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.     

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

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

Similar efficacy and safety of tenofovir in Asians and non-Asians with chronic hepatitis B

AIM:To compare the efficacy and safety of tenofovir disoproxil fumarate(TDF)in Asian and non-Asian chronic hepatitis B(CHB)patients.METHODS:The efficacy and safety of the initial 48wk of treatment with TDF was compared in a posthoc analysis of combined data from 217 Asians and299 non-Asians included in Studies 102 and 103and a post-approval,open-label trial(Study 123).Patient groups were compared according to baseline hepatitis B e antigen(HBe Ag)status and viral load.The main outcome measures included the proportion of patients who achieved a hepatitis B virus(HBV)DNA level400 copies/m L at Week 48 of treatment.Secondary measures included:HBV DNA and alanine aminotransaminase(ALT)levels over time;proportion of patients with normal ALT levels;proportion of patients with HBe Ag loss/seroconversion and proportion of patients with hepatitis B surface antigen loss/seroconversion;changes in liver histology.Safety and tolerability were evaluated by the occurrence of adverse events(AEs),serious AEs,laboratory abnormalities,discontinuation of the study drug due to AEs,or death.The primary efficacy and safety analysis set included all patients who were randomly assigned to treatment and received at least one dose of study drug.RESULTS:At week 48,similar proportions of Asians and non-Asians reached HBV DNA400 copies/m L(96%of Asian and 97%of non-Asian patients with HBe Ag-negative CHB and 83%of Asian and 79%of non-Asian patients with HBe Ag-positive CHB had HBV DNA)and normal ALT(78%of Asian and 81%of nonAsian patients with HBe Ag-negative CHB and 71%of Asian and 74%of non-Asian patients with HBe Agpositive CHB had normal ALT).On-treatment HBV DNA decline rates were similar between Asians and nonAsians regardless of baseline HBe Ag status and viralload.HBV DNA decline during the first four weeks was2.9 log10 copies/m L in HBe Ag-negative Asians and nonAsians,and in HBe Ag-positive non-Asians,and 3.1log10 copies/m L in HBe Ag-positive Asians.HBe Ag loss and seroconversion was achieved in 14%of Asians vs 26%and 24%,respectively,in non-Asians.Liver histology improved in 77.2%of Asians and 71.5%of non-Asians.No resistance to TDF developed.No renal safety signals were observed.CONCLUSION:TDF demonstrated similar viral suppression,normalization of ALT,improvements in liver fibrosis,and no detectable resistance in Asian and non-Asian patients regardless of baseline HBe Ag status.     

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。     

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

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

A survey of chronic hepatitis B patient management practices in the European Union

Summary. The current study sought to evaluate the characteristics of chronic hepatitis B virus (HBV) infection and current management practices in the European Union by surveying physician and patient records. A detailed survey of physician practices and management of patients with CHB was conducted between July and October 2006 in France, Germany, Italy and Spain. A total of 200 physicians participated in the survey, and data were collected from 2023 patients with chronic HBV infection. Most patients were men (69%), who had hepatitis B e antigen (HBeAg)‐negative disease (64%), and demonstrated evidence of significant disease [53%; moderate fibrosis (35%), compensated cirrhosis (14%), or decompensated cirrhosis (4%)]. Among the 1665 HBV‐monoinfected patients surveyed, 1184 (71%) were currently receiving treatment for chronic HBV infection. At treatment initiation, 70% of HBeAg‐positive patients had both pretreatment serum HBV DNA levels ≤9 log₁₀ copies/mL and alanine aminotransferase (ALT) levels ≥2 × the upper limit of normal (ULN), and 81% of HBeAg‐negative patients had HBV DNA levels of ≤7 log₁₀ copies/mL. Among untreated patients, HBV DNA levels ≤5 log_10, ALT levels <2 × ULN, and mild or no liver fibrosis were present in 48% and 84% of HBeAg‐positive and HBeAg‐negative patients, respectively. In conclusion, the majority of European patients with CHB surveyed were HBeAg negative, Caucasian, men, and presented with significant histologic liver disease. At treatment initiation, most HBeAg‐positive patients had pretreatment serum HBV DNA levels ≤9 log₁₀ copies/mL and ALT levels ≥2 × ULN, while the HBeAg‐negative patients had HBV DNA levels ≤7 log₁₀ copies/mL.     

Assessment of chronic hepatitis B: the importance of hepatitis B virus DNA testing

Background: Chronic hepatitis B (CHB) has an estimated prevalence of 90 000 to 160 000 in Australia. Cirrhosis and hepatocellular carcinoma are important complications of CHB and appropriate evaluation of hepatitis B surface antigen (HBsAg)‐positive individuals is vital to identify treatment candidates. Methods: A review of the database of a tertiary hospital was performed and 348 HBsAg‐positive individuals with baseline demographic, virological, serological and biochemical variables were identified and evaluated cross‐sectionally. A small subgroup of hepatitis B e antigen (HBeAg)‐negative patients with normal alanine aminotransferase (ALT) at baseline were identified and followed longitudinally. Results: 175/348 (50%) of patients were in the HBeAg‐negative, chronic hepatitis phase of disease, 22% in the HBeAg‐positive immune clearance and 6% in the immune tolerant phases. HBeAg‐negative patients were older and more likely to be male than HBeAg‐positive patients. The correlation between hepatitis B virus (HBV) DNA and ALT levels was examined. ALT and HBV DNA levels showed no correlation in HBeAg‐positive CHB and only a weak correlation in HBeAg‐negative patients. Furthermore, 35% of HBeAg‐negative patients with detectable HBV DNA had a normal ALT. Conversely 38% of HBeAg‐negative patients with no detectable HBV DNA had an elevated ALT. A persistently normal ALT over 24 months was seen in five of nine HBeAg‐negative patients with normal initial ALT and detectable HBV DNA. Conclusion: Appropriate evaluation of HBeAg‐negative CHB must include HBV DNA because the ALT is not a reliable guide to underlying viral replication.     

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

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

Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications

BACKGROUND: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria. AIM: To determine risk factors for the development of complications in Asian CHB patients. PATIENTS AND METHODS: A total of 3233 Chinese CHB patients (mean follow up 46.8 months) were monitored for liver biochemistry, viral serology, hepatitis B virus (HBV) DNA levels, acute exacerbation, hepatitis B e antigen (HBeAg) seroconversion, and development of cirrhotic complications and hepatocellular carcinoma. RESULTS: Median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years, respectively. Patients with alanine aminotransferase (ALT) levels of 0.5-1 times the upper limit of normal (ULN) and 1-2x ULN had an increased risk for the development of complications compared with patients with ALT levels <0.5x ULN (p<0.0001 for both). HBeAg/antibody to hepatitis B e antigen status, and number of episodes, duration, and peak ALT levels of acute exacerbations were not associated with an increased risk of complications. In patients with complications, 43.6% had HBV DNA levels less than 1.42x10(5) copies/ml. Male sex, stigmata of chronic liver disease, old age, low albumin, and high alpha fetoprotein levels on presentation were independently associated with increased cumulative risk of complications. Male sex, presence of hepatitis symptoms, old age, low albumin level, and presence of complications on presentation were independently associated with shorter survival. CONCLUSION: Prolonged low level viraemia causing insidious and continual liver damage, as reflected by ALT levels of 0.5-2x ULN, is the most likely pathway for the development of complications in Asian CHB patients.     

Serial HBV DNA levels in patients with persistently normal transaminase over 10 years following spontaneous HBeAg seroconversion

Earlier studies addressing the hepatitis B virus (HBV) DNA cut-off level for inactive chronic HBV infection largely involved patients with normal alanine aminotransferase (ALT) for only 1-2 years and based on a single time HBV DNA assay. This study was conducted to address this issue using serial HBV DNA assays in patients with persistently normal ALT (PNALT) over 10 years following spontaneous hepatitis B e antigen (HBeAg) seroconversion. Serial serum specimens (mean 9 samples per patient) of 62 patients with PNALT and no disease progression over 10 years (median 18.1 years) after spontaneous HBeAg seroconversion were assayed for HBV DNA. Excluding assays within 1 year after HBeAg seroconversion, 21% and 82.3% of the patients with PNALT had HBV DNA levels persistently lower than 4 log(10) and 5 log(10) copies/mL, respectively, and only 8% had a level ≥ 5 log(10) copies/mL in at least two assays. Of the 27 patients with PNALT defined by ALT <30 U/L for male and <19 U/L for female, only 33% had serum HBV DNA level persistently <4 log(10) copies/mL. There was no significant difference in the serial HBV DNA changes among patients with different gender, HBV genotype or age at HBeAg seroconversion. Liver biopsy in nine patients invariably showed minimal necroinflammation and one showed Ishak fibrosis score 4. These results suggest that 5 log(10) copies/mL (20,000 IU/mL) is a more appropriate cut-off HBV DNA level for inactive chronic HBV infection in the setting of PNALT.     

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.     

Effect of nucleoside analog‐interferon sequential therapy on patients with acute exacerbation of chronic hepatitis B

Aim: Nucleoside analog (NA)‐interferon (IFN) sequential therapy may enable the long‐term control of chronic hepatitis B (CHB) and the withdrawal of the nucleoside analog. We evaluated the efficacy of NA‐IFN sequential therapy for acute exacerbation of CHB. Methods: A total of 12 patients with acute exacerbation of CHB, nine of whom were positive for hepatitis B e antigen (HBeAg), were enrolled in this study. All the patients were treated with lamivudine 100 mg/day alone for 20 weeks, then with both IFN‐α 6 megaunits three times per week and lamivudine for 4 weeks, and lastly, with IFN‐α alone for 20 weeks. Patients whose serum alanine aminotransferase (ALT) level was normalized, whose serum hepatitis B virus (HBV) DNA level decreased to less than 5 log copies/mL, and HBeAg level was absent 24 weeks after the end of treatment were defined as having sustained virological response (SVR). The other patients were defined as having no response (NR). Results: Four out of nine (44.4%) HBeAg‐positive and all three HBeAg‐negative patients achieved SVR. The levels of serum alanine aminotransferase (ALT), HBV DNA and HBV core‐related antigen were similar between SVR and NR patients at baseline. Three of four patients (75.0%) whose serum HBeAg became negative at the end of treatment achieved SVR, while one of five (20.0%) whose serum HBeAg remained positive achieved SVR. Conclusion: NA‐IFN sequential therapy for patients with acute exacerbation of CHB enables the withdrawal of treatment and is particularly effective for patients whose serum HBeAg has become undetectable by the end of the IFN treatment.     

阿德福韦酯治疗HBeAg阴性慢性乙型肝炎疗效与HBV基因型的关系

目的探讨阿德福韦酯（ADv）治疗HBeAg阴性慢性乙型肝炎（chronic hepatitis B,CHB）的疗效与HBv基因型的关系。方法选择71例HBVDNA〉1×10^4copies／ml、ALT〉2倍正常值上限、TBIL正常的HBeAg阴性cHB患者,其中B基因型40例,C基因型31例,所有患者均口服ADV 10mg,1／d,治疗52周,动态观察治疗过程中HBV DNA和ALT水平的变化。结果在治疗12、24、52周时,B基因型患者ALT变化、血清HBVDNA水平下降≥2log。完全抑制比例与C基因型患者相比差异无统计学意义（P〉0．05）。结论ADV能有效抑制HBeAg阴性CHB患者HBV复制,促进肝功能好转,其疗效与HBV基因型B或C型无关。     

Effect and Predictive Elements for 52 Weeks' Telbivudine Treatment on Naïve HBeAg positive Chronic Hepatitis B

Background

Antiviral treatment with nucleoside analogs has been used for chronic hepatitis B (CHB). Each kind of nucleoside analog has its own characteristics and suitability for patients. Telbivudine (LdT, brand name: Sebivo, Beijing Novartis Pharma Ltd) is the newest nucleoside analog, with strong and rapid viral suppression. However, its resistance rate is relatively high during long-term application, due to low genetic barriers to resistance. So, it is necessary to increase the effect and reduce resistance with effective management, according to baseline factors and early on-treatment responses.

Objectives

To reveal possible predictive factors of the effect of telbivudine (LdT) treatment on naïve HBeAg-positive chronic hepatitis B (CHB) patients to optimize treatment.

Patients and Methods

A total 71 naïve chronic hepatitis B (CHB) patients who met the inclusion criteria were enrolled. All patients were treated with LdT 600 mg Qd for at least 52 weeks. Multiple logistic regression analyses were done to investigate the predictive values of baseline factors and responses at Week 24.

Results

The reduction in hepatitis virus B (HBV) DNA level was 6.44 ± 2.38 lg copies/mL at Week 52 compared with baseline. The complete virus response (CVR), biochemical response (BR), serological response (SR), and drug resistance (DR) were 61.99%, 77.46%, 35.21%, and 8.45% respectively. By multiple regression analysis, baseline alanine aminotransferase (ALT) levels significantly affected CVR (P = 0.024, OR = 1.008), and baseline ALT and baseline HBV DNA levels were independent compact factors of SR (P = 0.012, OR = 1.007; P = 0.001, OR = 0.423). The differences in CVR, SR, and DR in patients with ALT > 120 Iu/mL compared with patients with ALT ≤ 120 Iu/mL were statistically significant. The differences in SR in patients with HBV DNA > 107 copies/mL compared with patients with HBV DNA ≤ 107 copies/mL were statistically significant. Additionally, CVR, BR, and SR were differed significantly between patients with HBV DNA lower than 300 copies/mL at Week 24 and patients with HBV DNA higher than 300 copies/mL (P = 0.000, P = 0.0016, and P = 0.000, respectively).

Conclusions

There were more responders among naïve HBeAg-positive chronic hepatitis B patients with lower HBV DNA levels (especially lower than 107 copies/mL) and higher ALT values (especially higher than 120 Iu/mL at baseline) to LdT treatment. Adjustments for treatment strategy should be considered if HBV DNA > 300 copies/mL at Week 24 is observed.     

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.     

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.     

替比夫定治疗妊娠晚期慢性乙型肝炎孕妇的临床观察

目的研究慢性乙型肝炎孕妇妊娠晚期予替比夫定（LdT）抗病毒治疗对控制肝炎活动、阻断HBV母婴传播的意义。方法把116例HBsAg、HBeAg、抗-HBc阳性,HBV DNA≥1×105拷贝/ml,ALT≥2×ULN,伴或不伴TBil升高的慢性乙型肝炎孕妇,根据自愿原则分为两组,治疗组65例（孕28±2周）在护肝降酶的基础上服用LdT,600 mg/d,对照组51例仅予护肝降酶治疗,两组新生儿出生后均予主被动联合免疫。比较两组患者在分娩前及产后7个月HBV DNA、ALT、TBil水平的变化,比较两组新生儿在7个月时HBsAg携带率、抗-HBs阳转率,观察母婴并发症发生情况。结果治疗组孕妇分娩前及产后7个月HBV DNA、ALT、TBil值明显低于对照组,差异有统计学意义（P〈0.05）;治疗组和对照组新生儿7个月时HBsAg携带率分别为1.5%和15.7%,抗-HBs阳性率分别为95.4%和78.4%,差异有统计学意义（P〈0.05）。治疗组母婴并发症发生明显少于对照组。结论 LdT能有效控制肝炎活动,快速降低慢性乙型肝炎孕妇的HBV DNA水平,同时减少HBV母婴垂直传播,对母婴有利。     

Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus

BACKGROUND AND AIMS: Prolonged lamivudine therapy is associated with treatment-resistant YMDD mutant hepatitis B virus (HBV). We evaluated the efficacy and safety of adding adefovir dipivoxil to lamivudine in 135 patients with chronic hepatitis B (CHB) and YMDD mutant HBV. METHODS: Ninety-five patients with compensated CHB (group A) were randomized to adefovir 10 mg daily (n = 46) or placebo (n = 49) for 52 weeks while continuing treatment with lamivudine. Forty patients with decompensated hepatitis B or post-liver transplantation (group B) received adefovir and lamivudine. The primary end point was a decline in serum HBV DNA level to 10(5) copies/mL or a >2 log(10) reduction from baseline at weeks 48 and 52. RESULTS: HBV DNA response occurred in 85% of patients (39 of 46) in group A given combined therapy versus 11% (5 of 46) receiving lamivudine alone (P < 0.001), with a significant change in HBV DNA level from baseline (P < 0.001) between treatment groups (median, -4.6 vs. +0.3 log(10) copies/mL, respectively). Normalization of alanine aminotransferase levels occurred in 31% of patients (14 of 45) receiving combined therapy versus 6% (3 of 48) receiving lamivudine alone (P = 0.002). Ninety-two percent of patients (36 of 39) in group B had an HBV DNA response (median change of -4.6 log(10) copies/mL) and improved liver chemistries (P < or = 0.001). Both treatment regimens were well tolerated, and renal function abnormalities were not observed in either group. CONCLUSIONS: The addition of adefovir dipivoxil to lamivudine in patients with CHB with compensated or decompensated liver disease due to YMDD mutant HBV is associated with virologic and biochemical improvement during 52 weeks of treatment and is well tolerated.     

The Management of Chronic Hepatitis B in Asian Americans

Hepatitis B virus (HBV) infection is common with major clinical consequences worldwide. In Asian Americans, the HBsAg carrier rate ranges from 7 to 16%; HBV is the most important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Patients are first diagnosed at different stages of clinical disease, which is categorized by biochemical and virologic tests. Patients at risk for liver complications should be identified and offered antiviral therapy. The two antiviral agents recommended for first-line treatment of chronic hepatitis B (CHB) are entecavir and tenofovir. The primary goal of therapy is sustained suppression of viral replication to achieve clinical remission, reverse fibrosis, and prevent and reduce progression to end-stage liver disease and HCC. Asian patients with chronic hepatitis, either HBeAg-positive or -negative, with HBV DNA levels >10⁴ copies/mL (>2,000 IU/mL) and alanine aminotransferase (ALT) values above normal are candidates for antiviral therapy. HBeAg-negative patients with HBV DNA >10⁴ copies/mL (>2,000 IU/mL) and normal ALT levels but who have either serum albumin ≤3.5 g/dL or platelet count ≤130,000 mm³, basal core promoter mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive antiviral therapy. Considerations for treatment include pregnant women with high viremia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg-positive patients with risk factors, lifelong surveillance for HCC with alpha-fetoprotein testing and abdominal ultrasound examination at 6-month intervals is required. These recommendations are based on a review of relevant literature and the opinion of a panel of Asian American physicians with expertise in hepatitis B treatment.     

The Roadmap concept: using early on-treatment virologic responses to optimize long-term outcomes for patients with chronic hepatitis B

Several large observational, longitudinal studies of the natural history of chronic hepatitis B (CHB) have demonstrated that high levels of hepatitis B virus (HBV) replication are associated with long-term risk of cirrhosis, decompensation, hepatocellular carcinoma, and liver-related mortality. The corollary is also true—profound and sustained suppression either spontaneously or during antiviral therapy will prevent disease progression and complications. Multiple analyses of various baseline factors and on-treatment responses have identified the absolute HBV DNA level after 24 weeks of therapy as the best predictor of long-term efficacy. Lower 24-week serum HBV DNA levels after lamivudine, telbivudine, or entecavir are associated with higher rates of maintained HBV DNA nondetectability, ALT normalization, HBeAg seroconversion, and lack of resistance. Patients with undetectable serum HBV DNA levels after 24 weeks have the best long-term outcomes while those with levels remaining above 10,000 copies per ml are unlikely to benefit from long-term therapy with that particular agent and either the addition or switch to another antiviral agent with increased potency but without cross resistance could be considered at this time point. In the future, improved on-treatment monitoring should facilitate treatment strategies to optimize long-term outcomes among patients receiving oral antiviral therapy for CHB.