| Part Ⅰ Individualized study of pegylated interferon alfa-2a in the initial treatment of HBeAg-positive chronic hepatitis B patientsObjectivesTo investigate the clinical efficacy and related predictors of pegylated interferon(Peg-IFN)α-2a individualized treatment in the treatment-naive HBeAg-positive CHB patients.Methods139 HBeAg-positive patients with chronic hepatitis B were treated with Peg-IFNα-2a 180 μg subcutaneously once a week for 48 weeks and followed up for 48 weeks.Two milliliters of blood samples were obtained and separated before treatment,and the plasma supernatant was extracted and stored in the freezer at-20℃.Hepatitis B virus genotypes were measured in all patients,and HBV DNA,ALT,five hepatitis B quantitative,blood routine,thyroid function,antinuclear antibody panel and other in-dicators were measured before treatment and at 12 weeks,24 weeks,36 weeks,48 weeks and 72 weeks of treatment.All patients were divided into four groups and giv-en individualized treatment according to the HBVDNA response at 24 weeks.(1)Conventional treatment group:If HBVDNA decreased≥ 1 logcopies/ml at 24 weeks,the course of treatment was continued to 48 weeks.(2)Prolonged treatment group:If HBV DNA decreased<1 logcopies/ml at 24 weeks,treatment was continued until 72 weeks.(3)Combination therapy group:If HBV DNA decreased<1 logcopies/ml at 24 weeks,Entecavir(ETV)0.5 mg once a day combined with Peg-IFN a-2a was applied until 48 weeks.(4)Sequential treatment group:If HBVDNA decreased l<1 logcopies/ml at 24 weeks,Peg-IFNα-2a was discontinued and sequential ETV 0.5mg was given once a day for 48 weeks or more.The HBVDNA negative conversion rate,ALT recovery rate,HBeAg negative conversion rate and seroconversion rate,HBsAg quantitative decrease range,negative conversion rate and seroconversion rate were observed at 12 weeks,24 weeks,36 weeks 48 weeks and 72 weeks of treatment.The correlation between HBV genotypes and the therapeutic efficacy of Peg-IFN a-2a was analyzed.Adverse reactions during treatment were observed and recorded,and Peg-IFN a-2a was discontinued once serious adverse reactions occurred.According to the response of ALT,HBV DNA and HBeAg,the patients were di-vided into three groups:complete response(CR),partial response(PR)and nonre-sponse(NR).(1)CR:ALT returned to normal,HBVDNA<103 copies/ml,HBeAg serocon-version.(2)NR:None of the indicators meet the above criteria.(3)PR:between CR and NR.Statistical methods were applied for analysis,and P<0.05 was considered statiscally significant.Results1.Baseline characteristicsAmong the 139 patients,65 were included in the conventional treatment group,24 in the extended treatment group,23 in the combined treatment group,and 27 in the sequential treatment group.There were no statistical differences in gender,age,geno-type,and the ALT,HBVDNA and HBsAg quantitative before treatment among all groups(P>0.05),which showed a comparability.2.Comparison of curative effect between the groupsThe recovery rate of ALT,HBV DNA negative conversion rate,HBeAg negative conversion rate,seroconversion rate and average decrease of HBsAg level in the con-ventional treatment group were higher than those in the extended course group(67.7%vs 12.5%,66.2%vs 16.7%,53.8%vs 12.5%,33.8%vs 0%,1.62 ± 1.15 logIU/ml vs 0.39 ± 0.52 logIU/ml)(P<0.05);After 72weeks of Peg-IFNα-2a treatment,the above indicators were still lower than those in the conventional treatment group by 48 weeks(P<0.05).Comparison among the four groups showed that except for HBsAg negative conversion rate,which had no statistically difference(P>0.05),other indicators were statistically different(P<0.05).The HBeAg negative conversion rate(53.8%),seroconversion rate(33.8%)and mean decrease in HBsAg(1.62±1.15 logIU/ml)in the conventional treatment group were higher than those in the combined treatment group(13.04%,0%,0.41 ± 0.16 lo-gIU/ml)and the sequential treatment group(0%,0%,0.35±0.14 logIU/ml)(P<0.05),while there was no significant statistically difference in the ALT renormalizing rate and HBVDNA negative conversion rate among the three groups(P>0.05).The ALT normalization rate(29.2%)and HBVDNA negative conversion rate(16.7%)in the prolongation treatment group were lower than those in the other two groups(69.6%,66.7%;87.0%,85.2%)(P<0.05),the negative conversion rate of HBeAg(12.5%)and serum conversion rate(12.5%)were higher than those of the other two groups(13.04%,0%;0%,0%)(P<0.05).3.Comparison of the correlation between genotype and efficacy:There was no significant statistically difference in the clinical efficacy of geno-types B and C in each group(P>0.05).4.Analysis of influencing factors of Peg-IFNα-2a treatmentMultivariate logistic regression analysis was performed with age,gender,base-line HBVDNA load,HBV genotype,ALT level and HBsAg level as independent var-iables(X),and whether the response or not(HBVDNA decreased≥1 logcopies/ml by antiviral therapy after 24 weeks)(0=no,1=yes)as dependent variable(Y).The re-sults showed that gender and the HBsAg level before treatment was correlated with the HBV response at 24 weeks of Peg-IFNα-2a treatment,and female gender and HBsAg level≤4 logcopies/ml had higher HBVDNA response(P<0.05).5.Comparison of adverse reactionsThe adverse reactions of Peg-IFNα-2a treatment were compared among the three groups:conventional treatment group,prolonged treatment group and combined treatment group.The results showed that there was no difference in fever,influen-za-like symptoms,leukopenia,thrombocytopenia,fatigue,elevated ALT,alopecia and other adverse reactions among the three groups(P>0.05).139 patients did not have serious adverse reactions leading to discontinue the therapy.ConclusionsFor treatment-naive HBeAg-positive CHB patients,if they are female and the HBsAg level is less than or equal to 4 logIU/ml before treatment,Peg-IFNα-2a anti-viral therapy can be preferred,and individualized treatment can be given according to the HBVDNA response at 24 weeks;if the HBVDNA decline at 24 weeks is more than 1logcopies/ml,the patients can continue the original treatment;If the decrease was less than llogcopies/ml,it was recommended to discontinue Peg-IFNα-2a and replace it with NAs monotherapy for antiviral therapy such as ETV.In this study,no advantage of prolonging the course of Peg-IFNα-2a treatment nor combining NAs regimen was found for patients with HBVDNA decreased by<1 logcopies/ml at 24 weeks,so it was not recommended.Part Ⅱ Efficacy analysis of combined pegylated interferon alfa-2a in the treatment of entecavir-treated patients with chronic hepatitis BObjectivesTo investigate the efficacy of pegylated interferon alfa-2a in the treatment of pa-tients with chronic hepatitis B treated with entecavir;to analyze the influencing fac-tors related to the efficacy.MethodsNinety-five patients with chronic hepatitis B who were virologically negative and HBsAg quantification was<1500 IU/L for more than 6 months of antiviral thera-py with ETV were selected and divided into two groups according to the patient’s wishes:(1)Combination therapy group:a total of 35 patients,combined with Peg-IFNα-2a 180 ug subcutaneous injection once a week on the basis of the origin-al ETV treatment,the treatment lasted for 48 weeks.Symptomatic treatment w as given in case of adverse reactions,or the treatment was discontinued in sev-ere cases.(2)Monotherapy group:60 patients continue to use ETV.In the combination therapy group,two milliliters of blood samples were obtained and separated before treatment,and the plasma supernatant was extracted and stored in the freezer at-20℃.HBV genotypes were measured in all patients,and HBVDNA,ALT,five quantitative items of hepatitis B,blood routine,and thyroid function were measured before treatment and at 12,24,36 and 48 weeks of treatment.The HBsAg quantitative value,negative conversion rate and seroconversion rate were observed at 12 weeks,24 weeks,36 weeks and 48 weeks of treatment;the relat-ed factors of the efficacy of Peg-IFNα-2a combination therapy were analyzed;the ad-verse reactions during treatment were observed and recorded.Statistical methods were used for analysis,and P<0.05 was considered statisti-cally significant.Results1.Baseline characteristics of the two groupsThere were no statistically significant differences in gender,age,ALT level,HBeAg positive proportion,HBsAg quantitative level,and genotype proportion be-tween the two groups(P>0.05),which showed a comparability.2.Comparation of the HBsAg quantitative,HBsAg negative conversion rate at 48 weeks and HBsAg seroconversion rate between the two groups.The quantitative level of HBsAg in the combined treatment group was signifi-cantly lower than that in the single-agent group at 36 weeks and 48 weeks(P<0.05)At 48 weeks,7 patients(20%)had HBsAg seroconversion and 3 patients(8.57%)had HBsAg seroconversion in combination therapy group and there was no HBsAg seroconversion and seroconversion in the monotherapy group.There was a significant difference between the two groups(P<0.05).3.Prediction of curative effect of HBsAg reduction percentage on response to Peg-IFNα-2a combination therapyThe ROC curve was established to analyze the predictive value of the percentage decrease of HBsAg level at 12 weeks,24 weeks and 36 weeks for the efficacy at 48 weeks in 35 patients treated with combination therapy.The results showed that the area under the curve of the decrease percentage of HBsAg at 24 weeks was 0.824(95%CI=0.669～0.999),the optimal Cut-off was 51.52%,the sensitivity was 0.714,and the specificity was 0.893(P<0.05);the area under the curve of the decrease per-centage of HBsAg at 36 weeks was 0.878(95%CI=00.699～1),the optimal Cut-off was 90.22%,the sensitivity was 0.857,and the specificity was 0.929(P<0.05),indi-cating that the decrease of HBsAg level at 24 weeks and 36 weeks was significantly correlated with the HBsAg response at 48 weeks.4 Comparison of adverse reactionsIn the combined treatment group,28 patients(80%)developed fever at an early stage and 25 patients(71.4%)showed decreased counts of white blood cells,neutro-phils and platelets.No adverse reactions occurred in the monotherapy group.There were no discontinuations due to serious adverse effects in either group.ConclusionsFor patients who achieve virological suppression by entecavir and whose HBsAg quantitative level is less than 1500IU/ml,combined with a limited cour-se of Peg-IFNα-2a can significantly improve the HBsAg clearance and serocon version rate;the significant reduction of HBsAg at 24 and 36 weeks post-treat ment could indicate the possibility of HBsAg clearance and identify patients w ho had the greatest chance of success.Part Ⅲ Study on the correlation between CYP27B1-1260 gene polymorphism and the efficacy of pegylated interferon alfa-2a in the treatment of chronic hepatitis BObjectivesTo investigate the correlation between CYP27B1-1260 gene polymorphism and Peg-IFNα-2a monotherapy in the treatment of HBeAg-positive chronic hepatitis B;To investigate the correlation between CYP27B1-1260 gene polymorphism and Peg-IFNα-2a combined treatment of entecavir-treated chronic hepatitis B.MethodsA total of 174 blood samples obtained from patients treated with Peg-IFNα-2a in the first and second parts were used to detect the Cyp27B1-1260A/C polymorphism by polymerase chain reaction-restriction fragment length polymorphism analysis(PCR-RFLP).The efficacy judgment of interferon therapy in the first part of the study popula-tion was divided into three groups:CR,PR,and NR(the same as the first part);the efficacy judgment of patients treated with combination therapy in the second part of the study population was divided into two groups:(1)HBsAg negative group:HBsAg negative,normal liver function,and HBVDNA<103 copies/ml.(2)HBsAg positive group:HBsAg did not turn negative,normal liver function,HBVDNA<103 cop-ies/ml.The above indicators were analyzed by statistical methods,and P<0.05 was considered statistically significant.Results1 Results of study population in part 1Among the CYP27B1-1260 polymorphisms in 139 patients,49 cases(35.3%)were AAs,46 cases(33,1%)were CCs,and 44 cases(31.7%)were ACs.1.1 Association of CYP27B1-1260 polymorphism and HBVDNA response at 24 weeks of Peg-IFN-α-2a treatmentAccording to the different HBV DNA responses at 24 weeks of Peg-IFNα-2a treatment,the study subjects were divided into two groups:the group with significant decrease with the HBVDNA decrease≥1 logcopies/ml and the group with insignifi-cant decrease with the HBVDNA decrease<1 logcopies/ml to determine whether there was a correlation between CYP27B1-1260 polymorphism and HBV DNA re-sponse at 24 weeks.The results showed that the CC type of CYP27B1-1260 gene was statistically different between the two groups,and the frequency of CC type of gene was higher in the group with insignificant HBV DNA decrease at 24 weeks(33.8%)than in the group with significant decrease at 24 weeks(32.3%)(P<0.05).1.2 Analysis of the correlation between CYP27B1-1260 polymorphism and efficacy at 48 weeks of Peg-IFNα-2a treatmentSixty-five patients in the conventional treatment group were analyzed(the other groups were not analyzed due to the small number of cases),and the results showed that the CC type was significantly higher in the proportion of non-responders to Peg-IFN-α-2a treatment(55.0%)than the AA type(20.0%)and AC type(25.0%)(P<0.05).2 Results of study population in part 2Thirty-five CHB patients were selected from the combination therapy group in the second part of the study population,and the CYP27B1-1260 polymorphism results were 11 patients of AA type(31.4%),14 patients of AC type(40.0%),and 10 patients of CC type(28.6%).2.1 Relationship between CYP27B1-1260 Polymorphism and Efficacy of Combina-tion TherapyAccording to statistical analysis,CYP27B1-1260 polymorphism has no correla-tion with the efficacy of combination therapy(P>0.05).2.2 Analysis of influencing factors in combination therapyMultivariate logistic regression analysis was performed with four factors includ-ing age,gender,CYP27B1-1260 gene polymorphism,and HBV genotype as inde-pendent variables(X)and HBsAg negative conversion at 48 weeks of antiviral thera-py(0=none,1=yes)as dependent variables(Y),and the results showed that there were no correlations between the above indicators and HBsAg negative conversion at 48 weeks in combination therapy(P>0.05).ConclusionsCYP27B1-1260 gene polymorphism may be associated with Peg-IFNα-2a treat-ment response,and its CC type may be an influencing factor for poor response to Peg-IFNα-2a treatment in treatment-naive HBeAg-positive chronic hepatitis B. |
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