Viral level is an indicator of long-term outcome of hepatitis B virus e antigen-negative carriers with persistently normal serum alanine aminotransferase levels

Summary. The association between viral level and the long‐term outcomes of hepatitis B virus (HBV) carriers who test negative for hepatitis B virus e antigen (HBeAg) but have persistently normal serum alanine aminotransferase levels (PNALT) remains unclear. We examined hepatocarcinogenesis, hepatitis reactivation, predictive factors and the time course of HBV DNA levels during follow‐up in 104 HBeAg‐negative Japanese carriers with PNALT. During a mean follow‐up period of 6.4 ± 3.4 years, 5 patients (4.8%) had hepatocarcinogenesis and 14 (13.5%) had hepatitis reactivation. At 5 and 10 years, the cumulative rates of hepatocarcinogenesis were 2.4% and 9.9%, while those of hepatitis activation were 13.7% and 15.5%, respectively. An HBV DNA level of ≥5 log₁₀ copies/mL was the sole predictor of hepatocarcinogenesis with a univariate analysis. An HBV DNA level of ≥5 log₁₀ copies/mL and an alanine aminotransferase (ALT) level of >20 to ≤40 IU/L were independent predictors of hepatitis reactivation in a Cox model. Because there was no association between hepatocarcinogenesis and ALT activity, the HBV DNA level was considered an essential predictor. In addition, the baseline HBV DNA level was related to the future level and was not subject to wide fluctuations. Our results showed that an HBV DNA level of ≥5 log₁₀ copies/mL predicts subsequent hepatocarcinogenesis and hepatitis reactivation in HBeAg‐negative carriers with PNALT. As the baseline HBV DNA level reflects the future level, appropriate clinical management according to the viral level is expected to decrease future risk.     

Lower baseline ALT cut-off values and HBV DNA levels better differentiate HBeAg（-） chronic hepatitis B patients from inactive chronic carriers

AIM： To determine whether new cut-off values for aianine aminotransferase （ALT） and baseline hepatitis B virus （HBV） DNA levels better differentiate HBeAg（-） chronic hepatitis B （CriB） patients from inactive chronic carriers.
METHODS： Ninety-one patients [32 HBeAg（＋） CriB, 19 inactive carriers and 40 HBeAg（-） CriB] were followed up for 2 years and were tested for HBV DNA levels by a PCR-based assay. ALT was tested twice during the last 6 mo using new cut-off values： ULN （upper limit of normal） 30 IU/L for males, 19 IU/L for females. Diagnostic accuracy, sensitivity, specificity, positive and negative predictive values were calculated by discriminant analysis.
RESULTS： When using the revised ALT cut-off values, the lowest optimal HBV DNA level that differentiated HBeAg（-） CHB patients from inactive carriers was 50000 copies/mL. The diagnostic accuracy of HBV DNA to determine inactive carriers with a cut-off of 50000 copies/mL was similar to the previously recommended cut-off of 100000 copies/mL （91%）. HBV DNA levels were lower than the cut-off value in 95% of inactive carriers and in 28% of HBeAg（-） CHB patients. With ALT 〈 30 IU/L in men and 〈 19 IU/L in women and HBV DNA levels 〈 100000 copies/mL, the risk of CHB is 5%. On the other hand, if ALT values were 〉 30 IU in men and 〉 19 IU in women and baseline HBV DNA levels were 〉 100000 copies/mL, the risk is 86%.
CONCLUSION： New cut-off values for ALT together with HBV DNA levels proposed by AASLD （American Association for the Study of Liver Diseases） and NIH （National Institute of Health） consensus seem appropriate to characterize inactive carriers.     

恩替卡韦长期治疗核苷（酸）类药物初治H BeAg阳性慢性乙型肝炎患者的疗效和安全性

目的：了解恩替卡韦单药治疗至少5年对核苷（酸）类药物初治的 HBeAg 阳性慢性乙型肝炎患者的疗效和安全性。方法选择BMS463-012和BMS463-023研究项目在瑞金医院感染科入组的20例 HBeAg 阳性慢性乙型肝炎核苷初治患者。所有患者在第一阶段（第1～2年）口服恩替卡韦0．5 mg/d,第二阶段（第3～5年）口服恩替卡韦1．0 mg/d。检测并记录基线以及治疗48、96、144、192和240周时患者的ALT、HBV DNA、HBeAg和 HBsAg水平。如治疗240周时HBV DNA ≥300拷贝/mL,则进行基因序列测定以明确是否发生耐药。结果恩替卡韦治疗第48、96、144、192和240周,HBV DNA ＜300拷贝/mL的比例分别为60％、40％、50％、85％和85％,HBeAg消失率分别为15％、15％、20％、30％和65％。有3例患者在第192周发生 HBeAg 血清学转换。恩替卡韦治疗48周时血清 HBV DNA＜300拷贝/mL 与＞300拷贝/mL患者相比,240周病毒学应答率分别为100％和66．7％;240周 HBeAg 血清学转换率分别为27．3％和0。入组患者中基线ALT＞2倍和＜2倍患者相比,前者240周病毒学应答率为100％,后者为75％;前者240周 HBeAg 血清学转换率为37．5％,而后者为0。入组患者基线高病毒载量（＞10^8拷贝/mL）和低病毒载量（＜10^8拷贝/mL）比较,前者240周病毒学应答率为83．3％,后者为100％;前者240周 HBeAg血清学转换率为11．1％,而后者为50％。以上二者相比,均差异有统计学意义（P＜0．05）。基线、治疗48、96、144、192和240周血清 HBsAg 水平分别为（4．04±0．40）、（3．64±0．44）、（3．73±0．41）、（3．53±0．55）、（3．55±0．55）和（3．55±0．63）lg IU/mL。相对于基线,在第48周、144周、192周、240周 HBsAg效价有明显下降（P值分别为0．005、0．005、0．009、0．018）。治疗240周时 HBeAg消失和未消失的患者,其基线 HBsAg效价（3．95±0．54）lg IU/mL比（4．20?     

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels

Summary. Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on‐treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty‐two patients with HBeAg‐positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on‐treatment factors, on‐treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log₁₀ IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940–1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On‐treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut‐off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log₁₀ PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on‐treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg‐positive CHB patients with entecavir treatment.     

慢性乙型肝炎治疗中影响HBeAg转阴和定量的有关因素分析

背景：慢性乙型肝炎抗病毒治疗的完全应答包括血清HBVDNA低于检测水平和HBeAg血清学转换,HBeAg是评估乙型肝炎治疗效果和停药的监测指标。目的：探讨替比夫定治疗HBeAg阳性慢性乙型肝炎患者时影响HBeAg转阴的因素。方法：采用替比夫定治疗156例HBeAg阳性慢性乙型肝炎患者48周,观察ALT、HBVDNA、HBeAg治疗前后变化,分析治疗前基线HBVDNA载量、ALT水平、HBVDNA降至检测下限的时间对HBeAg转阴和定量的影响。结果：替比夫定治疗48周后,HBVDNA转阴128例（82．1％）,ALT恢复正常153例（98．1％）,HBeAg转阴52例（33．3％）;HBVDNA载量、HBeAg定量、ALT水平均显著降低（P〈0．01）。治疗前HBVDNA〈10^7 copies／mL、ALT≥200U／L组的HBeAg转阴率分别显著高于HBVDNA≥10^7 copies／mL、ALT〈200U／L组（46．4％对23．0％,P〈0．01;55．2％对16．9％,P〈0．叭）,且HBeAg定量显著降低（P〈0．01）。HBVDNA降至检测下限的不同时间组HBeAg转阴率和定量相比差异均有统计学意义（P〈0．05）。结论：基线HBVDNA〈10^7 copies／mL、ALT水平较高、治疗后HBVDNA降至检测下限的时间对替比夫定治疗48周时HBeAg转阴和定量具有明显的影响。     

Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B

Aim: The factors associated with hepatitis recurrence after discontinuation of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B were analyzed to predict the risk of relapse more accurately. Methods: A total of 126 patients who discontinued NA therapy were recruited retrospectively. The clinical conditions of a successful discontinuation were set as alanine aminotransferase (ALT) below 30 IU/L and serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL. Results: Relapse of hepatitis B were judged to occur when maximal serum ALT became higher than 79 IU/L or when maximal serum HBV DNA surpassed 5.7 log copies/mL following NA discontinuation since these values corresponded with mean values of ALT (30 IU/L) and HBV DNA (4.0 log copies/mL), respectively. At least 90% of patients with either detectable hepatitis B e antigen or serum HBV DNA higher than 3.0 log copies/mL at the time of NA discontinuation relapsed within one year. In the remaining patients, higher levels of both hepatitis B surface and core‐related antigens at the time of discontinuation, as well as a shorter course of NA treatment, were significantly associated with relapse by multivariate analysis. Conclusions: It appears that negative results for hepatitis B e antigen and serum HBV DNA lower than 3.0 log copies/mL are essential for successful NA discontinuation, which may be attained by a longer treatment period. Levels of hepatitis B surface and core‐related antigens are also significant factors independently associated with relapse of hepatitis.     

Hepatitis B virus DNA prediction rules for hepatitis B e antigen-negative chronic hepatitis B

After hepatitis B e antigen (HBeAg) seroconversion, hepatitis B may become inactive or progress to HBeAg-negative hepatitis with persistent or intermittent alanine aminotransferase (ALT) elevation. The aim of this study was to prospectively identify factors predictive of the clinical course in HBeAg-negative chronic hepatitis B (CHB). Patients were stratified by ALT and HBeAg status and followed every 3 months for up to 5 years. Kaplan-Meier and Cox regression analysis using the change from normal ALT to elevated ALT as endpoints were performed to determine factors associated with ALT elevation/normalization. Seventy-four HBeAg-negative and 32 HBeAg-positive patients were prospectively evaluated. For HBeAg-negative patients, hepatitis B virus (HBV) DNA was predictive of future ALT. Only 1 patient with normal ALT and an HBV DNA value lower than 10,000 copies/mL developed an elevated ALT within the subsequent year, whereas 67% with an HBV DNA value greater than 100,000 copies/mL had a rise in ALT above normal within 1 year. Patients with a previous history of ALT elevation and longer follow-up at all levels of HBV DNA were more likely to experience ALT elevations. For HBeAg-negative patients with elevated ALT and all HBeAg-positive patients, HBV DNA did not predict future ALT. Other viral and host factors were not predictive of future ALT. CONCLUSION: HBeAg-negative CHB has a fluctuating course. HBV DNA values lower than 10,000 copies/mL predict persistently normal ALT for at least 1 year. Patients with HBV DNA values between 10,000 and 100,000 copies/mL can safely be followed at 6 monthly intervals, whereas HBV DNA values greater than 100,000 copies/mL are highly predictive of future ALT elevation and should prompt regular follow-up.     

Comparison between quantitative hepatitis B surface antigen,hepatitis B e‐antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon‐α‐2b therapy in hepatitis B e‐antigen‐positive chronic hepatitis B

Aim: The aim of this study was to compare the clinical applicability of quantitative serum hepatitis B surface antigen (HBsAg), hepatitis B e‐antigen (HBeAg) and hepatitis B virus (HBV) DNA for predicting virological response (VR) to pegylated interferon (PEG‐IFN) therapy. Methods: Thirty HBeAg‐positive chronic hepatitis B patients who received PEG‐IFN‐α‐2b for 48 weeks were enrolled. Quantitative HBsAg, HBeAg and HBV DNA were measured before, during and after the therapy. Paired liver biopsies were performed before and after treatment for covalently closed circular (ccc)DNA and intrahepatic HBV DNA analysis. Results: VR at 48 weeks post‐treatment, defined as HBeAg seroconversion and HBV DNA less than 10 000 copies/mL was achieved in 10 (33.3%) patients. Responders had significantly lower baseline HBsAg, HBeAg, cccDNA and intrahepatic HBV DNA levels than non‐responders. Baseline and reduced levels of log₁₀ HBsAg and log₁₀ HBeAg correlated well with those of log₁₀ cccDNA and log₁₀ total intrahepatic HBV DNA. Responders showed consistent decrease in serum HBsAg, HBeAg and HBV DNA levels during therapy. HBeAg level of 2.0 log₁₀ sample to cut‐off ratio at week 24 on therapy provided the best prediction of sustained virological response, with sensitivity and negative predictive values of 85% and 92%, respectively. One patient (3.3%) who cleared HBsAg at follow up exhibited a more rapid decline in serum HBsAg during therapy than those who developed VR without HBsAg clearance. Conclusion: Quantitative measurement of serum HBeAg during therapy may be superior to serum HBsAg and HBV DNA as a prediction of HBeAg seroconversion. Kinetics of HBsAg levels on therapy may help predict HBsAg clearance after treatment.     

Switching to peginterferon for chronic hepatitis B patients with hepatitis B e antigen seroconversion on entecavir – A prospective study

Nucleos(t)ide analogues (NA) are effective in suppressing hepatitis B virus (HBV) replication, but most patients require long‐term treatment. This study aimed to investigate switching to peginterferon as a strategy to stop NA. Hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients who developed HBeAg seroconversion during NA treatment were studied. All patients received open‐label peginterferon alfa‐2a 180 μg/wk for 48 weeks, and NA was stopped at week 4 of peginterferon treatment. The primary endpoint was sustained response, which was defined as negative HBeAg, positive anti‐HBe and HBV DNA <2000 IU/mL at week 72. Other secondary endpoints including HBsAg loss at week 72 were also studied. Forty‐one patients treated with entecavir for 56 ± 23 months were recruited. Sustained response was achieved in 30 patients (73%, 95% confidence interval 58%‐84%). At week 72, 31 (76%) patients had HBeAg seroconversion, 56 (23%) patients had undetectable HBV DNA, 31 (76%) patients had normal ALT, and 6 patients (15%) had HBsAg loss. Baseline HBsAg level was the best predictor for both sustained response and HBsAg loss; the best HBsAg cut‐off for sustained response was <1500 IU/mL and that for HBsAg loss was <500 IU/mL by receiver operating characteristic curve analysis. Twenty‐two of 25 (88%) patients with baseline HBsAg <1500 IU/mL had sustained response. Five of 10 (50%) patients with baseline HBsAg <500 IU/mL developed HBsAg loss. Switching to peginterferon can be considered as a treatment option in NA‐treated patients with HBeAg seroconversion, particularly among those with lower HBsAg levels.     

Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection

The goals of this retrospective study were to determine whether there is a threshold hepatitis B virus (HBV) DNA value associated with spontaneous or antiviral therapy-related hepatitis B e antigen (HBeAg) clearance. We also investigated whether there is an HBV DNA value that can be used for differentiating inactive carriers from patients with HBeAg-negative chronic hepatitis B. HBV DNA levels in sequential serum samples of 165 Chinese patients with different stages of chronic HBV infection were quantified by a polymerase chain reaction (PCR)-based assay. Our results showed that almost all of the patients (89%) who remained HBeAg-positive had HBV DNA levels that were persistently above 10(5) copies/mL. Serum HBV DNA levels decreased by a mean of 3 log(10) in patients with HBeAg loss, but 51% had levels above 10(5) copies/mL at the time HBeAg first became undetectable. Mean serum HBV DNA levels were significantly lower in HBeAg-negative patients. HBV DNA value above 10(5) copies/mL would exclude all inactive carriers, but 45% of patients with HBeAg-negative chronic hepatitis would also be excluded if testing were only performed at presentation and 30% would be excluded if testing were performed on 3 occasions. In conclusion, serum HBV DNA levels decreased significantly in patients with HBeAg loss, but there was no threshold HBV DNA level associated with HBeAg clearance. Given the fluctuating course of HBeAg-negative chronic hepatitis, it is not possible to define a single cutoff HBV DNA value for differentiating inactive carriers from patients with HBeAg-negative chronic hepatitis.     

替比夫定治疗HBeAg阳性慢性乙型肝炎的疗效及相关预测因子的Logistic回归分析

目的观察替比夫定（LdT）治疗HBeAg阳性慢性乙型肝炎（CHB）患者3年的疗效,应用Logistic回归探讨HBeAg血清学转换的预测因子。方法收集58例采用LdT治疗的HBeAg阳性CHB患者,分析其性别、年龄、基线ALT水平、基线HBV DNA载量、基线HBeAg和HBsAg滴度与治疗3年时ALT复常率、HBV DNA阴转率、HBeAg阴转率和HBeAg血清转换率的相关性;采用Logistic回归分析HBeAg血清转换的相关因素。结果治疗3年时ALT复常率为84.48%,HBV DNA阴转率为70.69%,HBeAg阴转率为50.00%,HBeAg血清转换率为43.10%。与ALT≤2倍正常值上限（2×ULN）相比,基线ALT〉5×ULN的患者HBeAg转换率显著增高（P〈0.05）;与HBeAg≤100（S/CO）组相比,基线HBeAg〉200 S/CO的患者HBeAg的阴转率和血清转换率均显著下降（P〈0.05）;与HBV DNA≤6 log拷贝/ml组相比,HBV DNA〉7 log拷贝/ml的患者HBV DNA转阴率、HBeAg转阴率和HBeAg转换率下降显著（P〈0.05）;患者性别、年龄及基线HBsAg滴度对以上疗效指标无影响（P〉0.05）。多因素Logistic回归分析发现仅基线HBeAg滴度低的患者更易出现HBeAg血清学转换。结论 LdT能有效恢复肝功能,抑制HBV复制和提高HBeAg血清转换;基线HBeAg滴度可预测LdT治疗HBeAg阳性CHB患者的HBeAg血清转换率。     

The natural history and treatment of chronic hepatitis B: a critical evaluation of standard treatment criteria and end points

The definite indications for the treatment of chronic hepatitis B are serum hepatitis B virus (HBV) DNA levels greater than 10(5) copies/mL and alanine aminotransferase (ALT) levels more than 2 times the upper limit of normal. If cirrhosis is present, an HBV DNA level greater than 10(5) copies/mL is the sole criterion for treatment. Treatment end points include hepatitis B e antigen (HBeAg) seroconversion for HBeAg-positive patients, reduction of HBV DNA levels to less than 10(5) copies/mL, and normalization of ALT values. These guidelines may apply to patients who acquire the hepatitis B infection during adolescence or adulthood but are less suitable for most hepatitis B carriers, who are infected in early life. Cirrhosis complications, including hepatocellular carcinoma, often occur in this latter group despite HBeAg seroconversion, HBV DNA levels less than 10(4) copies/mL, or ALT levels between 0.5 and 2 times the upper limit of normal. Therefore, HBeAg seroconversion may not be an adequate end point for these patients; the ideal treatment end points are permanent suppression of HBV DNA to levels undetectable by polymerase chain reaction and reduction of ALT levels to less than 0.5 times the upper limit of normal.     

Dynamics of hepatitis B e antigen index ratio correlate with treatment response in chronic hepatitis B patients.

BACKGROUND/AIM: Hepatitis B e antigen (HBeAg) seroconversion is an important event in the natural history of chronic hepatitis B virus (HBV) infection. Whether early dynamics of HBeAg index ratio could predict therapeutic endpoint of HBeAg seroconversion in patients receiving lamivudine remains unclear and thus deserves investigation. METHODS: A total of 52 patients (males/females, 40/12; mean age, 31.1+/-7.5 years) with HBeAg-positive chronic hepatitis B and serum alanine aminotransferase (ALT) level > or = 5 x upper limit of normal were enrolled. They received daily 100 mg lamivudine for at least 1 year. Pretreatment HBeAg index ratio and the dynamics during treatment [early serologic response (ESR) and serologic breakthrough (SB)] between responders and non-responders were compared. RESULTS: Of these 52 patients, mean pretreatment serum ALT level was 580 IU/l and baseline HBeAg index ratio (S/N) was 37.9. The overall 1-year on-treatment combined response rate was 50%. By using linear regression analysis, HBeAg index ratio was positively correlated with serum HBV DNA level (Pearson's correlation coefficient: 0.62, P<0.0001). By using multivariate logistic regression analysis, ESR could predict the success of treatment response (P=0.0302), and SB had a 90% positive predictive value of treatment failure. CONCLUSIONS: HBeAg index ratio is closely correlated with serum HBV DNA level, and the dynamics of HBeAg index ratio may predict 1-year on-treatment combined response to lamivudine in HBeAg-positive chronic hepatitis B patients.     

Long-term follow-up of patients with hepatitis B e antigen negative chronic hepatitis B

Background and Aim: After hepatitis B virus (HBV) e antigen (HBeAg) seroconversion, HBV‐DNA continues to replicate, and HBeAg‐negative patients still face the risk of liver disease progression. We investigated the predictive factors for alanine aminotransferase (ALT) elevation, antiviral drug use, and hepatocellular carcinoma (HCC) occurrence in HBeAg‐negative patients. Methods: Age, sex, ALT, platelet counts, HBV‐DNA levels, genotype, antidiabetic drug use, body mass index, smoking, and alcohol consumption were analyzed for a total of 244 HBV carriers who were HBeAg‐negative. Results: Of 244 HBeAg‐negative patients, 158 (64.8%) showed normal ALT levels at baseline. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels and high ALT at baseline as independent risk factors for ALT elevation in the patients with normal ALT at baseline. The threshold ALT and HBV‐DNA levels were determined to be 31 IU/L and 5.3 logcopies/mL, respectively. Seventeen (7.0%) patients used antiviral drugs. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels (threshold, 5.7 log copies/mL), the use of antidiabetic drugs, and daily alcohol consumption at baseline as an independent risk factor for the use of antiviral drugs in HBeAg‐negative patients. In 10 patients (4.1%), HCC was detected, and a low platelet count (threshold, 10.0 × 10⁴/mm³) was associated with the occurrence of HCC. Conclusion: This study identified predictors of future active liver disease in HBeAg‐negative patients, i.e. ALT elevation, unavoidable use of antiviral drugs, and occurrence of HCC.     

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside‐naïve HBeAg‐positive patients with chronic hepatitis B*

Summary. This retrospective analysis was conducted to describe the characteristics of nucleoside‐naïve hepatitis B e antigen (HBeAg)‐positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg‐positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double‐blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off‐treatment follow‐up. Through a maximum duration of 96 weeks on‐treatment and 24 weeks off‐treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside‐naïve HBeAg‐positive patients treated with entecavir, and that HBsAg loss is associated with sustained off‐treatment suppression of HBV DNA.     

二十岁以下慢性HBV感染者HBVDNA与HBeAg的定量关系

目的:探讨20岁以下慢性乙型肝炎病毒(HBV)感染者血清中HBV DNA、乙型肝炎病毒e抗原(HBeAg)定量之间关系.方法:用实时荧光定量聚合酶链反应(FQ-PCR)及时间分辩荧光免疫分析(TRFIA)技术检测339例(1-20岁)慢性HBV感染者血清中HBVDNA、HBeAg含量,用速率法检测ALT水平.结果:HBeAg定量＞0.3 NCU/mL、HBV DNA定量＞105 copies/mL、而ALT水平正常者占总检测病例的92.3%;HBV DNA定量(对数值)与HBeAg定量之间存在正相关关系(r=0.769,P＜0.001)和线性回归关系(b=0.32,R2=0.59,P＜0.001).结论:20岁以下慢性HBV感染者血清中HBVDNA水平与HBeAg水平存在同时消长的关系,但是有极少患者例外.HBV DNA定量与HBeAg定量两种检测方法相结合应能够更客观地反映患者HBV感染状况,二者具有互补性.     

Relationship between hepatitis B virus DNA levels and liver histology in patients with chronic hepatitis B

AIM： To study the relationship between hepatitis B virus （HBV） DNA levels and liver histology in patients with chronic hepatitis B （CHB） and to determine the prevalence and characteristics of hepatitis B e antigen （HBeAg） negative patients.
METHODS： A total of 213 patients with CHB were studied, and serum HBV DNA levels were measured by the COBAS Amplicor HBV Monitor test. All patients were divided into two groups according to the HBeAg status.The correlation between serum HBV DNA levels and liver damage （liver histology and biochemistry） was explored.
RESULTS： Of the 213 patients with serum HBV DNA levels higher than 10^5 copies/mL, 178 （83.6%） were HBeAg positive, 35 （16.4%） were HBeAg negative. The serum HBV DNA levels were not correlated to the age,history of CHB, histological grade and stage of liver disease in either HBeAg negative or HBeAg positive patients. There was no correlation between serum levels of HBV DNA and alanine aminotransferanse （ALT）,aspartate aminotrans-ferase （AST） in HBeAg positive patients. In HBeAg negative patients, there was no correlation between serum levels of HBV DNA and AST,while serum DNA levels correlated with ALT （r = 0.351, P = 0.042）. The grade （G） of liver disease correlated with ALT and AST （P 〈 0.05, r = 0.205, 0.327 respectively）in HBeAg positive patients. In HBeAg negative patients,correlations were shown between ALT, AST and the G （P 〈 0.01, and r = 0.862, 0.802 respectively）. HBeAg negative patients were older （35 ± 9 years vs 30 ±9 years, P 〈 0.05 ） and had a longer history of HBV infection （8 ± 4 years vs 6 ± 4 years, P 〈 0.05） and a lower HBV DNA level than HBeAg positive patients （8.4± 1.7 Log HBV DNA vs 9.8 ± 1.3 Log HBV DNA, P 〈0.001）. There were no significant differences in sex ratio,ALT and AST levels and liver histology between the two groups.
CONCLUSION： Serum HBV DNA level is not correlated to histological grade or stage of liver disease in CHB patients with HBV DNA mor     

Quantitation of HBsAg predicts response to entecavir therapy in HBV genotype C patients

AIM:To analysis the factors that predict the response to entecavir therapy in chronic hepatitis patients with hepatitis B virus (HBV) genotype C. METHODS:Fifty patients [hepatitis B e antigen (HBeAg)-negative:HBeAg-positive = 26:24] with HBV genotype C, who received nave entecavir therapy for 2 years, were analyzed. Patients who showed HBV DNA levels ≥ 3.0 log viral copies/mL after 2 years of entecavir therapy were designated as slow-responders, while those that showed 3.0 log copies/mL were termed rapid- responders. Quantitative hepatitis B surface antigen (HBsAg) levels (qHBsAg) were determined by the Architect HBsAg QT immunoassay. Hepatitis B core-related antigen was detected by enzyme immunoassay. Pre-C and Core promoter mutations were determined using by polymerase chain reaction (PCR). Drug-resistance mutations were detected by the PCR-Invader method. RESULTS:At year 2, HBV DNA levels in all patients in the HBeAg-negative group were 3.0 log copies/mL. In contrast, in the HBeAg-positive group, 41.7% were slow-responders, while 58.3% were rapid-responders. No entecavir-resistant mutants were detected in the slow-responders. When the pretreatment factors were compared between the slow-and rapid-responders; the median qHBsAg in the slow-responders was 4.57 log IU/mL, compared with 3.63 log IU/mL in the rapid-responders (P 0.01). When the pretreatment factors predictive of HBV DNA-negative status at year 2 in all 50 patients were analyzed, HBeAg-negative status, low HBV DNA levels, and low qHBsAg levels were significant (P 0.01). Multivariate analysis revealed that the low qHBsAg level was the most significant predictive factor (P = 0.03). CONCLUSION:Quantitation of HBsAg could be a useful indicator to predict response to entecavir therapy.     

Characteristics of chronic hepatitis B patients who underwent liver biopsies

Summary. Significant liver disease has been reported in chronic hepatitis B patients with normal alanine aminotransferase (ALT) but most studies performed biopsies on selected patients only. The aims of this study were to determine the rate of liver biopsy, characteristics of patients who underwent a biopsy and factors associated with significant liver disease in a cohort of such patients. Records of patients with chronic hepatitis B during a 10‐year period were reviewed. Significant liver disease was defined as Knodell HAI ≥ 7 and/or Ishak fibrosis ≥ 3. Of 743 patients, 55.7% were Asian, 56.4% were men, and the mean age was 43.1 years. One hundred and ninety‐three (26%) had undergone a biopsy. Biopsied patients were more likely to be men, HBeAg positive, and had lower platelet and higher alkaline phosphatase, bilirubin, ALT and hepatitis B virus (HBV) DNA. Significant liver disease was observed in 20% of patients who had normal ALT at presentation, 14% of those with normal ALT at the time of biopsy and in none of the patients with persistently normal ALT. Patients with normal ALT who were biopsied had higher HBV DNA and higher ALT than those not biopsied. Multivariate analysis showed that low albumin at the time of biopsy and HBV DNA >5 log₁₀ copies/mL were predictors of significant liver disease. Significant liver disease is rare in patients with chronic HBV and persistently normal ALT and liver histology of chronic HBV infected patients with normal ALT cannot be generalized to other patients with normal ALT that were not biopsied.     

拉米夫定治疗慢性乙型肝炎出现血清转换的持续性研究

目的观察拉米夫定治疗慢性乙型肝炎患者5年的血清转换率和持续血清转换率及多元因素对两者的影响。方法81例慢性乙型肝炎患者,每天服用拉米夫定100 mg,持续5年。出现血清转换后, 继续服拉米夫定6个月以上(每3个月随访1次,至少2次以上),仍为乙型肝炎e抗原(-)和抗-HBe( ), 则停药并继续随访6-12个月。所需观察项目有丙氨酸氨基转移酶、血清病毒学标志物、乙型肝炎病毒DNA 载量及基因分型、YMDD变异等。结果(1)共有26例患者出现血清转换。总血清转换率为32.10% (26/81)。第1-5年,每年累积的血清转换率为16.05%、19.75%、27.16%、28.40%和32.10%。(2)停药后4例出现复发,持续血清转换率为84.62%(22/26)。(3)经Logistic多元回归分析,得出近期血清转换率和持续血清转换率与治疗前丙氨酸氨基转移酶水平呈正相关,与治疗前乙型肝炎病毒DNA水平呈负相关。持续血清转换与血清转换后继续服药时间有相关性。结论慢性乙型肝炎患者出现血清转换后继续应用拉米夫定治疗6个月以上,大多数患者可达到持续转换。对持续血清转换的影响因素为治疗前丙氨酸氨基转移酶和乙型肝炎病毒DNA水平(P<0.05)。