| Background:Chronic hepatitis B(CHB)infection remains a major global health problem,with approximately 257 million people infected with HBV according to the World Health Organization(WHO).HBV can cause liver inflammation,fibrosis,cirrhosis and hepatocellular carcinoma(HCC),and an estimated 887,000 people died of cirrhosis and HCC caused by hepatitis B virus(HBV)per year.Nucleos(t)ide analogs(NAs)are the most commonly used antiviral angients.Long term treatment can effectively inhibit the HBV replication,relieve the inflammatory and the proliferation of liver fibrous tissue,delay disease progression,improve patients’ quality of life and prolong survival time.NAs treatment requires long-term or even lifelong.However,long-term NAs treatment also brings a series of problems,such as the poor compliance,high economic cost,adverse drug reactions,drug resistance,and the long-term safety of NAs treatment for more than 10 years is still unknown.Different from the lifelong treatment of hypertension and diabetes,anti-HBV therapy is a pathogen treatment,it does have the characteristics of a limited course of treatment.Some patients can matained sustained off therapy response after NAs cessaton.How to effectively and safely stop NAs is the dream of the majority of patients(especially in young group),and it is also a hot and difficult topics in clinical.To this end,the guidelines for the prevention and treatment of CHB at home and abroad have formulated the relative course of antiviral treatment and the criteria for discontinuation.As HBeAg-positive CHB and HBeAg-negative CHB are different course in the natural history of chronic HBV infection,differented in immunity and pathogenesis,such as HBeAg-negative CHB patients have lower HBVDNA levels and more likely to fluctuate,with a later course and a higher risk of progression to advanced liver fibrosis or cirrhosis and HCC.Therefore,the criteria for discontinuation NAs and the evaluation indicators are different in HBeAg-positive CHB and HBeAg-negative CHB patients.The European Association for the Study of Liver Diseases(EASL),the American Association for the Study of Liver Diseases(AASLD)and the Asian Pacific Association for the Study of Liver Diseases(APASL)recommends that consolidation therapy for at least 12 months after HBeAg serological conversion with undetectable HBV DNA is an acceptable treatment endpoint for HBeAg-positive patients without cirrhosis.The recommendations for HBeAg-negative patients are different.APASL guidelines recommend that after undetectable of HBV DNA for no less than 2 years can stop NAs.EASL guidelines recommend that consolidation therapy should be not less than 3 years after HBV DNA undetectable.While AASLD guidelines suggested that HBsAg loss is the only acceptable end point.In addition,the discontinuation criteria issued at different times also differed,and the general trend was to tend to extend the course of treatment.Stopping NAs is still controversial.If the above discontinuation criteria are not met,stopping NAs can lead to virologic recurrence or clinical relapse with elevated alanine aminotransferase(ALT)in the vast majority of patients;Even if the above discontinuation criteria are met,there is a certain proportion of relapses.Therefore,in order to verify and explore the virological response and predictors of NAs cessation for HBeAg-positive and HBeAg-negative CHB patients,we established a real-world prospective research cohort of patients who met certain discontinuation criteria by continuous enrollment,and conducted relevant studies.The research papers have been cited by AASLD,APASL and CHB prevention and treatment guidelines issued by the World Health Organization(WHO).HBeAg-positive CHB is the early course of the HBV natural history,accompanied by high HBV DNA loads,high levels of HBsAg titers,and poor spefic immunity to HBeAg and HBsAg specific T cells.HBeAg seroconversion is associated with alleviation of inflammation,decreased liver fibrosis,and liver disease transfered to inactivity.HBeAg is not directly involved in HBV replication,causes immune tolerance or activation at different stages of CHB,and the mechanism of HBeAg is still unknown.In clinical practice,HBeAg seroconversion rate is not high.HBeAg slowly decrease with NAs treatment.While some patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg without HBeAb appears in NAs therapy,even with HBsAg loss.For HBeAg-positive patients,current guidelines recommend that patients with HBeAg seroconversion discontinue NAs after more than 12 months consolidation therapy.It remains unclear whether NAs can be discontinued in this subset of patients.Previous studies of HBeAg-positive CHB patients who achieved HBeAg serological conversion and discontinued NAs treatment involved this subset of patients,but did not systematically analysis.Moreover,all CHB prevention and treatment guidelines on drug discontinuation does not involve this subset of patients.Therefore,whether NAs in CHB patients with long-term HBeAg loss can be discontinued is still unknown,and the efficacy and indicators after NAs discontinuation are worth exploring.NAs mainly inhibit viral replication by inhibiting HBV DNA polymerase,and have no direct effect on the covalently closed circular DNA(cccDNA),which is the reservoir of HBV.Due to the persistence of cccDNA and HBV integration genes,as well as the impaired innate and adaptive immunity to HBV,it is difficult to achieve HBsAg loss which is the ideal treatment end point of CHB,It is necessary to explore alternative biomarkers for NAs discontinuation.So far,there is no exact and reliable predictor for NAs withdrawal.Although novel markers such as hepatitis B core-related antigen(HBcrAg)and serum HBV RNA level are considered to be related to cccDNA transcriptional activity and have attracted much attention,they still lack uniform standards in clinical practice and need further research.Studies have shown that low serum HBsAg levels at the end of treatment(EOT)are predictors of sustained virological response(SVR)and functional cure after NAs discontinuation.Low level of HBsAg seems to be a realistic and feasible indicator for NAs discontinuation,and causes a lot of attention recently.Nevertheless,the appropriate cut-off values are still controversial.Objective:We established a prospective observational cohort involving CHB patients with NAs off-therapy according to stringent criterias at our medical center since 2001.With the advantage of the long-term follow-up,the present study has several aimes as below:firstly,to explore and verified the virological response and predictors for VR in HBeAg-positive and HBeAg-negative CHB patients with NAs cessation;secondly,to systematically explore the outcomes of discontinuation of NAs and related factors in patients with HBeAg loss without HBeAb appearence;thirdly,to study the role of HBsAg in sustained virologic response and functional cure after discontinuation of NAs in different HBeAg status CHB patients.Methods:A prospective observational real world research cohort has been established in our medical center and conducted related studies since 2001.Patients were enrolled in the cohort after meeting disconuation criterias and stopped NAs treatment.All patients were initially given monodrug therapy including lamivudine,adefovir dipivoxil,telbivudine,entecavir and tenofovir dipivoxil fumarate.The criteria for NAs discontinuation refer to the domestic and foreign guidelines for the diagnosis and treatment of chronic hepatitis B at the time of patient enrollment.The details are as follows:(1)HBeAg-positive CHB patients:the consolidation treatment time should not be less than 6 months after HBeAg seroconversion,HBV-DNA undetectable and ALT normalization.The total treatment duration were no less than 12 months.Some patients have achieved HBeAg loss without HBeAb appearance,after HBeAg loss the patients were given no less than 6 months consolidation treatment and the total treatment durations were not less than 18 months.(2)HBeAg-negative CHB patients:after HBV-DNA undetectable and ALT normalized,the consolidation treatment times were no less than 18 months and the total durations were no less than 24 months.The response status of patients after NAs withdrawal was determined by virological relapse or not.VR was defined as HBV DNA>104copies/ml with an at least 2 weeks intervals re-examination.Patients with cirrhosis,decompensated liver diseases and NAs resistance were excluded.Patients with relapse were treated with individualized salvage treatment based on previous drug history,severity of liver injury,patient financial status,and personal wishes.No patients had suffered liver failure and decompensated liver diseases.Results:Part I:Two hundred and twenty three CHB patients(138 HBeAg-positive with HBeAg seroconversion patients and 85 HBeAg-negative patients)were included in the study.The median age was 28 years(4-70 years).The median consolidation period was 21 months(6-91 months).And the median total treatment duration was 29 months(12-101 months).After a 5 years median follow-up,87 patients relapsed,including 38 HBeAg-positive CHB patients and 49 HBeAg-negative CHB patients.The cumulative relapse rates(CRRs)at 1st,3rd,5th and 10th year were 20.3%,23.4%,27.9%,and 30.9%in the HBeAg-positive group and 44.7%,52.5%,57.4%and 62.3%in the HBeAg-negative group.The CRRs of HBeAg-positive patients was significantly lower than that of HBeAg-negative patients(logRank,P<0.001).Univariate and multivariate Cox regression analysis revealed age at EOT,consolidation time and time to HBeAg seroconversion were independent predictors of VR for HBeAg-positive patients.Patients aged less than 30 years,the 10 year CRR was only 15.1%lower than patients aged ≥30 years(55.6%).Young patients(<30 years)with a longer time to HBeAg seroconversion(>3 months)had a 10-year CRR as low as 12.5%.Univariate and multivariate Cox regression analysis revealed that age at EOT and HBV DNA negative time were VR predictors for HBeAg-negative patients.CRR was lower in patients<20 years old than in patients>20 years old(28.6%vs.69.3%,P<0.001).If short time to HBV DNA negative are added to this subgroup,the 10-year CRR was as low as 10%.Part Ⅱ:Eighty-three CHB patients(Cohort A)with long time HBeAg loss while had not achieved HBeAg seroconversion(without HBeAb appearence)stopped NAs were included in this study.190 HBeAg seroconversion patients with NAs cessation(Cohort B)during the same period were included as controls.We preliminarily screened 83 patients in Cohort A and 190 patients in Cohort B for propensity score matching(PSM).A total of 144 patients(72 pairs)were matched in the PSM cohort with baseline characteristics of the two groups,and the comparison results of the two groups showed that the CRRs in the HBeAg loss group were higher than those in the HBeAg seroconversion group and there were statistical differences(P=0.036).Eighty-three patients in cohort A with a mean age of 32.1±9.5 years,a median treatment duration of 49(IQR 36-61)months.The median follow-up time for patients with SVR was 72(IQR 36 to 108)months.38 patients relapsed.CRRs at 3rd,6th,12th,24th,36th,60th,120th and 180th months after discontinuation were 22.9%,36.1%,41.0%,43.5%,45.0%,45.0%,45.0%and 52.8%,respectively.68.4%patients relapsed within the first 3 months after NAs cessation and 92.1%patients relapsed within 1 year after NAs cessation.Cox regression analysis showed consolidation time(≥24 months vs.<24 months)(HR 0.506,P=0.043)and EOT HBsAg(≥100 IU/mL vs.<100 IU/mL)(HR 14.869,P=0.008)were independent predictors of VR after NAs cessation.The CRRs of 19 patients with EOT HBsAg<100 IU/mL were significantly lower than in patients with EOT HBsAg≥100 IU/mL(P<0.001).For 51 patients with long consolidation time(≥24 months),CRRs at months 3rd,6th,12th,24th,36th,60th,120th and 180th months were 17.6%,27.5%,31.4%,31.4%,33.8%,33.8%,33.8%and 44.9%,respectively,significantly lower than those with shorter consolidation time(<24 months)(P=0.012).Six of the 83 patients achieved HBsAg loss after NAs cessation.Univariate and multivariate cox regression analysis showed that lower HBsAg level at EOT(≥100 IU/ml vs.<100 IU/ml)(HR=4.867,P=0.004),shorter time to HBeAg loss(HR=1.013,P=0.031),and no-relapse(HR=0.21,P<0.001)were independent predictors of functional cure after NAs cessation.The cumulative functional cure rates at 1st,8.5th and 10th years after NAs cessation for patients with HBsA at EOT<100 IU/ml were 11.1%,20%and 46.7%respectively.Part III:A total of 168 CHB patients were included in this study,including 87 HBeAg positive(HBeAg seroconversion)(group A)and 81 HBeAg-negative patients(group B).For patients with HBeAg seroconversion,cox regression analysis showed that age(<30 years vs.≥ 30 years)(OR 9.867,95%CI 2.849-34.167,p<0.001),HBsAg at EOT(<1500 IU/mL vs.≥1500 IU/mL)(OR 2.067,95%CI 1.272-3.358,p=0.003),consolidation therapy time(OR 0.012,95%CI 0.0009-0.028,p=0.004),baseline HBV DNA loads(OR 1.934,95%CI 1.039 to 3.599,p=0.038),and initial treatment combined with IFN(OR 4.503,95%CI 1.386 to 14.627,p=0.012)were independent predictors of VR after NAs cessation.Only 1 patient younger than 30 years of age with HBsAg at EOT<1500 IU/mL had virologic relapse after NAs cessation.5 patients with HBsAg at EOT<100 IU/mL had no VR after NAs cessation.Eleven(12.6%)HBeAg-positive patients achieved functional cure after NAs cessation,none of the patients relapsed.Patients with functional cures had a younger age at EOT(P=0.013),lower level HBsAg at EOT[median 163.4(IQR 18.5 to 715)IU/ml vs.3219(IQR 378.6-10553.5)IU/ml,P<0.001],longer consolidation time(34.8± 11.9 months vs.23.7± 17.0 months,P=0.011),and longer follow-up time(P=0.012).Patients with EOT HBsAg<1500 IU/ml had higher functional cure rates(P=0.007),and the cumulative functional cure rates at 2nd and 5th years after NAs cessation were 10%and 75%,respectively.For patients with HBeAg-negative,cox regression analysis showed that HBsAg at EOT(≥250 IU/ml vs.<250 IU/ml)(HR 4.016,p=0.001),age(HR 1.069,p<0.001),and time to HBV DNA negative(HR 1.221,p=0.010)were independent predictors of VR after NAs cessation.Patients with EOT HBsAg<250 IU/mL the CRRs at 1st,2nd,3rd,5th and 10th years after NAs cessation were 18.7%,26.0%,44.9%,and 60.6%,respectively,lower than in patients with EOT HBsAg ≥250 IU/mL(p=0.004).Nineteen(19/81,23.5%)HBeAg-negative patients achieved HBsAg loss after NAs cessation.The functionally cure patients had a higher proportion of EOT HBsAg<100 IU/mL(63.2%vs.14.5%,p<0.001)and EOT HBsAg<250 mL(89.5%vs.24.2%,p=0.001),no-relapsed(P<0.001)and longer treatment duration(63.3 months vs.46.6 months,P=0.043).The cumulative functional cure rates were 28.1%,39.5%,43.4%and 53.5%at the 1st,2nd,3rd and 6th years for patients with HBsAg at EOT<250IU/ml after NAs cessation.Conclusions:1.HBeAg-positive CHB patient and HBeAg-negative CHB patients who meet the recommended discontinuation criteria of CHB guidelines had different virological responses rates after NAs discontinuation.HBeAg-positive CHB patients had a lower virological relapse rate than HBeAg-negative CHB patients after NAs cessation.HBeAg-negative CHB patients require more strict criteria for discontinue NAs treatment.2.For HBeAg-positive(e antigen seroconversion)CHB patients less than 30 years old with strong willings to discontinue NAs treatment,after a certain period of consolidation therapy,stopping NAs treatment maybe feasible.For HBeAg-negative CHB patients≤20 years old with strong willings to discontinue NAs treatment,and with a short time to HBV DNA negative(≤3 months),stopping NAs treatment maybe feasible.3.Firstly systematically explore the safety and efficacy of HBeAg-positive CHB patients with HBeAg loss after NAs discontinuation.HBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation(≥24 months),especially in patients with HBsAg at cessation<100 IU/mL.4.Low HBsAg level at the end of treatment was an independent predictor for sustained virologic response and functional cure for HBeAg-positive(e antigen seroconversion)CHB patients after NAs discontinuation.Young patients aged≤30 years with HBsAg<1500 IU/mL and a long-term consolidation(≥36 months),had a high rate of sustained virologic response after NAs discontinuation.Patients with HBsAg<1500 IU/mL had a high rate of functional cure after NAs discontinuation.Patients with HBsAg<100 IU/mL may be considered to discontinued NAs.5.Low HBsAg level at the end of treatment was an independent predictor for sustained virologic response and functional cure for HBeAg-negative CHB patients after NAs discontinuation.Young patients aged ≤ 40 years with HBsAg<250 IU/mL had a high rate of sustained virologic response after NAs discontinuation.Patients with HBsAg<250 IU/mL had a high rate of functional cure after NAs discontinuation.6.Long-term NAs treated CHB patients is relatively safe to discontinue NAs treatment.After NAs discontinuation,regular monitoring is necessary in the early stage,virological relapse mainly occurs within 1 year,especially within the first 3 months off-therapy. |
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