Meta Analysis Of Nucleo(S)tide Analogues Sequential /sequential Combinationtherapy With Pegylated Interferon For The Treatment Of HBeAg-positive Chronic Hepatitis B

Chronic hepatitis B(CHB),a chronic disease caused by hepatitis B virus,has become a global public health problem.The weighted prevalence of HBs Ag for Chinese population aged 1-59 years were 7.18%.Chronic hepatitis B is a high contagious disease with high fatality rate.HBV infection and the immune function of body are both important factors affecting the progress and clinical prognosis of CHB.The current main antiviral drugs include nucleo(s)tide analogues(NAs)and interferon(IFN).Both of NAs and IFN cannot completely eliminate the persistent covalently closed circular DNA(cccDNA).The goal of the treatment for chronic hepatitis B is maximizing the long-term inhibite HBV DNA replication and relieving inflammatory cell necrosis in the liver,to delay and reduce the liver failure,decompensated cirrhosis and HCC and other complications,so as to improve the quality of life and prolong survival time.Depending on different stages of CHB,sequential/sequential combination therapy strategies may be an effective way to achieve CHB clinical cure.Recently,several multicenter randomized clinical studies have shown that compared with using NAs for antiviral treatment,the use of NAs lower viral load then sequential/sequential combined with Peg-IFN were more efficiently in the decline in HBsAg and HBeAg seroconversion.Due to insufficient evidence of evidence-based medicine,this treatment therapy has not been clearly written into chronic hepatitis B guidelines.To systematicly evaluate the efficacy and safety of NAs sequential therapy with Peg-IFN for the treatment of chronic hepatitis B.we used Meta analysis to assess the evidence-based medicine results,in order to provide the basis for antiviral treatment of chronic hepatitis B.Studies of Pubmed,Cochrane Library,Embase,the Chinese Medical(CNKI,Wanfang and VIP)databases were conducted to identify all relevant randomized controlled trials(RCTs)published since inception to March 2017.We tracked the article and the authenticity of the data by phone or E-mail.Nine studies comparing NAs(entecavir,adefovir,tenofovir,lamivudine,telbivudine)monotherapy to NAs(treatment duration≥36 weeks)sequential therapy with Peg-IFN(combination therapy,n=5,Peg-IFN monotherapy,n=4;treatment duration: 48-52weeks)were involved.Two reviewers independently screened literature,extracted data and assessed the methodlogical quality of the included studies.Meta-analysis was performed with RevMan 5.3,comparing HBsAg clearance rate/ seroconversion rate,HBeAg clearance rate/ seroconversion rate and ALT normalization rate at the end of treatment.A total of 678 patients were enrolled,including 337 cases in the treatment group and 341 cases in the control group.The treatment group used NAs sequential or sequential combination with Peg-IFN.Compared with using NAs for antiviral treatment,NAs sequential/sequential combination therapy with Peg-IFN were more efficiently in HBsAg clearance rate(11.5%vs0.5%,OR=9.31,95%CI 2.72~31.89,P<0.01),HBsAg seroconversion rate(5.4%vs0%,OR=6.64,95%CI 0.8~54.95,P=0.08),HBeAg clearance rate(38.1%vs20.1%,OR=2.67,95%CI 1.83~3.90,P<0.01),HBeAg seroconversion rate(31.5%vs12.0%,OR=3.6,95%CI 为 2.38~5.45,P<0.01).According to the results of subgroup analysis,compared with NAs monotherapy,combination therapy and Peg-IFN monotherapy both achieved higher HBeAg clearance rate:(28.9%vs17%,OR=2.0,95%CI 1.19~3.55,P<0.01)and(48.9%vs24.1%,OR=3.7,95%CI2.11~6.49,P<0.01),higher HBeAg seroconversion rate(25.3%比 10%,OR=3.1,95%CI 为 1.66~5.79,P<0.01)and(37.4%vs14.0%,OR=4.05,95%CI 为 2.33~7.04,P<0.01).While,the ALT normalization rate of NAs monotherapy group was higher than that of NAs sequential/sequential combination therapy with Peg-IFN group(5.4 %vs0%,OR=6.64,95%CI 0.8~54.95,P=0.08).Sequential/sequential combinationtreatment group showed more adverse events,most of which can be tolerated or symptomatic improved.Subgroup analysis was also conducted by NAs drugs.Compared with using ETV for antiviral treatment,ETV sequential/sequential combination therapy with Peg-IFN were more efficiently in HBsAg clearance rate(10.3%vs0.5%,OR=9.65,95%CI2.51~37.19,P<0.01),HBeAg negative rate(50 % vs30.1 %,OR=2.53,95 % CI1.46 ~ 4.36,P < 0.01),HBeAg seroconversion rate(30.4%vs2.0%,OR=3.59,95%CI2.11~6.13,P<0.01).In the case of CHB antiviral therapy,after the use of NAs for virological response,sequential/sequential combination therapy with Peg-IFN for 48 weeks can significantly increase HBsAg clearance rate,HBeAg clearance rate and HBeAg seroconversion rate,with better tolerability.