Serum hepatitis B virus DNA levels differentiating inactive carriers from patients with chronic hepatitis B

OBJECTIVE: We compared serum hepatitis B virus (HBV)-DNA levels in different states of hepatitis B infection, and investigated whether there is an HBV-DNA value that can be used for differentiating inactive carriers from patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis. METHODS: A retrospective study using sera at a followed endpoint from 64 Japanese patients with chronic HBV infection seen in Kobe University Hospital between 1989 and 2002. Sera of patients were assayed using a polymerase chain reaction-based assay. RESULTS: Genotype C was dominant (95.4%). Patients with chronic hepatitis with an elevation of the serum alanine aminotransferase (ALT) level had significantly higher HBV-DNA levels than patients with persistently normal ALT. For one time observation at a followed endpoint, the mean HBV-DNA level of HBeAg-negative inactive carriers was significantly lower than that of HBeAg-negative chronic hepatitis patients (3.6+/-1.0 versus 4.8+/-1.5 log copies/ml, P<0.005). The use of a cutoff value of 4.5 or 5.0 log copies/ml misclassified 23 and 18% of HBeAg-negative inactive carriers and 50 and 55% of patients with HBeAg-negative chronic hepatitis. If testing were performed on two occasions with approximately a 4-month interval, the cutoff values of 4.5 and 5.0 log copies/ml would misclassify 20 and 10% of HBeAg-negative inactive carriers and 28.6 and 28.6% of patients with HBeAg-negative chronic hepatitis. CONCLUSIONS: The measurement of serum HBV DNA more than twice is useful for assessing chronic hepatitis B surface antigen carriers and confirms that 10 copies/ml may be an appropriate level of HBV for characterizing the inactive carrier state.     

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

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

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

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

Significance of IgM antibody to hepatitis B core antigen in a Greek population with chronic hepatitis B virus infection

IgM antibody to hepatitis B core antigen (IgM anti-HBc) may indicate an active immune response to persistent infection with hepatitis B virus (HBV). We studied 186 Greek HBsAg carriers for IgM anti-HBc and attempted to correlate it with other HBV and hepatitis delta virus (HDV) markers. Overall, IgM anti-HBc was detected more frequently than HBV DNA in this population (50% vs 34, p less than 0.001); this was also true for the 149 of the 186 HBsAg carriers with antibody to hepatitis B e antigen (anti-HBe) (48% vs 22%, p less than 0.001). The opposite was found in the carriers positive for hepatitis B e antigen (HBeAg): HBV DNA was observed in 93% and IgM anti-HBc in 64% of the cases (p less than 0.05). The detection of these markers was independent of sex. Serum alanine aminotransferase (ALT) levels were significantly more elevated in patients with positive tests for IgM anti-HBc and HBV DNA than in patients positive only for HBV DNA (p less than 0.001) irrespective of their HBeAg or anti-HBe status. Moreover, the detection of elevated ALT was independent of the intensity of the HBV DNA hybridization signal. Antibodies to hepatitis delta antigen (HDAg) were only found in 4 (2.4%) of 167 patients tested.     

Diagnosis and management of pre-core mutant chronic hepatitis B

Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease. Interferon-alpha (IFN-alpha) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg-negative CHB. A 12-month course of IFN-alpha achieves sustained biochemical remission in about 20% of patients, which has been associated with improvement in the long-term outcome of this subset. A 12-month course of lamivudine is rather ineffective, maintaining remission in less than 15% of patients after cessation of therapy. Long-term lamivudine is associated with progressively increasing rate of virological and subsequent biochemical breakthroughs due to YMDD mutants, with approximately 30% of patients remaining in remission in the third year of therapy. Several other antiviral agents are currently being evaluated in this setting with combined regimens being the most reasonable step for the near future.     

Virological profiles in hepatitis B virus inactive carriers: monthly evaluation in 1-year follow-up study.

STUDY SUBJECT: We longitudinally evaluated the virological behaviour and the hepatitis B virus (HBV) genomic variability in inactive HBV surface antigen (HBsAg) chronic carriers. PATIENTS AND METHODS: Fourteen HBsAg-positive healthy workers (13 inactive carriers and 1 with active HBV infection) were followed up for 12 months by monthly evaluation of aminotransferase, HBV DNA, and IgM anti HBV core antigen (IgM anti-HBc) values. Moreover, HBV serum isolates from each case were amplified, cloned and sequenced to evaluate the presence of the potentially clinical relevant core-promoter and precore mutations. The same technical procedures were used to examine the S gene of isolates from 3 randomly selected inactive carriers and the patients with active HBV infections. RESULTS: Aminotransferase values were constantly normal in all cases. Viremia levels appear to fluctuate widely over time in each individual case, although the HBV DNA remained below 2 x 10(4) copies/ml in all samples. Only four serum samples from two inactive carriers had IgM anti-HBc values higher than the specific cut-off limit of the assay. Either wild type or core-promoter/precore HBV variants or a mixture of them were detected in the inactive carriers. S gene nucleotide homology among the clones from the three inactive carriers and the subject with active infection was 98.9%, 98.3%, 98.1% and 98.2%, respectively. CONCLUSIONS: The degree of suppression of HBV replication in inactive carriers is variable over time, and the entity and quality of HBV variability is comparable between active and inactive carriers.     

Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers

BACKGROUND/AIMS: A recent NIH research workshop on hepatitis B virus (HBV) revisited the definition of healthy HBsAg carriers. The new definition inactive surface antigen (HBsAg) carriers includes an estimated serum HBV DNA level below 105 copies/ml. However, this cut-off value needs to be confirmed. METHODS: Eighty-five consecutive patients, HBsAg-positive/HBeAg-negative with persistently normal alanine aminotransferase (ALT) and undetectable serum HBV DNA with standard assay (Versant HBV DNA Assay (bDNA), Bayer) were prospectively followed for 3.2+/-2.6 (range 0.5-11) years; 58 underwent a liver biopsy. Serum HBV DNA was quantified with a sensitive polymerase chain reaction assay (Cobas Amplicor HBV Monitor, Roche) (sensitivity 200 copies/ml), and liver histology was assessed using the Ishak scoring system. RESULTS: The median serum HBV DNA level was 1300 copies/ml (<200-179 x 10(3) copies/ml), 16% of the subjects had no detectable serum HBV DNA and 98% had levels below 10(5) copies/ml. Histologic lesions were mild (total score <7) in all cases. Loss of HBsAg was observed in three patients, three patients experienced a transient increase in ALT (<2 x upper limit of normal), and serum HBV DNA levels remained stable (1-6 years) in 97% of the 38 patients retested. CONCLUSIONS: In our study of inactive HBsAg carriers, the median serum HBV DNA level was 1300 copies/ml, the serum HBV DNA level was below 10(5) copies/ml in 98% of the patients, and remained stable; histological lesions were mild in all cases.     

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

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

Serologic markers of hepatitis B virus (HBV) and hepatitis D virus infection in carriers of hepatitis B surface antigen who are frequently exposed to HBV

Serum hepatitis B e antigen (HBeAg) and HBV DNA are indicators of active replication of HBV, whereas IgM antibody to hepatitis B core antigen (IgM anti-HBc) may indicate an active immune response to chronic HBV infection. Fifty-eight carriers of hepatitis B surface antigen (HBsAg) who had frequent parenteral exposures were studied for the presence of HBeAg, HBV DNA, IgM anti-HBc and hepatitis delta virus (HDV) serologic markers. Active replication of HBV was detected in 36.2% (25% of drug addicts, 16.7% of thalassemia patients, and 46.9% of hemodialysis patients) and seropositivity for IgM anti-HBc in 55.2% of the HBsAg carriers. Among the 39 HBsAg carriers who were negative for HBeAg, IgM anti-HBc was detected significantly more frequently than HBV DNA (46.1% vs. 5.1%, p less than 0.001). Serologic evidence of HDV infection was detected in 35% of drug addicts, 50% of thalassemia patients and in 9.4% of hemodialysis patients. These data revealed that continued replication of HBV was more frequent in hemodialysis patients than in drug addicts and thalassemia patients who are HBsAg carriers and the opposite was true for the prevalence of HDV infection.     

Profile of hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Although chronic hepatitis B occurs in hepatitis B e antigen (HBeAg)-negative patients, its prevalence and clinical significance are not known. AIM: To determine the prevalence and profile of HBeAg-negative chronic hepatitis B virus (HBV) infection. METHODS: A retrospective analysis of 363 consecutive patients (mean age 36 y; 288 men) with chronic HBV infection was performed. All patients were HBsAg-positive. Tests for liver profile, HBeAg and anti-HBe antibody were performed in all patients. Serum HBV DNA was tested using branched DNA assay in 245 patients. The patients were classified into three groups: no cirrhosis with normal ALT levels, no cirrhosis with elevated ALT levels, and clinical or histological evidence of cirrhosis. RESULTS: Of 363 patients, 141 (39%) were HBeAg-positive and 222 (61%) HBeAg-negative. Of HBeAg-negative patients, 120 (54%) had normal ALT, 45 (20%) had elevated ALT and 57 (26%) had evidence of cirrhosis; corresponding figures in the HBeAg-positive patients were 40 (28%), 66 (47%) and 35 (25%). HBV DNA was positive in 53 of 131 (40%) HBeAg-negative patients tested; of these 53 patients, 9 (17%) had normal ALT, 20 (38%) had elevated ALT and 24 (45%) had cirrhosis. Thus, 72% of HBeAg-positive and 46% of HBeAg-negative patients had elevated ALT and/or cirrhosis. Among the latter group, 83% of HBV DNA-positive patients had elevated ALT and/or cirrhosis. Overall, 18% of HBsAg-positive patients had HBeAg-negative, HBV DNA-positive liver disease. CONCLUSION: HBeAg-negative chronic hepatitis B is not an uncommon and benign entity and chronic liver disease develops in a significant proportion of such patients.     

The HBV DNA cutoff value for discriminating patients with HBeAgnegative chronic hepatitis B from inactive carriers

Background

Patients with HBeAg-negative chronic hepatitis B (CHB) has a significantly different prognosis than inactive carriers; there is however, no reliable strategy for accurately differentiating these two disease conditions.

Objectives

To determine a strategy for discriminating patients with HBeAg-negative CHB from inactive carriers.

Materials and Methods

Consecutive inactive carriers (i.e. HBeAg-negativity, anti-HBe-positivity, normal ALT levels, and HBV DNA < 2000 IU/mL) were enrolled. HBV reactivation was defined as the elevation of the HBV DNA level to ≥ 2000 IU/mL. Patients were classified into true inactive carriers when their HBV DNA levels remained at < 2000 IU/mL or false inactive carriers when their HBV DNA levels increased to ≥ 2000 IU/mL during the first year.

Results

The Mean ± SD age of 208 inactive carriers (140 males) was 47.7 ± 12.6 years. The Mean ± SD serum ALT and HBV DNA levels were 22.8 ± 8.6 IU/L and 360 ± 482 IU/mL, respectively. HBV reactivation developed in 41 (19.7%) patients during the first year. Baseline HBV DNA and ALT levels differed significantly between true inactive and false inactive carriers. The AUROCs of the baseline ALT and HBV DNA levels for predicting a false inactive carrier were 0.609 and 0.831, respectively. HBV reactivation developed more often in patients with a baseline HBV DNA level of ≥ 200 IU/mL than in those with a baseline HBV DNA level of < 200 IU/mL during a Mean ± SD follow-up of 622 ± 199 days.

Conclusions

The HBV DNA level was useful for discriminating patients with HBeAg-negative CHB from true inactive carriers. The follow-up strategies applied to inactive carriers need to vary with their HBV DNA levels.     

Hepatitis B surface antigen monitoring and management of chronic hepatitis B

Serum hepatitis B surface antigen (HBsAg) levels reflect intrahepatic hepatitis B virus (HBV) covalently closed circular DNA and may be a valuable addition to HBV DNA in the management of patients with chronic hepatitis B (CHB). Among HBeAg-negative CHB patients with low HBV DNA levels, HBsAg quantification may help distinguish those with active CHB from true inactive carriers with a very favourable prognosis, thus limiting the need for long-term intensive monitoring of ALT and HBV DNA levels. In patients treated with peginterferon (PEG-IFN), achievement of a decline in HBsAg during therapy appears to be an important marker for treatment outcome, and several groups have proposed stopping rules based on HBsAg thresholds. A recently described stopping rule incorporating a combination of HBsAg and HBV DNA levels can accurately identify HBeAg-negative patients, especially those with HBV genotype D, not responding to PEG-IFN. Current applications of HBsAg levels in the monitoring of patients treated with nucleo(s)tide analogues are still being evaluated. First data from these studies show that HBsAg decline, and thus subsequent clearance, is confined to those with an active immune response to HBV, such as HBeAg-positive patients with elevated ALT, or those who achieve HBeAg clearance.     

Is anti-HBc IgM a useful clinical test in patients with HBsAg-positive chronic hepatitis or primary hepatocellular carcinoma?

Seventy HBsAg-positive patients, including 24 with primary hepatocellular carcinoma, 34 with chronic active hepatitis, 12 with chronic persistent hepatitis and 30 asymptomatic healthy hepatitis B virus carriers were tested for anti-HBc IgM using the Corzyme-M test. Anti-HBc IgM was detected in 50% of the primary hepatocellular carcinoma patients, 26.5% of the chronic active hepatitis patients, 25% of the chronic persistent hepatitis patients, but in none of the healthy hepatitis B virus carriers. There was no correlation between the presence of anti-HBc IgM and HBeAg, hepatitis B virus DNA, ALT or alpha-fetoprotein levels in either the chronic active hepatitis or chronic persistent hepatitis patients. However, a significantly higher positive rate of anti-HBc IgM was noted in the HBeAg-positive or HBV DNA-positive primary hepatocellular carcinoma patients than in those with negative markers of viral replication, but no correlation was noted between the presence of anti-HBc IgM and serum ALT or alpha-fetoprotein levels in these primary hepatocellular carcinoma patients. Also, no differences in positivity for HBeAg, HBV DNA or levels of serum ALT were noted when patients with high titers of anti-HBc IgM were compared to those with low titers. Thus, anti-HBc IgM cannot distinguish between HBsAg-positive patients with chronic active hepatitis, chronic persistent hepatitis or primary hepatocellular carcinoma, does not correlate with serum ALT or alpha-fetoprotein levels and is only associated with markers for viral replication in primary hepatocellular carcinoma patients. Based on this, anti-HBc IgM appears to have a limited usefulness for diagnosis of either chronic hepatitis B or primary hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylaxis of hepatitis B reactivation with immunosuppressive therapy in rheumatic diseases. Orientations for clinical practice

Reactivation of infection with hepatitis B virus (HBV) is a potentially serious complication of immunosuppression, which can be identified and efficiently prevented. There have been an increasing number of cases of HBV reactivation in patients receiving immunosuppression in the context of rheumatic diseases such as rheumatoid arthritis or systemic lupus erythematosus. The recommendations in this area should be individualized taking into account two aspects: immunosuppressive regimens used (high or low risk of reactivation) and the different stages of HBV infection: chronic hepatitis B, inactive HBV carrier, occult hepatitis B infection defined by HB surface antigen (HBsAg) negative and antibody anti-HB core (anti-HBc) positive. In patients with rheumatic diseases that will start high-risk immunosuppressive drugs, we propose a universal screening with serological tests for hepatitis B (HBsAg, anti-HBs and anti-HBc). Patients with chronic hepatitis B (HBsAg positive, HBV DNA ≥ 2000 IU/ml, elevated ALT) should initiate antiviral therapy. Inactive HBV carriers (HBsAg positive, HBV DNA <2000 IU / ml, normal aminotransferases) exposed to high risk immunosuppressive therapy should undergo prophylaxis of HBV reactivation. Prophylaxis should be started 2 to 4 weeks before the beginning of immunosuppressive therapy and maintained for at least 6 to 12 months after its suspension. It is recommended to use entecavir or tenofovir as first line antiviral agents. In inactive HBsAg carriers under low-risk immunosuppressive therapy and patients with HBsAg negative/anti-HBc positive (HBV infection in the past), the strategy should be monitoring of viral reactivation with aminotransferases and HBV DNA determination in every 6 months.     

Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection

Summary.  We evaluated the longitudinal changes of viraemia and predictors of progression in a prospectively followed cohort of 150 untreated patients with HBeAg-negative chronic hepatitis B virus (HBV) infection. According to the first year of follow-up, 85 patients were classified into inactive carrier state and 65 into chronic hepatitis B (CHB). Serum HBV DNA levels were determined at baseline in all patients, at year-1 in carriers or last pretherapy visit in CHB patients and during alanine aminotransferase (ALT) elevations in carriers progressing to CHB. HBV DNA levels at any occasion were ≥80, ≥2000 or ≥20 000 IU/mL in 81%, 23% or 0% of carriers and 100%, 95% or 83% of CHB patients. The cumulative progression rate from carrier to CHB was 11%, 16%, 24% at 2-, 3-, 4 years and was independently associated with higher baseline ALT (always within traditional normal range) and baseline HBV DNA ≥2000 or ≥5000 IU/mL. In 12 carriers progressed to CHB, HBV DNA increased by >1 log₁₀ IU/mL. During 7.5 months of median follow-up, HBV DNA change ≥1 log₁₀ IU/mL was observed in 49% of CHB patients. In conclusion, serum HBV DNA levels are detectable in the majority of inactive HBV carriers exceeding 2000 IU/mL in only 23% and 20 000 IU/mL in none of them. Carriers have approximately 15% 3-year risk of progression to CHB, which is associated with higher baseline ALT and viraemia ≥2000–5000 IU/mL, and thus should be closely followed. Approximately 20% of HBeAg-negative CHB patients have HBV DNA <20 000 IU/mL with fluctuations >1 log₁₀ occurring in many of them.     

The effect of recombinant hepatitis B vaccine therapy in chronic hepatitis B infection.

BACKGROUND/AIMS: Immune-modulator and antiviral treatments for carriers of hepatitis B virus are known to have poor efficacy with a high cost and frequent side effects, which has led to investigation of new treatment modalities. The aim of this study was to determine the efficacy of recombinant hepatitis B vaccine in the treatment of patients with chronic hepatitis B (HBV DNA >5 pg/ml, ALT>60) infection diagnosed histopathologically and asymptomatic carriers (HBV DNA<5 pg/ml, ALT <40, Anti Hbe positive) of the virus. METHODS: The vaccine (Gen Hevac B Pasteur) was administered at baseline and at months one and six to patients with chronic hepatitis and asymptomatic carriers. Ten cases with chronic hepatitis B infection were assigned to a control group to whom no treatment was given. Biochemical and microbiological investigations were performed at baseline and at months three, six and twelve in all cases. Seroconversion of Hbe Ag, loss of HBV DNA and normalization of ALT were considered as a positive response. RESULTS: Patients with chronic hepatitis B who were given the vaccine were found to have significantly low levels of HBV DNA at 12 months (63.2+/-20pg/ml) compared to baseline values (174.4+/-36.9pg/ml), while controls were found to have high levels of HBV DNA at 12 months (223.1+/-33pg/ml) compared to baseline values (165.2+/-33.2pg/ml) (p<0.05). At 12 months, HBV DNA had become negative in seven of 19 patients given the vaccine (36.8%) Four patients with chronic hepatitis (36.35%) were observed to have HBeAg seroconversion and one patient (5.2%) HBsAg seroconversion at the end of 12 months and there were four (21.05%) patients who responded positively to vaccine therapy in this group. Asymptomatic carriers and controls did not have seroconversion of HBs Ag. Also, HBV DNA did not become negative in controls. CONCLUSION: It may be concluded that recombinant hepatitis B vaccine is effective in the treatment of chronic hepatitis B.     

恩替卡韦治疗e抗原阴性慢性乙型肝炎停药后复发的分析

目的了解HBeAg阴性的慢性乙型肝炎(CHB)患者使用恩替卡韦抗病毒治疗的疗程及停药的标准。方法回顾性分析2006年1月至2015年12月复旦大学附属中山医院肝炎门诊确诊为HBeAg阴性的CHB并予恩替卡韦抗病毒治疗后停药6月以上的患者121例,观察其停药6个月、12个月的HBV DNA水平、肝功能。结果停药6个月后有33%的患者HBV DNA5×10~2拷贝/mL,19.8%患者出现ALT升高。停药12个月后累计有45.5%的患者HBV DNA5×10~2拷贝/mL,30.6%患者出现ALT升高,用药大于5年的患者复发率最低。此外,基线HBV DNA水平2×10~5拷贝/mL的患者停药后6个月、12个月的复发率较基线水平10~7拷贝/mL者低。结论 HBeAg阴性的CHB患者使用恩替卡韦治疗停药复发的比率随着抗病毒疗程的延长而减少,且基线HBV DNA水平与复发率相关。     

慢性乙型肝炎患者12周自发性HBV DNA水平变化分析

目的 分析慢性乙型肝炎患者12周内自发性HBV DNA水平下降情况.方法 回顾性分析2003-2005年未接受抗病毒药物治疗的慢性乙型肝炎患者12周内自发性HBV DNA水平下降情况,并根据患者基线ALT、总胆红素(TBil)水平进行分组,分析基线ALT、TBil对自发性HBVDNA水平下降的影响.两组间计量资料比较采用t检验或Wilcoxon符号秩和检验;多组数据均值比较采用方差分析;组间率的比较采用x2检验.结果 共收集213例慢性乙型肝炎患者,男性174例,女性39例,年龄18～65(33.0±10.0)岁.其中慢性乙型肝炎轻～中度124例,慢性乙型肝炎重度89例;12周时失访19例(8.92%).所有患者HBV DNA基线均值为(6.66±1.03)log10拷贝/ml,12周时为(5.98±1.53)log10拷贝/ml(P<0.01).慢性乙型肝炎重度患者基线时HBVDNA水平均值低于慢性乙型肝炎轻～中度患者,分别为(6.45±0.99)log10拷贝/ml与(6.81±1.04)log10拷贝/ml(P<0.05);但两组12周时HBV DNA水平均值及HBV DNA水平下降值的差异均无统计学意义.12周时HBV DNA≤3 log10拷贝/ml患者的基线ALT及TBil值高于HBVDNA>3 log10拷贝/ml组,但差异均无统计学意义.12周时HBV DNA水平下降值≥2 log10拷贝/ml与<2 log10拷贝/ml两组患者的基线ALT、TBil水平相近(P>0.05).基线ALT水平≤5倍正常值上限(ULN)与>5×ULN两组患者12周时HBV DNA水平均值及HBV DNA水平下降值的差异均无统计学意义;两组患者12周时HBV DNA≤3 log10拷贝/ml、HBV DNA水平下降值≥2 log10拷贝/ml的比例,差异也无统计学意义(P>0.05).基线时ALT≤5 × ULN及TBil≤5×ULN组HBV DNA水平均值高于其他3组(P<0.05),但12周时各组HBV DNA水平均值、HBV DNA下降值比较,差异无统计学意义. 结论 慢性乙型肝炎患者12周内存在一定程度的自发性HBV DNA水平下降,但肝脏炎症损伤程度与患者12周内自发性HBV DNA水平下降程度无明显的相关性.     

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.     

Diagnosis and treatment of chronic hepatitis B: an update

The diagnosis of chronic hepatitis B virus (HBV) infection is made using a combination of serological, virologic, biochemical, and histologic markers. The natural history of HBV infection can be divided into four phases: immune tolerance, immune clearance (HBeAg-positive chronic hepatitis B), inactive HBsAg carrier, and reactivation (HBeAg-negative chronic hepatitis B). Patients in the immune clearance and reactivation phases, with elevated alanine aminotransferase (ALT) and HBV DNA levels, are candidates for antiviral therapy. The primary goal of therapy for chronic hepatitis B is suppression of viral replication, which has been shown to reduce hepatic necroinflammation and retard progression of hepatic fibrosis. Long-term suppression of serum HBV DNA is likely to reduce progression to cirrhosis and hepatic decompensation and decrease the risk of hepatocellular carcinoma. Current antiviral therapy for chronic hepatitis B includes interferon alfa, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine. In patients with HBeAg-positive chronic hepatitis B, antiviral treatment is indicated when the serum HBV DNA level is = or > 10(5) copies/mL (20,000 IU/mL) and the ALT level is elevated. For HBeAg-negative patients, the threshold for initiation of therapy is lower, i.e., a serum HBV DNA level = or > 10(4) copies/mL (2,000 IU/mL) in association with an elevated ALT level. The presence of at least moderate necroinflammation and the presence of fibrosis on liver biopsy, which is optional and not mandatory before therapy, may be useful in supporting the decision to initiate therapy, particularly in patients with normal ALT levels. While undergoing therapy, patients require monitoring every 3 to 6 months to ensure compliance and to test for the development of resistance if an oral agent is used. Issues that remain controversial or need to be studied further are the necessity of a baseline liver biopsy, the HBV DNA and ALT thresholds for initiation of therapy, the optimal duration of antiviral therapy, selection of one agent over another, and the role of combination therapy.