HBsAg and HBeAg in the prediction of a clinical response to peginterferon α-2b therapy in Chinese HBeAg-positive patients.

BACKGROUND: This study aimed to evaluate the predictive values of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) levels in 171 Chinese patients with chronic hepatitis B who received a 48-week course of pegylated interferon alfa-2b therapy at 1.5 mcg/kg. METHODS: HBsAg, HBeAg, and hepatitis B virus (HBV) DNA levels were measured at baseline and weeks 12, 24, 48, and 72. Clinical responses were defined as a combined response (CR, HBeAg seroconversion [sustained response, SR] combined with HBV DNA level <2,000 IU/mL at week 72). The positive predictive value and negative predictive value were calculated for HBsAg alone and/or combined with HBeAg and HBV DNA at weeks 12 and 24. RESULTS: Of 171 patients included, 58 (33.9 %) achieved a SR. Of patients who achieved a SR, 33 (56.9 %) achieved a CR. Totally 19.3 % (33/171) patients achieved CR and 80.7 % (138/171) patients did not. Patients with HBsAg <1500 IU/mL at week 12 had a 47.4 % chance of achieving an off-treatment SR and patients with a HBsAg decrease >1.5 logIU/mL at week 12 had a 54.5 % chance. Patients with HBsAg >20,000 IU/mL at weeks 12 and 24 had a 93.8 and 100.0 % chance, respectively, of not achieving a CR. An HBsAg level or changes at weeks 12 and 24, combined with HBeAg or HBV DNA, increased the chance for a SR and CR. CONCLUSIONS: On-treatment HBsAg quantification, alone or in combination with HBeAg or HBV DNA, predicted off-treatment SR and CR after 48 weeks of PEG-IFNα-2b therapy, and thus, may guide clinicians in making a therapeutic decision to continue or terminate the therapy.

[Efficacy of pegylated-interferon alpha-2a treatment in patients with HBeAg-positive chronic hepatitis B and partial viral response to nucleoside analogue therapy].

OBJECTIVE: To investigate the efficacy and related factors of pegylated-interferon alpha-2a (PEG-IFN-2a) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) who achieved partial viral response with nucleoside analogue (NA) therapy. METHODS: Patients with HBeAg-positive CHB and partial viral response to NA treatment were administered a PEG-IFN-2a therapy regimen of 180 g subcutaneous injection once weekly for a personlized duration of time. The existing NA therapy was continued in combination with the new PEG-IFN-2a treatment for 12 weeks. Measurements of serum HBV DNA load, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), HBeAg and hepatitis B e antibody (anti-HBe) were taken at baseline (prior to addition of the PEG-IFN-2a therapy) and every 3 months afterwards.For determining response to treatment, primary efficacy was defined as undetectable HBsAg and seroconversion, and secondary efficacy was defined as HBsAg less than 10 IU/mL and HBeAg seroconversion.Statistical analysis was carried out using SPSS statistical software. RESULTS: A total of 81 consecutive patients with an average of 12.0 months (range: 6.0-24.0 months) of NA therapy were included in the study and received an average of 19.6 months (range: 15.5-33.3 months) of PEG-IFN-2a treatment. At the end of PEG-IFN-2a therapy, 7 (8.6%) of the patients achieved undetectable HBsAg and seroconversion, and 14 (17.3%) showed HBsAg less than 10IU/mL. In addition, 40.7% achieved undetectable HBeAg and seroconversion, a rate that was slightly higher than that (38.3%) seen in treatment-naive patients who received PEG-IFN-2a. Statistical analyses suggest that baseline level of HBsAg at less than 1500 IU/mL may predict end of PEG-IFN-2a treatment response for HBsAg less than 10 IU/mL, as evidenced by the area under the curve measure of 0.747, sensitivity measure of 87.3%, specificity measure of 33.3%, positive predictive value of 82.1% and negative predictive value of 42.8%. CONCLUSION: Patients with HBeAg-positive CHB and partial viral response to NA therapy can achieve undetectable HBsAg and HBeAg seroconversion after switching to PEG-IFN-2a treatment. Baseline HBsAg level may be predictive of response to this therapeutic strategy.

Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings.

BACKGROUND & AIMS: Even though various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few of them have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind, placebo-controlled, phase II B clinical trial of YIC has been reported previously, and herein we present the results of the phase III clinical trial of 450 patients. METHODS: Twelve doses of either YIC or alum alone as placebo were administered randomly to 450 CHB patients and they were followed for 24weeks after the completion of immunization. The primary end point was HBeAg seroconversion, and the secondary end points were decrease in viral load, improvement of liver function, and histology. RESULTS: In contrast to the previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in a decrease of the HBeAg seroconversion rate from 21.8% to 14.0% in the YIC group, but an increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups (p>0.05). CONCLUSIONS: Overstimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. An appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation.

[Comparative analysis of the efficacies of entecavir capsules and lamivudine in chronic hepatitis B patients].

OBJECTIVE: To investigate the efficacy profile of entecavir capsule (ETV) as a chronic hepatitis B therapy, as compared to lamivudine (LAM). METHODS: In this multicenter, randomized, double-blind, parallel group evaluation of ETV, 232 subjects were administered a 96-week course of 0.5 mg/day ETV or 100 mg/day LAM. PCR measurement of hepatitis B virus (HBV) was conducted throughout the treatment course to determine achievement of complete virologic response (CVR; defined as less than 500 copies/ml of HBV DNA) or experience of virology rebound ( more than 500 copies/ml of HBV DNA after achievement of CVR). RESULTS: After week-48 of treatment, the ETV group showed a higher CVR rate (90.3% vs. LAM: 59.4%) and lower virology rebound rate (1.9% vs. LAM: 13.9%). After week-96 of treatment, the ETV group continued to have a higher CVR rate (86.0% vs. LAM: 71.4%), and virology rebound was experienced by significantly less subjects in the ETV group (1.2% vs. LAM: 11.9%, P = 0.005). CONCLUSION: ETV therapy can quickly and continuously suppress HBV replication in chronic hepatitis B patients, and has a lower resistance rate than LAM. Compared to LAM, ETV may be a superior long-term treatment choice for chronic hepatitis B.

[High rates of HBsAg loss and seroconversion result from prolonged course of pegasys treatment].

OBJECTIVE: HBsAg loss and seroconversion in patients with chronic hepatitis B leads to long-lasting good clinical outcomes. The aim of this paper was to investigate to improve the rate of HBsAg loss and seroconversion in chronic hepatitis B patients by prolonged treatment of PEG-IFNa-2a. 217 cases of HBeAg-positive or negative patients were collected from inpatient and outpatient in Beijing Ditan Hospital from May 2005 to October 2009 and subcutaneous injection of 135 ug or 180 ug PEGASYS were given once a week according to body weights. The drug doses were adjusted according to the neutrophilic granulocyte and platelet counts during treatment course. Quantitative HBV DNA test was conducted using a commercially available real-time fluorescence quantitative PCR kit. The serum HBsAg/anti-HBs and HBeAg/anti-HBe were quantitatively detected by Abbott i 2000 chemiluminescent kit before and during treatment every three months. Patients with HBsAg steadily decreased and reached serum HBsAg level below 200 IU/ml after 48 weeks of treatment would receive prolonged treatment. Patients with more than 12 weeks of treatment entered into analysis. Main efficacy of prolonged treatment was evaluated by the incidences of HBsAg loss and seroconversion. RESULTS: The treatment courses of the 217 patients ranged from 12.0 to 197.6 weeks with an average of 53.1+/-33.4 weeks, 118 cases took more than 48 weeks and another 89 cases less than 48 weeks. 13.4% (29/217) of patients achieved HBsAg loss or HBsAg seroconversion with treatment courses from 17.6 to 197.6 weeks (average 75.4+/-42.8 weeks). Among these 29 patients 24 (82.8%) received more than 48 weeks of treatment, but the treatment courses of HBV DNA reached undetectable level were 20.8+/-8.9 weeks. In this study, 9.5% (14/148) of HBeAg-positive patients achieved HBsAg loss or seroconversion, all of them treated more than 48 weeks, from 48 to 194 weeks, average 81.32+/-39.36 weeks. 21.7% (15/69) of HBeAg-negative patients achieved HBsAg loss or seroconversion, significantly higher than that of HBeAg-positive patients (9.5%) (x2 = 6.129, P = 0.013). The average treatment course for HBeAg-negative patients with HBsAg loss was 70.2+/-48.0 weeks, shorter than that of HBeAg-positive patients with HBsAg loss (81.3+/-39.4 weeks), but no significant difference (t = -0.522, P = 0.602) found between. CONCLUSION: Higher rate of HBsAg loss and seroconversion could be obtained by individual extended treatment courses in patients with rapid HBV DNA and HBsAg response to PEG-IFNa-2a treatment and the HBeAg-negative patients could got higher rate of HBsAg loss than HBeAg-positive patients.

Efficacy and safety of intravenous stronger neo-minophagen C and S-adenosyl-L-methionine in treatment of pregnant woman with chronic hepatitis B: a pilot study.

BACKGROUND: There have been no studies evaluating the efficacy and potential risks of stronger neo-minophagen C (SNMC) in pregnant women with chronic hepatitis B CHB. MATERIAL/METHODS: A total of 36 pregnant women with CHB, but without severe complications, were randomized to intravenously receive SNMC or S-adenosyl-L-methionine (SAM) daily for 4 weeks or until birth. Normalization of serum alanine transaminase (ALT) and aspartate transaminase (AST) levels and changes in ALT and AST levels from baseline were determined. All neonates were regularly examined for up to 1 year. RESULTS: Treatment with SNMC and SAM resulted in normalization of ALT levels at 4 weeks in 64.3% and 21.4% of patients, respectively (OR=6.60, 95% CI: 1.23-35.44, P=0.0540). SNMC and SAM significantly decreased ALT (from 558.28+/-390.24 to 47.07+/-24.94 IU/L, P<0.0001 and from 525.61+/-483.87 to 117.43+/-85.44 IU/L, P=0.0041, respectively) and AST (from 419.72+/-409.49 to 38.14+/-18.87 IU/L, P=0.0016, and from 510.78+/-621.58 to 79.93+/-63.25 IU/L, P=0.0152, respectively) at 4 weeks relative to baseline values. Hypokalemia was observed in 4 SNMC-treated patients and in 2 SAM-treated patients and hypernatremia in 3 SNMC-treated and in 3 SAM-treated patients. Hypertension was observed in 1 SNMC-treated patient. There was no significant difference in the volume of amniotic fluid or meconium between SNMC-treated and SAM-treated groups. All the neonates were physically normal at birth and at the 1-year follow-up examination. CONCLUSIONS: Both SNMC and SAM improve liver function, with SNMC appearing more effective, in pregnant women with chronic hepatitis B without impact on fetal development.

[Comparison of lamivudine or interferon monotherapy and sequential therapy in chronic hepatitis B: a random controlled trial].

OBJECTIVE: To compare the efficacy and safety of lamivudine or interferon monotherapy and sequential therapy in HBeAg positive chronic hepatitis B patients. METHODS: A total of 225 patients with HBeAg positive chronic hepatitis B were randomized into 3 groups: sequential group (group A, 83 patients), lamivudine group (group B, 89 patients) and interferon group (group C, 53 patients). Group A was administrated with lamivudine 100 mg/d for 32 week, and 5 million units of interferon alpha 2b injected subcutaneously every other day lasting for 24 week were added since week 25. Group B was administrated with lamivudine 100 mg/d for 48 week. Group B was injected with 5 million units of interferon alpha 2b subcutaneously every other day for 24 week. All subjects were followed up for 24 week. Serum HBV DNAs were measured quantitatively by PCR. HBV mutations were analyzed by PCR-RFLP. RESULTS: For groups A, B and C, baseline HBV DNAs were 7.8±1.0, 7.9±1.1 and 8.0±0.9 log10 copies/mL, respectively, P>0.05. Baseline ALTs were 167.5 (99.0, 267.8), 134.0 (101.0,275.0) and 131.0 (99.0, 192.8)U/L, respectively, P>0.05. At the end of the treatment, HBV DNA decrease rates for groups A, B and C were 78.2%, 87.8% and 78.4% (P>0.05), respectively. At the end of the follow-up, HBV DNA decrease rates for groups A, B and C were 54.4%, 63.6% and 66.7% (P>0.05), respectively. At the end of the treatment, group B (83.5%, P<0.05) achieved the highest response rate and group C achieved the lowest (39.6%, P<0.05). At the end of the follow-up, the response rates for groups A, B and C were 36.2%, 54.4% and 42.1% (P>0.05), respectively. YMDD motif mutation rate in group A was lower than that of group B (10.5% vs 26.9%, P<0.05) at the end of the treatment. CONCLUSION: Sequential therapy decreased hepatitis B virus mutation. But no efficacy advantages were found in sequential therapy than in lamivudine or interferon monotherapy.

Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: Results at 1 year of a randomized, double-blind trial.

UNLABELLED: Chronic hepatitis B and its life-threatening sequelae are highly prevalent in China. There is a need for effective new therapies to suppress hepatitis B virus (HBV) replication and ameliorate liver disease. In this study, we compared the efficacy of telbivudine, a nucleoside analogue, with lamivudine in Chinese patients. In this phase III, double-blind, multicenter trial conducted in China, 332 patients with compensated hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B were randomly assigned to treatment with 600 mg of telbivudine or 100 mg of lamivudine daily for 104 weeks. The primary efficacy endpoint was reduction in serum HBV DNA levels at week 52 of treatment. Secondary endpoints included clearance of HBV DNA to undetectable levels, HBeAg loss and seroconversion, therapeutic response, and alanine aminotransferase (ALT) normalization. Viral resistance and safety were assessed. At week 52, among 290 HBeAg-positive patients, mean reductions of serum HBV DNA were significantly greater in telbivudine recipients than lamivudine recipients (6.3 log(10) versus 5.5 log(10), P < 0.001), and HBV DNA was polymerase chain reaction-negative in significantly more telbivudine recipients than lamivudine recipients (67% versus 38%, P < 0.001). ALT normalization (87% versus 75%, P = 0.007), therapeutic response (85% versus 62%, P = 0.001), and HBeAg loss (31% versus 20%, P = 0.047) were also significantly more common in the telbivudine group. Treatment effects showed similar patterns in the smaller HBeAg-negative group (n = 42). Viral resistance in telbivudine recipients was approximately half that observed with lamivudine; however, this difference was not statistically significant. Clinical adverse events were similar in the two treatment groups. CONCLUSION: In Chinese patients with chronic hepatitis B, telbivudine treatment for 52 weeks provided greater antiviral and clinical efficacy than lamivudine, with less resistance.

[Prediction of sustained viral response to combinational therapy with interferon and ribavirin in chronic hepatitis C by rapid viral response].

OBJECTIVE: To evaluate whether the rapid viral response (RVR) to combinational therapy with interferon and rabavirin can be used to predict the sustained viral response (SVR) in chronic hepatitis C patients. METHODS: According to their clinical characteristics, all patients in this study were given pegylated or conventional interferon injection and different dose of ribavirin according to their weight. Patients were injected Pegasys (pegierferon alpha-2a) 180 microg or 135 microg once a week, or pegyintron 50-80 microg once a week, or conventional interferon 3-5 MU every two days, in combination with a dose of 600-1500 mg/d ribavirin. The serum HCV RNA load was determined at 0, 4, 12 week, and then every 12 weeks. After the viral response obtained, the patients were treated for another 24-72 weeks and followed up 24 weeks. The main parameter to evaluate the efficacy was SVR rate. The influence factors associated with rapid viral response were investigated. RESULTS: RVR was obtained at week 4 in 84.2% of the 120 patients. The HCV RNA baseline of RVR group was (5.883+/-1.246) lg copies/ml, which was significantly lower than that of the group without RVR [(6.502+/-0.693) lg copies/ml, t=2.15, P=0.034]. 97 patients with RVR who finished treatment and follow-up, 90.7% of these patients obtained SVR, but the SVR rate in patients (82.4%) without RVR was lower than that in patients with RVR (x2=0.371, P=0.543). In this study, RVR rate was not associated with HCV genotype and the dose of interferon used. In the naive patients, the RVR to pegylated interferon was 87.8%, which was significantly higher than that in retreat patients (x2=4.651, P=0.031). CONCLUSION: High RVR rate could be obtained in chronic hepatitis C patients treated combined with interferon and ribavirin. RVR rate is associated with the HCV RNA baseline load in both naive and retreat patients but not correlated to HCV genotype. RVR could predict the SVR.

[Results of 3 years of continuous entecavir treatment in nucleos(t)ide-naive chronic hepatitis B patients].

OBJECTIVE: To evaluate the virological, serological and biochemical outcomes of 3 years of entecavir (ETV) treatment in nucleoside-naive chronic hepatitis B patients. METHODS: This study was divided into two stages: Patients receiving either ETV 0.5 mg/d (n = 258) or lamivudine (LAM) 100 mg/d (n = 261) entered the initial 96-week randomized, double blind, controlled efficacy study. Patients not achieving a consolidated response (HBV DNA less than 0.7 MEq/ml, ALT less than 1.25 times*ULN, and if HBeAg-positive at baseline, loss of HBeAg for >or= 24 weeks), or those experienced viral breakthrough or relapse, entered a 48-week entecavir rollover study. RESULTS: 96 weeks after the treatment, 79% of ETV treated and 46% of LAM treated patients had HBV DNA less than 300 copies/ml (P < 0.0001), 96% of ETV treated and 92% of LAM treated patients had normalized ALT (P = 0.06). 21% of ETV treated and 23% of LAM treated patients achieved HBeAg seroconversion. Among the 160 patients received continuous ETV for 144 weeks, 89% had undetectable serum HBV DNA, 86% showed ALT normalization, and 27% achieved HBeAg seroconversion. ETV resistance was rare: only 3 patients showed ETV resistance 96 weeks after the treatment, and additional 2 patients developed ETV resistance during the following 48 weeks, genotyping indicated the ETV resistance was caused by gene mutation. Adverse event rates in ETV-treated patients were similar to those in LAM-treated patients, but fewer ALT flares were observed in ETV-treated patients. CONCLUSIONS: This study demonstrates that ETV treatment results in long-term HBV suppression and ALT normalization in Chinese CHB patients, and is associated with low rate of drug resistance.

[Factors associated with HBeAg seroconversion in chronic hepatitis B patients treated with interferon alfa-2a].

OBJECTIVE: The aim of this paper was to investigate the factors associated with viral response and HBeAg seroconversion and the relationship between them at different stages of interferon treatment in HBeAg-positive chronic hepatitis B patients. METHODS: PEG-IFN alfa-2a was injected subcutaneously in doses of 180 microg once a week for 48 weeks to HBeAg-positive chronic hepatitis B patients, and the patients were followed for another 24 weeks after the treatment. The serum HBV DNA load was measured by real-time quantitative PCR assay. Microparticle enzyme immunoassay analysis (MEIA) was then carried out by an automatic enzyme immunoassay analysis instrument to measure HBeAg and anti-HBe. Virological response and HBeAg seroconversion rates, and the factors associated with them were analyzed. RESULTS: The differences in ALT baselines between viral responding and non-responding groups were significant at treatment time and at the end of the follow-up period. These differences were also significant in patients with HBeAg seroconversion at 12 weeks and at the end of the follow-up period compared with the non-conversion group. No significant difference of HBV DNA baseline was observed between the HBeAg seroconversion and non-conversion group. At 12, 24 and 48 weeks, in patients with viral response during the treatment, their HBeAg seroconversion rates were 43.8%, 21.4% and 18.9% respectively; their respective HBeAg seroconversion rates remaining at 72 weeks were 42.9%, 33.3% and 27.6%. HBeAg seroconversion was related to HBV DNA negativity at 48 weeks treatment in the multivariate analysis (OR=2.15, 95.0% CI=1.744-2.664, P less than 0.01). CONCLUSIONS: Viral response and early and sustained HBeAg seroconversion were associated with pretreatment ALT levels. HBeAg seroconversion was related to viral response during IFN treatment, but not to the baseline HBV DNA load.

[The degree of HBV suppression with 24 week telbivudine- or lamivudine-treatment in hepatitis B patients predicts the efficacy of the treatment at week 52].

OBJECTIVES: To investigate the possibilities of an association between the degrees of HBV suppression with nucleoside treatments at week 24 and week 52 in hepatitis B patients and to find a useful predictor for treatment efficacy. METHODS: In this phase III, double-blind, multicenter trial, we compared the efficacy of telbivudine treatment with lamivudine treatment in 332 Chinese compensated chronic hepatitis B patients. The patients were randomly assigned to a daily 600 mg telbivudine treatment group or daily 100 mg lamivudine group for 24 weeks. They were then categorized into 4 groups according to their serum HBV DNA levels (copies/ml) at week 24: a PCR-undetectable group (< 300 copies/ml); a QL- < 10(3) copies/ml group; a 10(3)-<10(4) copies/ml group; and a > or = 10(4) copies/ml group. The treatments were continued as they previously had been for another 28 weeks and the patients serum HBV DNA levels were examined again. RESULTS: At week 52, mean reductions of serum HBV DNA were significantly greater in the telbivudine-treated patients than in the lamivudine-treated group (6.2 log10 vs 5.4 log10, t = 3.6, P < 0.01). Viral resistance was twice as common in lamivudine-treated patients compared to those receiving telbivudine. Telbivudine was well-tolerated with an adverse event profile similar to that of lamivudine. The lower the HBV DNA level achieved at week 24, the higher HBV DNA non-detectable by PCR. ALT normalization and HBeAg seroconversion achieved at week 52, and viral resistance at week 48 decreased parallel to the degree of HBV DNA inhibition. CONCLUSION: HBV DNA PCR-undetectable at week 24 in nucleoside-treated hepatitis B patients suggests a better efficacy at week 52 and lower viral resistance at week 48. The degree of suppression of HBV at week 24 may be used as a predictor of 1-year outcome.

Analysis of immunological mechanisms exerted by HBsAg-HBIG therapeutic vaccine combined with Adefovir in chronic hepatitis B patients.

An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4+ T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8+ T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4+ and CD8+ T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-ß and Foxp3) in CD4+ T cells. In the alum immunized group, slight increase of IL-10, TGF-ß and Foxp3 in CD4+ T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-α in CD8+T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.

[A double-blind, double-dummy, randomized, controlled study of entecavir versus lamivudine for treatment of chronic hepatitis B].

OBJECTIVE: This study was to evaluate the antiviral efficacy and safety in nucleoside naive Chinese patients with chronic hepatitis B (CHB) treated with entecavir (ETV) or lamivadine (LVD). METHODS: The trial was a randomized, double-blind, double-dummy and control design. 519 nucleoside naive CHB patients were treated with daily dose of ETV 0.5 mg (258 patients) or LVD 100 mg (261 patients) for at least 52 weeks. The primary endpoint was a composite endpoint of HBV DNA < 0.7 MEq/ml by bDNA assay and ALT < 1.25 x ULN at week 48. HBV DNA levels were also measured by the Roche Cobas Amplicor(TM) PCR assay at weeks 12, 24, 36 and 48. Clinical and laboratory adverse events were recorded every 4 weeks. RESULTS: Baseline characteristics were well balanced between treatment groups. The primary end point were achieved in 90% of ETV treated patients versus 69% of LVD treated patients (P < 0.0001). The mean HBV DNA level decreased 5.9 lg copies/ml (by PCR assay) from baseline in ETV group versus 4.3 lg copies/ml in LVD group (P < 0.0001). The serum HBV DNA become undetectable (< 300 copies/ml by PCR) in 76% of ETV group versus 43% of LVD group (P < 0.0001). The normalization of ALT were 90% in ETV group versus 78% in LVD group (P = 0.0003). The difference of HBeAg seroconversion rates between this 2 groups (15% vs 18%) at week 48 was no statistically significant. The overall incidence of adverse events (AEs) was comparable: 60% of ETV patients and 56% of LVD patients reported AEs; and 3% of ETV patients and 5% of LVD patients reported serious AEs. CONCLUSIONS: ETV achieves better virologic and biochemical improvements in nucleoside-naive patients with CHB while the safety profile is comparable to LVD.

[The impact of HBeAg positivity/negativity and HBV DNA loads on the prognosis of chronic severe hepatitis B].

OBJECTIVE: To explore the impact of HBeAg positivity/negativity and HBV DNA loads on the prognosis of chronic severe hepatitis B. METHODS: 206 patients with chronic severe hepatitis B hospitalized in Beijing Ditan Hospital from July 2002 to Dec. 2004 were analyzed. HBeAg positivity/negativity, HBV DNA loads and other factors relating to the prognosis of the patients were studied with univariate and multivariate analyses. RESULTS: Chi2 univariate analysis showed that there was no significant difference in the prognosis between different HBeAg groups (chi2 = 0.440, OR = 0.777, 95% CI 0.424-1.425, P = 0.50). But there was a significant difference in the prognosis between different HBV DNA load groups: the prognosis of patients with lower HBV DNA loads was better than those with higher loads (chi2 = 9.806, OR = 3.055, 95% CI 1.554-6.007, P = 0.002), and the improving rates of the two groups were 53.1% and 27.0% respectively. Using multivariate logistic regression analysis, 9 screened factors showed great impact on the prognosis of chronic severe hepatitis B. Cirrhosis, hepatorenal syndrome, hepatic encephalopathy, PTA < 20%, TBil > 513 mmol/L, Alb < 30 g/L, CHO < 1.6 mmol/L, PLT < 5 x 10(9)/L, and higher HBV DNA loads (HBV DNA > 3 x 10(4) copies/ml in HBeAg negative patients and > 1 x 10(5) copies/ml in HBeAg positive patients) were shown to be associated with a poor prognosis. Coefficients of regression of the above factors were 1.539, 21.356, 1.398, 1.650, 2.440, 2.266, 1.738, 2.631 and 2.656 respectively. The coefficients of regression of HBV DNA loads were: B = 2.656, Wald = 7.768, P = 0.005, EXP(B) = 14.235, and 95.0% CI for EXP(B) = 2.199-92.133. CONCLUSIONS: Our results indicate that the HBV DNA loads were one of the most important factors influencing the prognosis of the chronic severe hepatitis B patients, the importance is only next to hepatorenal syndrome and over grade II hepatic encephalopathy. HBeAg positivity/negativity has no influence on the prognosis, but HBV DNA loads are important; the lower the viral loads, the better the prognosis.

[Immune response for phase I clinical trial of a hepatitis B immunogenic complex therapeutic vaccine, YIC].

OBJECTIVE: A hepatitis B immunogenic complex therapeutic vaccine, yeast-derived recombinant HBsAg combined with human anti-HBs immunoglobulin (YIC), was evaluated for safety and immune response in phase I clinical trial. METHODS: The subtypes IgG1, IgG2, IgG3 and IgG4 of serum anti-HBs collected from 20 immunized subjects were analyzed by ELISA. The lymphocyte proliferation assay was carried out in five subjects and was analyzed by 3H-thymidine incorporation. The assays for IFNgamma, IL-2, IL-4, IL-6, IL-10 and TNFalpha were measured using Human Cytometric Bead Array Kit with FACSCalibur. RESULTS: The results showed that the subtypes of anti-HBs antibodies induced by 30, 60 and 90 microg YIC-immunized groups among all of the adult volunteers (20/20) were IgG1 and IgG3. The level of IgG1 was higher than that of IgG3 in each volunteer but the strength was different from each other. The rHBsAg-stimulated lymphocyte proliferation induced by three injections of 90 microg of YIC showed that the stimulation index was more than 2.0 in four out of the five individuals (4/5), ranging from 2.70 to 4.75. PHA-stimulated lymphocyte proliferation was not related to rHBsAg-stimulated lymphocyte proliferation. In the 60 microg YIC-immunized group there was no significant difference between the levels of IFNgamma, IL-2, IL-4, IL-6 and IL-10 at day 0 and day 42. At day 71, in comparison to day 0, the level of IFNgamma was higher in all eight subjects studied (P = 0.015) and the level of IL-2 was also increased in seven out of eight subjects (P = 0.002). In contrast, the levels of IL-4, IL-6, IL-10 and TNFalpha showed no significant difference in all the subjects (P-values: 0.298, 0.976, 0.202 and 0.996). CONCLUSION: Our results indicate that this hepatitis B immunogenic complex therapeutic vaccine (YIC) can induce a potent anti-HBs response.

[The factors associated with viral relapse after interferon treatment in chronic hepatitis C patients].

OBJECTIVE: To investigate the relationship between hepatitis C virus (HCV) genotype, serum viral load and ALT levels, and the factors associated with the viral relapse after IFN treatment in patients with chronic hepatitis C. METHODS: The HCV RNA levels were determined with Cobas Amplicor Monitor Test, version 2.0, and HCV genotypes were examined by means of PCR products of 5' NTR digested with restriction endonucleases. The patients with chronic hepatitis C were treated with PEG-IFN alpha -2a and Roferon-A for 24 weeks. Those with a viral response after 24 week treatment were followed for an additional 24 weeks. The association of clinical characteristics, such as sex, age, the way of the HCV infection, IFN treatment history and platelet counts, and the HCV genotype, virus load and medicine used for the viral relapse after IFN treatment were analyzed. RESULTS: Of the 208 chronic hepatitis C patients, the ALT levels were not related to HCV RNA levels (r = 0.093, P > 0.05). No difference of ALT levels between HCV genotypes was found, and the HCV RNA load was also of no difference between HCV genotype 1 patients and non 1 patients. Of the 119 patients with viral response after 24 week treatment, 58 cases (48.7%) relapsed after another 24 week's follow-up. Relapse was not significantly related to the clinical characteristics, such as sex, age, mode of the infection, treatment history of IFN, AST/ALT ratio, platelet counts and the baseline viral load. Among patients with genotype 1 virus, the relapse rate was significantly higher than those patients with non-genotype 1 virus (54.5% vs 32.1%, P=0.039). The relapse rate after PEG-IFN alpha -2a treatment was lower than that of Roferon-A treatment (47.0% vs. 52.8%), but not significantly. CONCLUSION: The viral relapse of chronic hepatitis C patients after IFN treatment was significantly associated with the genotypes of the HCV.

[Retreatment with interferon of relapsed chronic hepatitis C patients].

OBJECTIVE: To evaluate the efficacy and investigate the influencing factors of the interferon (IFN) retreatment for patients with chronic hepatitis C relapsed after a previous IFN treatment. METHODS: A retrospective study was designed to analyze the retreatment with IFN of 60 relapsed chronic hepatitis C patients. All patients were from a randomized, opened and multi-center clinical trial about the efficacy and security of PEG-IFNalpha-2a compared to CIFNalpha-2a in the treatment of chronic hepatitis C in China. There were 35 patients treated with PEG-IFNalpha-2a and 25 with CIFNalpha-2a. The main parameter to evaluate the efficacy was sustained viral response (SVR) rate. The influence of viral concentration in serum, genotype and drug categories on the responses to IFN were analyzed. RESULTS: For all the patients, the end of treatment virus response (ETVR) and SVR rates were 55.00% and 35.00% respectively. ETVR rate of PEG-IFNalpha-2a was significantly higher than that of CIFNalpha-2a (74.29% and 28.00% respectively, P < 0.01). SVR rate of PEG-IFNalpha-2a was also markedly higher than that of CIFNalpha-2a (45.71% and 20.00% respectively, P < 0.05). However, there was no significant difference between the high and low viral load groups. Among the patients with genotype 1, ETVR and SVR rates of PEG-IFNalpha-2a (75.00%, 45.83%) were significantly higher than those of CIFNalpha-2a (22.22%, 11.11%), (P < 0.01, P < 0.05 respectively), but in patients with genotype non-1, there were no such differences between the two groups. CONCLUSION: Some relapsed patients were not responsive to the IFN retreatment. The efficacy of PEG-IFNalpha-2a was superior to CIFNalpha-2a. The conventional IFN was not suggested to be used in the relapsed cases with genotype 1. The viral load was not associated with the efficacy of IFN retreatment.

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 (HBsAg) in inactive HBsAg carriers. METHODS: This was a retrospective cohort study in inactive HBsAg carriers, who were treatment-naive, with a serum HBsAg level < 100 IU/mL and an undetectable hepatitis B virus (HBV) DNA level (< 100 IU/mL). 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 HBsAg, 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 HBsAg loss, 12 of whom achieved HBsAg seroconversion. Mean HBsAg level in treated patients decreased to 6.69 ± 13.04 IU/mL after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/mL. Serum HBV DNA level remained undetectable (< 100 IU/mL) in all treated patients during the study. HBsAg level of the control group decreased from 25.72 ± 25.58 IU/mL at baseline to 17.11 ± 21.62 IU/mL at week 96 (P = 0.108). In the control group, no patient experienced HBsAg loss/seroconversion, and two (5.0%) developed HBV reactivation. CONCLUSION: IFN treatment results in HBsAg loss and seroconversion in a considerable proportion of inactive HBsAg carriers with low HBsAg concentrations.

Clearance of HCV RNA in peripheral blood mononuclear cell as a predictor of response to antiviral therapy in patients with chronic hepatitis C.

BACKGROUND: The resolution of hepatitis C, evidenced by normalization of liver function and disappearance of hepatitis C virus RNA from serum as determined by conventional laboratory assays, reflects virus eradication. But in interferon treated patients the HCV RNA in serum sometimes could not show the virus in cells. Such factors as virus genotype, HCV RNA contents in serum, HCV specific cellular immunities after treatment were reported to predict the response to interferon therapy. In most patients, HCV RNA could detect the virus in peripheral blood mononuclear cell. The aim of this study was to investigate the predictive value of HCV RNA in PBMC of patients with chronic hepatitis C after interferon treatment. METHODS: Sixteen patients with chronic hepatitis C were treated with interferon for 24 weeks, and they all get complete responses at 12 weeks of treatment. At the end of treatment, the HCV RNA in PBMC and serum were detected by RT-PCR, and after stopping treatment, HCV RNA in serum was monitored continually. RESULTS: In 9 patients who were HCV RNA positive in their PBMC at the end of treatment, 8 showed serum HCV RNA positive after 24 weeks and another 1 after 1 year. In 7 patients with negative HCV RNA in their PBMC, only 2 patients relapsed in serum HCV RNA after 1-year follow-up, and others remained viral response after 3.5 years. CONCLUSION: HCV RNA in PBMC at the end of IFN treatment is a predictor of durable response to antiviral therapy in patients with chronic hepatitis C.