Core promoter mutations 3 years after anti-hepatitis B e seroconversion in patients with chronic hepatitis B or hepatitis B and C infection and cancer remission

OBJECTIVES: In this study, we aimed to evaluate the persistence of hepatitis B virus (HBV) DNA and the role of HBV core promoter and precore region mutations in 28 young cancer survivor patients with HBV or HBV and hepatitis C virus (HCV) infections, and persistently normal ALT levels, after spontaneous or interferon (IFN)-induced anti-hepatitis B e (HBe) seroconversion. METHODS: Sera from 15 patients with HBV and 13 with dual HBV-HCV infection were analyzed for the presence of HBV-DNA and HCV-RNA by polymerase chain reaction 3 yr after anti-HBe seroconversion. A total of 21 patients had seroconverted spontaneously and seven did so after IFN treatment. The core promoter and the precore regions were amplified sequenced directly. RESULTS: Among patients with HBV infection, HBV-DNA was detected in five of nine (55%) with spontaneous anti-HBe and in all six treated patients (p = 0.092). In the coinfected patients, four had cleared both HBV-DNA and HCV-RNA, five were HBV-DNA negative/HCV-RNA positive and four had the reverse viral pattern. Among the 15 patients with persistence of HBV-DNA, a 7-base pair nucleotide deletion in the core promoter (1757-1763) was present in seven of 10 patients with spontaneous and in one of five patients with IFN-induced seroconversion (p = 0.033). The G1896A precore stop codon mutation was never observed. HBV-DNA levels were significantly lower in patients with the core promoter deletion (p = 0.011). The 7-base pair deletion generated a truncated X protein at amino-acid position 132. CONCLUSIONS: A core promoter deletion after anti-HBe seroconversion was associated with low HBV-DNA levels, probably because of downregulation of pregenomic RNA production and truncation of the X protein. HBV-DNA persistence was a frequent event, even in the absence of active liver disease.     

Three-phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B

Alpha-interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)-DNA was evaluated during treatment and core-promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV-DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti-HBe seroconversion. One patient presented core-promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three-phase sequential combined lamivudine/IFN treatment reduced HBV-DNA serum level, but did not lead to HBeAg and HBV-DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.     

Detection of HBeAg/anti-HBe immune complexes in the reactivation of hepatitis B virus replication among anti-HBe chronic carriers

Sixty-four chronic hepatitis B surface antigen (HBsAg) carriers with hepatitis B e antibody (anti-HBe) were followed in order to detect reactivations of hepatitis B virus (HBV) infection and to assess the incidence and specificity of hepatitis B e antigen/hepatitis B e antibody (HBeAg/anti-HBe) immune complexes (ICs). In 18 out of 19 patients who suffered an increase in alanine transaminase (ALT) values, serum HBV-DNA reappeared co-occurring with the peak(s) of transaminases. HBeAg/Anti-HBe immune complexes were detected in 17/18 (94.4%) patients positive for HBV-DNA. In nine of them, the appearance of immune complexes co-occurred with prednisone therapy, in two following seroconversion after recombinant interferon alpha-2A treatment, and spontaneously in the remaining seven patients. When ALT levels dropped to normal values, immune complexes as well as HBV-DNA became undetectable. In conclusion, the detection of HBeAg/anti-HBe immune complexes seems to be a specific method to detect HBV replication among anti-HBe positive patients.     

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.     

拉米夫定与α干扰素联合治疗慢性乙型肝炎

目的 观察拉米夫定(LAM)联合干扰素α1b(IFNα1b)治疗慢性乙型肝炎的近期疗效和安全性。方法 HBV DNA和HBeAg均阳性的90例慢性乙型肝炎患者，按1：1：1的比例进入三个不同的治疗组。联合治疗组：用IFNα1b 5MU，隔日肌肉注射，及口服LAM 100mg／d，共6个月，随后单用口服LAM 100mg／d6个月；LAM组：口服LAM 100mg／d共12月：IFN组：IFN α1b 5MU，隔日肌肉注射，共6个月。结果 治疗结束时，HBV DNA转阴率，联合治疗组为90．0％，LAM组为80％，IFN组为46．7％。丙氨酸氨基转移酶(ALT)复常率，联合治疗组为90．0％，LAM组为80．0％，IFN组为53．3％。HBeAg／抗HBe血清转换率，联合治疗组为46．7％，LAM组为13．3％，IFN组为33．3％。联合治疗组患者治疗结束时无一例检测到YMDD变异。结论 联合治疗组对HBV DNA抑制作用及ALT复常率高于单用干扰素组，与单用拉米夫定组接近。HBeAg／抗HBe血清转换率高于拉米夫定组，与单用干扰素组相近。初步显示联合治疗组发生YMDD变异较少。     

Precore and core promoter mutations of hepatitis B virus and hepatitis B e antigen-negative chronic hepatitis B in Korea

BACKGROUND/AIMS: The aims of this study were to determine the frequency of precore/core promoter mutations and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB) in Korea. METHODS: Patients with chronic hepatitis B virus (HBV) infection were tested for HBeAg, anti-HBe, liver profile and HBV-DNA by a branched DNA (bDNA) assay. Serum HBV-DNA was amplified by a polymerase chain reaction and the precore/core promoter sequence was determined. RESULTS: Among the 413 consecutive HBeAg-negative patients, 19.6% were bDNA-positive. Evidence of liver disease was found in 90.1% of bDNA-positive and 41.7% of bDNA-negative patients. Overall, 17.7% of HBeAg-negative patients had e-CHB. Precore mutation (A1896) was detected in 93.7% of HBeAg-negative bDNA-positive and 93.9% of HBeAg-negative bDNA-negative patients. In 59 HBeAg-positive patients, 78% had wild-type and 22% had a mixture of wild-type and A1896 mutant. Core promoter TA mutation was detected in 89.9% of HBeAg-negative bDNA-positive patients, 89.8% of HBeAg-negative bDNA-negative patients, and 74.6% of HBeAg-positive patients. No correlation was found between the presence of precore/core promoter mutations and HBV-DNA levels or disease severity. CONCLUSIONS: In Korean patients infected with HBV genotype C, precore mutation occurred almost invariably along with HBeAg seroconversion and core promoter TA mutation was frequent irrespective of viral replication levels or disease severity.     

Failure of therapeutic vaccination using hepatitis B surface antigen vaccine in the immunotolerant phase of children with chronic hepatitis B infection

AIM: The aim of this study was to investigate the efficacy of specific hepatitis B virus (HBV) vaccination as active immunotherapy in treating chronic hepatitis B (CHB) infection during the immune-tolerant phase in children with normal aminotransferase levels and high viral load. METHODS: Fifty-one immunotolerant patients were randomly and prospectively recruited into two groups. Group 1 included 23 patients that were vaccinated with three standard injections of the GenHevac B vaccine in the deltoid or quadricep muscle, initially, and at 30 days and 60 days, for specific immunization. Group 2 contained 28 patients who did not receive any medication or vaccination and were recruited as the control group. Post-vaccination evaluation was performed at 6 months from the first injection and at the end of the 12th month by serological and virological analyses. A response criterion to therapy was defined as loss of HBV-DNA in serum and hepatitis B early antigen (HBeAg) seroconversion (loss of HBeAg, development of antibody to HBeAg (anti-HBe)). RESULTS: The mean alanine aminotransferase (ALT) value in group 1 at the beginning of the vaccination was 33.6 +/- 8.1 IU/L; this changed to 31.7 +/- 9.0 IU/L at 6 months after first injection and 29.2 +/- 7.1 IU/L at the end of 12 months (P > 0.05). In this group, mean HBV-DNA load at the starting point of the vaccination was 3,709 +/- 1,126 pg/mL; this value changed to 3,569 +/- 726 pg/mL at the sixth month and 3,295 +/- 832 pg/mL at the 12th month (P > 0.05). In group 2, the mean ALT values at the beginning of therapy, and at the 6th and 12th month were 32 +/- 8 IU/L, 31.8 +/- 8 IU/L, and 29.7 +/- 7 IU/L, respectively (P > 0.05), and the mean viral load of HBV-DNA values were 3,827 +/- 1,375 pg/mL, 3,498 +/- 886 pg/mL, and 3,059 +/- 731 pg/mL, respectively (P > 0.05). The load of HBV DNA of all patients in both groups was greater than 2,000 pg/mL. There was no statistically significant difference in the mean ALT values and mean viral load of HBV DNA (P > 0.05) between group 1 and group 2 at the end of the 6th and 12th months. Except for one each patient in each group, hepatitis B surface antigen (HBsAg) and HBeAg clearance or antibody to HBsAg (anti-HBs) and anti-HBe seroconversion were not observed during the follow-up period (P > 0.05). CONCLUSION: In this study, comparison of vaccinated and unvaccinated groups of immunotolerant children with CHB infection showed no difference in the clearance of HBV DNA and seroconversion of HBeAg to anti-HBe. Different immunization protocols should be considered for future investigations in the immunotolerant phase of children with CHB infection.     

Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Asian Hepatitis Lamivudine Trial Group.

In the reported Asian lamivudine trial, the rate of hepatitis B e antigen (HBeAg) seroconversion, defined as HBeAg/hepatitis B virus (HBV) DNA seroclearance and development of anti-HBe, during 52 weeks of treatment was only 13% to 16%. To evaluate whether any factors influenced HBeAg seroconversion, data from 345 patients in that trial were reanalyzed to correlate HBeAg seroconversion with variables including treatment, age, gender, body build, histology, baseline HBV-DNA levels, and alanine transaminase (ALT) levels. Exploratory analysis using stepwise modeling revealed that HBeAg seroconversion correlated highly with pretherapy ALT (P <.001) followed by lamivudine therapy (P =.013), but only marginally with baseline HBV-DNA (P =.071) and cirrhosis (P =.066) for lamivudine 100 mg and placebo comparison. Among these four variables, only pretherapy ALT still had a highly significant (P <.001) correlation and lamivudine therapy had a borderline association (P =.066) for lamivudine 25 mg and placebo comparison. Categorical analysis revealed that HBeAg seroconversion occurred earlier and the cumulative rate was significantly higher in patients with pretherapy ALT values over 2 times the upper limit of normal (ULN) as compared with treated patients with lower ALT levels or untreated control patients with the same ALT levels (P <.001, respectively). The highest HBeAg seroconversion rate was observed in 100 mg lamivudine-treated patients with ALT levels greater than 5 times the ULN (64%) compared with patients with ALT 2 to 5 times the ULN (26%, P =.03); and ALT less than 2 times the ULN, (5%, P <.001). These results suggest that pretherapy ALT is the strongest determinant for HBeAg seroconversion during lamivudine therapy, and should be considered in selecting patients for treatment.     

Diverse virological, histopathological and prognostic implications of seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection

The evolutions of serum hepatitis B virus (HBV)-DNA, liver histology and intrahepatic expressions of HBV antigens were longitudinally investigated in 24 serum HBeAg+/HBV-DNA+ chronic hepatitis B patients who subsequently seroconverted to anti-HBe. After HBeAg conversion, serum HBV-DNA still persisted in 10 patients, and liver HBcAg in 7 of them. Of the 24 patients, 3 subgroups with diverse prognoses were identified. Ten patients progressed from chronic active hepatitis to cirrhosis, and in 7 of them HBV-DNA and/or HBcAg persisted. Eight patients with undetectable HBV-DNA and HBcAg recovered. In the remaining 6 patients, chronic liver diseases persisted; in 3 of them, HBV-DNA and in one HBcAg. These findings indicate that continued viral replication is present in a significant number of patients after HBeAg seroconversion in Taiwan, and is responsible for disease progression. In addition to HBcAg and HBV-DNA, the severity of underlying liver histology, when HBeAg seroconversion occurred, was critical for the outcome of the disease. Another remarkable finding was that clusters of ground-glass hepatocytes, well correlated with the marginal expression of HBsAg, were demonstrated in 14 of 16 biopsies with serum anti-HBe+/HBV-DNA-, but found in only 4 of 44 biopsies with positive serum HBV-DNA, indicating a strong association of the expressions of liver histology and hepatocyte HBsAg with the status of viral replication.     

The natural history of chronic hepatitis B

Summary.  The natural history of chronic hepatitis B is dependent on the age of acquiring the hepatitis B infection. Those who are infected at adolescence or adulthood (including most of the Caucasians) tend to have stable disease after hepatitis B e antigen seroconversion with normal serum alanine aminotransaminase (ALT) and hepatitis B virus (HBV) DNA levels <10⁵ copies/mL (20 000 IU/mL). In contrast, those who are infected at birth or early childhood (including the majority of the world's hepatitis B carriers, i.e. Asians) have a prolonged immune tolerance phase followed by a prolonged immune clearance phase. A proportion of these patients have progressive disease after HBeAg seroconversion with HBV DNA <10⁴ copies/mL (<2000 IU/mL) and ALT between 0.5 and 2× upper limit of normal. Core promoter mutations may play a part in the development of cirrhosis-related complications. However, continuing viral replication, even at a relatively low level of <10⁴ copies/mL (<2000 IU/mL), is probably the most important factor for the development of complications.     

Efficacy of Pre-S-containing HBV Vaccine Combined with Lamivudine in the Treatment of Chronic HBV Infection

Treatment of chronic hepatitis B (CHB) is difficult. The response rate to interferon (IFN) as well as nucleoside analogs is not more than 30% in general. While interferon has many side effects, development of resistance in most of the nucleoside analogs precludes long-term use. Both groups of drugs are most efficacious in patients who already had or develop strong cellular immunity with treatment. A pre-S2-containing vaccine was shown to enhance cellular immunity and suppress hepatitis B virus (HBV)-DNA in subjects with chronic hepatitis B. We aimed to test the efficacy of short-term use of a nucleoside analog in combination with a pre-S2-containing vaccine in patients with CHB. In this open study, 48 consecutive patients (32 males and 16 females, mean age ± SD: 33 ± 12 years) with CHB without cirrhosis were treated with 100 mg/day lamivudine and four weekly intramuscular injections of Genhevac B 20 mcg (six doses) for 24 weeks. While 19 patients were hepatitis B e antigen (HBeAg) positive (+ve), 29 patients were Anti-HBe/HBV-DNA +ve at the outset. Response was defined as seroconversion to anti-HBe in HBeAg +ve subjects and normalization of alanine aminotransferase (ALT) with loss of HBV-DNA in anti-HBe/HBV-DNA +ve subjects. HBeAg seroconversion occurred in 5/19 subjects (26%). Eighteen of 29 anti-HBe/HBV-DNA +ves responded. In the follow-up, while relapse was not observed in any of the patients who seroconverted, 11/18 from the anti-HBe/HBV-DNA +ve group relapsed, resulting in a sustained response (SR) rate of 24% in this group. All the relapses happened in the first 48 weeks of follow-up, with no relapse thereafter. Pretreatment high serum HBV-DNA was a strong negative predictor of sustained response (SR) in HBeAg +ve group. Pretreatment serum ALT over 2 × upper limit of normal and HBV-DNA less than 200 pg/ml appeared positive predictors. None of HBeAg +ve previous interferon failures responded. Twenty-four weeks of lamivudine and hepatitis B vaccine treatment induces SR in around 1/4 of the patients with CHB. Most of the responders had high ALT and relatively low DNA.     

Efficacy of 6-month interferon therapy in chronic hepatitis B virus infection in Japan

Background In Japan, there are few studies of long-term (more than 1 month) interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy and predictors of response to 6-month IFN therapy.Methods We analyzed 66 Japanese patients with CHB who were treated with IFN for 6 months. They comprised patients who were hepatitis B e antigen (HBeAg)-positive (n = 45) and -negative (n = 21). One (2%), 8 (12%), and 51 (77%) patients were infected with hepatitis B virus (HBV) genotypes A, B, and C, respectively. Responders in patients positive for HBeAg were defined as those who showed normalization of serum alanine aminotransferase (ALT) level, HBeAg loss, and HBV DNA negativity at 6 months after completion of IFN therapy. In patients negative for HBeAg, responders were defined as those patients who showed normalization of ALT level and HBV DNA negativity at the same 6-month time point.Results Of the 45 patients with HBeAg at the commencement of IFN therapy, 9 (20%) were responders. Young patients, especially those with a high serum ALT level, were significantly more likely to respond to IFN therapy. Of the 21 patients negative for HBeAg, 13 (62%) were responders. There were no significant differences in clinical characteristics between responders and nonresponders among patients negative for HBeAg. Multivariate analyses identified HBeAg negativity and young age as independent factors associated with a positive response to 6-month IFN therapy. However, long-term follow-up of the treated patients showed a fall in the response rate.Conclusions The response rate to 6-month IFN therapy among HBeAg-positive patients was low. However, young patients may require long-term IFN therapy.     

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。     

Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion

BACKGROUND & AIMS: This study investigated the viremia profiles in children with chronic hepatitis B virus (HBV) infection and spontaneous hepatitis B e antigen (HBeAg) seroconversion. METHODS: Fifty-eight children with chronic HBV infection met the following criteria: normal alanine aminotransferase (ALT) level at enrollment, followed up for more than 10 years, no antiviral treatment, and having undergone spontaneous HBeAg seroconversion during follow-up evaluation. They were grouped according to the post-HBeAg seroconversion HBV-DNA levels: (1) low viremia: transient or never 10(4) copies/mL or greater (n=35) (2) fluctuating high viremia: 10(4) copies/mL or greater at least twice at intervals more than 1 year apart (n=23). Abdominal sonography, ALT, and HBV-DNA levels were assessed annually. Another 14 nonseroconverted children served as controls. The precore mutant (nt1896) and genotypes were examined. RESULTS: The initial HBV-DNA level of the 58 seroconverters was 10(8.4+/-1.0) copies/mL and decreased to 10(2.9+/-2.0) copies/mL at the end of follow-up period. Their mean ages at enrollment, at peak HBV-DNA, at peak ALT, at HBeAg seroconversion, and at final follow-up were 7.0 +/- 3.7, 13.4 +/- 5.8, 16.3 +/- 6.0, 17.2 +/- 5.8, and 23.7 +/- 4.1 years, respectively. The precore mutant appeared more often in the fluctuating-high-viremia group than in the low-viremia group (60.9% vs 22.9%, P=.004). HBV genotypes had no effect on the viremia profiles. After HBeAg seroconversion, none had persistent abnormal ALT levels. CONCLUSIONS: Generally, these young seroconverters had decreased viral loads, normal ALT levels, and uneventful courses after HBeAg seroconversion. A longer follow-up period is necessary to elucidate the significance of HBeAg seroconversion occurring in childhood and young adulthood.     

Hepatitis B virus precore mutations and HBeAg negative reactivation of chronic hepatitis B after interferon therapy

The objective of this study was to look for HBV precore mutations in three patients with chronic active hepatitis B who developed HBV-DNA-positive/HBeAg-negative reactivation after HBe seroconversion induced by interferon therapy. Direct sequencing of polymerase chain reaction products was performed on serum collected before and after HBe seroconversion. In two patients precore sequence showed only wild-type HBV before and after interferon therapy. In one patient, precore sequence showed only wild-type HBV before interferon therapy and a mixed infection by wild-type HBV and precore mutant viruses (1858 and 1896 nucleotide mutations) after treatment. The presence of HBeAg/anti-HBe immune complexes was found after HBe seroconversion in all cases. Our results suggest that: 1) precore mutations are not always found in patients with chronic hepatitis B who develop HBV DNA-positive/HBeAg-negative reactivation; and 2) HBeAg negativity, despite the presence of wild-type HBV, might be due to HBeAg/anti-HBe immune complexes. We speculate that the production of these immune complexes may be favored by interferon therapy.     

Lamivudine therapy for children with chronic hepatitis B

AIM: To assess the effectiveness and side-effects of lamivudine therapy for children with chronic hepatitis B (CHB) who fail to respond to or have contraindications to interferon-α(IFN-α) therapy. METHODS: Fifty-nine children with CHB were treated with 100 mg lamivudine tablets given orally once daily for 12 mo. Alanine aminotransferase (ALT) activity was evaluated monthly during the therapy and every 3 months after its discontinuation. HBe antigen, anti-HBe antibodies, HBV DNA level in serum were evaluated at baseline and every six months during and after the lamivudine therapy. Sustained viral response (SVR) to lamivudine therapy was defined as permanent (not shorter than 6 mo after the end of the therapy), namely ALT activity normalization, seroconversion of HBeAg to anti-HBe antibodies, and undetectable viral HBV-DNA in serum (lower than 200 copies per mL). The analysis of the side-effects of the lamivudine treatment was based upon interviews with the patients and their parents using a questionnaire concerning subjective and objective symptoms, clinical examinations, and laboratory tests performed during clinical visits monthly during the therapy, and every 3 mo after the therapy. RESULTS: ALT normalisation occurred in 47 (79.7%) patients between the first and 11th mo of treatment (mean 4.4±2.95 mo, median 4.0 mo), and in 18 (30.5%) of them after 2 mo of the therapy. There was no correlation between the time of ALT normalization and the children's age, the age of HBV infection, the duration of HBV infection, inflammation activity score (grading), staging, ALT activity before treatment, serum HBV DNA level, and lamivudnie dose per kg of body weight. HBeAg/anti HBe seroconversion was achieved in 27.1% of cases. The higher rate of seroconversion was connected with lower serum HBV DNA level and longer duration of HBV infection. There was no connection between HBeAg/ anti HBeAb seroconversion and the children's age, age of HBV infection, grading, staging, ALT activity before treatment, and lamivudnie dose per kg of body weight. No complaints or clinical symptoms were observed during lamivudine therapy. Impairment of renal function or myelotoxic effect was noted in none of the patients. CONCLUSION: One year lamivudine therapy for children with chronic hepatitis B is effective and well tolerated. Seroconversion of HBeAg/HBeAb and SVR are connected with lower pre-treatment serum HBV DNA level.     

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。     

Interferon treatment in hepatitis B surface antigen-positive hepatitis B e antibody-positive chronic hepatitis B: role of hepatitis B core antibody IgM titre in patient selection and treatment monitoring

Chronic hepatitis B infection with the hepatitis B e antigen (HBeAg)-negative variant is associated with a severe clinical course and a low response rate to interferon (IFN). In an attempt to improve the chances of sustained response to interferon we designed a pilot study, using titres of IgM antibodies to hepatitis B core antigen (HBcAb IgM) to guide treatment initiation. Eighteen adults who were HBeAg-negative with biopsy-proven chronic active hepatitis (seven with cirrhosis) entered the study. They were followed-up bimonthly with routine liver function tests, and HBcAb IgM titres were also determined. Treatment (lymphoblastoid IFN 5 million units (MU) m^–2 three times weekly for 6 months) was started when the HBcAb IgM titre was increasing. Fifteen (83.3%) patients had normal alanine aminotransferase (ALT) levels and undetectable HBV DNA at the end of treatment. HBcAb IgM decreased in all responders. We observed a relapse in four patients (three with cirrhosis), in the first year after treatment, with an increase in ALT, HBV DNA and titre of HBcAb IgM. Eleven patients (61.1%) had a sustained response and eight of these 11 patients were followed-up for more than 18 months; two responders cleared hepatitis B surface antigen (HBsAg). Hence, the rate of sustained response to IFN in HBeAb-positive patients with chronic hepatitis is improved if treatment is started when HBcAb IgM levels are increasing.     

Early upsurge in anti-HBs titer possibly caused by the immunomodulative, not by the mutagenetic effect of interferon and ribavirin

A patient with chronic hepatitis B and C undergoing treatment with interferon and ribavirin showed an upsurge in hepatitis B virus surface antibody (anti-HBs) titer, accompanied by a decrease in hepatitis B virus surface antigen (HBsAg) during the early treatment phase. Simultaneously, elevation of alanine aminotransferase (ALT) was observed. Subsequently, the hepatitis B virus (HBV) DNA titer decreased and HBV e antigen (HBeAg) to anti-HBe seroconversion occurred. The anti-HBs titer gradually returned to the pretreatment level after cessation of ribavirin treatment and HBV-DNA became undetectable. We found no nucleotide mutations in HBV-DNA that could explain the sudden elevation in anti-HBs titer. The appearance of anti-HBs was considered to be a break in immune tolerance against some epitopes in HBsAg, possibly the r epitope, stimulated by interferon/ribavirin treatment. The immunomodulatory effect of ribavirin might have caused this unexpected early immune response to HBsAg that preceded seroconversion to anti-HBe.     

Fluctuations in viremia,aminotransferases and IgM antibody to hepatitis B core antigen in chronic hepatitis B patients with disease exacerbations

We studied the relationships between the serum levels of viremia, aminotransferases and IgM anti-HBc, measured by monthly quantitative assays, in 52 untreated chronic hepatitis B patients (41 anti-HBe+, 11 HBeAg+) followed up for 12–20 months. Forty hepatitis exacerbations were observed in 17/41 anti-HBe+ (41.5%) and in 6/11 HBeAg+ patients (54.5%) (p = NS); all but one were clinically asymptomatic. We analyzed the fluctuations in the serum levels of the three parameters before, during and after the hepatitis exacerbations and found this chronological sequence of events in 96.2% of them: HBV-DNA increase→ALT flare→IgM anti-HBc increase. These results suggest that both antiviral immune reactions and ALT flares were triggered by quantitative variations in viremia. HBV-DNA baseline levels before flares were lower in anti-HBe+ (3.9±1.2 pg/ml) than in HBeAg+ patients (35.3±5.4 pg/ml) (p<0.0001) and there was an inverse correlation between basal values and viremia level increases at the time of disease exacerbations (p< 0.001). This suggests that for a hepatitis exacerbation to occur, low basal viremia needed to increase markedly, while moderate increases in HBV-DNA serum levels were sufficient to trigger ALT flares in patients with elevated basal viremia. In conclusion, asymptomatic hepatitis B exacerbations are frequent in the natural history of chronic HBV infection, and monthly monitoring of HBV-DNA, ALT and IgM anti-HBc appears to be a suitable method to evaluate their frequencies and entities. This method can be a helpful guide for clinical and therapeutic decision-making in the single patient with chronic hepatitis B.