIU/mL).The differences between the two groups of HBV DNA-negative(16/23,69.6% vs.12/23,52.2%;P = 0.365)rate,the decline of HBeAg(1.51 lgCOI vs.1.31 lgCOI;P = 0.405)and HBeAg seroconversion levels(6/23,26.1% vs 7/23,30.4%;P = 1.000)were not statistically significant at week 48.The HBe Ag and HBsAg levels of the PEG-IFN monotherapy group slowly declined from week 48 to 72 but persistently reduced in the ETV combination group(0.23lgCOI;0.15 lgIU/mL vs.1.50 lgCOI;1.43 lgIU/mL).The decline of HBeAg(2.01 lgCOI vs.1.43 lgCOI;P = 0.021)and HBV DNA-negative levels(<20 IU/ml;23/23,100% vs 16/23,69.6%;P = 0.009)were higher in the ETV combination group than that in the PEG-IFN monotherapy group at week 72.The mean decline of HBsAg levels was not statistically significant in the total of 72 weeks.2.When ETV combination,the levels of HBe Ag,HBsAg and HBV DNA were all positive and different of the 12 patients(HBsAg: 517~21542 IU/mL;HBeAg:7~1003 COI;HBV DNA : 1.1*10^2 ~1.4*10^8 IU/m L).Four cases achieved the HBeAg seroconversion and HBV DNA-negative(The minimum detection limit 20IU/m L)when ETV cessation.The HBeAg and HBV DNA levels remained negative,and the HBsAg level persistently declined to low level(<300 IU/mL)during PEG-IFN monotherapy for 24 weeks after stopping ETV of the four cases,and the courses of combination therapy with PEG-IFN and ETV were relatively long(36~84weeks).There were five individuals the HBV DNA levels were negative but the HBeAg levels were positive when stopping ETV.Three fifths of patients yielded a positive HBV DNA level when 24 weeks of ETV discontinuation,and the HBeAg,HBsAg levels slowly declined and remained positive;The decline of HBeAg level was higher in the 2 cases who did not rebound of the HBV DNA than that in the 3patients who rebounded of the HBV DNA.There were three patients that HBeAg and HBV DNA levels were positive when ETV cessation.They did not achieve HBeAg seroconversion and HBV DNA-negative when 24 weeks of ETV discontinuation,and the decrease in HBeAg and HBsAg levels was not evident.3.The decline of HBeAg levels of the negative group was more significant than that of the positive group at week 12 after HBV DNA-negative by low sensitive detection method,the difference were statistically significant(0.32 lgCOI vs.0.14 lgCOI,P = 0.002).However,the HBsAg declined and the HBeAg seroconversion levels of the negative group were not more significant than that of the positive group,the difference were not statistically significant(0.07 lgIU/ml vs.0.01 lgIU/ml,P =0.067;10/33,30.30% vs.8/50,16.00%,P = 0.174).The HBeAg and HBsAg declined and the HBeAg seroconversion levels of the negative group were more significant than that of the positive group at week 24 after HBV DNA-negative by low sensitive detection method,the difference was statistically significant(0.13 lgIU/ml vs.0.08lgIU/ml,P = 0.021;0.44 lgCOI vs.0.16 lgCOI,P = 0.002;12/33,36.36% vs.8/50,16.00%,P = 0.040).The HBeAg and HBsAg declined and the HBeAg seroconversion levels of the negative group were more significant than that of the positive group at week 36 after HBV DNA-negative by low sensitive detection method,the difference was statistically significant(0.16 lgIU/ml vs.0.03 lgIU/ml,P= 0.018;0.51 lgCOI vs.0.24 lgCOI,P < 0.001;19/33,39.39% vs.9/50,18.00%,P =0.042).Conclusions:1.The efficacy of PEG-IFN monotherapy should be evaluated timely in HBeAg-positive patients.ETV could be added to improve efficacy when poor response and HBV markers slightly changed into a relative plateau.2.In the combination therapy with PEG-IFN and ETV for chronic hepatitis B e antigen positive patients,ETV could be safely discontinued after HBV DNA-negative and HBeAg seroconversion were observed in order to continuously sustain an immune response after ETV discontinuation.3.In order to judge the antiviral efficacy accurately,highly sensitive detection method of HBV DNA should be applied in the treatment of HBeAg-positive chronic hepatitis B with PEG-IFN. |
PDF Full Text Request