Hai-Ying Zhang

Natural history and disease progression in Chinese chronic hepatitis B patients in immune‐tolerant phase

In view of the findings that high hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is associated with increased risk of chronic hepatitis B (CHB)–related complications, disease progression in CHB patients in the immune‐tolerant phase is uncertain. We evaluated disease progression in 57 immune‐tolerant CHB patients with high HBV DNA. Each subject underwent an initial liver biopsy. In those who remained in the immune‐tolerant phase, a follow‐up liver biopsy was performed after 5 years of follow‐up. Patients who developed elevated serum alanine aminotransferase (ALT) levels were discontinued from the study after a follow‐up liver biopsy. Disease progression was defined as a 1‐point increase in fibrosis stage. Initial liver biopsies showed the median fibrosis stage of the study patients was 1 (range 0–1). By the end of follow‐up, 9 of the 57 patients (15.8%) had developed elevated serum ALT. In those who remained in the immune‐tolerant phase, follow‐up fibrosis stage was comparable with the initial fibrosis stage (P = 0.58). However, disease progression was greater in patients who developed elevated serum ALT when compared with those who remained in the immune‐tolerant phase (5 of 9 vs. 3 of 48, respectively, P = 0.001). The median rate of fibrosis progression of patients who remained in the immune‐tolerant phase was lower than that of patients with high serum ALT (0 U/year [range −0.40–0.20 U/year] versus 0.21 U/year [range 0–1.11 U/year], respectively, P = 0.04). Conclusion: CHB patients in the immune‐tolerant phase have mild disease. In those who remained in the immune‐tolerant phase in the present study, disease progression was minimal. However, immune‐tolerant patients who progressed to the immune clearance phase often faced disease progression. (HEPATOLOGY 2007.)

Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy

Background: The hepatic outcome of hepatitis B surface antigen (HBsAg) positive patients undergoing chemotherapy after withdrawal of pre-emptive lamivudine is unknown. Aims: To examine the occurrence of hepatitis B virus (HBV) reactivation after withdrawal of pre-emptive lamivudine. Methods: Pre-emptive lamivudine was started one week before initiation of chemotherapy in 46 consecutive HBsAg positive patients and continued for the entire duration of chemotherapy. Pre-emptive lamivudine was stopped at a median 3.1 (range 3.0–3.4) months after completion of chemotherapy. Patients were longitudinally followed up after withdrawal of pre-emptive lamivudine. Results: Median time of follow up after withdrawal of lamivudine was 25.7 (range 5.7–75.7) months. Eleven of the 46 patients (23.9%) developed HBV reactivation after withdrawal of pre-emptive lamivudine. Eight of the 16 patients with high pre-chemotherapy HBV DNA (⩾104 copies/ml) compared with three of the 30 patients with low pre-chemotherapy HBV DNA (<104 copies/ml) developed HBV reactivation (50.0% v 10.0%, respectively; p<0.001). Hepatitis B e antigen positive patients were also more likely to develop HBV reactivation (5/11 (45.5%) v 6/35 (17.1%), respectively; p = 0.041). A high pre-chemotherapy HBV DNA (⩾104 copies/ml) was the most important risk factor for HBV reactivation after withdrawal of pre-emptive lamivudine on Cox proportional hazards analysis (relative risk 16.13, (95% confidence interval 2.99-87.01; p = 0.001). Conclusions: HBV reactivation is more likely to occur in patients with high pre-chemotherapy HBV DNA after withdrawal of pre-emptive lamivudine. A more prolonged course of antiviral therapy may be necessary in these patients after completion of chemotherapy in order to reduce post-chemotherapy HBV reactivation.

96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B

BACKGROUND/AIMS In order to prevent the occurrence of drug-resistant mutants associated with treatment for chronic hepatitis B virus (HBV) infection, combination therapy is being developed. To determine the efficacy of adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy in chronic HBV infection. METHODS Thirty treatment-nai ve, HBeAg-positive patients were randomized to combination ADV plus FTC (n=14) or ADV plus placebo monotherapy (n=16) for 96 weeks. HBV DNA was measured by polymerase chain reaction. Treatment was stopped in those with HBeAg seroconversion. RESULTS The median decrease in HBV DNA at week 96 was higher in the combination group (-5.30 vs. -3.98 log(10)copies/ml, p=0.05). More patients in the combination group had normalization of alanine aminotransaminase and HBV DNA<300 copies/ml at week 96 when compared with the monotherapy group [11 of the 14 patients (78.6%) vs. 6 of the 16 patients (37.5%), p=0.03]. However, HBeAg seroconversion at week 96 was similar in the 2 groups [2/14 (14.3%) vs. 4/16 (25.0%), p=NS]. No ADV or FTC resistance was detected at week 96. In those with HBeAg seroconversion, 50.0% had post-treatment relapse. CONCLUSIONS Combination ADV plus FTC resulted in more potent suppression of HBV DNA over 96 weeks of therapy.

Effectiveness of prophylactic anti-HBV therapy in allogeneic hematopoietic stem cell transplantation with HBsAg positive donors

Use of hepatitis B surface antigen (HBsAg) positive donors for allogeneic hematopoietic stem cell transplantation (HSCT) causes serious hepatitis B virus (HBV)‐related liver morbidity and mortality in the recipient. We compared the effectiveness of anti‐HBV therapy in 29 recipients who underwent HSCT using HBsAg positive marrow (group I) against a historical control group of 25 patients who received HBsAg positive marrow without pre‐HSCT prophylaxis (group II). Anti‐HBV therapy consisted of lamivudine for HBsAg‐positive donors and all recipients (n = 29) as well as HBV vaccination to all HBsAg‐negative recipients (n = 10) before HSCT. After transplantation, HBV‐related hepatitis was significantly higher in group II than group I recipients [12 of 25 recipients (48%) vs. 2 of 29 recipients (6.9%), p = 0.002] and in recipients whose donors had detectable serum HBV DNA by Digene Hybrid Capture II assay [8 of 14 recipients (57.1%) vs. 6 of 40 recipients (15.0%), p = 0.02]. Six recipients in group II and none in group I died of HBV‐related hepatic failure (24.0% vs. 0%, p = 0.01). By multivariate Cox analysis, anti‐HBV therapy effectively reduces post‐HSCT HBV‐related hepatitis (p = 0.01, adjusted hazards ratio 7.27, 95%CI 1.62–32.58). Our data support the use of prophylactic therapy in preventing HBV‐related hepatitis after allogeneic HSCT from HBsAg‐positive donor.

Comparison of Real-Time PCR Assays for Monitoring Serum Hepatitis B Virus DNA Levels during Antiviral Therapy

ABSTRACT The performance characteristics of the RealART and Molecular Beacons assays were compared with those of the Digene Hybrid Capture II assay (ultrasensitive). The results of the RealART and Digene Hybrid assays were related (r = 0.94; P < 0.001) and diverged by 2 orders of magnitude. The RealART assay can be used to effectively monitor serum hepatitis B virus DNA levels.

48 weeks pegylated interferon alpha‐2a is superior to 24 weeks of pegylated interferon alpha‐2b in achieving hepatitis B e antigen seroconversion in chronic hepatitis B infection

Background/aim  Although 48‐week therapy with pegylated‐interferons has been shown to be effective for the treatment of chronic hepatitis B virus infection, the efficacy of a shorter duration of therapy with pegylated interferons is unknown.

Disease progression in Chinese chronic hepatitis C patients with persistently normal alanine aminotransaminase levels

Although chronic hepatitis C virus‐infected patients with persistently normal alanine aminotransaminase levels usually have mild liver disease, disease progression can still occur. However, it is uncertain which group of patients is at risk of disease progression.

Changes in liver histology as a "surrogate" end point of antiviral therapy for chronic HBV can predict progression to liver complications

Background The modified histology activity index (HAI) score has been extensively used as an additional primary or secondary end point in most phase III pivotal therapeutic clinical trials on chronic hepatitis B. Improvement in modified HAI after antiviral therapy has usually been defined as a 2-point reduction in modified HAI score. Aim We studied whether a 2-point change in modified HAI score after antiviral therapy for chronic hepatitis B is associated with progression to liver complications (decompensated cirrhosis or hepatocellular carcinoma). Method Eighty-nine patients treated with interferon-α with liver biopsy before and at 6 to 12 months after the end of therapy were followed-up for a median 119.4 months. Results At the time of analysis, 11 patients (12.4%) had liver complications. Liver complications were higher in patients with a 2-point increase in modified HAI score [8 of 19 patients (42.1%) vs. 3 of 70 patients (4.3%), P=0.0002] and in those with severe fibrosis at end of therapy [6 of 19 patients (31.6%) vs. 5 of 70 patients (7.1%), P=0.010]. On Cox regression analysis, a 2-point increase in modified HAI score was associated with increased liver complications (relative risk 5.564, P=0.036). Conclusions A 2-point increase in modified HAI score after antiviral therapy is associated with increased progression to liver complications.

48 Weeks pegylated interferon alfa-2a is superior to 24 weeks of pegylated interferon alfa-2b in achievingHBeAg seroconversion in chronic hepatitis B infection

Background and Aims Asian patients have traditionally been considered to respond poorly to interferon-based treatment. We explored the effect of peginterferon alfa-2a (PEGASYS) in Asian patients with HBeAg-negative CHB enrolled in a large randomized clinical trial investigating the response to PEGASYS +/− lamivudine versus lamivudine (Marcellin et al. NEJM 2004). Patients and Methods 177 patients with HBeAg-negative CHB received 48 weeks of PEGASYS (180 μg once-weekly) + placebo. Patients were assessed 24 weeks post-treatment. Results Of the 177 patients, 108 (61%) were of Asian origin. Almost all the Asian patients (97%) were infected with genotypes B or C (42 patients with B, 63 with C, one with D and two other).The rate of combined response (ALT normalization and HBV DNA <20,000cp/ml) in Asian patients treated with PEGASYS was 45% (49/108), which was higher than that observed in the overall ITT population (36%). Response to PEGASYS was equally good in Asian patients infected with HBV genotype B (43%) and genotype C (49%). HBV DNA suppression of <400cp/ml was achieved in 26% of Asian patients compared with 19% in the overall ITT population. A total of three (3%) Asian patients treated with PEGASYS achieved HBsAg seroconversion after only 6 months of follow-up. Conclusions Asian patients responded favorably to PEGASYS treatment; 45% of Asian patients had a virological and biochemical response which was sustained 24 weeks after the end of treatment. Response rates were similar in patients infected with genotypes B or C.

Viral specific T cells phenotypes and toll like receptors mRNA expression in CD8 cells of chronic hepatitis B patients

Background Hepatitis B is a major public health problem in Vietnam. However, estimates of the prevalence of hepatitis B virus (HBV) and hepatitis Delta virus (HDV), and risk factors in rural Vietnam are limited. Methods A cross-sectional seroprevalence study was undertaken in two rural districts in Thai Binh province. The study population was randomly selected using multi-stage sampling. Demographic and behavioral risk information and serological samples were obtained from 837 participants. Results Mean age was 42.3 years ± 15.8 (range, 16–82 years) and 50.8% were female. Prevalence of HBcAb and HBsAg was 68.2% and 19.0%, respectively, and eAg was detected in 16.4% of the HBsAg positive group. Prevalence of HDV was 1.3% in the HBsAg positive group. Factors associated with HBV infection (HBcAb or HBsAg positive) were age sixty years or older (OR 3.82, 1.35–10.80; p = 0.01), residence in Vu Thu district (OR 3.00, 2.16–4.17; p < 0.0001), hospital admission (OR 2.34, 1.33–4.13; p = 0.003) and history of acupuncture (OR 2.01, 1.29–3.13; p = 0.002). Household contact with a person with liver disease (OR 2.13, 1.29–3.52; p = 0.003), reuse of syringes (OR 1.81, 1.25–2.62; p = 0.002) and sharing of razors (OR 1.69, 1.03–2.79; p = 0.04) were independent predictors of HBsAg positivity. Alanine aminotransferase (ALT) level was elevated (>40U/L) in 43% of the HBsAg positive group. Conclusion HBV infection and HBV related liver disease remains a serious public health problem in rural Vietnam. Poor infection control activities in health care settings partly accounted for the high HBV prevalence in this region. Universal HBV infant vaccination and improved infection control procedures are required for improved HBV control in Vietnam. #077 Dose-response relation of interferon-alpha in patients with HBeAg positive chronic hepatitis B: meta-analysis and meta-regression of randomized trials XIN SUN, WENXIA QIN, RONGLE ZHOU, YOUPING LI Chinese Evidence-Based Medicine Center,West China Hospital, Sichuan University, Department of Clinical Pharmacy,West School of Pharmcy, Sichuan University, West China Medical School, Sichuan University This study examined dose-response effect of interferon-α in HBeAgpositive CHB patients. We searched 5 electronic databases, all updated to September 2005. Randomized trials of interferon-α vs. non-antivirals were eligible. Quality of trials was assessed by standard instrument. Meta-regression and meta-analysis were used to examine the dose-response relation. Thirty-three trials were included (n = 2164). Dose of interferon-α ranged from 1–10 MU, and duration from 4–24 weeks. Eighteen trials were medium-to-high in quality. HBeAg clearance was responsive to dose (coef = 0.156, 95%CI = 0.028–0.28) and duration (coef = 0.076, 95%CI = 0.0048–0.15), but not for HBV-DNA clearance. Stratified analyses showed that ≥5 MU and 16–24 week interferon-α could effectively clear HBeAg (OR = 3.28, 95%CI = 2.31–4.66; OR = 3.28, 95%CI = 2.16–5.00), and HBV-DNA (OR = 2.80, 95%CI = 2.03–3.86; OR = 2.58, 95%CI = 1.62–4.12). HBeAg seroconversion could be seen in all-dose groups (OR = 2.02, 95%CI = 1.37–2.97). In conclusion, HBeAg clearance dose-responsive. A ≥5 MU and 16–24 week interferon-α could effectively clear virological and serological markers. 0 0.5 1 1.5 2 2.5 Day O D in 4 50 n m 10 microgram HCV core pcDNA3+PBS 25 microgram HCV core pcDNA3+PBS 50 microgram HCV core pcDNA3+PBS 10 microgram HCV core pcDNA3+CpG motif 25 microgram HCV core pcDNA3+CpG motif 50 microgram HCV core pcDNA3+CpG motif 10 microgram HCV core pcDNA3+CpG motif+Alum 25 microgram HCV core pcDNA3+CpG mitif+Alum 50 microgram HCV core pcDNA3+CpG motif+Alum 10 microgram HCV core pcDNA3+Dendrosome 25 microgram HCV core pcDNA3+Dendrosome 1 17 42 62 Table Immunization of HCV core pcDNA3 with four different adjuvants Figure 1. The dose (left) and duration (right) of interferon-α in relation to the HBeAg clearance (log scale). Y-axis means the log scale of HBeAg clearance, X-axis means the dose of interferon-α. Each trial is represented by a circle, the area of which represents the trial’s precision. Larger circles represent trial that contribute more information. Regression equation: log OR(HBeAg clearance) = 0.34 + 0.156 × dose, and log OR (HBeAg clearance) = −0.51 + 0.076 × durationThis journal suppl. entitled: Abstract and Proceeding of the Shanghai-Hong Kong International Liver Congress