Clinical utility of a simple quantitative determination of hepatitis B e antigen

The titre of serum hepatitis B e antigen (HBeAg) was determined by using a simple quantitative system which is a slight modification of a commercially available enzyme immunoassay, and the relationship of serum HBeAg titre, hepatitis B virus (HBV)-associated DNA polymerase activity and HBV DNA level was evaluated. The HBeAg titre was found to have a significant correlation with DNA polymerase activity (r= 0.8153) and HBV DNA level (r= 0.8001). In 12 acute exacerbations of hepatitis in 10 patients with chronic type B hepatitis, these three parameters were found to be elevated either prior to or concurrent with the elevation of serum alanine aminotransferase, and the HBeAg titre peaked either simultaneously with or 1–4 weeks after the peaks of DNA polymerase activity and HBV DNA level, with average time lags of 1.00 weeks (s.d. = 1.29) and 1.08 weeks (s.d. = 1.25), respectively. Quantified HBeAg can be considered as a serum marker indicative of HBV replication, as is the case with DNA polymerase and HBV DNA. Furthermore, the HBeAg assay has the advantages of simplicity and low cost and it does not require special equipment. Therefore, quantification of HBeAg should be employed widely in clinical practice.     

A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine‐treated chronic hepatitis B patients

Background/Aims: A pretherapy serum alanine aminotransferase (ALT) level above five times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B patients. However, whether an even higher pretherapy serum ALT value or other viral factors could affect treatment responses remains unclear. Patients and methods: A total of 253 HBeAg‐positive chronic hepatitis B patients who had a pretherapy serum ALT level over five times ULN and received lamivudine for 12–18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non‐responders at the end of treatment and 6 months post‐treatment. Results: At the end of therapy, the overall HBeAg seroconversion rate was 33.6%. For lamivudine‐naïve patients, the HBeAg seroconversion rate was 37.8%. Subgroup analysis showed that patients with pretherapy ALT levels over 10 times ULN had a significantly higher HBeAg seroconversion rate than those with a pretherapy ALT level between five and 10 times ULN at 3 months (P=0.045) and 6 months (P=0.037) of lamivudine treatment. No significant difference was found in terms of pretherapy serum ALT values, viral load and genotypes between seroconverters and non‐seroconverters. Conclusions: For lamivudine‐treated HBeAg‐positive patients with pretherapy ALT levels over five times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12–18 months of treatment.     

Sex differences in relation to serum hepatitis B e antigen and alanine aminotransferase levels among asymptomatic hepatitis B surface antigen carriers

This study aimed to investigate sex differences in relation to hepatitis B e antigen (HBeAg) and serum alanine aminotransferase (ALT) levels in chronic asymptomatic hepatitis B virus (HBV) infection. HBeAg and ALT level were determined in 636 asymptomatic hepatitis B surface antigen carriers. There was no significant sex differences in the age-adjusted prevalence of HBeAg. Abnormal ALT level (>45 IU/l) was more frequent in carriers with HBeAg (17.5% vs 7.6%; P = 0.001). Multivariate analysis indicated that male sex (odds ratio, 2.0; 95% confidence interval, 1.1–3.6) and HBeAg (odds ratio, 2.6; 95% confidence interval, 1.6–4.3) were independent risk factors for abnormal ALT levels. Male sex and HBeAg-positivity are independent risk factors for abnormal ALT activity in chronic HBV infection. This observation may be related to sex differences in chronic HBV infection. Received: June 7, 1999 / Accepted: April 28, 2000     

Are alanine aminotransferase,hepatitis B virus DNA or IgM antibody to hepatitis B core antigen serum levels predictors of histological grading in chronic hepatitis B?

Abstract: Paired sera and liver biopsies from 105 patients with chronic hepatitis B virus infection (34 HBeAg positive and 71 anti-HBe positive) were studied to investigate the relation between the degree of histological activity and alanine aminotransferase (ALT), hepatitis B virus DNA (HBV-DNA) or IgM antibody to hepatitis B core antigen (IgM anti-HBc) levels. ALT levels were significantly higher in patients with piecemeal necrosis (155±124 vs 75±42, p=0.0017), but there were no differences in the ALT values of patients with or without intralobular necrosis. ALT values were within normal range in 29% of 31 patients without versus 15% of 65 with piecemeal necrosis (p=0.19). Serum HBV-DNA levels were not related to the grade of lobular or portal/periportal activity in HBeAg-positive patients. Anti-HBe-positive subjects with piecemeal necrosis had higher HBV-DNA levels (34±93 vs 4±6, p=0.01). IgM anti-HBc indexes were significantly higher in patients with intralobular necrosis (0.635±0.600 vs 0.356±0.367, p=0.0005) or piecemeal necrosis (0.671 ±0.633 vs 0.321 ±0.219, p=0.0002). In summary, since serum IgM anti-HBc-IMx indexes can reflect the grade of histological activity, the quantitative assessement of this antibody could be useful for non-invasive monitoring of hepatocellular damage in chronic hepatitis B.     

Clinical features of hepatitis B virus genotype A in Japanese patients

Background. Hepatitis B virus (HBV) genotype A is predominant in northern Europe and central Africa. In the present study, we examined the clinical features associated with HBV genotype A disease in the Tokyo metropolitan area. Methods. We investigated 53 cases of HBV surface antigen (HBsAg)-positive Japanese patients with HBV genotype A. The 53 cases were further classified as to their serum alanine aminotransferase (ALT) status being within the normal range (asymptomatic carriers, n = 17), chronic hepatitis (n = 15), liver cirrhosis (n = 4), and acute hepatitis (n = 17). Results. Chronic hepatitis patients had significantly higher HBV DNA levels (P = 0.003) and hepatitis B e antigen (HBeAg) positivity rates at the initial visit than did asymptomatic carriers or patients with liver cirrhosis (P = 0.003 and P = 0.054, respectively). The efficacy of treatment (HBeAg seroconversion rate) was 75% in 12 chronic hepatitis patients, which was excellent. A family history of HBsAg positivity was identified in eight (15%) families (five asymptomatic carriers, three with chronic hepatitis). However, none of the mothers in the study was positive for HBV genotype A. Conclusions. Maternal transmission of HBV has often been reported in Japan, but our present findings suggest that horizontal infection of HBV genotype A is more prevalent in the Tokyo metropolitan area. Our data indicate that HBV genotype A exhibits a mode of infection different from that of conventional HBV previously seen in Japan.     

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.     

Clinical outcomes of chronic hepatitis B patients with persistently detectable serum hepatitis B virus DNA during lamivudine therapy

BACKGROUND AND AIM: A small proportion of chronic hepatitis B patients have persistently detectable serum hepatitis B virus (HBV) DNA despite lamivudine therapy. The incidence and clinical outcomes of patients who persistently have detectable serum HBV-DNA during lamivudine therapy was investigated. METHOD: We enrolled 221 chronic hepatitis B patients who underwent lamivudine therapy for more than 6 months. Among them, 180 were HBeAg positive. Serum HBV-DNA, HBeAg, anti-HBe and alanine aminotransferase (ALT) levels were serially monitored. The study groups were defined, using a hybridization assay, as patients with reductions in serum HBV-DNA below the detectable level (group I) or patients with persistently detectable serum HBV-DNA (group II) during the initial 6 months of lamivudine therapy. RESULTS: The incidence of patients who had persistently detectable HBV-DNA was 7.7%. After the first year, the rates of viral breakthrough, HBeAg loss and serum ALT normalization of group I versus group II were 21% versus 63%, 38% versus 0%, and 71% versus 28%, respectively (P < 0.001). The log(10) reduction of serum HBV-DNA at 6 months was -4.58 log(10) for group I and -1.97 log(10) for group II (P < 0.001, bDNA assay). There were no pretreatment lamivudine-resistant mutants in group II. CONCLUSION: Lamivudine had little effect on serum HBV-DNA suppression, viral breakthrough suppression and rate of HBeAg loss and ALT normalization in chronic hepatitis B patients with persistently detectable serum HBV-DNA during the initial 6 months of therapy. Early termination of lamivudine therapy is advocated for these patients.     

The change of the quantitative HBsAg level during the natural course of chronic hepatitis B

Background: There is insufficient information about HBsAg levels and their correlation with serum hepatitis B virus (HBV) DNA in chronic hepatitis B (CHB). Aims: We aimed to describe HBsAg levels during various phases of CHB and to investigate the correlation with serum HBV DNA levels. Methods: A total of 645 treatment‐naïve Korean CHB patients were included in this retrospective cross‐sectional study. They were categorized into immune tolerance (IT, n=56), HBeAg‐positive hepatitis (EPH, n=150), inactive carrier (IC, n=274) and HBeAg‐negative hepatitis (ENH, n=165). The baseline HBsAg and HBV DNA levels were measured. Results: The mean HBsAg titres (log IU/ml) differed (P<0.001): IT 4.29, EPH 3.64, IC 2.05 and ENH 3.23. In 645 patients, HBsAg and HBV DNA showed a significant correlation (r=0.693, P<0.001), and this was also observed in the IT, EPH and IC groups (r=0.664, r=0.541, r=0.505, respectively, all P<0.001), but not in the ENH group (r=0.093, P=0.321). Age had a negative correlation with HBsAg (r=?0.451, P<0.001). The cirrhotic patients had a significantly lower HBsAg level than the non‐cirrhotic patients (2.41 ± 1.36 vs. 3.02 ± 1.21 log IU/ml, P<0.001). Conclusions: The HBsAg level varied significantly in different phases of CHB and was correlated with HBV DNA during the IT, EPH and IC phases. These findings can provide additional information to understand the natural course and pathogenesis of CHB.     

Relationships between serum aminotransferase levels, liver histologies and virological status in patients with chronic hepatitis C in Taiwan

In patients with chronic hepatitis C, the relationships between serum alanine aminotransferase (ALT) levels, histological liver injury and serum hepatitis C virus (HCV) RNA titres remain controversial. To evaluate these relationships, 93 Chinese patients with histological diagnosis of chronic hepatitis C were enrolled for this study. Serum ALT levels, HCV-RNA titres and HCV genotypes were examined. The histology was evaluated according to a modified histological activity score based on the degree of periportal necro-inflammation, intralobular necro-inflammation, portal inflammation, total necro-inflammation and fibrosis. The mean serum ALT level was significantly higher in patients with severe intralobular necro-inflammation activity than in patients with mild or no activity (P= 0.013). However, scores of intralobular activity were only weakly correlated with serum ALT levels (r= 0.27) and could not be used to adequately predict ALT values. Serum ALT levels showed no significant correlation with the scores of portal inflammation, periportal necro-inflammation, total necro-inflammation and fibrosis. Also, there was no significant difference in the mean serum ALT level among different serum HCV-RNA levels and HCV genotypes. Serum HCV-RNA titres and genotypes showed no significant correlation with liver histology and serum HCV-RNA titres were only weakly correlated with the total necro-inflammatory score (r= 0.27). In conclusion, although serum ALT levels were higher in patients with more severe intralobular necro-inflammatory activity, the correlation was not strong enough to adequately predict ALT values. Serum HCV-RNA titres and genotypes also showed no significant correlation with serum ALT levels and liver histologies.     

Increasing hepatitis B viral load is associated with risk of significant liver fibrosis in HBeAg‐negative but not HBeAg‐positive chronic hepatitis B

Background/aims: To evaluate the association between demographical features, serum ALT and HBV DNA and the prevalence of significant fibrosis and inflammation on liver biopsy in patients with chronic hepatitis B. Methods: In this cross‐sectional study of patients on St Vincent's Hospital HBV database, patients were classified into three groups on the basis of HBeAg status and HBV DNA level and the prevalence of significant (F2/3/4) fibrosis and (A2/3) inflammation in each group was established. Patients were also divided into HBeAg‐positive and ‐negative groups and examined for the prevalence of significant fibrosis/inflammation in the strata of HBV DNA and ALT. Predictors of significant fibrosis and inflammation in HBeAg‐positive and ‐negative patients were examined by logistic regression. Results: Three hundred and ninety four patients (HBeAg positive=198; HBeAg negative=196) with liver biopsy were identified. Fifty‐eight percent of HBeAg‐negative patients with HBV DNA >25 000 IU/ml had F2/3/4 fibrosis. HBV DNA and F2/3/4 were positively correlated in HBeAg‐negative patients [odds ratio (OR) 1.42, P=0.001] but inversely correlated in HBeAg‐positive patients (OR 0.71, P=0.03). HBV DNA was an independent predictor of significant fibrosis in HBeAg negative (P=0.03) but not HBeAg‐positive patients. In HBeAg‐positive patients, age was the only predictor of significant fibrosis (P=0.001) and ALT the only predictor of significant inflammation (P=0.003). In the whole cohort there was a close positive association between inflammation and fibrosis. Conclusion: Increasing levels of HBV DNA are associated with increasing prevalence of significant fibrosis only in patients with HBeAg‐negative CHB.     

Combined lamivudine and famciclovir therapy for patients with chronic hepatitis B

OBJECTIVE: No single antiviral drug is able to eradicate hepatitis B virus (HBV) infection. It has been shown in vitro that lamivudine and panciclovir (the active metabolite of famciclovir) act synergistically to inhibit HBV replication. To study the therapeutic efficacy of combined lamivudine and famciclovir therapy in patients with chronic hepatitis B. METHODS: Twenty‐one patients with chronic hepatitis B, who had been given lamivudine monotherapy for more than 6 months without improve­ment, had increased serum alanine aminotransferase (ALT) and HBV‐DNA levels, and were positive for hepatitis B surface antigen (HBsAg); 17 were positive for HBeAg. The diagnosis was verified by histology in 12 HBeAg‐positive cases. All patients were given combined therapy with lami­vudine (100 mg q.d.) and famciclovir (500 mg t.i.d.) orally for 4 months, and then with lamivudine alone for 5?10 months. RESULTS: Serum HBV‐DNA levels were initially 1 × 10^{8.19 ± 1.18} copies/mL, then decreased to 1 × 10^{5.25 ± 1.18} copies/mL at the end of the combined treatment and 1 × 10^{5.25 ± 1.82} copies/mL in the follow‐up period (P < 0.01). Serum ALT decreased from 225 ± 110 U/L before the trial to 79 ± 50 U/L at the end of the combined treatment and 81 ± 48 U/L in the follow‐up period (P < 0.01). In 17 HBeAg‐positive patients, eight (47.1%) had HBeAg/anti‐hepatitis B e antigen (HBeAg) seroconversion with a significant decrease of HBV‐DNA (<1 × 10⁴ copies/mL) and normal ALT (P < 0.01). Of four HBeAg‐negative patients, three had decreased levels of HBV‐DNA, to below 1 × 10⁴ copies/mL, which was associated with a significant decrease in ALT. Two patients had recurrent flare‐ups in the follow‐up period, but both HBV‐DNA and ALT were lower than the pretreatment levels. In 10 patients who underwent a second liver biopsy, improvements in inflammatory activity and fibrosis were seen in eight (80%) and four (40%) cases, respectively (P < 0.05). CONCLUSIONS: The combination treatment of lamivudine and famciclovir has synergistic or additive anti‐HBV effects, and may be an alternative therapy for patients with active chronic hepatitis B.     

Factors associated with the virological response of lamivudine-resistant hepatitis B virus during combination therapy with adefovir dipivoxil plus lamivudine

Background The aim of this study was to investigate the factors associated with the response of lamivudine-resistant hepatitis B virus (HBV) during combination therapy with adefovir dipivoxil plus lamivudine. Methods Sixty-three patients with breakthrough hepatitis received a 10-mg once-daily dose of oral adefovir dipivoxil. Results The rates of undetectable serum HBV-DNA were 49.2% after 24 weeks, 61.9% after 48 weeks, and 67.2% after 72 weeks. The cumulative hepatitis B e antigen (HBeAg) loss rates in patients with alanine aminotransferase (ALT) levels of more than twice the upper limit of normal (ULN) were significantly higher than in patients with ALT less than twice the ULN (P = 0.0145). Multivariate analysis revealed that baseline ALT level (P = 0.003) and HBeAg status (P = 0.049) were associated with early virological response. Conclusions Baseline ALT level was associated with HBeAg loss and seroconversion, and baseline ALT level and HBeAg status were associated with the virological response of lamivudine-resistant HBV during combination therapy with adefovir dipivoxil plus lamivudine.     

Long‐term effect of maternal HBeAg on delayed HBeAg seroconversion in offspring with chronic hepatitis B infection

Background and aims: This cohort study investigated the long‐term effect of maternal hepatitis B virus (HBV) sero‐status on the spontaneous HBeAg seroconversion in offspring with chronic HBV infection. Methods: A total of 185 HBeAg‐positive chronic HBV‐infected children, with maternal HBV seromarkers checked, were enrolled. The median age at enrolment and follow‐up duration was 5.7 years (range, neonate to 16.5 years) and 20.2 years (range, 4.2–31.0 years) respectively. These children were grouped according to the initial maternal HBsAg and HBeAg status: (i) children of non‐carrier mothers (n=48); (ii) children of HBeAg‐negative chronic HBV‐infected mothers (n=57); (iii) children of HBeAg‐positive chronic HBV‐infected mothers (n=80). HBV seromarkers and liver function profiles of these children were performed at 6‐month intervals. Results: One hundred and twenty‐one (65.4%) subjects had achieved spontaneous HBeAg seroconversion at the end of this follow‐up study. Spontaneous HBeAg seroconversion was achieved in 83.3% of children with non‐carrier mothers, 73.7% of children with HBeAg‐negative chronic HBV‐infected mothers and 48.8% of children with HBeAg‐positive mothers during similar duration (P<0.001). Positive maternal HBeAg and genotype C were associated with delayed spontaneous HBeAg seroconversion in multivariate analysis (P=0.01 and P=0.002 respectively). In children of HBeAg‐positive chronic HBV‐infected mothers, persistent presence of maternal HBeAg showed a trend of association with delayed HBeAg seroconversion in their offspring (P=0.06). Children of late maternal HBeAg seroconversion (>40 years old) had delayed HBeAg seroconversion compared with those of early HBeAg seroconversion mothers (P=0.06). Conclusions: Persistence of maternal HBeAg is an important risk factor for delayed spontaneous HBeAg seroconversion in children with chronic HBV infection.     

Efficacy of ribavirin in patients with chronic hepatitis B

This study aimed to evaluate the efficacy and safety of a 6-month course of ribavirin (Rb) (1200 mg/day) in the treatment of chronic hepatitis B (CHB). Sixty patients with CHB were randomly assigned in a double-blind placebo (Pl) controlled study; 30 patients received oral Rb (1200 mg/day) and 30 received Pl for 24 weeks. Patients were hepatitis B surface antigen (HBsAg); hepatitis B envelope antigen (HBeAg); and hepatitis B virus (HBV)-DNA-positive, with alanine aminotransferase (ALT) levels 1.5 times higher than normal values. Clinical evaluations and laboratory tests were carried out at regular intervals; tests included total blood cell count, liver function tests, and HBV serum markers. Baseline and control liver biopsies were carried out. HBeAg seroconversion occurred in 50.0% of the patients in the Rb group (vs 6.6% in the Pl group; P = 0.00019); HBV DNA negativization occurred in 33.3% in the Rb group (vs 6.6% in the Pl group; P = 0.009); and improvement in the necroinflammatory index occurred in 53.3% in the Rb group (vs 23.3% in the Pl group; P = 0.02). The drug was well tolerated; the most important side effect in the Rb group was hemoglobin reduction, which was reversible once the treatment was stopped. Ribavirin was an effective treatment, demonstrated by decreased ALT levels, alleviation of histological damage, seroconversion of HBeAg, and HBV-DNA negativization; Rb may be an alternative agent in the treatment of CHB, without significant side effects. Received: June 1, 1999 / Accepted: October 22, 1999     

A 7‐year study of lamivudine therapy for hepatitis B virus e antigen‐positive chronic hepatitis B patients in China

OBJECTIVE: To evaluate the long‐term efficacy and safety of lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily or a placebo in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were administered with lamivudine 100 mg/d for 5 years and followed up for 2 years. RESULTS: After 12 weeks of the lamivudine treatment, serum HBV DNA levels decreased rapidly and HBV DNA negativity (<1.6 pg/mL) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. At the end of 5 years, serum HBV DNA continued to be substantially suppressed. The loss of HBeAg and seroconversion were significantly correlated with baseline alanine aminotransferase (ALT) levels, in patients with baseline ALT > 2 × upper limits of normal, the loss of HBeAg was 54% and seroconversion rate was 50%, respectively. YMDD mutation developed in 70.8% of the patients at years 5. In YMDD mutant patients, HBV DNA levels were increased moderately and with mild to moderate elevations of ALT. ALT flares (ALT > 5ULN) occurred in 22 patients, 16 with YMDD variants and six with non‐variants. One year durability of seroconversion after stopping lamivudine was 80%. CONCLUSION: Lamivudine is effective and tolerable for chronic hepatitis B.     

Long-term treatment outcomes of clevudine in antiviral-naive patients with chronic hepatitis B

AIM: To evaluate the treatment outcomes of clevudine compared with entecavir in antiviral-naive patients with chronic hepatitis B (CHB).METHODS: We retrospectively analyzed the clinical data of CHB patients treated with clevudine 30 mg/d and compared their clinical outcomes with patients treated with entecavir 0.5 mg/d. The biochemical response, as assessed by serum alanine aminotransferase (ALT) activity, virologic response, as assessed by serum hepatitis B virus DNA (HBV DNA) titer, serologic response, as assessed by hepatitis B e antigen (HBeAg) status, and virologic breakthrough with genotypic mutations were assessed.RESULTS: Two-hundred and fifty-four patients [clevudine (n = 118) vs entecavir (n = 136)] were enrolled. In clevudine-treated patients, the cumulative rates of serum ALT normalization were 83.9% at week 48 and 91.5% at week 96 (80.9% and 91.2% in the entecavir group, respectively), the mean titer changes in serum HBV DNA were -6.03 and -6.55 log₁₀ copies/mL (-6.35 and -6.86 log₁₀ copies/mL, respectively, in the entecavir group), and the cumulative non-detection rates of serum HBV DNA were 72.6% and 83.1% (74.4% and 83.8%, respectively, in the entecavir group). These results were similar to those of entecavir-treated patients. The cumulative rates of HBeAg seroconversion were 21.8% at week 48 and 25.0% at week 96 in patients treated with clevudine, which was similar to patients treated with entecavir (22.8% and 27.7%, respectively). The virologic breakthrough in the clevudine group occurred in 9 (7.6%) patients at weeks 48 and 15 (12.7%) patients at week 96, which primarily corresponded to genotypic mutations of rtM204I and/or rtL180M. There was no virologic breakthrough in the entecavir group.CONCLUSION: In antiviral-naive CHB patients, long-term treatment outcomes of clevudine were not inferior to those of entecavir, except for virologic breakthrough.     

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.     

HBeAg阴性和阳性慢性乙型肝炎患者血清HBV DNA水平与肝组织炎症的关系

目的:探讨HBeAg阴性和HBeAg阳性慢性乙型肝炎(CHB)HBVDNA水平和肝组织炎症损害的关系.方法:采用荧光定量聚合酶链反应分别对331例CHB(101例HBeAg阴性和230例HBeAg阳性)患者进行血清HBVDNA定量检测和肝组织活检病理炎症分级,对比分析结果.结果:331例CHB患者血清HBVDNA水平与肝组织炎症活动度及肝纤维化程度之间无明显相关性;101例HBeAg阴性CHB患者中31例(31%)血清HBVDNA>108copies/L,随着G1-G4肝组织炎症损害级别的增高其所占例数也相应增高.HBVDNA水平与肝组织炎症病理分级的相关性有显著意义(r=0.271,P<0.005);在230例HBeAg阳性的患者中,血清HBVDNA水平与肝组织炎症呈明显的负相关(r=-0.659,P<0.001).结论:血清HBVDNA水平可作为判断HBeAg阴性CHB患者肝组织炎症损害程度的指标,在HBeAg阳性的患者中,血清HBVDNA水平与肝组织炎症呈负相关.     

Long‐term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide‐naïve chronic hepatitis B patients

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long‐term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide‐naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow‐up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed‐up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.     

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.