Long-term Results Of Interferon Alpha Therapy In Patients With Chronic Hepatitis B Virus Infection

Objective In chronic hepatitis B(CHB)patients treated with interferon alpha (IFNα)to investigate the relapse,the development of serious complications,and the remote beneficial effect with their related factors,a long-term follow-up was conducted.Method Five hundred and twenty three patients with chronic hepatitis B were hospitalized patients or outpatients in department of infectious diseases of Nanfang hospital during May 1998 to September 2004,and the diagnosis of CHB was followed by ThePrevention andTreatmentProposal of Viral Hepatitis established in Xian Viral Hepatitis conference 2000.Liver biopsy was conducted in every patient within one year before therapy initialed,inflammation grade and fibrosis stage of hepatic tissue was identified as GO to G4 and SO to S4 respectively.All patients had been treated with IFNαlb subcutaneously at a dose of 5 MU thrice weekly for 6 to 28(median 9)months,and therapy would be ceased when severe adverse effect appeared,or combined response obtained,or time of treatment longer than 6 months and decrease of serum HBV DNA level discontinued for two months even if combined response was not achieved.Patients were monitored monthly to every three months for serum alaine transaminase(ALT)activity,serum HBV DNA by a fluorescent-quantitative polymerase chain reaction(PCR)with a detection limit of 10³ copies/ml,hepatitis B surface antigen(HBsAg)and e antigen (HBeAg)by an Abbott enzymimmunoassay kits(Abbott Laboratires,U.S.A.)during therapy,and every three months during the first 12 months of follow-up,and thereafter at a 6 month interval which should be adjusted properly in active patients. If a patient didn't visit us in time we should go to visit him in order to obtain the information of him.Normalization of ALT,loss of HBeAg if positive previously,and undetectable HBV DNA all three treatment end-points together was defined as combined response (CR),only normalization of ALT defined as biochemical response(BR), undetectable HBV DNA and loss of HBeAg together defined as viral response(VR), and non-combined response(NCR)should be considered if one or more of the three treatment end-points mentioned above not achieved.The sustained response(SR) implied the maintained response during follow-up,and SR₆,SR₁₂,SR₂₄,SR₃₆,SR₄₈, and SR₆₀implied the maintained response at 6-month,12-month,24-month, 36-month,48-month and 60-month of follow-up period.Reached CR at end of treatment defined as end-of-treatment response(EOTR),achieved CR at end of treatment and/or during first 6-month follow-up defined as early response(ER),and maintained response at end of follow-up defined as remote response(RR).Relapse referred to reappearance of either elevated ALT level,detectable serum HBV DNA, or HBeAg positive if positive before treatment in early responders.Statistical analysis of data was performed by nonparametric test,Chi-square test, t test,and multiple binary logistic regression analysis using the SPSS v.10.0 statistical package.Results Of 523 CHB patients,403 were HBeAg positive,and 120 HBeAg negative.In HBeAg positive patients,liver biopsies were performed in 392 ones. The median treatment duration was 9.0 months(range 6.0 to 28.0),and the median time length of follow-up was 36.0 months(range 12.0 to 98.0).At the end of therapy and the time of 12-month,24-month,36-month,48-month,60-month and end of follow-up,the rates of combined response were 45.2%,42.1%,41.7%,37.6%, 42.9%,35.6%,39.8%respectively(P=0.536),the rates of HBeAg loss were 52.6%, 52.0%,55.2%,54.5%,58.8%,56.2%,56.4%respectively(P=0.792),the rates of ALT normalization were 53.8%,51.3%,49.0%,47.5%,51.3%,39.7%,and 49.2% respectively(P=0.380),the rates of serum HBV DNA suppression were 48.0%, 43.1%,43.4%,39.6%,45.4%,42.5%,and 40.6%respectively(P=0.421),the rates of HBsAg loss were 1.8%,4.1%,4.5%,6.1%,10.9%,9.6%,and 6.9%respectively (P=0.001).By mono-factor analysis,female gender,higher serum ALT level,higher HBV DNA level,younger age(＜20 years),and higher histological activity index (G＞2)were the related factors of predictive EOTR,and all of them except higher serum ALT level were the related factors of predictive RR.Multiple binary logistic regression analysis discovered that gender,age and pretreatment serum HBV DNA level were the independent predictive factors of HBeAg-positive patients response to interferon alpha therapy.Six non-responders(1.5%)developed severe vital events correlated to HBV infection including hepatic failure in two patients,decompensate cirrhosis in three patients and hepatocellular carcinoma in one patient,and no patient died during the long-term follow-up period.Liver biopsies were performed in all 120 HBeAg-negative chronic hepatitis B patients.The median treatment duration was 9.0 months(range 6.0 to 28.0),and the median time length of follow,up was 38.0 months(range 12.0 to 94.0)in HBeAg-negative group.Compared HBeAg-positive group,the differences of the treatment duration and the time length of follow-up were not significantly different. At the end of therapy and the time of 12-month,24-month,36-month,48-month, 60-month and end of follow-up,the rates of combined response were 55.8%,50.8%, 46.8%,43.3%,378%,34.5%,and 37.5%respectively(P=0.049),the rates of ALT normalization were 61.7%,55.0%,53.2%,47.8%,46.7%,44.8%,and 40.8% respectively(P=0.052),the rates of serum HBV DNA suppression were 68.3%, 53.3%,50.0%,47.8%,44.4%,41.7%,and 42.5%respectively(P=0.004),and the HBsAg lost in two patients(1.7%)of HBeAg-negative group.Compared HBeAg-positive group,the EOTR rate was higher,and the differences of sustained response rates at the time of 12-month,24-month,36-month,48-month,60-month and end of follow-up were all not significant.The accumulative rate of HBsAg loss was lower in HBeAg-negative group than in HBeAg-positive group(x²=4.687, P=0.030).None of six baseline factors was discovered being the influencing factors of EOTR and RR in HBeAg-negative patients by mono-factor analysis.Multiple binary logistic regression analysis demonstrated that pretreatment serum HBV DNA level was the independent predictive factors of HBeAg-negative patients SR₁,SR₂ and RR to interferon alpha therapy,and non factor was the independent predictive factor of EOTR,SR₃,SR₄ and SR₅.Four non-responders(1.6%)developed severe vital events correlated to HBV infection including hepatic failure in one patient, decompensate cirrhosis in one patient and hepatocellular carcinoma in two patients, and no patient died during the long-term follow-up period.The development of severe vital events was same in both HBeAg-negative group and HBeAg-positive group(x²=1.047,P=0.307).Three hundred and two patients(57.7%)acquired EOTR and/or SR₆ to interferon-alpha,and 39.4%(119/302)of them relapsed during 39.2±21.5-month follow up.Age,pretreatment status of HBeAg,and time of follow-up were the predictive factors for post-treatment relapse.Mean age of relapsed patients was higher than sustained responders(t=4.887,df=300,P=0.000),and relapse rates in HBeAg negative group(55.8%,43/77)were higher than those in HBeAg positive group(33.8%,76/225)at the end of follow up(x²=19.335,P=0.000).Divided the follow-up period into six fragments as 1～12 months,13～24 months,25～36 months, 37～48 months,48～60 months and≥61 months,we found that the differences of relapse incidence were significant(x²=73.518,df=5,P=0.000),and accumulative relapse rates were significant too(x²=32.167,df=5,P=0.000)in all follow-up periods. But the difference of accumulative relapse rates were not significant in latest four follow-up periods(x²=1.552,df=3,P=0.670).There was no relationship between relapse and other parameters as gender,and pretreatment serum ALT,HBV DNA and liver biopsy finds(grade of liver inflammation and stage of liver fibrosis),and time of treatment.However,in HBeAg positive patients,the mean HBV DNA was higher in relapse group than in sustained response group(t=2.414,df=223, P=0.017). Conclusion In HBeAg positive chronic hepatitis B patients underwent 36.0 months(range 12.0 to 98.0)follow-up after interferon alpha treatmen,the rates of remote response were 39.8%,accumulative HBsAg loss 6.9%and development of severe vital events correlated to HBV infection 1.5%respectively,and in HBeAg negative ones were 37.5%,1.7%and 1.6%respectively.Gender,age and pretreatment serum HBV DNA level were the independent predictive factors of HBeAg-positive patients response to interferon alpha therapy.Age and pretreatment serum HBV DNA level were the independent predictive factors of HBeAg-positive patients response to interferon alpha therapy.Age,pretreatment status of HBeAg, and time of follow-up were independent predictive factors for post-treatment relapse, and in HBeAg positive patients,pretreatment serum HBV DNA was also one of the risk factors for relapse.