慢性乙型肝炎肝病急性加重的原因探讨

目的 为了弄清慢性乙型肝炎病程中肝病急性加重的原因。方法 用酶联免疫吸附试验检测慢性乙型肝炎病程中肝病急性加重时甲、丙、丁或戊型肝炎病毒的重叠感染以及HBeAg和抗-HBe的血清学状态。结果 在83例慢性乙型肝炎的92次肝病急性加重中,甲、丙、丁或戊型肝炎病毒重叠感染分别为3.3％(3/92)、5.4％(5/92)、3.3％(3/92)和5.4％(5/92),共为17.4％(16/92);使用肝损害药物为1.1％(1/92);HBeAg至抗-HBe的自发血清转换为9.8％(9/92);HBeAg至抗-HBe的不稳定自发血清转换状态为12.0％(12/92);保持HBeAg至抗-HBe血清学状态不变为59.8％(55/92)。重叠其它嗜肝病毒感染、HBeAg至抗-HBe的不稳定自发血清转换以及保持HBeAg和抗-HBe的状态不变均可出现致死性肝衰竭。结论 重叠其它嗜肝病毒感染、使用肝损害药物和HBeAg至抗-HBe的自发血清转换与慢性乙型肝炎病程中40％左右的肝病急性加重有关,大约60％的肝病急性加重与HBeAg和抗-HBe血清学状态无关。促使致死性肝衰竭发生的原因更为复杂。     

Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma

BACKGROUND & AIMS: The aim of this study was to investigate the influence of hepatitis B virus (HBV) genotypes on the clinical outcome of chronic childhood HBV infection and hepatocellular carcinoma (HCC). METHODS: A total of 460 HBV carrier children were followed-up for 15 years and 26 children with HBV-related HCC were recruited. HBV genotyping was examined at enrollment and the latest follow-up of these carrier children and at diagnosis in HCC children. Viral load was checked at enrollment for the carrier children. These carriers were grouped based on their initial hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe) status. The HBeAg positive (+) group was divided further into an HBeAg(+/+) group and HBeAg(+/-) group, depending on whether spontaneous HBeAg seroconversion occurred during the follow-up period. RESULTS: Genotype B constituted 73%, 86%, and 76% in the HBeAg(+/+), HBeAg(+/-), and anti-HBe(+) groups, respectively. Genotype C was found in 27%, 8%, and 6% in the HBeAg(+/+), HBeAg(+/-), and anti-HBe(+) group, respectively. Genotype C carriers were more prevalent in the HBeAg(+/+) group than the other 2 groups (P = .01), and had a delayed HBeAg seroconversion compared with the genotype B carriers (P < .001). Changes of genotype during the follow-up period were rare (2.8%). In those with HCC, genotype B was also the major type (74%). There was no difference in the baseline viral load between genotypes B and C. CONCLUSIONS: Although HBV genotype B dominates in children with chronic HBV infection and HCC in Taiwan, genotype C delays HBeAg seroconversion in pediatric chronic HBV infection.     

Quantitative detection of hepatitis B virus DNA in sera from patients with acute hepatitis B

Two hundred forty-four serial serum samples from 30 adults hospitalized with benign (nonfulminant) acute hepatitis B were tested for the presence of hepatitis B virus (HBV) DNA by a quantitative solution hybridization assay using a¹²⁵I-labeled DNA probe complementary to HBV-DNA sequences. Acute hepatitis B was self-limiting in 28 and progressed to chronicity in the remaining two patients. Of the 28 patients with self-limiting hepatitis, 21 (75%) were hepatitis B e antigen (HBeAg) positive, 26 (93%) were HBV-DNA positive, and one patient (3.6%) was negative for both markers on admission to the hospital. HBV-DNA cleared after HBeAg clearance in 20 (71.4%), before HBeAg clearance in five (17.9%) and simultaneously with the loss of HBeAg in the remaining two (7.1%) of the 27 initially HBV-DNA- and/or HBeAg-positive patients. Moreover, HBV-DNA remained detectable in serum for 13.3±6.6 (range: 4–22) days after the appearance of anti-HBe in 71.4% of these patients. In contrast, HBV-DNA and HBeAg remained persistently positive in the two patients who developed chronic HBV infection. These data show that: (1) viremia frequently persists after disappearance of HBeAg and (2) appearance of anti-HBe does not indicate the cessation of HBV replication in adults with acute self-limiting hepatitis B.     

肝活检对HBV携带者的诊断意义

目的探讨肝活检对HBV携带者的诊断意义。方法回顾性分析134例HBV携带者,在B超引导下行1秒钟快速肝穿刺活检术,行肝组织病理学检查。结果在134例患者中,仅2例（1.49%）肝组织病理学检查完全正常（G0S0）;在105例HBV DNA≥10^5copies/ml（或HBeAg阴性者HBV DNA≥10^4copies/ml）的HBV携带者中,肝组织炎症活动度≥G2者80例（76.19%）,即可实施抗病毒治疗;在100例HBeAg（＋）与34例HBeAg（-）感染者,肝组织炎症活动度和纤维化程度比较无明显统计学差异（P=0.308）;在不同肝组织炎症活动度和纤维化程度感染者,HBV DNA载量无明显的统计学差异（P=0.557）,HBV DNA≥10^7copies/ml与HBV DNA〈10^7copies/ml感染者比,肝组织炎症活动度和纤维化程度存在统计学差异（P=0.007,P=0.001）。结论对于慢性HBV携带者,应及时进行肝组织活检。     

扶正祛邪饮与替比夫定联合治疗对慢性乙型肝炎HBeAg血清转换作用的非随机对照研究临床观察

目的:探讨扶正祛邪饮与替比夫定联合治疗慢性乙型肝炎的疗效,重点观察HBeAg血清转换指标。方法:96例患者按意愿分为联合组50例和对照组46例,联合组患者口服替比夫定片,1次/d,600mg/次,疗程12个月。另加服扶正祛邪饮,2次/d,150ml/次,疗程6个月;对照组患者单用替比夫定,用法和疗程与联合组相同。观察两组患者治疗前后的临床症状改善、肝功能好转、HBV DNA下降、HBeAg转阴及HBeAg/抗-HBe血清转换的效果。结果:两组患者治疗后的ALT、AST、TBil、HBeAg转阴率、HBeAg/抗-HBe血清转换率、HBV DNA转阴率,与治疗前比较差异有显著性意义(P<0.01或P<0.05);两组患者治疗后的比较,联合组在ALT水平、HBeAg转阴率、HBeAg/抗-HBe血清转换率等早期应答方面优于对照组(P<0.05),联合组HBeAg转阴率、HBeAg/抗-HBe血清转换率在治疗12月时高于对照组,但差异无统计学意义(P>0.05)。结论:扶正祛邪饮联合替比夫定片治疗慢性乙型肝炎早期疗效明显,肝功能恢复较快,且能促进HBeAg转阴和HBeAg/抗-HBe血清转换提前应答,可作为慢性乙型肝炎治疗的辅助药物。     

Histological improvement of chronic hepatitis B,and non-A,non-B with interferon treatment: Application of a numerical scoring system for evaluating sequential morphologic changes

In order to assess the sequential changes of liver pathology after interferon therapy, 70 liver biopsy specimens, collected from 23 HBeAg-positive patients with chronic hepatitis B and 12 patients with chronic non-A, non-B hepatitis, were studied using a numerical scoring system proposed by Knodell et al. The biopsy specimens were obtained immediately prior to the administration of interferon and within one week following the termination of interferon therapy. Three patients with chronic hepaitits B were negative for DNA-polymerase (DNA-P) prior to the interferon administration. Ten patients (50%) lost DNA-P activity. HBeAg became negative in 8 patients (34.8%), of whom 2 seroconverted to anti-HBe. Serum alanine aminotransferase levels normalized in 9 patients with chronic hepatitis B, and non-A, non-B hepatitis. The total Histological Activity Index (HAI) scores in both patients with chronic hepatitis B, and non-A, non-B decreased significantly (P<0.001 and P<0.005, respectively) after interferon treatment. There was also a significant improvement (0.02<P<0.001) in each histological category except for fibrosis. When the changes of the HAI scores in patients with chronic hepatitis B were correlated to the outcome in the DNA-P and HBeAg/anti-HBe system after treatment, the histological improvement did not significantly correlate to the outcome of these serological parameters.     

Meta-analysis: the effect of interferon on development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Purpose  In patients chronically infected with hepatitis B virus, interferon has been used for the purpose of viral suppression by loss of hepatitis B e antigen (HBeAg) with or without seroconversion to antibody to HBeAg (anti-HBe). However, discussion about the effect of interferon on the development of hepatocellular carcinoma (HCC) has been controversial. Methods  We conducted a meta-analysis of published studies. Eight studies were retrieved (1,303 patients), including two randomized controlled trials (RCTs) and six non-RCTs (553 patients received interferon treatment). Results  The pooled estimate of the preventive effect of treatment was significantly in favor of interferon (risk difference −5.0%; 95% CI −9.4 to −0.5, P = 0.028). By subgroup analyses, the preventive effect of interferon treatment was shown in the Asian population (risk difference −8.5%; 95%CI −13.6 to −3.6, P = 0.0012), the population with the incidental rate of HCC ≥10% if untreted with interferon (risk difference −9.4%; 95%CI −14.2 to −4.6, P = 0.0001), and the population with the proportion of HBeAg-positive patients to the study population ≥70% (RD −6.0%; 95%CI −11.8 to −0.2, P = 0.043). However, the preventive effect of interferon was not shown in the European population, the population with a lower incidental rate of HCC if untreated with interferon, and the population with the lower proportion of HBeAg-positive patients to the study population. An evaluation using the Begg method indicated no evidence of publication bias. Conclusions  Interferon treatment is considered to restrain HCC development in patients with chronic hepatitis B virus infection, especially in HBeAg-positive Asians.     

Hepatitis E virus as an etiology of acute exacerbation of previously unrecognized asymptomatic patients with hepatitis B virus-related chronic liver disease

Background and Aim: Hepatitis E virus (HEV) has recently been implicated in episodes of acute decompensation in patients having underlying chronic liver disease (CLD) of varying etiology. However, HEV as a cause of acute exacerbation of previously asymptomatic and unrecognized hepatitis B virus (HBV)‐infected patients is less well described. The aim of the present study was to investigate the etiology of acute exacerbation of previously asymptomatic and unrecognized HBV‐infected patients and to evaluate the relative role of HEV. We also investigated the effect of superinfection on the clinical spectrum of underlying HBV infection. Methods: Forty‐three patients presented with the following were retrospectively analyzed: (i) clinical features suggestive of acute hepatitis; (ii) with hepatitis B surface antigen (HBsAg) (+); (iii) IgM hepatitis B core antibody (IgM anti‐HBc) (?); (iv) no previous history of liver disease; (v) no features suggestive of CLD at presentation; (vi) HBsAg remaining (+) for at least 12 months on follow up; and (vii) having a follow‐up biopsy during the convalescent phase showing evidence of chronic hepatitis B. Results: Of the 43 patients, 21 were hepatitis e antigen (HBeAg) (+) (Gr.1) and 22 HBeAg (?) (Gr.2) at presentation. In Gr.1, only two (9.5%) had superinfection (both with hepatitis A virus), whereas in Gr.2, 11 (50%) had superinfection (27.3% hepatitis E, 13.6% hepatitis A and 9.1% both) (P = 0.007). In Gr.1, the remaining 19 (90.5%) patients had spontaneous exacerbation (immune clearance with spontaneous seroconversion) whereas in Gr.2, the remaining 11 (50%) had spontaneous exacerbation (due to reactivation). Overall, HEV superinfection contributed to 20% of acute exacerbation episodes and, in particular, 36% of episodes in initially HBeAg (?) patients. Time to alanine aminotransferase normalization was longer in patients with superinfection (n = 13) as compared to spontaneous exacerbation (n = 30) (median [range] 36 [8–48]vs 16 [6–36] weeks, P = 0.001). During convalescence, there was no significant difference between histological activity index score (median [range] 8 [4–11]vs 8 [4–16] weeks, P = 0.629) and fibrosis scores (median [range] 3.5 [1–4]vs 2 [1–4] weeks, P = 0.099] on liver biopsy after recovery among patients with acute exacerbation due to superinfection and spontaneous exacerbation. Conclusions: Acute exacerbations in HBeAg (+) patients are most often due to spontaneous viral activation, while in HBeAg (?) patients, superinfection with non‐B hepatitis viruses and spontaneous viral activation are equally common. HEV is an important cause of acute exacerbation in previously asymptomatic and unrecognized patients with HBV‐related CLD.     

HBeAg negative serological status and low viral replication levels characterize chronic hepatitis B virus-infected women at reproductive age in Greece： A one-year prospective single center study

AIM: To evaluate the seroprevalence of hepatitis B surface antigen (HBsAg) in 13 581 women at reproductive age and the hepatitis B e antigen (HBeAg)/anti-HBe status as well as serum hepatitis B virus (HBV)-DNA levels in a subgroup of HBsAg(+) pregnant women at labor in Greece. METHODS: Serological markers were detected using enzyme immunoassays. Serum HBV-DNA was determined by a sensitive quantitative PCR assay. Statistical analysis of data was based on parametric methodology. RESULTS: Overall, 1.156% of women were HBsAg(+) and the majority of them (71.3%) were Albanian. The prevalence of HBsAg was 5.1% in Albanian women, 4.2% in Asian women and 1.14% in women from Eastern European countries. The prevalence of HBsAg in African (0.36%) and Greek women (0.29%) was very low. Only 4.45% of HBsAg (+) women were also HBeAg(+) whereas the vast majority of them were HBeAg(-)/anti-HBe(+). Undetectable levels of viremia (<200 copies/mL) were observed in 32.26% of pregnant women at labor and 29.03% exhibited extremely low levels of viral replication (<400 copies/mL). Only two pregnant women exhibited extremely high serum HBV-DNA levels (>10 000 000 copies/mL), whereas 32.26% exhibited HBV-DNA levels between 1 500 and 40 000 copies/mL. CONCLUSION: The overall prevalence of HBsAg is relatively low among women at reproductive age in Greece but is higher enough among specific populations. The HBeAg(-)/anti-HBe(+) serological status and the extremely low or even undetectable viral replicative status in the majority of HBsAg(+) women of our study population, suggest that only a small proportion of HBsAg(+) women in Greece exhibit a high risk for vertical transmission of the infection.     

HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B

During the natural history of chronic hepatitis B virus (HBV) infection, the loss of serum hepatitis B e antigen (HBeAg) and the development of anti-HBe antibodies (HBeAg seroconversion) mark a transition from the immune-active phase of disease to the inactive carrier state. This review examines the evidence from natural history and cohort studies on the relationship between HBeAg seroconversion and disease progression. The role of HBeAg seroconversion as an important milestone in the management of HBeAg-positive patients with chronic hepatitis B (CHB), as well as the advantages and disadvantages of administering a finite course of therapy for HBeAg-positive CHB, is also discussed. The evidence from natural history and cohort studies indicates that spontaneous or treatment-induced HBeAg seroconversion is associated with lower rates of disease progression to cirrhosis and hepatocellular carcinoma, a potential of hepatitis B surface antigen seroconversion, and improved survival rates. Updated guidelines developed by major liver associations recommend stopping oral therapy for HBeAg-positive patients who achieve sustained HBeAg seroconversion with polymerase chain reaction-undetectable HBV-DNA on two separate occasions for 6 or more months apart, taking into consideration the individual’s clinical and virologic response to therapy, as well as the severity of liver disease. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogues has important clinical and socioeconomic implications for the management of CHB.     

Changes in levels of hepatitis B virus markers in patients positive for low-titer hepatitis B surface antigen

Aim: Recently, patients positive for the low-titer hepatitis B surface antigen (HBsAg) have been found occasionally owing to the increase in the accuracy of detection methods. The aim of this study is to clarify the clinical status of acute hepatitis B virus (HBV) infection in patients positive for low-titer HBsAg. Method: Eight patients, who were positive for HBsAg at low titers and diagnosed as having acute HBV infection, were enrolled in this study. Assays of HBsAg, hepatitis B core antibody (anti-HBc), hepatitis B e-antigen (HBeAg), hepatitis B e-antibody (anti-HBe), hepatitis B surface antibody (anti-HBs) and HBV DNA, and biochemical tests were basically conducted every 4 weeks for at least 24 weeks. Result: The average cut-off index of HBsAg was 8.7 ± 9.6 (range, 1.0–25.7). All the patients were negative for anti-HBc, HBeAg, anti-HBe and HBV DNA on their initial visit. The genotype of HBV could be determined in four patients: two were infected with genotype B/HBV, one was infected with genotype A/HBV, and the remaining patient was infected with genotype C/HBV. Although HBsAg clearance was observed within 4 months in all the patients, none of the other HBV markers seroconverted during the observation period. Conclusion: HBV infection terminating with seronegativity for HBV markers may occur in transient HBV infection.     

Chronic carriers of hepatitis B virus in Bangladesh: a comparative analysis of HBV-DNA,HBeAg/anti-HBe,and liver function tests

Serological markers of hepatitis B virus (HBV), liver function tests and quantitative estimation of HBV-DNA are important in the assessment of the state of infection and prognosis following treatment for hepatitis B. This study aimed to determine whether low-cost assays, eg hepatitis B e antigen (HBeAg) and liver function tests, could be used for the assessment of infectivity as an alternative to HBV-DNA estimation. We tested 125 hepatitis B carriers for HBeAg, antibody to HBeAg (anti-HBe), and serum HBV-DNA; we also carried out a range of standard liver function tests. Seventy-three subjects were positive and 52 were negative for HBeAg. Of the HBeAg positive cases, 3 were also positive for anti-HBe; of the HBeAg negative cases, 5 were also negative for anti-HBe. Of these 8 cases, 7 had no detectable HBV-DNA. Most of the HBeAg positive but anti-HBe negative subjects were positive for HBV-DNA (74.3%; 52/ 70) whereas most of the HBeAg negative and anti-HBe positive subjects (93.6%; 44/47) were also negative for HBV-DNA. Of 56 HBV-DNA positive individuals, alanine transaminase (ALT) was found to be raised in 69.6% (p=0.066) and aspartate transaminase (AST) was raised in 66.1% (p=0.011), while 67.9% had normal alkaline phosphatase (ALP) (p=0.054). HBeAg (p=0.018) and raised ALT (p=0.008) were found to be independent predictors for HBV-DNA positivity among HBV carriers. This study suggests that HBeAg positive and anti-HBe negative hepatitis B carriers with raised ALT and AST are likely to be positive for HBV-DNA; the combination of routine serology and biochemical tests may be considered as an alternative to HBV-DNA in evaluating the state of chronic HBV infection. However, HBV-DNA should be specifically assessed if discordance is observed between seromarkers and transaminases.     

Clinical significance of liver biopsy in chronic hepatitis B patients with persistently normal transaminase

OBJECTIVE: The aim of this study was to study the clinical significance of liver biopsy for individuals who had chronic hepatitis B virus infection and persistently normal serum transaminases for more than 6 months. METHODS: A total of 452 patients with positive hepatitis B surface antigen for over 6 months underwent percutaneous liver biopsy. All liver biopsy specimens were assessed by experienced liver pathologists blinded to the liver biochemistry, and were scored according to the modified criteria of grade and stage of chronic hepatitis. Patients were divided into four groups: group A and group C patients had normal transaminases, and were hepatitis B e antigen (HBeAg) positive and HBeAg negative, respectively; group B and group D patients had elevated transaminases, and were HBeAg positive and HBeAg negative, respectively. RESULTS: All patients had necrosis and inflammation in the liver. Patients with increased serum transaminases had a significantly higher grade (G) of hepatic necrosis and inflammation and more severe (S) fibrosis compared with patients with normal transaminases (P < 0.05). However, in the latter patients, G3 was seen in 10 (5.5%) and 13 cases (9.1%), S3 in seven (3.8%) and 16 cases (11.1%), and S4 in three (1.6%) and seven cases (4.9%) in Group A and Group C, respectively. Moreover, in patients with normal transaminases, the HBeAg‐negative group had more severe fibrosis than the HBeAg‐positive group (P < 0.05). CONCLUSION: Although more severe pathological changes were more frequent in patients with elevated transaminases, significant hepatic pathology could still be found in cases with persistently normal transaminases. Liver biopsy in cases of chronic hepatitis B virus infection is helpful to accurately assess both the activity of the disease and the degree of fibrosis, and to estimate if antiviral therapy is justifiable. Patients with normal transaminases and serious hepatic necrosis, inflammation and fibrosis need proper management.     

Factors related to post-treatment relapse in chronic hepatitis B patients who lost HBeAg after lamivudine therapy

BACKGROUND AND AIM: It is uncertain if a patient's lamivudine response after HBeAg loss is durable. In Korean chronic hepatitis B patients, the relapse rate is high after termination of lamivudine therapy for patients with HBeAg loss. We evaluated the factors related to relapse in chronic hepatitis B patients with HBeAg loss after lamivudine therapy. METHODS: A total of 132 chronic hepatitis B patients, who initially had HBeAg and did not have decompensated features, were analyzed in this study. These patients lost the HBeAg after lamivudine therapy and then their therapy was stopped. Post-treatment serum alanine aminotransferase (ALT), HBeAg, anti-HBe and hepatitis B virus (HBV) DNA were monitored until relapse. RESULTS: Seventy-five patients relapsed (cumulative relapse rate: 56% at 6 months). Upon univariate analysis, the factors of age, serum total bilirubin, presence of anti-HBe after HBeAg loss, and the duration of additional lamivudine therapy after HBeAg loss were associated with relapse. Upon multivariate analysis, older age, a higher serum total bilirubin and the shorter duration of additional lamivudine therapy were significant risk factors for relapse. Patterns of relapse were the re-elevation of ALT, re-emergence of HBV DNA (69 patients) and reappearance of HBeAg (55 patients). CONCLUSIONS: To prevent relapse in patients with chronic hepatitis B infection after lamivudine therapy, age and serum bilirubin level of patients as well as a prolonged duration of additional lamivudine therapy should be considered.     

Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B

Seventy consecutive HBsAg- and HBeAg-positive patients with biopsy-proven chronic hepatitis were followed prospectively with serial determinations of SGPT levels and hepatitis B virus serum markers including HBsAg, HBeAg, anti-HBe and hepatitis B virus DNA. During a period of 1 to 11 years (mean +/- S.D.: 5.0 +/- 2.3 years), 28 patients remained persistently HBeAg positive, most with continuing biochemical and histologic activity, while 41 cases seroconverted to anti-HBe. One patient became HBeAg and anti-HBe negative. After seroconversion, 87.8% of the cases showed sustained normalization of SGPT, and clearance of hepatitis B virus DNA from serum and histologic improvement was documented in 79% of the cases who had a control liver biopsy, while 15.8% developed cirrhosis. In two patients (4.9%), the disease remained active despite seroconversion, and both cases had evidence of continuing hepatitis B virus replication. Finally, reactivation of liver damage and of hepatitis B virus replication was observed in three additional patients (7.3%) who had transiently normalized SGPT after seroconversion. All 70 patients were analyzed for hepatitis delta virus markers, and only two persistently HBeAg-positive cases were found positive for antibody to hepatitis delta virus in serum, one also having hepatitis delta antigen in the liver. These findings indicate that, in chronic hepatitis type B, termination of virus replication is associated in most patients with biochemical and histologic regression of inflammatory activity. After anti-HBe seroconversion has occurred, virus replication and liver disease may persist or reactivate in a small proportion of patients thus giving origin to the well-recognized group of anti-HBe positive, hepatitis B virus DNA-positive chronic hepatitis type B.     

The value of quantiative detection of HBV-DNA amplified by PCR in the study of hepatitis B infection

Background/Aims: This study aimed to evaluate the usefulness of quantifying HBV-DNA amplified by polymerase chain reaction in chronic hepatitis B infection.Methods: Serum samples were obtained from 32 asymptomatic HBV carriers and 99 chronic hepatitis B patients (62 positive for anti-HBe and 37 positive for HBeAg). In addition, serial serum samples were analyzed from 15 HBeAg positive patients undergoing antiviral therapy and 17 anti-HBe positive patients with precore mutation. HBV-DNA quantification was carried out using an enzyme immunoassay with an HBV-DNA plasma standard.Results: The digoxigenin-incorporated polymerase chain reaction method detected HBV-DNA in 34.3% of the asymptomatic HBV carriers with a median HBV-DNA concentration of about 0.18×10⁵ mol/ml (range 0.08–0.4), in 87%, of the anti-HBe positive chronic hepatitis cases with a range of 0.2 to >2×10⁵ mol/ml and in 100% of the HBeAg positive patients, with a value in all cases over 2×10⁵ mol/ml. We observed that after treatment, HBV-DNA tested negative in only two of the eight HBeAg positive chronic hepatitis patients who seroconverted to anti-HBe, and was positive in the seven remaining, with a median HBV-DNA value of about 0.2×10⁵ mol/ml (0.09–0.4). In the precore mutants HBV-DNA values ranged from 0.2 to >×10⁵ mol/ml.Conclusions: Polymerase chain reaction HBV-DNA quantification is a sensitive method for managing chronic hepatitis B patients, especially those with low viremia, and may be a valuable tool for evaluating the efficacy of antiviral therapy.     

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.     

免疫活性细胞回输法治疗慢性乙型肝炎不引起肝组织损害

目的 明确免疫活性细胞回输法治疗慢性乙型肝炎(CHB)时肝组织损害情况。方法 随机选择16例CHB患者用自体免疫活性细胞回输法治疗,追踪52周。治疗前后行两次肝穿刺获得肝组织,苏木精-伊红染色评价肝脏组织炎症情况,Masson染色评价肝组织纤维化情况,检测乙型肝炎病毒(HBV)复制指标以及肝功能,评价免疫治疗对肝组织的影响。结果 完整随访14例患者,4例患者治疗前后完成2次肝穿刺,其中1例患者结果显示治疗后肝细胞坏死和小叶内炎症程度明显减轻(G_3→G_1),纤维化程度改善(S_2→S_1)。其余3例肝脏组织学变化不明显,但无加重或恶化。免疫活性细胞体外培养前后,进行免疫荧光抗体染色,经流式细胞仪分析,细胞表型有明显的改变,CD_4′细胞比例逐渐下降,CD_8′细胞比例从20%上升至60%～80%。回输治疗后52周的随访结果,HBV DNA阴转率为42.86%(6/14),乙型肝炎e抗原阴转并伴有抗-HBe阳性的血清转换率为42.86%(6/14),无1例发生乙型肝炎表原抗原阴转。丙氨酸氨基转移酶的复常率为42.86%(6/14)。在回输治疗时以及治疗后的随访中未发生严重的不良反应。结论 免疫活性细胞回输法治疗CHB不引起肝组织损害,其免疫调节作用是通过非细胞毒机制途径达到对病毒抑制或清除的作用。     

Effect of seasonal variation on the clinical course of chronic hepatitis B

Background Seasonal variation in immunity has been found in healthy individuals and in association with some diseases. It is still unknown whether seasonal variation affects the clinical course of chronic hepatitis B. Our aim in this study was to explore the effect of seasonal variation on the clinical course of chronic hepatitis B. Methods The flare and remission time of chronic hepatitis B were observed in patients with hepatitis B virus (HBV) infection. All patients enrolled were followed up at least every 3 months for a mean follow-up time of 24.0 (range, 12–60) months. Seasonal decomposition was employed to analyze the relationship between seasonal variation and flares, remission, and hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B patients during follow-up. Results A total of 2238 patients were observed in our study. Flare and HBeAg seroconversion were seldom seen in 1076 patients (48.08%) with alanine aminotransferase (ALT) levels of less than 2.0 × upper limit of normal (ULN) during follow-up (mean, 36 months). The remaining 1162 patients (51.92%) (766, HBeAg positive; 387 anti-HBeAg positive; 9 negative for both HBeAg and anti-HBeAg) with ALT levels ≥2.0 × ULN were followed longitudinally for 12 months to judge flare, remission, and HBeAg seroconversion. Flare, remission, and HBeAg seroconversion in patients with ALT levels ≥2.0 × ULN showed clear seasonal patterns (P < 0.001), with high peaks during spring, summer, and summer, respectively. An autocorrelation correlogram showed that flares, remission, and HBeAg seroconversion occurred with distinct periodicity in winter, spring, summer, and autumn. Conclusions Seasonal variation might affect the clinical course of chronic hepatitis B. The role of seasonal triggering factors should be further investigated.     

拉米夫定治疗慢性乙型肝炎的临床观察及病理学研究

目的观察拉米夫定治疗慢性乙型肝炎患者的临床疗效、肝组织学改变及肝组织内乙型肝炎病毒(HBV)标志物的变化。方法随机选择70例慢性乙型肝炎患者予口服拉米夫定100mg／d，连用1年。观察HBVDNA、血清HBeAg／抗-HBe、肝功能以及血清肝纤维化指标的变化；对其中35例患者行治疗前后肝穿刺活检，行Knodell病理学评分，检测肝细胞内HBsAg、HBcAg、α平滑肌肌动蛋白(α-SMA)。结果治疗结束时，完全应答率为23．73％，部分应答率为69．49％，无应答率为6．78％。发生HBeAg血清学转换的患者治疗前血清ALT水平明显高于未发生血清HBeAg转换的患者。41．18％患者肝组织学活动指数得以改善，汇管区坏死、门静脉炎症及纤维化明显改善。血清HBeAg转换组肝组织内HBcAg、α-SMA的表达明显减少．HBsAg的表达无显著性改变。治疗期间不良反应轻，安全性良好。结论拉米夫定100mg／d可以迅速降低血清HBvDNA和ALT的水平，促进HBeAg血清转换，减轻肝脏炎症坏死活动度，延缓肝纤维化的进展。