替比夫定对妊娠后期乙型肝炎病毒宫内感染的阻断作用

目的 探讨妊娠后期替比夫定对HBV宫内感染的阻断作用.方法 妊娠后期慢性乙型肝炎患者61例,31例给予替比夫定600mg,口服,1次/d;30例为对照,不给予抗病毒药物.观察两组患者母体HBV DNA水平的变化情况和新生儿HBsAg的阳性率.对HBsAg阳性率的差异分析采用x2检验,对计量资料采用t检验分析.结果 替比夫定组母体HBV DNA水平较服药前明显下降(t=19.09,P<0.01),且分娩前HBV DNA水平明显低于对照组(t=23.64,P<0.01).两组新生儿7月龄时HBV感染率分别为0和13.3%(4/30),x2=4.29,P<0.05.结论 妊娠后期应用替比夫定具有良好的安全性.替比夫定可显著抑制妊娠晚期孕妇血清HBV DNA水平,降低新生儿HBV感染率,可有效阻断HBV宫内感染.     

Baseline HBsAg predicts response to pegylated interferon-α2b in HBeAg-positive chronic hepatitis B patients

AIM: To evaluate the predictive effect of baseline hepatitis B surface antigen (HBsAg) on response to pegylated interferon (PEG-IFN)-α2b in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.METHODS: This retrospective analysis compared the treatment efficacy of PEG-IFN-α2b alone in 55 HBeAg-positive CHB patients with different baseline HBsAg levels. Serum HBV DNA load was measured at baseline, and at 12, 24 and 48 wk of therapy. Virological response was defined as HBV DNA < 1000 IU/mL. Serum HBsAg titers were quantitatively assayed at baseline, and at 12 and 24 wk.RESULTS: Eighteen patients had baseline HBsAg > 20 000 IU/mL, 26 patients had 1500-20000 IU/mL, and 11 patients had < 1500 IU/mL. Three (16.7%), 11 (42.3%) and seven (63.6%) patients in each group achieved a virological response at week 48, with a significant difference between groups with baseline HBsAg levels > 20000 or < 20000 IU/mL (P = 0.02). Thirteen patients had an HBsAg decline > 0.5 log₁₀ and 30 patients < 0.5 log₁₀ at week 12; and 6 (46.2%) and 10 (33.3%) in each group achieved virological response at week 48, with no significant difference between the two groups (P = 0.502). Eighteen patients had an HBsAg decline > 1.0 log₁₀ and 30 patients < 1.0 log₁₀ at week 24, and 8 (44.4%) and 11 (36.7%) achieved a virological response at week 48, with no significant difference between the two groups (P = 0.762). None of the 16 patients with HBsAg > 20000 IU/mL at week 24 achieved a virological response at week 48.CONCLUSION: Baseline HBsAg level in combination with HBV DNA may become an effective predictor for guiding optimal therapy with PEG-IFN-α2b against HBeAg-positive CHB.     

Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance

AIM:To study the effect of rescue monotherapy with adefovir(ADV) in patients with chronic hepatitis B(CHB) who developed drug resistance to lamivudine(LAM).METHODS:A total of 76 treated CHB patients with resistance to LAM were enrolled in the present study.The patients’ baseline characteristics,such as age,gender,blood tests and hepatitis B virus(HBV) DNA were collected;therapy duration and the response of each patient were also recorded.ADV monotherapy was set as the observation group A.Twenty-four patients with LAM resistance,who were set as group B,accepted combined therapy with LAM + ADV.Patients were followed up at 0,12,24,52,104 and 156 wk.Hepatitis B surface antigen status,hepatitis B e antigen(HBeAg)/anti-HBe status,HBV DNA level and biochemical indexes were monitored.Sequencer of HBV polymerase gene was performed on the ABI 3730 automated sequencer.If no desired effects had been achieved during the course of treatment,patients’ choices were also taken into account.The control group was tested at the same time.RESULTS:In the two groups,27 cases developed viral breakthrough after LAM treatment response.The remaining 49 cases underwent biochemical rebound accompanied by rtM204I/V or rtL180M mutation.In group A,52 cases finished 156 wk of ADV monotherapy;of whom,36 cases were HBeAg positive and 16 HBeAg negative.In patients whose baseline HBV DNAs were 10 3-10 5 copies/mL,88.8% of patients’ HBV DNAs were lower than the lower test limit(10 3 copies/mL) after 12 to 156 wk of ADV treatment.In patients whose baseline HBV DNAs were ≥ 10 6 copies/mL,41.1%-47.0% of patients’ HBV DNAs were lower than the lower test limit after the same course of ADV therapy(χ 2 were 4.35-5.4,41.1%-47.0% vs 88.8% group 10 3-10 5 copies/mL,P < 0.01).In group A,seroconversion of HBeAg developed in 8 of 36 cases(22.2%).In group B,24 cases finished 156 wk of LAM + ADV;of whom,17 cases were HBeAg positive and 7 HBeAg negative.In patients whose baseline HBV DNAs were 10 3-10 5 copies /mL,81.8% of patients’ HBV DNAs were lower than the lower test limit(10 3 copies/mL) after 12 to 156 wk of treatment.In the patients whose baseline HBV DNAs were ≥ 10 6 copies/mL,46.1%-53.8% of patients’ HBV DNAs were lower than the lower test limit after the same course of LAM + ADV therapy(χ 2 were 4.1-5.0,46.1%-53.8% vs 81.8% group 10 3-10 5 copies/mL,P < 0.05-0.01).In group B,4 of 17 cases(23.5%) developed seroconversion of HBeAg.Treatment outcomes in groups A and B were comparable.CONCLUSION:In both group A and B,the ratios of virological response have similar efficacy in patients with lower baseline HBV DNAs.     

A pilot study of extended duration peginterferon alfa-2a for patients with hepatitis B e antigen-negative chronic hepatitis B

OBJECTIVES: Forty-eight weeks of peginterferon alfa-2a is the approved regimen for chronic hepatitis B (CHB). Standard interferon is more effective for hepatitis B e antigen (HBeAg)-negative CHB when given for longer than 1 yr. This study evaluated peginterferon alfa-2a for 60 wk, alone or in combination with lamivudine. METHODS: Thirteen patients with HBeAg-negative CHB received peginterferon alfa-2a (180 microg/week) for 60 wk or peginterferon alfa-2a (180 microg/week) for 12 wk followed by 48 wk of peginterferon alfa-2a plus lamivudine. The primary end point, sustained virologic response (SVR), was defined as a reduction in hepatitis B virus deoxyribonucleic acid (HBV DNA) of >or=2 log10 copies/mL and HBV DNA<20,000 copies/mL at 24 wk of follow-up (week 84). Hepatitis B surface antigen (HBsAg) concentrations were analyzed and compared to changes in HBV DNA. RESULTS: SVR was achieved by 9/13 patients (69%). At week 84, HBV DNA was undetectable by polymerase chain reaction in 5/13 (38%) patients, and 3 additional patients had a sustained 2-3 log reduction in HBV DNA. Five patients demonstrated a >90% decrease in HBsAg concentration at week 60, including 3 with undetectable HBV DNA at week 84 and a fourth who met criteria for SVR. CONCLUSIONS: Sixty weeks of peginterferon alfa-2a with or without lamivudine resulted in a higher rate of SVR compared to historical controls with HBeAg-negative CHB treated with 48 wk of pegylated interferon. Larger studies are necessary to assess if longer duration therapy is more effective than the standard regimen and results in a greater decline in HBsAg concentration.     

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level( 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable( 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.     

IL-21 Is Associated With Virological Relapse of HBeAg Positive Chronic Hepatitis B After Discontinuance of Entecavir

Background: To investigate the association between interleukin-21 (IL-21) expression level and virological relapse (VR) of HBeAg positive chronic hepatitis B (CHB) after discontinuance of entecavir (ETV).Methods: The serum IL-21 level of 112 CHB patients was measured at 0, 12, 24, 52, and 104 weeks after ETV discontinuance. ELISA was used for the measurement of serum IL-21 level. VR was defined as two continuous examinations with an interval of 1 month with both showing HBV DNA >10 000 copies/mL after drug discontinuance.Results: The serum IL-21 levels at 0, 12, 24, 52, and 104 weeks after discontinuance of ETV were significantly higher in the durable virological remission (DVR) group than in the VR group (all P < .01). The area under the ROC curve (AUC) was 0.728 (95% CI: 0.630-0.827, P < .001), while the best cut-off value was 49.8 pg/mL. Multivariate Cox model showed that the factors affecting the relapse included age, followed by HBsAg level at the serological conversion of HBeAg and serum IL-21 level (all P < .05).Conclusion: Serum IL-21 level at ETV discontinuance is an independent risk factor for CHB relapse. IL-21 acts as an immunomodulatory factor in maintaining DVR in HBeAg positive CHB patients after ETV discontinuance.     

Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis

Summary. Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double‐blind trial randomized 232 treatment‐naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once‐daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child‐Turcotte‐Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent‐to‐treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol‐defined composite endpoint in intent‐to‐treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.     

Tenofovir rescue therapy in pregnant females with chronic hepatitis B

AIM:To evaluate the safety and efficacy of tenofovir monotherapy in pregnant females resistant to lamivudine or telbivudine.The effect of tenofovir on the fetus was also assessed.METHODS:The clinical data of 17 females were reviewed in this study.Adverse events and pregnancy outcomes from January 1,2011 to June 30,2013 were evaluated in the Department of Gynecology and Obstetrics of BeijingDitan Hospital,Capital Medical University,Beijing,China.These pregnant females developed lamivudine(LAM)-or telbivudine(Ld T)-resistant chronic hepatitis B and received tenofovir(TDF)therapy(300 mg/d),and its curative effect,maternal and perinatal adverse events,fetal growth and development,and neonatal prognosis were evaluated.RESULTS:The median hepatitis B virus(HBV)DNA level in the pregnant females with LAM or Ld T resistance was 5.9(range,4.2-7.2)log10 copies/m L before the initiation of TDF.Ten of these females had abnormal alanine aminotransferase(ALT)levels.The patients were treated with TDF for a median of 24 wk(range,12-40 wk).Fourteen females(82.4%)had an HBV DNA level of500 copies/m L at the time of delivery.This decrease was statistically significant(P0.0001).Serum ALT levels were normalized in all subjects with an elevated serum ALT level at baseline(P=0.0003).There were no significant changes in serum creatinine and phosphorus levels during TDF treatment.In addition,no adverse events related to TDF treatment were observed.Seventeen females delivered 17 live infants,and all infants had good Apgar scores.The mean birth weight was 3226.5±331.7 g,and the mean length at birth was 50.4±1.1 cm.The growth and development of the infants was normal at birth,and no infants had birth defects related to TDF treatment.Eleven infants completed HBV vaccination and had no evidence of vertical transmission.CONCLUSION:The use of TDF in pregnant females with chronic HBV and LAM or Ld T resistance was safe and effective.     

Efficacy of switching to telbivudine in chronic hepatitis B patients treated previously with lamivudine

Background: Telbivudine showed greater antiviral suppression than lamivudine in phase II and III clinical trials. Aims: The present phase IIIb, randomized, double‐blind, multicentre global trial assessed the antiviral efficacy and safety of telbivudine switch in chronic hepatitis B (CHB) patients who exhibited persistent viraemia under lamivudine therapy. Methods: HBeAg‐positive and HBeAg‐negative adult patients (N=246) with persistent viraemia [hepatitis B virus (HBV) DNA>3 log₁₀ copies/ml] under lamivudine treatment for 12–52 weeks were randomized (1:1) to continue lamivudine 100 mg/day or switch to telbivudine 600 mg/day for 1 year. Primary endpoint was the reduction in serum HBV DNA levels from baseline at Week 24. Results: The mean reduction in serum HBV DNA levels from baseline with telbivudine was significantly higher than lamivudine at Week 24 (?1.9 ± 0.18 vs. ?0.9 ± 0.27 log₁₀ copies/ml; P<0.001) and maintained through 1 year. The rate of treatment failure was significantly lower (P<0.001) for patients who switched to telbivudine (5%) compared with those who continued lamivudine (20%) after 52 weeks of treatment. In the telbivudine group, treatment failure occurred in only five patients with >24 weeks of prior lamivudine treatment, all associated with pre‐existent lamivudine‐resistant mutations. Genotypic resistance rates were higher in patients continuing lamivudine compared with those who switched to telbivudine with <24 weeks of lamivudine exposure. Both treatments were well tolerated with similar safety profiles. Conclusions: Early (≤24 weeks) switch to telbivudine improves virological outcomes in CHB patients with persistent viral replication under lamivudine treatment.     

替比夫定治疗慢性乙型肝炎疗效及其影响因素

目的评价替比夫定治疗慢性乙型肝炎52周的疗效及其影响因素。方法采用替比夫定治疗22例慢性乙型肝炎患者52周,对治疗前后ALT、HBVDNA、HBeAg消失、HBeAg血清转换、组织学改善、基因型耐药进行比较。同时根据患者治疗前状况的评估和治疗4周、8周、12周和24周的HBVDNA来预测影响疗效的因素。结果治疗52周,HBV DNA和ALT与治疗前相比明显下降,差异有统计学意义（P〈0．001）。患者治疗前的评估对52周的疗效无明显影响,而治疗24周HBV DNA水平低于300拷贝／ml时,52周HBV检测不到、ALT复常、HBeAg消失和HBeAg血清转换的比例明显增高,基因型耐药明显减少,差异有统计学意义（P〈0．05）。结论替比夫定能明显抑制HBV DNA复制,使ALT复常,促进HBeAg血清转换。治疗24周的HBV DNA抑制水平可预测治疗52周的疗效。     

阿德福韦治疗乙型肝炎e抗原阳性慢性乙型肝炎3年的临床研究

目的评价阿德福韦酯（ADV）10 mg／d治疗HBeAg阳性的慢性乙型肝炎患者52、104、156周末的临床疗效和安全性。方法第一阶段：为随机、双盲、安慰剂对照研究,患者按3：1的比例随机接受ADV 10 mg（36例）或安慰剂（12例）治疗,每日1次,持续12周。第二阶段：患者均接受开放的ADV 10mg治疗,每日1次,持续28周。第三阶段：完成40周的治疗后,最初接受ADV治疗的患者重新按2：1的比例随机分入ADV组（24例）或安慰剂组（12例）接受相应的治疗,持续12周。即分为A、B、C 3组,A组：12例,前12周为安慰剂治疗,后40周为ADV治疗;B组：24例,52周均为ADV治疗;C组：12例,前40周为ADV治疗,后12周为安慰剂治疗。第四阶段：所有仍在研究中的患者继续接受开放的ADV 10 mg治疗共208周（4年）。结果（1）治疗12周后,HBV DNA水平降低,安慰剂组为-0．2 log10拷贝／ml,ADV组为-3．7 log10拷贝／ml,差异有统计学意义（t=8．0,P〈0．01）。（2）治疗12周后,ALT复常率,安慰剂组为0（0／11）,ADV组为10／36（27．8％）,差异有统计学意义（χ^2=3．9,P〈0．05）。（3）治疗40周后,3个治疗组ALT复常率相似。在B组,ALT复常率呈累积性增加。而在C组,ALT复常率显著降低。（4）治疗40周后,3个治疗组HBV DNA水平对数值降低中位数相似。40周后继续12周ADV治疗可以保持HBV DNA水平持续降低至52周。而在C组,HBV DNA水平降低被显著逆转。（5）治疗40周后,3个治疗组HBV DNA转阴率相似。在C组,52周时HBV DNA转阴率显著降低。（6）对于B组,HBeAg消失患者在52周时为12．5％（3／24）。两因素（血清HBeAg转阴,血清抗-HBe转阳）和三因素（血清HBeAg转阴,血清抗-HBe转阳且HBV DNA水平下降到≤10^5拷贝／ml）血清转换比率均为8．3％（2／24）。（7）治疗104周末及156周末,HBV DNA被持续抑制,104周HBV DNA水平对数值降低中位数为-4．2 log10拷贝／ml,156周为-4．3 log10拷贝／ml。HBV DNA阴转率均为31．0％,ALT复常率分别为46．3％、85．4％,HBeAg阴转率分别为23．8％、31．0％,HBeAg血清转换率均为23．8％。（8）研究期间各治疗组肌酐及血磷值平均水平与基线相比无变化,无数据表明肾脏安全性问题。结论ADV 10 mg／d治疗HBeAg阳性慢性乙型肝炎,可明显抑制HBV DNA的复制,使ALT复常,促进HBeAg的血清学转换,使用安全且耐受性良好。     

Management of patients with hepatitis B in special populations

The development of effective nucleos(t)ide analogs(NAs)against hepatitis B virus(HBV)has improved the outcome of patients with chronic hepatitis B(CHB).This review updates issues related to the management of CHB patients included in special populations.Entecavir(ETV)and tenofovir(TDF)represent the currently recommended first-line NAs in patients with HBV decompensated cirrhosis.The combination of HBV immunoglobulin(usually for a finite duration)and NA is considered the standard of care for prophylaxis against HBV recurrence after liver transplantation.TDF is the best choice for hemodialysis patients and in patients with chronic kidney disease with nucleoside resistance.ETV and telbivudine are the preferred options in na?ve renal transplant recipients and with low viremia levels,respectively.All hepatitis B surface antigen(HBs Ag)-positive candidates should be treated with NAs before renal transplantation to achieve undetectable HBV DNA at the time of transplantation.Conventional interferon or NAs can also be used in children,on the basis of well-established therapeutic indication.Pregnant women at high risk of perinatal transmission could be treated with lamivudine,telbivudine or TDF in the last trimester of pregnancy.HBs Ag-positive patients under immunosuppression should receive NA preemptively(regardless of HBV DNA levels)up to 12 mo after its cessation.In HBs Ag negative,anti-HBc positive patients under immunosuppression,further studies are needed to form a final conclusion;however,it seems that anti-HBV prophylaxis is justified in such patients with hematological diseases and/or for those receiving rituximab-containing regimens,regardless of their antiHBs or serum HBV DNA status.     

Hepatitis B surface antigen levels during natural history of chronic hepatitis B: A Chinese perspective study

AIM: To determine the baseline hepatitis B surface antigen (HBsAg) levels during the different phases of chronic hepatitis B (CHB) patients in China.METHODS: Six hundred and twenty-three hepatitis B virus or un-infected patients not receiving antiviral therapy were analyzed in a cross-sectional study. The CHB patients were classified into five phases: immune-tolerant (IT, n = 108), immune-clearance (IC, n = 161), hepatitis B e antigen negative hepatitis (ENH, n = 149), low-replicative (LR, n = 135), and liver cirrhosis (LC, n = 70). HBsAg was quantified (Abbott ARCHITECT assay) and correlated with hepatitis B virus (HBV) DNA, and serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) in each phase of CHB was also determined.RESULTS: Median HBsAg titers were different in each phase of CHB (P < 0.001): IT (4.85 log₁₀ IU/mL), IC (4.36 log₁₀ IU/mL), ENH (2.95 log₁₀ IU/mL), LR (3.18 log₁₀ IU/mL) and LC (2.69 log₁₀ IU/mL). HBsAg titers were highest in the IT phase and lowest in the LC phase. Serum HBsAg titers showed a strong correlation with HBV viral load in the IC phase (r = 0.683, P < 0.001). No correlation between serum HBsAg level and ALT/AST was observed.CONCLUSION: The mean baseline HBsAg levels differ significantly during the five phases of CHB, providing evidence on the natural history of HBV infection. HBsAg quantification may predict the effects of immune-modulator or oral nucleos(t)ide analogue therapy.     

A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B

BACKGROUND & AIMS: A previous 4-week trial of telbivudine in patients with chronic hepatitis B indicated marked antiviral effects with good tolerability, leading to the present 1-year phase 2b trial. METHODS: This randomized, double-blind, multicenter trial evaluated the efficacy and safety of telbivudine 400 or 600 mg/day and telbivudine 400 or 600 mg/day plus lamivudine 100 mg/day (Comb400 and Comb600) compared with lamivudine 100 mg/day in hepatitis B e antigen (HBeAg)-positive adults with compensated chronic hepatitis B. RESULTS: A total of 104 patients were randomized 1:1:1:1:1 among the 5 groups. Median reductions in serum hepatitis B virus (HBV) DNA levels at week 52 (log(10) copies/mL) were as follows: lamivudine, 4.66; telbivudine 400 mg, 6.43; telbivudine 600 mg, 6.09; Comb400, 6.40; and Comb600, 6.05. At week 52, telbivudine monotherapy showed a significantly greater mean reduction in HBV DNA levels (6.01 vs 4.57 log(10) copies/mL; P < .05), clearance of polymerase chain reaction-detectable HBV DNA (61% vs 32%; P < .05), and normalization of alanine aminotransferase levels (86% vs 63%; P < .05) compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion (31% vs 22%) and less viral breakthrough (4.5% vs 15.8%) (P = NS for both). Combination treatment was not better than telbivudine alone. All treatments were well tolerated. In exploratory scientific analyses, clinical efficacy at 1 year appeared related to reduction in HBV DNA levels in the first 6 months of treatment. CONCLUSIONS: Patients with chronic hepatitis B treated with telbivudine exhibited significantly greater virologic and biochemical responses compared with lamivudine. Results with the combination regimens were similar to those obtained with telbivudine alone. These data support the ongoing phase 3 evaluation of telbivudine for treatment of patients with chronic hepatitis B.     

Hepatitis B Surface Antigen Quantification across Different Phases of Chronic Hepatitis B Virus Infection Using an Immunoradiometric Assay

Background/AimsQuantification of hepatitis B surface antigen (HBsAg) is an emerging serologic test and may be useful for identifying treatment strategies for chronic hepatitis B (CHB). This study aimed to evaluate HBsAg titers during the natural course of CHB and identify correlations between HBsAg titers and hepatitis B virus (HBV) DNA concentrations across different CHB phases measured using an immunoradiometric assay (IRMA).MethodsCHB phases were defined on the basis of HBV DNA concentrations, the presence of hepatitis B e antigen/antibody (HBeAg/Ab) and serum alanine aminotransferase levels. Serum HBsAg titers and paired HBV DNA concentrations in the different phases of CHB were compared using 627 serum samples.ResultsMean HBsAg titers were significantly higher in the immunotolerant (IT) phase and immunoreactive (IR) HBeAg-positive phase than in the low-replicative (LR) and HBeAg-negative CHB (ENH) states. The correlation between HBsAg titers and HBV DNA concentrations was modest in the IT (n=36, r=0.804, p<0.001) and IR (n=48, r=0.773, p<0.001) phases, and it was poor in the LR state (n=116, r=0.289, p=0.002); however, no significant correlation was observed in the ENH state (n=67, r=0.146, p=0.237) or in the oral nucleos(t)ide analogue-treated group (n=267).ConclusionsHBsAg quantification using IRMA might be useful for discriminating different CHB phases and different stages of chronic liver disease.     

Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients

The impact of prolonged direct antiviral therapy on hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B is poorly understood. We quantitatively assessed serum HBsAg levels during 3 years of telbivudine treatment, as well as their relationship with virologic and biochemical characteristics in 162 hepatitis B e antigen-positive patients who maintained undetectable serum hepatitis B virus (HBV) DNA long-term. Telbivudine treatment progressively reduced serum HBsAg levels (mean ± SD) from baseline (3.8 ± 0.6 log?? IU/mL) to treatment week 24 (3.4 ± 0.7 log?? IU/mL), treatment year 1 (3.3 ± 0.8 log?? IU/mL), and treatment year 3 (3.0 ± 1.4 log?? IU/mL) (P <0.0001). In this patient population, HBsAg loss was observed in nine (6%) of 162 patients through year 3. During the first year of treatment, three patterns of HBsAg decline were observed: rapid (≥ 1 log?? IU/mL) in 32 patients, slow (0-1 log?? IU/mL) in 74 patients, and steady levels in 56 patients. These findings were associated with different likelihoods of HBsAg loss during long-term telbivudine therapy. Eight of 32 patients with rapid HBsAg decline versus none of 56 patients with steady HBsAg levels achieved HBsAg loss at year 3 (P = 0.0024). HBV genotype was a significant determinant for HBsAg kinetics, with the fastest decline in genotype A patients. In patients with subsequent HBsAg loss, viral antigens were already undetectable in liver biopsy samples after 1 year of treatment. This was associated with markedly enhanced antiviral T cell reactivity. CONCLUSION: In patients who have effective suppression of viral replication during telbivudine treatment, a rapid decline in serum HBsAg levels during the first year may identify those with a greater likelihood of achieving HBsAg clearance.     

Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B

Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN ± lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.     

Kinetics in HBsAg after Stopping Entecavir or Tenofovir in Patients with Virological Relapse but Not Clinical Relapse

This study investigated the kinetics in HBsAg and the HBsAg loss rate after entecavir or tenofovir disoproxil fumarate (TDF) cessation in patients with chronic hepatitis B (CHB) who achieved virological suppression after virological relapse without clinical relapse. A total 504 HBeAg-negative, non-cirrhotic patients who previously received entecavir or TDF with post-treatment and who were followed up for at least 30 months were included. Of the 504 patients, 128 achieved sustained virological suppression (Group I), and 81 experienced virological relapse without clinical relapse. Of the 81 patients, 52 had intermittent or persistent HBV DNA > 2000 IU/mL (Group II), and 29 achieved persistent virological suppression (HBV DNA < 2000 IU/mL) for at least 1.5 years (Group III) after virological relapse. A generalized estimating equations analysis showed that Groups I and III experienced larger off-treatment HBsAg declines than Group II (both, p < 0.001). The post-treatment HBsAg declines of Group I and Group III were similar (p = 0.414). A multivariate analysis showed that there were no differences in the HBsAg change and HBsAg decline (p = 0.920 and 0.886, respectively) or HBsAg loss rate (p = 0.192) between Group I and Group III. The patients who achieved persistent viral suppression after HBV relapse without clinical relapse have a similar decline in HBsAg and the HBsAg loss rate as the sustained responders.     

替比夫定或拉米夫定抗乙型肝炎病毒的疗效预测探讨

目的观察替比夫定、拉米夫定治疗24周时对HBV的抑制程度,与治疗1年疗效的相关性,探讨临床实用的疗效预测指标。方法Ⅲ期临床研究,采用随机、对照、双盲、双模拟、多中心设计。共入组慢性乙型肝炎患者332例,其中替比夫定组167例,拉米夫定组165例。根据治疗24周时血清HBV DNA的水平,将患者分为4组：PCR低于检测下限（QL）组（〈300拷贝／ml）、QL-〈10^3拷贝／ml组、10^3-〈10^4拷贝／ml组和≥104拷贝／ml组。结果治疗52周时,替比夫定组血清HBV DNA自基线下降6．2log10,拉米夫定组下降5．4log10,t=3．6,P〈0．01,差异有统计学意义。HBV DNA低于检测下限的比例分别为69．6％和43．4％,χ^2=6．5,P〈0．01,差异有统计学意义。不论替比夫定组还是拉米夫定组治疗24周时HBV DNA水平越低,在52周HBV DNA达到PCR检测不到的水平、HBeAg血清转换和ALT复常的比率越高,48周病毒耐药的发生率越低。24周时替比夫定组HBV DNA低于检测下限的患者在52周时达到HBeAg血清转换的比率为43．3％,≥300拷贝／ml患者为8．8％,χ^2=21．6,P〈0．01,差异有统计学意义。结论替比夫定或拉米夫定治疗24周时,PCR检测不到HBV DNA,提示在52周可达到较佳疗效;24周时病毒水平下降不理想提示发生耐药的可能性增加。24周对HBV DNA的抑制程度可作为1年疗效的预测指标。     

Telbivudine therapy for chronic hepatitis B: A journey to identify super‐responders and to optimize treatment using the roadmap model

Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so‐called super‐responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log₁₀ copies/mL (2 × 10⁸ IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg‐positive patients and HBV DNA < 7 log₁₀ copies/mL (2 × 10⁶ IU/mL) in HBeAg‐negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre‐treatment characteristics and on‐treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age.