240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

[Analysis of a randomized, double-blind, double-dummy, controlled, multicenter study confirmed the similar therapeutic efficacies of entecavir maleate and entecavir for treatment of HBeAg-positive chronic hepatitis B].

OBJECTIVE: To evaluate the efficacy and safety of entecavir maleate (ETV) versus ETV in Chinese patients with hepatitis B e antigen(HBeAg)-positive chronic hepatitis B(CHB). METHODS: The patient population of this previously published randomized, double-blind, double-dummy, controlled, multicenter study was expanded by patients in the 0.5 mg/day ETV maleate group (total n = 110) and patients in the 0.5 mg/day ETV group (total n = 108). At treatment weeks 12, 24 and 48, hepatitis B virus (HBV) DNA levels were measured by the Roche Cobas Ampliprep/Cobas Taqman PCR assay. Adverse events (AE) were recorded. RESULTS: As in the original analysis, the two treatment groups showed similar characteristics at baseline. In addition, the results for the all therapeutic effects showed identical trends to the results obtained in the original analysis, including the statistically similar effects of ETV and ETV maleate treatment-induced decreases in mean HBV DNA level at weeks 12, 24, and 48 (ETV: by 4.28, 5.00, and 5.53 log10 IU/ml vs. ETV maleate: by 4.46, 4.99, and 5.51 log10 IU/ml, respectively; all vs. baseline P more than 0.05), achievement of undetectable levels of serum HBV DNA ( less than 20 IU/ml) at week 48 (ETV: 38.18% vs. ETV maleate: 35.19%; P more than 0.05), HBeAg loss rates at week 48 (ETV: 10.91% vs. ETV maleate: 12.96%; P more than 0.05), HBeAg seroconversion rates at week 48 (ETV: 7.77% vs. ETV maleate: 10.38%; P more than 0.05), normalization of alanine aminotransferase at week 48 (ETV: 75.47% vs. ETV maleate: 82.86%; P more than 0.05), and overall incidence of AE (ETV: 18.02% vs. ETV maleate: 17.43%; P more than 0.05). CONCLUSION: Performing analysis of the therapeutic efficacies of entecavir maleate versus entecavir with a larger study population confirmed our original findings of similar efficacy and safety profiles for these two drugs in patients with HBeAg-positive CHB.

[A randomized, double-blind, double-dummy, controlled, multicenter study of entecavir maleate versus entecavir for treatment of HBeAg-negative chronic hepatitis B: results at week 48].

OBJECTIVE: To evaluate the efficacy and safety of entecavir (ETV) maleate versus ETV in Chinese patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). METHODS: This was a randomized, double-blind, double-dummy, controlled, multicenter study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A; n = 26) or 0.5 mg/day ETV maleate (n = 31). Hepatitis B virus (HBV) DNA levels were measured at weeks 12, 24, and 48 by the Roche Cobas Ampliprep/Taqman PCR assay. Adverse events (AE) were recorded. RESULTS: Baseline characteristics were similar between the two groups. At weeks 12, 24, and 48, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 4.24, 4.61 and 4.88 log10 IU/mL vs. B: 4.01, 4.50 and 4.99 log10 IU/mL, respectively; all P more than 0.05). Patients who achieved undetectable levels of serum HBV DNA (less than 20 IU/mL) at week 48 were similar in the two groups (A: 69.23% vs. B: 80.65%; P more than 0.05). Both groups achieved similar normalization of ALT at week 48 (A: 96.00% vs. B: 83.87%; P more than 0.05). The overall AE incidence was similar for the two groups (A: 22.22% vs. B: 9.38%; P more than 0.05). CONCLUSION: Entecavir maleate and entecavir showed similar efficacy and safety in patients with HBeAg-negative CHB.

One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C.

BACKGROUND: Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144. AIM: To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C. METHODS: In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations. RESULTS: Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV. CONCLUSION: Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

Tenofovir disoproxil fumarate in Chinese chronic hepatitis B patients: Results of a multicenter, double-blind, double-dummy, clinical trial at 96 weeks.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is a prodrug of a nucleotide analogue. As an antiviral drug, TDF has been proposed in the first-line treatment of chronic hepatitis B (CHB). Qingzhong, a brand name of TDF, commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd., and Viread, another brand name of TDF, commercialized by GlaxoSmithKline, have both been approved by the State Food and Drug Administration, China. AIM: To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients. METHODS: This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857. A total of 330 Chinese CHB patients, among which 232 were hepatitis B e antigen (HBeAg)-positive, were included in this 5-year-long, multicenter, double-blinded, double-dummy, randomized-controlled, non-inferiority phase III trial. The participants were initially randomized into two groups: Group A (n = 161), in which the participants received 300 mg Qingzhong once a day for 48 wk; and Group B, in which the participants received 300 mg Viread once a day for 48 wk. Starting from week 49, all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week. In this study, the primary endpoint was the decrease in plasma level of hepatitis B virus (HBV) DNA at the 96th week, while the secondary endpoints were suppression of HBV replication, alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion rates. RESULTS: For the participants with HBeAg-positive CHB, the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B (5.77 vs 5.73 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA, HBeAg loss, and HBeAg seroconversion (71.05% vs 77.97%, 31.00% vs 27.27%, and 20.22% vs 15.79%, respectively, in Group A vs Group B; P > 0.05). For the participants with HBeAg-negative CHB, the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B (4.46 vs 4.70 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA (87.23% vs 94.12% in Group A vs Group B, respectively; P > 0.05). Finally, similar percentages of CHB patients (HBeAg-positive or HBeAg-negative) in the two groups exhibited normalization of ALT (80.14% vs 84.57% in Group A vs Group B, respectively; P > 0.05), and similar incidences of adverse events were observed (106 vs 104 in Group A vs Group B, respectively; P > 0.05). CONCLUSION: Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

[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.

[A clinical study of viral dynamic change in patients with hepatitis B e antigen positive chronic hepatitis B by lamivudine treatment].

OBJECTIVE: To observe viral dynamic change in patients with HBeAg positive chronic hepatitis B by lamivudine treatment. METHODS: A multi-center clinical trial. Both outpatients and inpatients with HBeAg positive chronic hepatitis B have been administrated lamivudine 100 mg/d for 24 weeks. To detect the hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels of the baseline, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 4 weeks, 12 weeks, 24 weeks after lamivudine treatment by real time polymerase chain reaction (PCR). To estimate the parameters of viral dynamics through regression analysis. RESULTS: 172 patients were enrolled, 145 male, 30.8 +/- 9.7 (16 - 65) years old. Significant decrease of HBV DNA level occurred 12 hours after administration, the average decrease was 0.45 lg(copies/ml), maximum was 3.86 lg(copies/ml), 4 patients decreased not less than 2 lg(copies/ml). On day 2 and 7, the average decrease was 1.20 lg(copies/ml) and 2.01 lg(copies/ml), maximum was 4.41 lg(copies/ml) and 5.79 lg(copies/ml), respectively. Then HBV DNA level continued decreasing until week 24. 24-week administration of lamivudine cause 4.10 lg(copies/ml) decrease of HBV DNA averagely and 6.68 lg(copies/ml) mostly. Half life of free virion was 2.57 days. Half life of infected hepatocyte was 63.0 days. CONCLUSION: Lamivudine could rapidly decrease the HBV DNA level of patients with HBeAg positive chronic hepatitis B rapidly.

A randomized, double-blind, double-dummy, controlled, multicenter study of Qingzhong (tenofovir disoproxil fumarate) versus Viread for the treatment of chronic hepatitis B: First-stage results at week 48.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been widely recommended as a first-line antiviral agent to treat chronic hepatitis B (CHB). Qingzhong and Viread, formulations of TDF commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd and GlaxoSmithKline, respectively, have both been approved by the State Food and Drug Administration, China. This study analyzed the efficacy and safety of these 2 TDF agents in Chinese patients with CHB. METHODS: In this multicenter, randomized, double-blind, double-dummy, noninferiority phase 3 clinical trial (ClinicalTrials.gov identifier: NCT02287857), 330 Chinese patients with CHB [hepatitis B envelope antigen-positive (HBeAg) (+): 232] were randomly assigned to receive Qingzhong (group A: 161 patients) or Viread (group B: 169 patients) 300 mg once daily for 48 weeks. Subsequently, all patients were administered Qingzhong 300 mg once daily from week 49 to week 240. The primary end point was the degree of decline of plasma hepatitis B virus (HBV) DNA levels at week 48 and the secondary endpoints were viral suppression, normalization of alanine aminotransferase (ALT) levels, hepatitis B surface antigen (HBsAg)/HBeAg loss or seroconversion, and virological breakthrough. RESULTS: Among patients with CHB who were HBeAg (+), the mean HBV DNA titer decreased similarly between the groups at week 48. The percentages of patients who achieved undetectable HBV DNA were similar between the groups (85.11% and 82.35% in groups A and B, respectively) and similar losses of HBeAg and HBeAg seroconversion rates were achieved. Moreover, for patients with CHB who were HBeAg (-), reductions in HBV DNA were similar. Among all patients with CHB, the rates of normalization of ALT and the loss of HBsAg were similar. The overall incidence of adverse events was comparable between the groups. CONCLUSION: In conclusion, the 48-week administration of Qingzhong showed noninferior efficacy and safety profiles compared to Viread in Chinese patients with CHB.

Effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA in HBeAg-positive chronic hepatitis B patients.

AIM: To evaluate the effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA (ccc DNA) in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one patients received lamivudine (n = 35), or sequential therapy with lamivudine- interferon alpha 2b (IFN-alpha 2b, n = 24) for 48 wk, or IFN-alpha 2b (n = 12) for 24 wk. All subjects were followed up for 24 wk. Intrahepatic ccc DNA was measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: Sequential lamivudine- INF-alpha therapy, lamivudine and INF-alpha monotherapy reduced ccc DNA of 1.7 log, 1.4 log and 0.8 log, respectively (P < 0.05). Seventeen out of the 71 patients developed HBeAg seroconversion, the reduction of ccc DNA in the HBeAg seroconversion patients was more significant than that in the HBeAg positive patients (3.0 log vs 1.6 log, P = 0.0407). Twenty-four weeks after antiviral therapy withdrawal, 16 patients had a sustained virological response, the baseline intrahepatic ccc DNA in the patients with a sustained virological response was significantly lower than that in the patients with virological rebound (4.6 log vs 5.4 log, P = 0.0472). HBV genotype C accounted for 85.9% (n = 61), and genotype B for 14.1% (n = 10), respectively, in the 71 patients. There was no significant difference in the change of ccc DNA level between HBV genotypes C and B (2.1 log vs 1.9 log). CONCLUSION: Forty-eight week sequential lamivudine-INF-alpha therapy and lamivudine monotherapy reduce ccc DNA more significantly than 24-wk INF-alpha monotherapy. Low baseline intrahepatic ccc DNA level may predict the long-term efficacy of antiviral treatment. HBV genotypes C and B have no obvious influence on ccc DNA load.

[Effects of antiviral agents on intrahepatic ccc DNA in HBeAg-positive chronic hepatitis B patients].

OBJECTIVE: To evaluate the effects of antiviral agents on intrahepatic HBV covalently closed circular DNA (cccDNA) in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one HBeAg positive chronic hepatitis B patients were enrolled in this study. Lamivudine was administered to 35 patients for 48 weeks, sequential therapy with lamivudine-IFN alpha-2b to 24 of the 71 patients for 48 weeks, and interferon alpha (IFN alpha-2b) was administered to 12 for 24 weeks. All subjects were followed-up for 24 weeks. Serum HBV DNA, intrahepatic HBV DNA and cccDNA were measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: Forty-eight weeks of sequential lamivudine-IFN alpha-therapy and lamivudine monotherapy and 24 weeks of IFN alpha monotherapy reduced the intrahepatic HBV DNA to (4.7+/-1.1) log10, (4.6+/-1.5) log10 and (5.6+/-1.5) log10, and cccDNA to (3.4+/-1.3) log10, (3.8+/-1.1) log10 and (5.0+/-1.5) log10, significantly lower than therapy (P < 0.05). Seventeen of the 71 patients developed HBeAg seroconversion, and the reduction of cccDNA in the HBeAg seroconverted patients was significantly more than that of the HBeAg positive patients (P < 0.05). After 24 weeks of antiviral therapy withdrawal, 18 patients achieved sustained virological response, and the baseline intrahepatic cccDNA in the patients with sustained virological response was significantly lower than that of patients with virological rebound (P < 0.05). The change in intrahepatic cccDNA correlated positively with the reduction in intrahepatic HBV DNA (P < 0.05). The cccDNA levels correlated with the serum HBeAg titers at the end of the treatment (P < 0.01). Of the total 71 cases, HBV genotype C accounted for 85.9% (n = 61), and genotype B for 14.1% (n = 10). There was no significant difference in the changes of intrahepatic HBV DNA and cccDNA levels between HBV genotypes C and B (P >0.05). CONCLUSIONS: Both 48 weeks of sequential lamivudine-IFN alpha and lamivudine monotherapy strongly reduced intrahepatic HBV DNA and cccDNA more than 24 weeks of IFN alpha monotherapy. Low baseline intrahepatic cccDNA levels might predict a good long-term efficacy of antiviral treatment. The reduction of intrahepatic cccDNA correlated positively with the changes of intrahepatic HBV DNA, and intrahepatic cccDNA levels correlated with serum HBeAg titers. HBV genotypes had no obvious influence on intrahepatic HBV DNA load or cccDNA load.

Genotype B and younger patient age associated with better response to low-dose therapy: a trial with pegylated/nonpegylated interferon-alpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China.

BACKGROUND: Cost and clinically significant adverse effects are the major limiting factors of interferon (IFN) use in therapy for chronic hepatitis B virus (HBV) infection. A clinical trial was conducted in China to study the efficiency and clinical relevance of low-dose regimen of IFN treatment for chronic HBV infection and to reveal factors predicting sustained combined response. METHODS: During a randomized, open-label control study, hepatitis B e antigen (HBeAg)-positive patients with chronic HBV infection (n=230) were assigned to receive pegylated IFN- alpha -2b (1.0 micro g/kg) (n=115) or IFN- alpha -2b (3 MIU; n=115) for a 24-week period. Sustained combined response was assessed 24 weeks after the completion of treatment. RESULTS: The greater rate of HBeAg loss in the pegylated IFN-group (23%) was the only statistically significant difference between the 2 treatment arms observed at the end of follow-up. The results of the multivariate statistical analysis revealed that HBV genotype B and patient age (< or =25 years) were 2 independent factors associated with sustained combined response. A total of 40% of patients with HBV genotype B aged < or =25-years achieved sustained combined response. Only 4 (1.7%) of 230 patients discontinued therapy because of clinically significant adverse effects. CONCLUSIONS: The choice of low-dose IFN regimen might be a relevant clinical option to reduce the cost and adverse effects of therapy for younger patients with chronic HBV infection and genotype B infection in countries where it is prevalent.

Intrahepatic HBV DNA as a predictor of antivirus treatment efficacy in HBeAg-positive chronic hepatitis B patients.

AIM: To evaluate the effect of antiviral agents on intrahepatic HBV DNA in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one patients received treatment with lamivudine, interferon alpha (IFN-alpha 2b) or sequential therapy with lamivudine-IFN-alpha 2b for 48 wk. All subjects were followed up for 24 wk. Serum and intrahepatic HBV DNA were measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: At the end of treatment, the intrahepatic HBV DNA level in 71 patients decreased from a mean of (6.1 +/- 1.0) log10 to (4.9 +/- 1.4) log10. Further, a larger decrease was seen in the intrahepatic HBV DNA level in patients with HBeAg seroconversion. Intrahepatic HBV DNA level (before and after treatment) was not significantly affected by the patients' HBV genotype, or by the probability of virological flare after treatment. CONCLUSION: Intrahepatic HBV DNA can be effectively lowered by antiviral agents and is a significant marker for monitoring antivirus treatment. Low intrahepatic HBV DNA level may achieve better efficacy of antivirus treatment.

[A clinical study of adefovir dipivoxil in treating lamivudine refractory HBeAg-positive chronic hepatitis B].

OBJECTIVE: To evaluate the efficacy and safety of adefovir dipivoxil (ADV) in treating patients with lamivudine (LAM) refractory HBeAg-positive chronic hepatitis B. METHODS: It is a randomized, double-blind, placebo-controlled, multicenter study. 226 eligible patients with HBeAg-positive chronic hepatitis B were randomized (randomization ratio was 2:1) into two groups. One group received ADV 10 mg/d and LAM 100 mg/d for 12 weeks and followed by ADV 10 mg/d for 36 weeks (ADV + LAM-->ADV group); the other received placebo and LAM 100 mg/d for 12 weeks and followed by ADV 10 mg/d for 36 weeks (placebo + LAM-->ADV group). The primary efficacy measure was virological response. The secondary efficacy measure was serological response (HBeAg loss rate and HBeAg seroconversion rate) and ALT normalization rate. RESULTS: After 12 weeks of therapy, mean reduction of HBV DNA level, the percentage of patients with HBV DNA lower than 5 l g copies/ml and the percentage of patients with HBV DNA level decrease of more than 2 l g copies/ml in patients of ADV + LAM-->ADV group were significantly higher than those in patients of placebo + LAM-->ADV group (2.69 lg copies/ml vs. 1.06 lg copies/ml, 92.7% vs. 33.3%, 78.1% vs. 27.8%), all the P values were 0.00. HBV DNA undetectable (<3l g copies/ml) rate and serological response (HBeAg loss rate and HBeAg seroconversion rate) in patients of ADV + LAM-->ADV group was slightly higher than those in patients of placebo + LAM-->ADV group (12.2% vs 5.6%, 5.1% vs 0, 4.9% vs 0), but did not reach statistical significance. Much more patients in both treatment arms achieved virological response, serological response and ALT normalization after another 36 weeks of therapy. The overall safety profile of ADV was similar to that of placebo. rtN236T and rtA181V mutation was not found in this 48-week study. CONCLUSION: ADV is an effective and well-tolerated treatment option for patients with LAM refractory HBeAg-positive chronic hepatitis B.

[An analysis of the pathohistology of liver tissues, clinical features and prognostic factors of chronic hepatitis B virus carriers].

OBJECTIVE: To study the correlations between clinical features and liver pathohistological changes of chronic hepatitis B virus (HBV) carriers and to discuss the factors which may influence the prognosis. METHODS: Ninety HBV carriers who had liver biopsies were enrolled in this study. RESULTS: (1) The mean follow-up period of the patients was 118 weeks. (2) Fifty-four patients (60.0%) had G1 hepatitis and 21 (23.3%) had G2 hepatitis. The fibrosis stages were graded as S1(42) and S2(21). (3) There were significant age differences among S0, S1 and S2. (4) There were significant differences in aminotransferase levels between patients who had a normal liver histology and those who had mild hepatitis. (5) The grades of liver inflammation were not correlated with the titers of HBeAg and HBV DNA in sera. The stages of liver fibrosis were not correlated with the titers of HBVDNA in sera. Most of the HBeAg negative patients progressed to S2. (6) There were significant differences in spleen dimensions measured by ultrasonography between S0, S1 and S2 patients. (7) During the follow-up period serum aminotransferase (ALT) levels remained normal in 60 patients (group A); 22 patients had transient elevations (group B), and 8 patients had persistent increases (group C). There were significant differences of the ratios of S0 and S2 cases among patients in groups A, B and C. (8) Age and fibrosis stages were predictive factors of liver cirrhosis. CONCLUSIONS: Most chronic HBV carriers had mild inflammatory histological changes in their livers and also had different degrees of liver fibrosis. This follow-up study shows that some of those carriers should have had antiviral therapy.

[A multicenter, randomized, open-label study of the safety and effectiveness of pegylated interferon alpha 2b and interferon alpha 2b in treating HBeAg positive chronic hepatitis B patients].

OBJECTIVE: To compare the efficacy and safety of PEG-IFNalpha-2b (Peg-Intron) with IFNalpha-2b (Intron A) in treating HBeAg positive chronic hepatitis B patients. METHODS: Two hundred thirty chronic hepatitis B (CHB) patients eligible to the following criteria were enrolled into this study: HBsAg and HBeAg(Abbott kit) positive for at least 6 months, serum HBV DNA > or =10(5) copies/ml (real time PCR, LLQ <10(3) copies/ml) and ALT > or =2 x ULN. After 1:1 randomization, the patients received PegIntron (group A: 1.0 microg/kg body weight, SC, once a week) or Intron A (group B: 3 MIU SC, three times a week) for 24 weeks, and followed up for 24 weeks. RESULTS: (1) In groups A and B, respectively, 80.87% and 83.48% were males; their median ages were 31.0 and 32.0 years old; their median body weights were 65.6 and 65.5 kg; mean serum HBV DNA loads were 8.06 log10 and 7.99 log10; their mean ALT values were 4.17 x ULN and 3.77 x ULN. All of the above parameters between the two groups had no statistically significance differences. (2) At the end of treatment and after follow-up, compared to the Intron A group, the PegIntron group showed better response (including complete and partial response rate, HBV DNA undetectable rate, HBeAg seroconversion rate), but the differences of all of them had no statistical significance. The rate of HBeAg loss was higher in patients receiving PegIntron after follow-up (P = 0.0424). (Table 2) (3) PegIntron and Intron A reduced serum HBV DAN persistently during the therapy. Mean reduction at the end of the treatment was much higher in the PegIntron group than in the Intron group (2.22 log10 copies/ml vs 1.66 log10 copies/ml, P = 0.0283). (4) The overall incidence of adverse events (AEs) in the PegIntron group was similar to that of the Intron A group (94.78% vs 95.65%). The AEs associated with PegIntron administration were similar in nature to those with Interon A, such as influenza-like symptoms, fever, fatigue, headache, nausea, etc and the differences of their incidences had no statistical significance. CONCLUSIONS: The efficacy and safety of PEG-IFNalpha-2b treatment for CHB patients seems to be better than that of IFNalpha-2b; however, further studies are needed to confirm it.

[Foscarnet sodium for treatment in patients with severe chronic hepatitis B].

OBJECTIVE: To investigate the effectiveness of foscarnet sodium in the treatment of severe chronic hepatitis B. METHODS: Two hundred and eight patients were enrolled in a multicenter, double-blind, controlled study. The patients received foscarnet sodium (foscarnet group) or saline (control group) injections for 4 weeks, and were then followed for 24 weeks. RESULTS: HBV DNA negative rate was 12.8% in the foscarnet group and 7.1% in the control group at the end of treatment; and it was 5.5% and 3.0% at the end of the follow-up period respectively (P > 0.05). The rate of HBV DNA decrease of more than 2 log copies/ml was 53.2% in the foscarnet group and 16.2% in the control group at the end of treatment, and 23.9% and 8.1% (P < 0.01) respectively at the end of the follow-up period. The rate of HBV DNA < 10(5) copies/ml was 64.2% and 30.3% at week 4 in the two groups respectively, and 40.4% and 22.2% (P < 0.01) at the end of the follow-up period. HBeAg negative rate was 17.3% and 5.8% at the end of the treatment, and 22% and 5.4% at the end of the follow-up period (P < 0.01). The rate of HBeAg seroconversion was 12.7% and 3.7% at week 4, and 16.7% and 1.5% at the end of the follow-up period. Response rate was 60.6% and 21.2% at the end of week 4 (P < 0.05). CONCLUSION: Foscarnet sodium injection has a good effect on severe chronic hepatitis B patients and it is safe to use on them.

[A clinical study of adefovir dipivoxil, made in China, for treatment of hepatitis B e antigen-positive patients with chronic hepatitis B].

OBJECTIVE: To evaluate the efficacy and safety of a China made adefovir dipivoxil (ADV) treatment for hepatitis B e antigen-positive patients with chronic hepatitis B. METHODS: Two hundred and thirty patients with chronic hepatitis B who were positive for hepatitis B e antigen (HBeAg) were randomly put into groups A or B, and 58 patients with lamivudine-resistant chronic hepatitis B were randomly put into groups C or D. During the first 12 weeks of the trial, 112 patients in group A and 115 patients in group B received 10 mg of ADV and a placebo once a day; 28 patients in group C received 100 mg of lamivudine (LMV) and 10 mg of ADV; 29 patients in group D received 100 mg of LMV and a placebo once a day. In the second trial period, all patients received ADV for 36 weeks. The primary checking criterion was the serum HBV DNA change during the treatment. The secondary ones were alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion. RESULTS: At week 12, the median serum hepatitis B virus (HBV) DNA level of group A (ADV-ADV) was reduced 2.8 log10 copies/ml, significantly greater than that of group B (placebo-ADV) of 0.3 log10 copies/ml reduction (P = 0.000). At week 48, the median serum HBV DNA level of group A and group B were reduced 3.6 and 3.4 log10 copies/ml respectively. At week 12, the median serum HBV DNA level of group C (LMV+ADV) was reduced 3.0 log10 copies/ml, significantly greater than that of the group D (LMV+placebo) of 0.16 log10 copies/ml reduction (P = 0.000). At week 48, the median serum HBV DNA level of group C and group D were reduced 3.6 and 3.8 log10 copies/ml respectively. Only 5.56% (16/288) patients had adverse events that were mild to moderate. There was no significant difference in the change of serum creatinine compared with their baseline levels. CONCLUSION: In our HBeAg positive lamivudine-resistant chronic hepatitis B patients, 48 weeks of ADV treatment was safe and resulted in significant virological and biochemical improvements.

Relationship between virological response and FIB-4 index in chronic hepatitis B patients with entecavir therapy.

AIM: To investigate whether long-term low-level hepatitis B virus (HBV) DNA influences dynamic changes of the FIB-4 index in chronic hepatitis B (CHB) patients receiving entecavir (ETV) therapy with partial virological responses. METHODS: We retrospectively analyzed 231 nucleos(t)ide (NA) naïve CHB patients from our previous study (NCT01926288) who received continuous ETV or ETV maleate therapy for three years. The patients were divided into partial virological response (PVR) and complete virological response (CVR) groups according to serum HBV DNA levels at week 48. Seventy-six patients underwent biopsies at baseline and at 48 wk. The performance of the FIB-4 index and area under the receiver operating characteristic (AUROC) curve for predicting fibrosis were determined for the patients undergoing biopsy. The primary objective of the study was to compare the cumulative probabilities of virological responses between the two groups during the treatment period. The secondary outcome was to observe dynamic changes of the FIB-4 index between CVR patients and PVR patients. RESULTS: For hepatitis B e antigen (HBeAg)-positive patients (n = 178), the cumulative probability of achieving undetectable levels at week 144 was 95% and 69% for CVR and PVR patients, respectively (P < 0.001). In the Cox proportional hazards model, a lower pretreatment serum HBV DNA level was an independent factor predicting maintained viral suppression. The cumulative probability of achieving undetectable levels of HBV DNA for HBeAg-negative patients (n = 53) did not differ between the two groups. The FIB-4 index efficiently identified fibrosis, with an AUROC of 0.80 (95%CI: 0.69-0.89). For HBeAg-positive patients, the FIB-4 index was higher in CVR patients than in PVR patients at baseline (1.89 ± 1.43 vs 1.18 ± 0.69, P < 0.001). There was no significant difference in the reduction of the FIB-4 index between the CVR and PVR groups from weeks 48 to 144 (-0.11 ± 0.47 vs -0.13 ± 0.49, P = 0.71). At week 144, the FIB-4 index levels were similar between the two groups (1.24 ± 0.87 vs 1.02 ± 0.73, P = 0.06). After multivariate logistic regression analysis, a lower baseline serum HBV DNA level was associated with improvement of liver fibrosis. In HBeAg-negative patients, the FIB-4 index did not differ between the two groups. CONCLUSION: The cumulative probabilities of HBV DNA responses showed significant differences between CVR and PVR HBeAg-positive CHB patients undergoing entecavir treatment for 144 wk. However, long-term low-level HBV DNA did not deteriorate the FIB-4 index, which was used to evaluate liver fibrosis, at the end of three years.

Down-regulation of CXCR4 expression in MT4 cells by a recombinant vector expressing antisense RNA to CXCR4 and its potential anti-HIV-1 effect.

CXC-chemokine receptor (CXCR4) is one principle co-receptor for the entry of T cell line (T)-tropic HIV-1 virus into a cell. In order to find more efficacious therapeutic possibilities for people with an HIV-1 infection, we explored the inhibitory effects of antisense RNA on CXCR4 expression in MT4 cells. First, we used to RT-PCR to obtain DNA fragments from healthy adult peripheral blood mononuclear cells; these fragments targeted the initiation region of CXCR4 mRNA translation. We then constructed a recombinant retroviral vector, pLXSN-X4a (containing antisense RNA to CXCR4). After packaging by PA317 cells, the pseudovirion of the recombinant vector had formed and succeeded in transfecting MT4 cells (a kind of T-tropic HIV-1 susceptibility cell line). The PCR and RT-PCR results showed that the recombinant vector had integrated into the genome of MT4 cells and had been transcribed. The expression of CXCR4 on the surface of MT4 cells transfected with antisense RNA was reduced by 30%, compared with those cells transfected with blank vector or untransfected cells. No change in the DNA synthesis rates or in cell proliferation was found in any of the transfected cells. After a challenge with HIV-1 SF33, the cells transfected with antisense RNA vector (pLXSN-X4a) produced reduced p24 levels compared with the cells transfected with blank vector (pLXSN) or untransfected cells. These results indicated that these CXCR4-antisense expressing cells could resist T-tropic HIV-1 infection and could retain normal biological functions. These studies provide useful data for further experiments in this area.

Promoting hepatic growth factor in the treatment of heavy type hepatitis and severe chronic hepatitis: a multicenter clinical study.

BACKGROUND: The mortality rate of heavy type hepatitis is high. No special treatment is available except general treatment. This multicenter clinical study was designed to observe the safety and efficacy of promoting hepatic growth factor (PHGF) in the treatment of heavy type hepatitis and severe chronic hepatitis. METHODS: 347 patients with heavy type hepatitis and 324 with severe chronic hepatitis were subjected to administration of 120 microg of PHGF per day for 4 weeks on the basis of general treatment. Those who were being effectively treated would last additional 2 to 4 weeks. Blood routine, urine routine, blood urea nitrogen (BUN), blood creatinine (Cr), blood ammonia, alpha fetoprotein (AFP), electrolyte, alanine transaminase (ALT), aspartate transaminase (AST), serum total bilirubin (TBIL), serum direct bilirubin (DBIL), prothrombin time activity (PTA), total protein (TP) and albumin (ALB) were detected in the patients before treatment, 2 weeks after treatment, and at the end of the treatment. Any side-effect would be recorded. RESULTS: In the patients with severe chronic hepatitis, the total effective rate of the treatment was 88.9%. The levels of ALT, AST and TBIL decreased significantly (P<0.001), whereas those of PTA and ALB increased significantly (P<0.001), and the level of AFP increased slightly. In patients with heavy type hepatitis, the total effective rate of this treatment was 78.4%, and patients at different stage showed different results. The total effective rates of patients with early, medium and terminal stage heavy type hepatitis were 89.9%, 84.8% and 27.5%, respectively. No severe side-effect was shown. CONCLUSION: PHGF is effective and safe in the treatment of patients with heavy type hepatitis and severe chronic hepatitis. But it should be administered early in patients with heavy type hepatitis so as to get better curative effects.