Antiviral efficacy of adefovir dipivoxil versus lamivudine in patients with chronic hepatitis B sequentially treated with lamivudine and adefovir due to lamivudine resistance

AIM： To compare the antiviral efficacy of adefovir （ADV） in lamivudine （LMV）-resistant patients with LMV treatment in nucleoside-naive patients, using serum samples collected sequentially during the course of treatment progressing from LMV to ADV.
METHODS： Forty-four patients with chronic hepatitis B （CHB） were included. The patients were initially treated with LMV and then switched to ADV when LMV resistance developed. Antiviral efficacy was assessed by measuring the following： reduction in serum HBV DNA from baseline, HBV DNA negative conversion （defined as HBV DNA being undectable by the hybridization assay）, and HBV DNA response （either HBV DNA level ≤ 10^s copies/mL or a ≥ 2 log10 reduction from baseline HBV DNA level）.
RESULTS： After two and six months of treatment, HBV DNA reduction was greater with LMV compared to ADV treatment （P = 0.021）. HBV DNA negative conversion rates were 64% and 27% after one month of LMV and ADV treatment respectively （P = 0.001）. Similarly, HBV DNA response rates were 74% and 51% after two months of LMV and ADV treatment respectively （P = 0.026）. The time taken to HBV DNA negative conversion and to HBV DNA response were both delayed in ADV treatment compared with LMV.
CONCLUSION： The antiviral efficacy of ADV in LMV-resistant patients is slower and less potent than that with LMV in nucleoside-naive patients during the early course of treatment.     

Serum hepatitis B virus RNA is a predictor of HBeAg seroconversion and virological response with entecavir treatment in chronic hepatitis B patients

BACKGROUND Characteristics of alterations of serum hepatitis B virus(HBV) RNA in different chronic hepatitis B(CHB) patients still cannot be fully explained. Whether HBV RNA can predict HBeAg seroconversion is still controversial.AIM To investigate whether HBV RNA can predict virological response or HBeAg seroconversion during entecavir(ETV) treatment when HBV DNA is undetectable.METHODS The present study evaluated 61 individuals who were diagnosed and treated with long-term ETV monotherapy at the Department of Infectious Diseases of Peking University First Hospital(China) from September 2006 to December 2007.Finally, 30 treatment-naive individuals were included. Serum HBV RNA were extracted from 140 μL serum samples at two time points. Then they were reverse transcribed to cDNA with the HBV-specific primer. The product was quantified by real-time quantitative PCR(RT-PCR) using TAMARA probes. Statistical analyses were performed with IBM SPSS 20.0.RESULTS Level of serum HBV RNA at baseline was 4.15 ± 0.90 log10 copies/mL. HBV RNA levels showed no significant difference between the virological response(VR)and partial VR(PVR) groups at baseline(P = 0.940). Serum HBV RNA significantly decreased among patients who achieved a VR during ETV therapy(P < 0.001). The levels of HBV RNA in both HBeAg-positive patients with seroconversion group and those with no seroconversion increased after 24 wk of treatment. Overall, HBV RNA significantly but mildly correlated to HBsAg(r =0.265, P = 0.041), and HBV RNA was not correlated to HBV DNA(r = 0.242, P =0.062). Furthermore, serum HBV RNA was an independent indicator for predicting HBeAg seroconversion and virological response. HBeAg seroconversion was more likely in CHB patients with HBV RNA levels below4.12 log10 copies/mL before treatment.CONLUSION The level of serum HBV RNA could predict HBeAg seroconversion and PVR during treatment. In the PVR group, the level of serum HBV RNA tends to be increasing.     

Durability of viral response after off-treatment in HBeAg positive chronic hepatitis B

AIM:To evaluate the durability in hepatitis B e antigen (HBeAg) positive chronic hepatitis B patients who discontinued antiviral treatment. METHODS:A total of 48 HBeAg positive chronic hepatitis B patients who were administered nucleoside analogues and maintained virological response for ≥ 6 mo [hepatitis B virus (HBV) DNA 300 copies/mL and HBeAg seroconversion] before cessation of treatment were enrolled between February 2007 and January 2010. The criteria for the cessation of the antiviral treatment were defined as follows:(1) achievement of virological response; and (2) duration of consolidation therapy (≥ 6 mo). After treatment cessation, the patients were followed up at 3-6 mo intervals. The primary endpoint was serologic and virologic recurrence rates after withdrawal of antiviral treatment. Serologic recurrence was defined as reappearance of HBeAg positivity after HBeAg seroconversion. Virologic recurrence was defined as an increase in HBV-DNA level 104 copies/mL after HBeAg seroconversion with previously undetectable HBV-DNA level. RESULTS:During the median follow-up period of 18.2 mo (range:5.1-47.5 mo) after cessation of antiviral treatment, the cumulative serological recurrence rate was 15 % at 12 mo. The median duration between the cessation of antiviral treatment and serologic recurrence was 7.2 mo (range:1.2-10.9 mo). Of the 48 patients with HBeAg positive chronic hepatitis, 20 (41.6%) showed virological recurrence. The cumulative virologic recurrence rates at 12 mo after discontinuing the antiviral agent were 41%. The median duration between off-treatment and virologic recurrence was 7.6 mo (range:4.3-27.1 mo). The mean age of the virological recurrence group was older than that of the non-recurrence group (46.7 ± 12.1 years vs 38.8 ± 12.7 years, respectively; P = 0.022). Age ( 40 years) and the duration of consolidation treatment (≥ 15 mo) were significant predictive factors for offtreatment durability in the multivariate analysis [P = 0.049, relative risk (RR) 0.31, 95% CI (0.096-0.998) and P = 0.005, RR 11.29, 95% CI (2.054-65.12), respectively]. Patients with age (≤ 40 years) who received consolidation treatment (≥ 15 mo) significantly showed durability in HBeAg positive chronic hepatitis B patients (P = 0.014). These results suggest that additional treatment for more than 15 mo after HBeAg seroconversion in patients who are ≤ 40 years old may be beneficial in providing a sustained virological response. CONCLUSION:Our data suggest that HBeAg seroconversion is an imperfect end point in antiviral treatment. Long-term consolidation treatment (≥ 15 mo) in younger patients is important for producing better prognosis in HBeAg positive chronic hepatitis B.     

IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection

AIM To investigate the association between interferoninduced protein with tetratricopeptide repeats 1(IFIT1) polymorphisms and interferon-α(IFNα) treatment efficiency among Chinese hepatitis B virus(HBV) infection patients.METHODS Two hundred and twenty five newly diagnosed chronichepatitis B(CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen(HBe Ag) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms(SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes.RESULTS At the end of the treatment, HBe Ag seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218(A G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64(95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response(response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype(response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBe Ag seroconversion, combined response or sustained response was observed.CONCLUSION IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation.     

Entecavir as treatment for reactivation of hepatitis B in immunosuppressed patients

AIM: To study the efficacy and safety of entecavir (ETV) as first-line therapy for hepatitis B virus (HBV) reactivation due to immunosuppression. METHODS: Four patients that were treated with different immunosuppressive regimens for hematological malignancies, who presented with HBV reactivation were treated with ETV. Clinical outcome, biochemical and virological factors, including quantitative hepatitis B surface antigen (HBsAg) were studied. RESULTS: In all patients, ETV induced suppression of HBV, and rapid clinical improvement without side effects. In one patient with an alanine aminotransferase (ALT) flare, tenofovir was added after 3 mo of treatment. Until death from disease progression at 6 mo after treatment initiation, this patient did not clear HBV infection. Retrospectively, it is highly probable that thepatient had been non-adherent. In the other three patients, the virological responses were associated with an expeditious decrease in quantitative HBsAg titers with negativity after 2 mo, and all three had HBsAg seroconversion. In one patient, HBV DNA reached a plateau after 3 mo, before becoming undetectable after 1 year, despite early ALT normalization and undetectable quantitative HBsAg. CONCLUSION: ETV seems to be effective and safe treatment for HBV reactivation. Monitoring of quantitative HBsAg might be an additional useful tool to monitor treatment response.     

干扰素α与阿德福韦酯不同联合方法治疗HBeAg阳性慢性乙型肝炎的疗效

目的 观察IFNα联合阿德福韦酯(ADV)治疗HBeAg阳性慢性乙型肝炎(CHB)的临床疗效,探讨理想的联合治疗方案.方法 2005年1月至2009年6月纳入河北医科大学第三医院HBeAg阳性CHB患者156例.56例患者HBV DNA≥1×107拷贝/mL、或纤维化分期≥S3、或既往单药治疗失败(复发)者,予以初始IFNα联合ADV治疗;52例未达上述指标患者接受初始IFNα单药治疗.24周时依据患者HBV DNA、HBeAg、HBsAg变化调整治疗方案:16例取得早期应答的初始IFNα联合ADV治疗组患者调整为IFNα单药维持治疗,其余患者与初始IFNα单药治疗组未达到早期应答者共同接受IFNα联合ADV治疗.另选48例作为标准治疗组,接受全程IFNα单药治疗.48周时复评全部患者HBV DNA、HBeAg、HBsAg定量,并决定是否延长疗程.最终于72周评估患者疗效、安全性、耐药复发等,数据行卡方检验.结果 治疗24周,初始IFNα联合ADV治疗组早期应答率达28.6%,其中HBV DNA阴转率、ALT复常率(53.6%,62.5%)与初始IFNα单药治疗组(32.7%,x2=4.78;40.4%,x2=5.21)、标准治疗组(27.1%,x2=5.28;37.5%,x2=6.46)比较,差异均有统计学意义(均P<0.05),且HBeAg阴转率较标准治疗组更高(39.3%比18.8%,x2=7.48,P<0.05).48周时,初始IFNα联合ADV治疗组16例取得早期应答者停用ADV后,5例HBeAg复阳,3例病毒学反弹;HBV DNA阴转率为73.2%,HBeAg转换率为41.1%,HBsAg清除率为12.5%.其中96例接受不同联合方法治疗的患者HBV DNA阴转率、HBeAg转换率、HBsAg清除率分别为65.6%、33.3%和8.3%.72周时不同联合方法治疗组患者整体复发率与标准治疗组相当,HBsAg清除率上升2.7%.结论 IFNa联合ADV抗病毒治疗对提高应答率优势明显.结合患者基线特征、治疗反应,制订不同联合方案,不失为当前CHB抗病毒优化治疗理想策略之一.

Abstract：

Objective To investigate the efficacy of interferon α(IFNα)and adefovir dipivoxil (ADV)combination therapy in HBeAg positive chronic hepatitis B(CHB)patients and to explore the optimized strategy for individualized treatment.Methods A total of 156 HBeAg positive CHB patients were enrolled in the study from January 2005 to June 2009 in the Third Affiliated Hospital of Hebei Medical University.Fifty-six CHB patients with hepatitis B virus(HBV)DNA≥1 X 107copy/mLand/or liver fibrosis stage≥S3,or previous monotherapy failure(relapse)were treated with initial IFNα and ADV combination therapy.Fifty-two patients who didn't meet any of the above baseline characteristics received initial IFNα monotherapy.The remaining 48 patients treated with IFNα monotherapy for full treatment duration were considered as control.At week 24 of treatment,the treatment regimens were adjusted according to quantitative changes of HBV DNA,HBeAg and HBsAg:16 patients who achieved early response in group of initial IFNα and ADV combination therapy subsequently received IFNα monotherapy,the other patients in group of initial combination therapy together with patients who did not achieved early response in group of initial IFNα monotherapy subsequently received IFNα and ADV combination treatment.The HBV DNA levels,HBeAg and HBsAg titers were detected at the end of 48 weeks of treatment to determine the treatment duration.The treatment efficacy,safety,drug resistance and relapse rates were finally evaluated at week 72.All data were analyzed using chi square test.Results At week 24,the early response rate in group of initial combination therapy was 28.6%,and the HBV DNA negative rate and alanine aminotransferase(ALT)normalization rate were significantly higher than those in groups of initial IFNα monotherapy and control(53.6%vs 32.7%vs 27.1%and 62.5%vs 40.4%vs 37.5%,respectively,P<0.05);in addition,HBeAg loss rate was higher than control group(39.3%vs 18.8%,x2=7.48;P<0.05).At week 48,five of 16 patients who achieved early response developed HBeAg reversion and three cases accompanied with virological breakthrough in group of initial combination therapy after switching to IFNα monotherapy,while the rates of HBV DNA negative,HBeAg seroconversion and HBsAg clearance were 73.2%,41.1%and 12.5%,respectively.The HBV DNA negative rate,HBeAg seroconversion rate and HBsAg clearance rate in 96 patients Who had received different combination treatment regimens were 65.6%,33.3%and 8.3%,respectively.At week 72,the relapse rate in individualized treatment group was comparable to those in control group,while HBsAg clearance rate increased 2.7%in individualized treatment group.Conclusions IFNα and ADV combination treatment could improve early biochemical and virological responses.Individualized treatment strategy based on baseline characteristics and treatment responses may be helpful for optimizing antiviral treatment in CHB patients.     

Treatment of genotype 2 and 3 chronic hepatitis C virus-infected patients

AIM: Before pegylated interferon alpha (IFN) was introduced for the therapy of chronic hepatitis C virus (HCV)-induced hepatitis, conventional thrice weekly IFN therapy was supplemented by ribavirin. Also, at that time, higher and more frequent doses of IFN were expected to be more effective than the standard regimen of 3 MU thrice weekly. As ribavirin significantly increases side effects and negatively influences the quality of life particularly in young patients, we started a prospective non-randomized study with a daily IFN-2a monotherapy as an initial treatment for chronic hepatitis C. METHODS: Forty-six consecutive chronic HCV-infected patients received 3 MU IFN-2a per day as an initial treatment. Patients with genotype 2 or 3 (n = 12) were treated for 24 wk, and patients with genotypes other than 2 or 3 (n = 34) for 48 wk. Treatment outcome was followed up for 48 wk after the end of treatment (EOT). Virological response was defined as the absence of detectable serum HCV-RNA. Patients without virological response at 12 wk after the start of treatment received low-dose ribavirin (10 mg(kg·d)) additionally. RESULTS: During treatment, three genotype 3 patients were excluded from the study due to incompliance. The remaining patients (n = 9) infected with genotype 2 or 3 showed an initial virological response rate of 100%. Six patients (66.7%) were still found to be virus-free at the end of follow-up period. In these patients, initial virological response was evident already after 2 wk of treatment. In contrast, initial virological response occurred first after 4 wk of treatment in the three patients who relapsed (33.3%). In comparison, patients infected with genotypes other than 2 or 3 (n = 34) showed an initial virological response rate of only 23.5% (n = 8), and even in combination with ribavirin a sustained virological response (SVR) rate of only 11.8% (n = 4) could be achieved. CONCLUSION: In chronic HCV-infected patients with genotype 2 or 3, a SVR can be expected after 24 wk of daily dose IFN-2a treatment without ribavirin, if initial virological response develops early. This finding is worth to be confirmed in a prospective randomized study with pegylated IFN.     

Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance

AIM:To study the effect of rescue monotherapy with adefovir(ADV) in patients with chronic hepatitis B(CHB) who developed drug resistance to lamivudine(LAM).METHODS:A total of 76 treated CHB patients with resistance to LAM were enrolled in the present study.The patients’ baseline characteristics,such as age,gender,blood tests and hepatitis B virus(HBV) DNA were collected;therapy duration and the response of each patient were also recorded.ADV monotherapy was set as the observation group A.Twenty-four patients with LAM resistance,who were set as group B,accepted combined therapy with LAM + ADV.Patients were followed up at 0,12,24,52,104 and 156 wk.Hepatitis B surface antigen status,hepatitis B e antigen(HBeAg)/anti-HBe status,HBV DNA level and biochemical indexes were monitored.Sequencer of HBV polymerase gene was performed on the ABI 3730 automated sequencer.If no desired effects had been achieved during the course of treatment,patients’ choices were also taken into account.The control group was tested at the same time.RESULTS:In the two groups,27 cases developed viral breakthrough after LAM treatment response.The remaining 49 cases underwent biochemical rebound accompanied by rtM204I/V or rtL180M mutation.In group A,52 cases finished 156 wk of ADV monotherapy;of whom,36 cases were HBeAg positive and 16 HBeAg negative.In patients whose baseline HBV DNAs were 10 3-10 5 copies/mL,88.8% of patients’ HBV DNAs were lower than the lower test limit(10 3 copies/mL) after 12 to 156 wk of ADV treatment.In patients whose baseline HBV DNAs were ≥ 10 6 copies/mL,41.1%-47.0% of patients’ HBV DNAs were lower than the lower test limit after the same course of ADV therapy(χ 2 were 4.35-5.4,41.1%-47.0% vs 88.8% group 10 3-10 5 copies/mL,P < 0.01).In group A,seroconversion of HBeAg developed in 8 of 36 cases(22.2%).In group B,24 cases finished 156 wk of LAM + ADV;of whom,17 cases were HBeAg positive and 7 HBeAg negative.In patients whose baseline HBV DNAs were 10 3-10 5 copies /mL,81.8% of patients’ HBV DNAs were lower than the lower test limit(10 3 copies/mL) after 12 to 156 wk of treatment.In the patients whose baseline HBV DNAs were ≥ 10 6 copies/mL,46.1%-53.8% of patients’ HBV DNAs were lower than the lower test limit after the same course of LAM + ADV therapy(χ 2 were 4.1-5.0,46.1%-53.8% vs 81.8% group 10 3-10 5 copies/mL,P < 0.05-0.01).In group B,4 of 17 cases(23.5%) developed seroconversion of HBeAg.Treatment outcomes in groups A and B were comparable.CONCLUSION:In both group A and B,the ratios of virological response have similar efficacy in patients with lower baseline HBV DNAs.     

Long-term lamivudine treatment for chronic hepatitis B in Japanese patients： A project of Kyushu University Liver Disease Study

AIM:To determine the efficacy of long-term lamivudinetreatment of a large number of Japanese patients withchronic hepatitis B.METHODS:In this retrospective,multi-center trial,318 Japanese patients with chronic hepatitis B received100 mg of lamivudine daily for up to 36(median 21)mo.Virological response was a decline to a serumHBV DNA level less than 3.7 log copies/mL.Virological breakthrough was defined as the reappearance of aserum HBV DNA level to more than 10-fold the minimumduring treatment.RESULTS:Lamivudine produced virological responsein 86.8% of the 318 patients at 6 mo,in 80.2% of252 patients at 12 mo,in 69.2% of 133 patients at 24mo,and in 53.6% of 28 patients at 36 mo.Forwardstepwise logistic regression analysis showed an HBV DNAlevel less than 6.8 log copies/mL(P<0.0001),HBeAgnegativity(P<0.0001),a platelet count of 100×10~9/L ormore(P=0.0162)at baseline,and a decline of the HBVDNA level of more than 3.2 log copies/mL as comparedwith the baseline level at 3 mo after the start oftreatment(P=0.0003)to be significantly associated withvirological response.Among patients with a virologicalresponse,virological breakthrough was seen in 5.3%of 19 patients who responded virologically at 1 mo,in20.7% of 203 patients at 3 mo,in 27.5% of 51 patientsat 6 mo,in 33.3% of 12 patients at 9 mo,and in 100%of 3 patients at≥15 mo.A virological breakthrough wasfound significantly more often in patients with delayedvirological response.CONCLUSION:Lamivudine treatment could suppressserum HBV DNA in most of the tested Japanese patients.Long-term efficacy might be seen in patients withoutHBeAg at baseline,in the absence of cirrhosis,and inpatients with a decline in HBV DNA level soon after thestart of treatment.     

Sequential changes of serum ferritin levels and their clinical significance in lamivudine-treated patients with chronic viral hepatitis B

AIM: To study the sequential changes of serum ferritin levels in lamivudine-treated patients with chronic viral hepatitis B and the clinical implications. METHODS: Thirty-eight patients with chronic viral hepatitis B were prospectively studied during their treatment with lamivudine. Each patient received 100 mg oral lamivudine daily for 12 mo, and was observed and tested for blood biochemistry and hepatitis B virus (HBV) DNA levels and serum ferritin levels at baseline and at 3, 6 and 12 mo during the treatment. Serum HBV DNA levels were quantitatively determined using fluorescent quantitative polymerase chain reaction (FQ-PCR), and serum ferritin levels were measured by radioimmunoassay. The sequential changes of serum ferdtin levels and their relationships with virological, serological and biochemical responses in the patients were analyzed. RESULTS: All the patients had a baseline HBV DNA level higher than 1&#215;10^7 copies/L as determined by FQ-PCR and positive HBsAg and HBeAg and abnormal ALT levels. At the end of the 12-mo treatment, 19 of the 38(50.00%) patients had undetectable serum HBV DNA levels by FQ-PCR, and 12(31.58%) became negative for serum HSeAg and 10(26.32%) had seroconversion from HBeAg to HBeAb. Nineteen out of the 38(50.00%) patients had biochemically normal ALT levels after 12-mo lamivudine treatment. Sequential determination showed bhat lamivudine treatment significantly reduced ferritin levels in chronic hepatitis B patients. When the patients were divided into different groups according to their posttreatment virological, serological and biochemical responses for analysis of the sequential changes of ferritin levels, it was found bhat the decrease of ferritin levels in HBV DNA-negative group was significantly more obvious than that in HBV DNApositive group at 6 mo during the treatment (P=-0.013). Consecutive comparisons showed that ferritin levels at 3 mo of treatment were obviously decreased as compared with the baseline levels (P&lt;0.05) in HBeAg-negative group, and the decrease of serum ferritin levels in patients with normalized ALT was more significant than that in patients with abnormal ALT at the end of the 12-mo treatment (P=0.048). CONCLUSION: Lamivudine treatment can reduce the serum ferritin levels in chronic viral hepatitis B patients and decreases of ferdtin levels can be more significant in patients exhibiting virological, serological and biochemical responses, indicating that dynamic observation of serum ferritin levels in patients with chronic viral hepatitis B during lamivudine treatment might be helpful for monitoring and predicting patients‘ responses to the therapy.     

HBeAg血清学转换对核苷（酸）类似物治疗慢性乙型肝炎患者停药后复发的影响

目的探讨HBeAg血清学转换对核苷（酸）类似物治疗慢性乙型肝炎（CHB）患者停药后复发的影响。方法回顾性分析60例HBeAg阳性接受核苷（酸）类似物治疗的CHB患者,疗程至少1年的停药患者,于基线、治疗后每个月、HBV DNA转阴后每3个月检测ALT,HBV DNA,HBeAg和抗-HBe。停药后继续随访至少6个月,观察停药后复发情况。分析停药时是否发生HBeAg消失/转换对复发的影响;比较发生HBeAg/抗HBe血清转换后巩固治疗≤12个月、12～24个月、〉24个月三组患者的复发率。结果 60例患者中,60%（36例）的患者在停药后6个月内复发。8例患者未发生HBeAg消失（A组）,停药后4个月内100%复发;6例患者发生HBeAg消失,但无抗-HBe（B组）,停药后6个月内83.3%（5例）复发;46例发生HBeAg血清学转换（C组）,停药后6个月内50%（23例）复发,χ2=11.585,P=0.003,A组与C组相比,χ2=6.84,P=0.015,差异有统计学意义;B组与A组、C组相比,χ2=1.333,P=0.248,χ2=2.327,P=0.199,差异无统计学意义;HBeAg/抗-HBe血清转换后继续用药≤12个月（11例）、12～24个月（23例）、〉24个月（C组12例）,停药后6个月内复发率分别为100%（11例）、47.8%（11例）、8.3%（1例）,χ2=19.377,P=0.000,A组与B组、C组相比,χ2=8.609,P=0.003,χ2=19.326,P=0.000,B组与C组相比,χ2=5.303,P=0.027,均有统计学意义。结论 HBeAg血清学转换是HBeAg阳性CHB患者治疗终点的基本指标,HBeAg/抗-HBe血清转换后治疗≤12个月仍有较高的复发率,HBeAg/抗-HBe血清转换继续治疗〉24个月有望获得持久的病毒学应答,但对停药患者6个月内应密切随访观察。     

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUNDNucleos(t)ide analogs (NAs) cessation in chronic hepatitis B (CHB) patients remains a matter of debate in clinical practice. Current guidelines recommend that patients with hepatitis B e antigen (HBeAg) seroconversion discontinue NAs after relatively long-term consolidation therapy. However, many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg, even if hepatitis B surface antigen (HBsAg) loss occurs. It remains unclear whether NAs can be discontinued in this subset of patients.AIMTo investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss (without hepatitis B e antibody) after cessation of NAs.METHODSWe studied patients who discontinued NAs after achieving HBeAg loss. The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs. The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves; we confirmed the cut-off value of HBsAg according to a previous study. The log-rank test was used to compare cumulative relapse rates among groups. We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates. Propensity score matching analysis (PSM) was used to balance baseline characteristics between the groups.RESULTSWe included 83 patients with HBeAg loss. The mean age of these patients was 32.1 ± 9.5 years, and the majority was male (67.5%). Thirty-eight patients relapsed, and the cumulative relapse rate at months 3, 6, 12, 24, 36, 60, 120, and 180 were 22.9%, 36.1%, 41.0%, 43.5%, 45.0%, 45.0%, 45.0%, and 52.8%, respectively. Twenty-six (68.4%) patients relapsed in the first 3 mo after NAs cessation, and 35 patients (92.1%) relapsed in the first year after NAs cessation. Consolidation period (≥ 24 mo vs < 24 mo) (HR 0.506, P = 0.043) and HBsAg at cessation (≥ 100 IU/mL vs < 100 IU/mL) (HR 14.869, P = 0.008) were significant predictors in multivariate Cox regression. In the PSM cohort, which included 144 patients, there were lower cumulative relapse rates in patients with HBeAg seroconversion (P = 0.036).CONCLUSIONHBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation, especially in patients with HBsAg at cessation < 100 IU/mL. Careful monitoring, especially in the early stages after cessation, may ensure a favorable outcome.     

Hepatitis B surface antigen levels of cessation of nucleos(t)ide analogs associated with virological relapse in hepatitis B surface antigen-negative chronic hepatitis B patients

AIM: To investigate the virological relapse rate in hepatitis B e antigen (HBeAg)-negative patients after antiviral therapy discontinuation and analyze the factors associated with virological relapse.METHODS: Among patients diagnosed with chronic hepatitis B infection between May 2005 and July 2010, 204 were eligible for analysis. The Kaplan-Meier method and log-rank test were used to calculate the cumulative rate of relapse and compare cumulative relapse rates between groups. The Cox proportional hazards regression model was used to evaluate the predictive factor of virological relapse.RESULTS: The 2 and 1 year cumulative risks of virological relapse after antiviral therapy discontinuation were 79.41% (162/204) and 43.82% (71/162), respectively. Multivariate analysis revealed that only post treatment hepatitis B surface antigen (HBsAg) level was associated with virological relapse (P = 0.011). The cumulative risk of virological relapse was higher in the patients with HBsAg levels ≥ 1500 IU/L than in those with HBsAg levels < 1500 IU/L (P = 0.0013). The area under the curve was 0.603 (P = 0.033). The cutoff HBsAg value for predicting virological relapse was 1443 IU/L.CONCLUSION: We found that the virological relapse rate remained high after antiviral therapy discontinuation in the HBeAg-negative patients and that the post treatment HBsAg levels predicted virological relapse.     

Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues

Quantification of hepatitis B surface antigen(HBsAg)has been suggested to be helpful in the management of chronic hepatitis B(CHB)patients.Nucleos(t)ide analogs(NAs)are the therapy of choice for CHB and are used in the majority of CHB patients.NAs are able to induce hepatitis B virus(HBV)viral suppression,normalization of alanine aminotransferase(ALT)levels,and improvement in liver histology.Automated quantitative assays for serum HBsAg have recently become available,facilitating standardized quantification of serum HBsAg.This has led to increased interest in the clinical application of quantitative serum HBsAg for predicting therapeutic response to NAs.Recent studies have shown that a decline in serum HBsAg levels in patients receiving peginterferon may signal successful induction of immune control over HBV,and can therefore be used to predict therapeutic response.NA treatment typically induces a less rapid decline in HBsAg than interferon treatment;it has been estimated that full HBsAg clearance can require decades of NA treatment.However,a rapid HBsAg decline during NA therapy may identify patients who will show clearance of HBsAg.Currently,there is no consensus on the clinical utility of serum HBsAg monitoring for evaluating patient responses to NA therapy.This review focuses on recent findings regarding the potential application of HBsAg quantification in the management of CHB patients receiving NA therapy.     

Clearance of hepatitis B surface antigen during long-term nucleot(s)ide analog treatment in chronic hepatitis B: results from a nine-year longitudinal study

Background

Clearance of hepatitis B surface antigen (HBsAg) is considered the ultimate goal in chronic hepatitis B treatment. One treatment option is long-term nucleot(s)ide analog (NA) therapy. We followed a group of long-term NA therapy patients to evaluate the efficacy of this treatment in promoting clearance and longitudinal declines of HBsAg.

Method

The study included 791 NA therapy patients who received lamivudine as their first drug. At the baseline, 442 patients were hepatitis B e antigen (HBeAg)+ and 349 were HBeAg?. All analyses were performed after separating the HBeAg+ and HBeAg? cohorts. Cox proportional hazards models were used to determine which factors were associated with HBsAg clearance.

Results

HBsAg clearance was observed in 18 (4.1 %) of the HBeAg+ patients and 20 (5.7 %) of the HBeAg? patients at baseline, giving seroclearance rates of 6.4 and 6.9 %, respectively, over the nine-year study period. HBsAg clearance was influenced by several independent factors that varied according to HBeAg cohort. For HBeAg+ patients, these included previous interferon therapy, infection with hepatitis B virus (HBV) genotype A, a ≥0.5 log IU/mL decline in HBsAg level within six months, and clearance of HBeAg at six months. For HBeAg? patients, these included infection with HBV genotype A, decline in HBsAg at six months, and a baseline HBsAg level of <730 IU/mL.

Conclusion

This study suggests that both direct antiviral potential and host immune response are needed to achieve HBsAg clearance by NA therapy. Viral genotype strongly influenced HBsAg clearance during NA therapy.     

48 weeks outcome after cessation of nucleos(t)ide analogue therapy in chronic hepatitis B patients

Introduction and objectiveThe aim of the present study was to investigate the significance of serum HBsAg levels in treatment cessation of nucleoside analogues (NAs) in patients with chronic hepatitis B (CHB) infection.MethodsIn 158 CHB patients with long-term NAs treatment, 74 patients were in HBeAg negative and had a HBsAg level <1500 IU/mL, 36 of whom were informed and consented to cease NAs. HBsAg, HBV DNA and liver function were examined in the 1st, 3rd, 6th, 9th and 12th month after treatment cessation.ResultsThe sustained response rate was 88.89% (32/36) within one year after NAs cessation. Sub-group analysis was based on HBsAg levels of patients with NAs cessation, there was no relapse case in 11 patients whose HBsAg <50 IU/mL, and the negative predictive value (NPV) was 100%. Seroconversion of HBsAg occurred in 3 patients. 2 patients from 21 cases whose HBsAg was between 50 IU/mL and 1000 IU/mL relapsed. 2 of 4 patients whose in HBsAg >1000 IU/mL relapsed. HBsAg of patients with a sustained response decreased slowly. In contrast, HBsAg levels increased gradually in relapsed patients, and the increase of HBsAg was precedent to relapses of HBV DNA and ALT. Multivariate analysis suggested that only HBsAg level showed a close correlation with HBV DNA relapses. ROC curve analysis suggested that the increase of HBsAg level in the 3rd and 6th month after NAs cessation had a great predictive value for relapses.ConclusionMonitoring of base line HBsAg level can predict outcomes of NAs cessation in HBeAg-negative chronic hepatitis B. HBsAg <50 IU/mL has higher predictive values of better sustained responses in HBeAg-negative CHB patients.     

Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients

A newly developed O-glycosylated M-hepatitis B surface antigen (HBsAgGi) measurement system can detect hepatitis B surface antigen (HBsAg) associated with infectious particles. We investigated the association of HBsAgGi levels with clinical parameters and a history of hepatocellular carcinoma (HCC) development in a cross-sectional cohort analysis (Study 1) as well as the quantitative changes in HBsAgGi during nucleos(t)ide analogue (NA) therapy in a longitudinal cohort analysis (Study 2). A total of 124 patients with genotype C chronic HBV infection were analysed in Study 1 to evaluate correlations of HBsAgGi with conventional HBV markers and HCC history. Among those, 36 patients receiving NA therapy were enrolled in Study 2 for quantitative comparisons between pre-treatment baseline and 48 weeks of NA therapy. In Study 1, serum HBsAgGi was significantly associated with HBsAg (r = .5857, p < .00001) and weakly but significantly correlated with HBV DNA (r = .2936, p = .001). Although HBsAgGi (p = .111) was comparable between HCC history (+) group and HCC history (−) group, the HBsAgGi/HBsAg ratio (p = .011) was significantly higher in HCC history (+) patients. In Study 2, HBsAgGi was significantly decreased after 48 weeks of NA therapy (p < .001). HBsAg findings were similar (p = .005) along with an HBV DNA reduction (p < .001). In the baseline hepatitis B e antigen (HBeAg) (+) subgroup, HBsAgGi decreased significantly between baseline and 48 weeks of NA (p = .005), while HBsAg was comparable (p = .051). Low HBsAg and high HBsAgGi were associated with a history of HCC development. HBsAgGi decreased significantly by 48-week NA therapy.     

Association of on‐treatment serum hepatitis B surface antigen level with sustained virological response to nucleos(t)ide analog in patients with hepatitis B e‐antigen positive chronic hepatitis B

Aim: This study evaluated the on‐treatment serum hepatitis B surface antigen (HBsAg) level during nucleos(t)ide analog (NUC) therapy and the correlation with off‐treatment sustained virological response (SVR). Methods: Fifty‐one consecutive patients with hepatitis B e‐antigen (HBeAg) positive chronic hepatitis B who achieved HBeAg loss/seroconversion after NUC therapy and completed 12 months or more of additional therapy were included. Serum HBsAg and hepatitis B virus (HBV) DNA levels were determined at baseline, 3, 6, 9 and 12 months, and at the end of treatment. SVR was defined as HBV DNA levels of less than 10 000 copies/mL until 6 or 12 months off‐treatment without reappearance of HBeAg. Results: Twenty‐two (43.1%) and 13 (25.5%) patients maintained SVR at 6 and 12 months off‐treatment, respectively. In univariate analyses, a decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months (P = 0.006) and 12 months (P = 0.013), the mean change in HBsAg level at 6 months (P = 0.024), and lamivudine or entecavir treatment (P = 0.019) were significant predictive factors for SVR at 6 months off‐treatment. A decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months and lamivudine or entecavir treatment were independent factors on multivariate analyses (odds ratio [OR], 16.67; 95% confidence interval [CI], 1.86–142.86 [P = 0.012]; and OR, 14.83; 95% CI, 1.18–185.73 [P = 0.036]; respectively). Conclusion: On‐treatment serum HBsAg level predicted early off‐treatment SVR to NUC therapy in patients infected with genotype C.     

The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients

This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)‐positive and ‐negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg‐positive and 104 HBeAg‐negative patients) who were previously treated with TDF and had post‐treatment follow‐up for at least 6 months (median: 55, IQR 36‐85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg‐positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg‐negative patients. Cox regression analysis revealed that the higher end‐of‐treatment HBsAg levels were an independent factor of virological relapse in HBeAg‐positive and HBeAg‐negative patients. The end‐of‐treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg‐positive and HBeAg‐negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg‐positive and HBeAg‐negative patients who achieved HBsAg ≤200 IU/mL and HBsAg ≤80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off‐therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end‐of‐treatment HBsAg ≤80 IU/mL and ≤50 IU/mL, respectively. In conclusions, the end‐of‐treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg‐positive and HBeAg‐negative CHB patients.     

Hepatitis B virus pregenomic RNA status can reveal the long‐term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues

We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long‐time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment‐naïve and had begun a 7‐year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real‐time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg‐negative rates also increased. After 48 weeks’ NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA‐positive. After 7 years of treatment, more HBV pgRNA‐negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA‐positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA‐positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75‐31.08). The median time to HBeAg clearance in the HBV pgRNA‐positive patients was longer than that of the HBV pgRNA‐negative patients (152 weeks vs 72 weeks). The HBV pgRNA‐positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33‐144.67 vs 48 weeks, 95% CI: 34.80‐61.20). The HBV pgRNA status after NA treatment can predict the long‐term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA‐positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.