Sofosbuvir plus ribavirin with or without peginterferon for the treatment of hepatitis C virus: Results from a phase 3b study in China.

BACKGROUND AND AIM: Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6. METHODS: Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment-naïve, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87-98%) for HCV genotype 1 and 97% (95% CI, 84-100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87-99%) for genotype 1, 100% (95% CI, 40-100%) for genotype 6, and 95% (95% CI, 90-98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83-97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three (< 1%) discontinued treatment because of adverse events, of whom one died because of treatment-unrelated adverse events. CONCLUSIONS: Sofosbuvir-based regimens were highly effective and safe in Chinese patients with HCV genotype 1, 2, 3, or 6, suggesting sofosbuvir could serve as the backbone for HCV treatment in China irrespective of genotype.

Long-term lamivudine treatment achieves regression of advanced liver fibrosis/cirrhosis in patients with chronic hepatitis B.

BACKGROUND AND AIM: Antiviral therapy is important in advanced liver fibrosis/cirrhosis with chronic hepatitis B (AdLF-CHB) patients, but complete regression of cirrhosis remains to be the challenge. We aimed to investigate whether up to 10 years lamivudine treatment achieves liver fibrosis/cirrhosis regression in AdLF-CHB patients. METHODS: Improvement of hepatic fibrosis/cirrhosis, virological response and disease progression were evaluated in 28 AdLF-CHB patients with up to 10 years lamivudine treatment. Liver biopsy was performed in all of the 28 patients at baseline, but only 19 patients had second biopsy at year 10. RESULTS: There were 24 hepatitis B e antigen (HBeAg)-positive and 4 HBeAg-negative patients within the original 28 AdLF-CHB patients. At the end of 10 years lamivudine treatment, 20 of the 24 HBeAg-positive patients had HBeAg loss. HBeAg seroconversion was detected in 10 of these 20 HBeAg loss patients. HBsAg loss was observed in 4 of the original 28 patients. Among these four HBsAg loss patients, three had HBsAg seroconversion. All patients achieved hepatitis B virus DNA (HBV DNA) undetectable. Histopathology was evaluated between paired original and final liver biopsies among 19 patients as follows: 4/19 achieved complete liver fibrosis/cirrhosis regression; 9/19 improved in Ishak fibrosis score; whereas 6/19 showed no fibrosis improvement. About 75% patients achieved inflammatory/fibrotic improvement. No significant disease progression was observed in 24/28 patients. Furthermore, no significant difference in histopathology improvement, cirrhosis regression, disease progression between non-resistance and rescue for resistance was observed. CONCLUSION: Long-term lamivudine therapy achieves regression of fibrosis/cirrhosis and improvement of histological and disease progression in AdLF-CHB patients.

Five-year Treatment with Tenofovir Alafenamide Achieves High Rates of Viral Suppression, Alanine Aminotransferase Normalization, and Favorable Bone and Renal Safety in Chinese Chronic Hepatitis B Patients.

Background and Aims: After 3-years (144 week) of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies, tenofovir alafenamide (TAF) showed similar efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety. In this study, we aimed to report the 5-year results from 2 years into the open-label TAF treatment phase. Methods: All participants completing the 144-week double-blind treatment were eligible to receive open-label TAF 25 mg once daily up to week 384. Serial analysis of viral suppression (hepatitis B virus DNA <29 IU/mL), alanine aminotransferase normalization, serological responses, and safety outcomes at year 5 (week 240) was performed. Results: The open-label phase included 93% (311/334) of the enrolled participants, which included 212 who switched from double-blind TAF to open-label TAF (TAF-TAF) and 99 who switched from double-blind TDF to open-label TAF (TDF-TAF). Baseline characteristics were comparable. Week 240 viral suppression rates were similar between groups [93.4% vs. 93.9%; difference: -1.5%, (95% CI: -6.4 to -3.5), p=0.857]. Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group. The frequencies of adverse events and laboratory abnormalities were low and similar between groups. Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5 (week 240, -2.85 mL/min vs. -3.29 mL/min, p=0.910). The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF. Conclusions: The 5-year TAF treatment efficacy was high and similar to that of 3-year TDF followed by 2-year TAF in Chinese chronic hepatitis B patients. Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

3-year Treatment of Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate for Chronic HBV Infection in China.

BACKGROUND AND AIMS: Tenofovir alafenamide (TAF) has similar efficacy to tenofovir disoproxil fumarate (TDF) but with improved renal and bone safety in chronic hepatitis B patients studied outside of China. We report 3-year results from two phase 3 studies with TAF in China (Clinicaltrials.gov: NCT02836249 and NCT02836236). METHODS: Chinese hepatitis B e antigen (HBeAg)-positive and -negative chronic hepatitis B patients with viremia and elevated alanine aminotransferase were randomized 2:1 to TAF or TDF treatment groups and treated in a double-blind fashion for 144 weeks (3 years). Efficacy responses were assessed by individual study while safety was assessed by a pooled analysis. RESULTS: Of the 334 patients (180 HBeAg-positive and 154 HBeAg-negative) randomized and treated, baseline characteristics were similar between groups. The overall mean age was 38 years and 73% were male. The mean HBV DNA was 6.4 log10 IU/mL. The median alanine aminotransferase was 88 U/L, and 37% had a history of antiviral use. At week 144, the proportion with HBV DNA <29 IU/mL was similar among the two groups, with TAF at 83% vs. TDF at 79%, and TAF at 93% vs. TDF at 92% for the HBeAg-positive and -negative patients, respectively. In each study, higher proportions of TAF than TDF patients showed normalized alanine aminotransferase (via the American Association for the Study of Liver Diseases and the China criteria) and showed loss of HBsAg; meanwhile, the HBeAg seroconversion rates were similar. Treatment was well-tolerated among the TAF patients, who showed a smaller median decline in creatinine clearance (-0.4 vs. -3.2 mL/min; p=0.014) and less percentage change in bone mineral density vs. TDF at hip (-0.95% vs. -1.93%) and spine (+0.35% vs. -1.40%). CONCLUSIONS: In chronic hepatitis B patients from China, TAF treatment provided efficacy similar to TDF but with better renal and bone safety at 3 years.

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.

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.

[Magnesium isoglycyrrhizinate in the treatment of chronic liver diseases: a randomized, double-blind, multi-doses, active drug controlled, multi-center study].

OBJECTIVE: To evaluate the efficacy and safety of Magnesium isoglycyrrhizinate in treatment of chronic liver diseases. METHODS: It is a randomized, double-blind, multi-doses, active drug controlled, multi-center study. 480 proper patients were randomly divided into group A (180 patients), group B (180 patients) or group C (120 patients). Patients in group A received magnesium isoglycyrrhizinate 100 mg once daily. Patients in group B received magnesium isoglycyrrhizinate 150 mg once daily. Patients in group C received compound glycyrrhizin 120 mg once daily. The treatment course was 4 weeks. Patients were followed up 2 weeks after the treatment. Patients visited once every 2 weeks. Clinical symptoms, ALT, AST were evaluated in all the patients before treatment, at week 2, at week 4 and at 2 weeks later after treatment. The other liver function test was done before treatment and at week 4. RESULTS: 412 patients completed the study according to the protocol,152 in group A, 160 in group B and 100 in group C. ALT and AST level were significantly decreased in all groups at week 2 and week 4 (P < 0.05). The degree of ALT decrease is greater in group B than in group C at week 2 (P < 0.01). The degree of ALT decrease was not significant different among three groups at week 4 (P > 0.05). The rates of ALT improvement at week 4 in group A, B, C were 92.59%, 91.76%, 88.29%, respectively (P > 0.05). The rates of symptoms improvement at week 4 in group A, B, C were 90.41%, 89.86%, 86.46% and 72.22%, 73.53%, 68.47%, respectively (P > 0.05). No relapse were found in all three groups after treatment. The rate of adverse event in three groups was similar (P > 0.05). CONCLUSION: Magnesium isoglycyrrhizinate is an effective and safe treatment for chronic liver diseases.

Comparison of the long-term efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naïve HBeAg-positive patients with chronic hepatitis B: A large, multicentre, randomized controlled trials.

OBJECTIVE: We conducted this study to compare the efficacy and safety of entecavir and tenofovir in the treatment of treatment-naïve HBV e antigen (HBeAg)-positive patients with chronic hepatitis B (CHB) for 144 weeks. METHODS: A total of 320 treatment-naïve HBeAg-positive CHB patients who received randomly a single regimen of either entecavir capsule (ETV) (n = 160) or tenofovir disoproxil fumarate capsule (TDF) (n = 160) for 144 weeks were consecutively enrolled from 14 tertiary hospitals or university hospitals in China between January 2012 and December 2014. RESULTS: Two groups showed no difference in baseline characteristics. After 144 weeks of treatment, HBV DNA levels were similarly suppressed in both groups (ETV vs TDF; -6.6485 vs -6.692 log10IU/mL, P = .807). At the same time, both groups showed no difference in terms of the serologic and biochemical response. Of all patients, 2 dropped out due to adverse events and 5 experienced serious adverse reactions. CONCLUSION: Both capsules (ETV or TDF) were equally effective in nucleos(t)ide-naive CHB patients with a comparable side-effect profile even in a long-term of 144 weeks.

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.

Long-term efficacy and safety of tenofovir disoproxil fumarate in Chinese patients with chronic hepatitis B: 5-year results.

BACKGROUND AND AIM: Long-term treatment with tenofovir disoproxil fumarate (TDF) has demonstrated suppression of viral replication outside of China. This study aims to assess efficacy, resistance and safety of TDF for up to 240 weeks in Chinese patients with chronic hepatitis B virus (HBV) infection. METHODS: Patients (HBeAg-positive or HBeAg-negative) who were randomised to receive TDF 300 mg or adefovir dipivoxil (ADV) 10 mg once daily in the 48-week double-blind phase (N = 498) were eligible to enter the open-label TDF phase (TDF-TDF and ADV-TDF groups) for additional 192 weeks. RESULTS: Overall, 457/512 (89.3%) randomised patients completed 240 weeks of treatment. Virological suppression was achieved in 84.5% and 87.9% in HBeAg-positive patients and 89.6% and 89.5% in HBeAg-negative patients in TDF-TDF and ADV-TDF groups, respectively, at week 240. The majority of patients from both groups had normalized alanine transaminase levels. More patients had HBeAg loss (41.7% vs. 36.4%) and HBeAg seroconversion (32.0% vs. 28.3%) in TDF-TDF than in ADV-TDF group, respectively. Only one HBeAg-positive patient in TDF-TDF group had HBsAg loss at week 240. No evidence of resistance to TDF was observed. The incidence of adverse events was similar in both groups (TDF-TDF, 56.4% vs. ADV-TDF, 51.6%). One patient had serum creatinine elevation ≥ 0.5 mg/dL above baseline, and three patients had confirmed grade 3/4 phosphorus abnormalities (< 2 mg/dL). CONCLUSION: In Chinese patients with chronic HBV, long-term treatment with TDF showed sustained viral suppression without development of resistance up to 240 weeks. No new safety concerns were found with TDF in this patient population. Clinical Trial Registration ClinicalTrial.gov Identifier NCT01300234; GSK Clinical Study Register 114648.

Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.

BACKGROUND: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes. METHODS: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed. FINDINGS: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment. INTERPRETATION: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis. FUNDING: Gilead Sciences.

Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection. METHODS: Chinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing. RESULTS: All 206 enrolled patients achieved SVR12 (100%; 95% CI 98-100%), including 106 treatment-naive patients (100%; 95% CI 97-100%), which was superior to a historical SVR rate of 57% (p < 0.001). All patients with baseline NS5A and NS5B RASs (14 and 1% of patients, respectively) achieved SVR12. The most common adverse events were viral upper respiratory tract infection (17%), upper respiratory tract infection (14%), and cough (6%). There were no discontinuations due to adverse events; and no treatment-related serious adverse events were reported. CONCLUSION: Ledipasvir/sofosbuvir is a well tolerated and highly effective treatment for Chinese patients with genotype 1 HCV, regardless of prior treatment experience, cirrhosis status, or the presence of pretreatment RASs.

[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.

A multicenter, randomized, double-blind trial comparing the efficacy and safety of TUDCA and UDCA in Chinese patients with primary biliary cholangitis.

AIM: Tauroursodeoxycholic acid (TUDCA) is a taurine conjugated form of ursodeoxycholic acid (UDCA) with higher hydrophility. To further evaluate the efficacy and safety of TUDCA for primary biliary cholangitis (PBC), we performed this study on Chinese patients. METHODS: 199 PBC patients were randomly assigned to either 250 mg TUDCA plus UDCA placebo or 250 mg UDCA plus TUDCA placebo, 3 times per day for 24 weeks. The primary endpoint was defined as percentage of patients achieving serum alkaline phosphatase (ALP) reduction of more than 25% from baseline. RESULTS: At week 24, 75.97% of patients in the TUDCA group and 80.88% of patients in the UDCA group achieved a serum ALP reduction of more than 25% from baseline (P = 0.453). The percentage of patients with serum ALP levels declined more than 40% following 24 weeks of treatment was 55.81% in the TUDCA group and 52.94% in the UDCA group (P = 0.699). Both groups showed similar improvement in serum levels of ALP, aspartate aminotransferase, and total bilirubin (P > 0.05). The proportion of patients with pruritus/scratch increased from 1.43% to 10.00% in UDCA group, while there's no change in TUDCA group (P = 0.023). Both drugs were well tolerated, with comparable adverse event rates between the 2 groups. CONCLUSIONS: TUDCA is safe and as efficacious as UDCA for the treatment of PBC, and may be better to relieve symptoms than UDCA.

Grading and staging of hepatic fibrosis, and its relationship with noninvasive diagnostic parameters.

AIM: To explore the grade and stage of pathology and the relationship between grading and staging of hepatic fibrosis and noninvasive diagnostic parameters. METHODS: Inflammatory activity and fibrosis of consecutive liver biopsies from 200 patients with chronic liver disease were determined according to the Diagnostic Criteria of Chronic Hepatitis in China, 1995. A comparative analysis was made in these patients comparing serum markers, Doppler ultrasonography, CT and/or MR imaging with the findings of liver biopsy. RESULTS: With increase of inflammatory activity, the degree of fibrosis also rose. There was a close correlation between liver fibrosis and inflammatory activity. AST, GGT, albumin, albumin/globulin, ALP, AFP, hyaluronic acid, N-terminal procollagen III(P III NP), collagen type IV(Col IV), tissue inhibitors of metalloproteinases-1 (TIMP-1), alpha-2-macroglobulin, natural killer cells(NK), some parameters of Doppler ultrasonography, CT and/or MR imaging were all related to the degree of inflammatory activity. GGT, albumin, albumin/globulin, ALP, AFP, hyaluronic acid, Col IV, TIMP-1, alpha-2- macroglobulin, transforming growth factor-beta 1 (TGFbeta1), NK, some parameters of Doppler ultrasonography, CT and/or MR imaging were all related to the staging of fibrosis. By regression analysis, the parameters used in combination to differentiate the presence or absence of fibrosis were age, GGT, the parameter of blood flow of portal vein per minute, the maximum oblique diameter of right liver by B ultrasound, the wavy hepatic surface contour by CT and/or MR. The sensitivity, specificity and accuracy of the above parameters were 80.36%, 86.67%, and 81.10%, respectively. CONCLUSION: There is close correlation between liver fibrosis and inflammatory activity. The grading and staging of liver fibrosis are related to serum markers, Doppler ultrasonography, CT and/or MR imaging. The combination of the above mentioned noninvasive parameters are quite sensitive and specific in the diagnosis of hepatic fibrosis.

Capsule oxymatrine in treatment of hepatic fibrosis due to chronic viral hepatitis: a randomized, double blind, placebo-controlled, multicenter clinical study.

AIM: To evaluate the efficacy and safety of oxymatrine capsule in treatment of hepatic fibrosis in patients with chronic viral hepatitis. METHODS: It was a randomized, double blind, placebo-controlled, multicenter clinical study. One hundred and forty-four patients were divided into oxymatrine capsule group(group A) and placebo group (group B). The course was 52 wk. Patients were visited once every 12 wk and the last visit was at 12 wk after cessation of the treatment. All patients had liver biopsy before treatment. part of them had a second biopsy at the end of therapy. Clinical symptoms, liver function test, serum markers of hepatic fibrosis were tested. Ultrasound evaluation was performed before, during and at the end of therapy. RESULTS: One hundred and forty-four patients enrolled in the study. Of them 132 patients completed the study according to the protocol,49 patients had liver biopsy twice (25 patients in group A and 24 in group B). At the end of therapy, significant improvements in hepatic fibrosis and inflammatory activity based on Semi-quantitative scoring system (SSS) were achieved in group A. The total effective rate of the treatment was 48.00%, much higher than that of 4.17% in group B (P<0.05). Significant improvement in serum markers of hepatic fibrosis such as hyaluronic acid (HA) and type III procollagenic peptide (P III P) in group A was seen (P<0.05). The total effective rate of serum markers at the end of therapy in group A was 68.19%, much higher than that of 34.85% in group B (P<0.05). The total effective rate of noninvasive markers at the end of therapy in group A was 66.67%, much higher than that of 30.30% in group B (P<0.05). The rate of adverse events was similar in two groups. CONCLUSION: Oxymatrine capsule is effective and safe in treatment of hepatic fibrosis due to chronic viral hepatitis.

Oxymatrine therapy for chronic hepatitis B: a randomized double-blind and placebo-controlled multi-center trial.

AIM: To evaluate the efficacy and safety of capsule oxymatrine in the treatment of chronic hepatitis B. METHODS: A randomised double-blind and placebo-controlled multicenter trial was conducted. Injection of oxymatrine was used as positive-control drug. A total of 216 patients with chronic hepatitis B entered the study for 24 weeks, of them 108 received capsule oxymatrine, 36 received injection of oxymatrine, and 72 received placebo. After and before the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reaction were observed. RESULTS: Among the 216 patients, six were dropped off, and 11 inconsistent with the standard were excluded. Therefore, the efficacy and safety of oxymatrine in patients were analysed. In the capsule treated patients, 76.47% became normal in ALT level, 38.61% and 31.91% became negative both in HBV DNA and in HBeAg. In the injection treated patients, 83.33% became normal in ALT level, 43.33% and 39.29% became negative both in HBV DNA and in HBeAg. In the placebo treated patients, 40.00% became normal in ALT level, 7.46% and 6.45% became negative both in HBV DNA and in HBeAg. The rates of complete response and partial response were 24.51% and 57.84% in the capsule treated patients, and 33.33% and 50.00% in the injection treated patients, and 2.99% and 41.79% in the placebo treated patients, respectively. There was no significance between the two groups of patients, but both were significantly higher than the placebo. The adverse drug reaction rates of the capsule, injection and placebo were 7.77%, 6.67% and 8.82%, respectively. There was no statistically significant difference among them. CONCLUSION: Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.

Relationship between clinical and pathologic findings in patients with chronic liver diseases.

AIM: To explore the relationship between clinical findings of patients with chronic liver diseases and the pathologic grading and staging of liver tissues. METHODS: The inflammatory activity and fibrosis of consecutive liver biopsies from 200 patients were determined according to the diagnosis criteria of chronic hepatitis in China established in 1995. A comparative analysis was carried out for 200 patients with chronic liver diseases by comparing their clinical manifestations, serum biochemical markers with the grading and staging of liver tissues. RESULTS: It was revealed that age, index of clinical symptoms and physical signs were obviously relevant to the pathologic grading and staging of liver tissues (P<0.05). Blood platelet, red blood cells, aspartate aminotransferase (AST), N-terminal procollagen III (PIII NP) were apparently correlated with the degree of inflammation. PGA (prothrombin time, GGT, apoprotein A1) index, PGAA (PGA+delta2-macroglobulin) index, albumin and albumin/globulin were relevant to both inflammation and fibrosis. Hyaluronic acid (HA) was an accurate variable for the severity of hepatic inflammation and fibrosis. The combination of serum markers for fibrosis could increase the diagnostic accuracy. It was notable that viral replication markers were not relevant to the degree of inflammation and fibrosis. CONCLUSION: There is a good correlation between clinical findings and the pathologic grading and staging of liver tissues, which may give aid to the noninvasive diagnosis of liver fibrosis.

The relationship between staging of hepatic fibrosis and the levels of serum biochemistry.

OBJECTIVE: To study the relationship between the degree of hepatic fibrosis and serum fibrosis markers. METHODS: Liver biopsies were performed in 67 patients with hepatitis. The sections were stained with hematoxylin eosin and immunohistochemical stain. Staging of hepatic fibrosis was made microscopically. The serum levels of hyaluronic acid(HA), type III procollagen(PC-III), laminin(LN), and type IV collagen (IV-C) were measured by radioimmunoassay. RESULTS: The serum levels of HA, PC-III, LN and IV-C were elevated from S1 to S4 because of the increase of hepatic fibrosis. The serum concentrations of HA, PC-III, LN and IV-C were increased with the progress of disease, with the highest concentration at the stage of cirrhosis. CONCLUSION: The stages of hepatic fibrosis are correlated with the serum levels of HA, PC-III, LN and IV-C, which as markers may play a role in detecting the degree of hepatic fibrosis.

[Oxymatrine in the treatment of chronic hepatitis B for one year: a multicenter random double-blind placebo-controlled trial].

OBJECTIVE: To evaluate the efficacy and safety of oxymatrine in the treatment of chronic hepatitis B. METHODS: A multicenter randomized double-blind placebo-controlled trial was conducted. A total of 144 patients with chronic hepatitis B entered the study for 52 weeks; of them 72 received oxymatrine, and 72 received a placebo. Before and after the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reactions were observed. RESULTS: In 144 patients, 14 were dropped and excluded due to inconsistencies in the included standard. Therefore, the efficacy and safety of 130 patients were analyzed. After being treated for 52 weeks, 70.77% of the patients in the study group had a normal ALT level, and in 43.08% and 33.33% their HBV DNA and HBeAg became negative. In the placebo group, 39.68% had normal ALT level, and 12.31% and 3.33% had their HBV DNA and HBeAg become negative. The rates of complete response and partial response in the oxymatrine group were 23.08% and 58.46%, and in the placebo group they were 3.08% and 44.62%. They were significantly higher in the oxymatrine group than in the placebo group. In the oxymatrine treated patients, 12 weeks after its withdrawal, 60.00% had a normal ALT level, 41.54% and 23.33% had both HBV DNA and HBeAg negative. In the placebo group, 31.75% had a normal ALT level, 3.08% and 1.67% had both HBV DNA and HBeAg negative. The rates of complete response and partial response in the oxymatrine group were 21.54% and 47.69%, and in the placebo group they were 0 and 41.54%. They were significantly higher in the study group than in the placebo group. The adverse reaction rates of oxymatrine in the study and the placebo group were 7.69% and 6.15%, respectively, but there was no statistical significant difference between them. CONCLUSION: Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.