Two years efficiency of lamivudine and adefovir dipivoxil combined therapy in chronic hepatitis B patients.

BACKGROUND: Lamivudine (LAM) and adefovir (ADV) are widely used in most Asian countries, though monotherapy is associated with the occurrence of resistance. AIM: To evaluate the efficiency of LAM and ADV combined treatment of chronic hepatitis B patients with compensated cirrhosis. PATIENTS AND METHODS: 206 eligible Chinese patients were randomly assigned in a 1:1 ratio to receive either LAM or ADV for the first 24 weeks. According to virologic response at 24 weeks, the patients either continued to monotherapy or switched to combined therapy for 48 weeks. After 48 weeks, all patients received LAM and ADV combined therapy for 96 weeks. RESULTS: Serum HBV DNA levels significantly decreased in patients with ADV or LAM monotherapy and continuously reduced after the combined therapy. Serum ALT normalized rate were 88.24% and 81.37% at week 48, and 95.74% and 87.36% at week 96 in ADV and LAM group respectively, comparing to 60.78% and 56.73% in ADV and LAM groups at baseline. The accumulated virological breakthrough rate at week 48 and 96 was significantly higher in LAM group. CONCLUSIONS: Both combination strategies were resulted in the long term virological, biochemical improvement in Chinese chronic hepatitis B patients with compensated cirrhosis.

Virological, serological and biochemical outcomes through 3 years of entecavir treatment in nucleoside-naive Chinese chronic hepatitis B patients.

Hepatitis B virus (HBV) infection has a high prevalence in China. Entecavir has shown superior efficacy over lamivudine in Chinese nucleoside-naive chronic hepatitis B (CHB) patients over 48 weeks, with continued clinical benefit to 96 weeks. The present study evaluates the long-term efficacy of entecavir in Chinese CHB patients who continued entecavir treatment for 144 weeks. Patients receiving either entecavir 0.5 mg/day (n = 258) or lamivudine 100 mg/day (n = 261) entered the initial 96-week randomized, double-blind, controlled efficacy study. Patients who did not achieve a consolidated response [HBV DNA <0.7 MEq/mL; alanine aminotransferase (ALT) <1.25 x upper limit of normal; and if hepatitis B e antigen (HBeAg) positive at baseline, loss of HBeAg for ≥ 24 weeks] or who experienced viral breakthrough or relapse entered a 48-week entecavir rollover study. A total of 160 patients received continuous entecavir for 144 weeks; of these, 89% had undetectable serum HBV DNA, 86% showed ALT normalization, 20% reported HBeAg loss and 8% experienced HBeAg seroconversion. The cumulative rates of HBeAg loss and seroconversion were 36% and 27% at Week 144, respectively. The development of resistance was low, with three patients up to Week 96 and an additional two patients in Weeks 96-144 showing evidence of associated genotypic mutations. Entecavir was well tolerated. Adverse event rates were similar to those in lamivudine-treated patients, but patients receiving entecavir experienced fewer ALT flares. This study demonstrates that entecavir provides durable, long-term suppression of HBV DNA and ALT normalization in Chinese CHB patients, and is associated with low rates of emerging resistance. The results are consistent with the findings using entecavir globally and in Japan.

Long-term efficacy of recombinant interferon alpha 2a in the treatment of chronic hepatitis C: a randomized prospective study comparing two dose schedules in Chinese patients.

BACKGROUND/AIMS: This study is the first randomized prospective clinical trial of interferon in hepatitis to be conducted according to the guidelines of Good Clinical Practice (GCP) in China. The object of this study is to compare the long-term efficacy of a dose of 3MU of recombinant IFN alpha 2a (rIFN-alpha 2a) three times a week (t.i.w.) for 6 months with a starting dose of 6MU for 3 months and subsequent reduction to 3 MU t.i.w for a further 3 months. METHODOLOGY: Sixty-eight serological and histologically proven chronic hepatitis C patients with elevated serum ALT were randomized into two groups. A total of 63 patients were studied with full course of treatment. Five patients were withdrawn from the trial, 2 due to personal reasons and 3 due to adverse drug reactions during treatment. Thirty patients received 6MU IFN-alpha 2a t.i.w. for 3 months followed by 3MU t.i.w. for another 3 months (group A). Thirty-three patients received 3MU IFN-alpha 2a t.i.w. for 6 months (group B). RESULTS: The sex, age, baseline serum bilirubin, ALT and AST levels were matched in both groups. At the end of 6 months the complete and partial response rates in group A were 60.0% and 16.7%, respectively, and the clearance of serum HCV-RNA was 53.3%. In group B, the complete and partial response rates were 72.7% and 3.0%, respectively, and the clearance of HCV-RNA was 61.3%. These patients were followed up for 6, 12, and 18 months after stopping treatment. In group A, the rates of complete normalization of ALT and clearance of serum HCV-RNA at 24 months were 50.0% and 60.0%, respectively. In group B, the rates of normalization of ALT and clearance of HCV-RNA at 24 months were 54.4% and 41.9%, respectively. The efficacy between the two groups showed no statistically significant difference; the response rates of treatment were similar to the patients with HCV genotype 1b and 2a. Six patients (10.8% of the study population) developed neutralization antibodies to IFN-alpha 2a during treatment, 4 of them responded to the treatment. Adverse drug reactions (ADR) were common, but most of them were tolerable and the incidence of ADR was similar in both groups. CONCLUSIONS: IFN-alpha 2a is effective in the treatment of Chinese patients with chronic hepatitis C. The sustained response rates and ADR among two dose schedule groups are similar.

Expression and secretion of preS containing hepatitis B surface antigen in vaccinia virus system.

The expression and secretion of preS containing hepatitis B surface antigen in vaccinia virus system was investigated. The human TK- 143 cells were infected with the recombinant vaccinia viruses vTMS-1 or vTLS-1. Cells infected with vTMS-1, which contains the preS2 + S gene, produced preS2 containing middle HBsAg proteins. Similarly, cells produced preS1 containing large HBsAg proteins upon infection with vTLS-1, which carries the preS1 + preS2 + S gene. The expression products could be secreted and form 22 nm particles. They reacted specifically with anti-preS1 and/or anti-preS2 monoclonal antibodies, and exhibited pHSA-receptor (for polymerized human serum albumin) activity. In addition, the major S components of hepatitis B surface antigen were also present in the products expressed by vTMS-1 and vTLS-1.

Importance of perinatal versus horizontal transmission of hepatitis B virus infection in China.

China has one of the highest rates of hepatitis B virus (HBV) endemicity in the world. In a survey of five provinces, the overall HBV infection rate in the general population was found to be 42.6%, with 10.3% testing positive for hepatitis B surface antigen (HBsAg). Higher rates were found in rural than in urban areas. The prevalence of HBsAg among children under 1 year of age is quite low but increases rapidly thereafter, reaching a peak among 5 to 9 year olds. The pattern of age distribution suggests that horizontal transmission is an important route of HBV infection during early childhood, and the proportion of chronic HBsAg carriage attributable to perinatal transmission has been estimated at only 13-20%. Contact with infected family members probably accounts for much of the horizontal transmission in children. In a nationwide survey, 27.2% of families were found to have one or more HBsAg positive members and a strong tendency for family clustering has been identified. The strategy for prevention of HBV infection includes vaccination of all newborns, whether their mothers are HBsAg positive or negative, together with vaccination of high risk populations, and improved control measures in clinics and blood transfusion centres.

Management of hepatitis B in China.

A randomised, multicentre, double-blind, placebo controlled trial was conducted in Chinese patients with chronic hepatitis B to compare the efficacy of once-daily lamivudine and placebo on serum HBV DNA, and to assess the long-term efficacy and safety of lamivudine. Patients received lamivudine 100 mg (n = 322) or placebo (n = 107) once daily for 12 weeks, and were then offered open-label lamivudine treatment for 2 years. Lamivudine therapy resulted in increased hepatitis B e antigen (HBeAg) loss and seroconversion (loss of HBeAg plus the development of antibodies to HBeAg) in patients with high baseline serum alanine aminotransferase (ALT) concentrations. At 2 years, loss of HBeAg was achieved by 27% (38/140), 38% (25/66) and 60% (9/15), and seroconversion was achieved by 17% (24/140), 24% (16/66) and 33% (5/15) of patients with baseline serum alanine aminotransferase (ALT) concentrations of >1 x upper limit of normal (ULN), >2 x ULN and >5 x ULN, respectively. With lamivudine treatment, serum HBV DNA decreased rapidly to very low concentrations and remained low throughout the 2 years of the study. At 1 year, 15% (43/295) of patients in the lamivudine group had developed YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. These patients derived clinical benefit with continued lamivudine therapy, demonstrated by serum HBV DNA and ALT concentrations below baseline, or normal serum ALT concentrations. Lamivudine was well tolerated and an effective once-daily oral therapy for Chinese patients with chronic hepatitis B with viral replication and liver disease.

The interaction between native serum albumin and hepatitis B virus.

Purified hepatitis B virus particles were obtained from HBeAg positive serum by sucrose gradient ultracentrifugation and sephadex G-200 gel filtration. These virions formed a precipitation line in counterimmune electrophoresis with anti-albumin antibody, but the reaction could be inhibited by anti-HBs. After two months at 4 degrees C, another precipitating line was formed under the same condition which could not be inhibited by anti-HBs and was, thus, due to free albumin. When that sample was incubated at 37 degrees C overnight, the line of free albumin disappeared. The virion bound albumin was monomeric in non-denaturing gel electrophoresis. These results suggest that a reversible binding between virion and albumin may occur in vivo and does not require chemical modification or cross-linking.

IgM anti-preS2 monitoring during combined corticosteroid/interferon-alpha 2b therapy in chronic hepatitis B.

The biological significance of antibody reactivities towards the preS2 gene encoded proteins of HBV is not yet well known. We investigated the pretreatment IgM anti-preS2 (1-55) ad reactivity in 22 Chinese and 11 Swedish patients with active HBV disease. Significantly enhanced IgM anti-preS2 levels (titers greater than 1/1000) were observed in 48% (16/33) of these patients. The OD405 values for sera from patients with indolent HBsAg carriership were within the range of that obtained for "normal" control-sera when tested at dilutions from 1/1000 to 1/128,000. Five Chinese patients were treated with a short course of corticosteroids, followed by alpha-interferon 2b (IFN-alpha 2b) treatment for 16 weeks. The IgM anti-preS2 response was consecutively monitored during treatment. A beneficial effect on the outcome of the combined treatment was associated with rising titers of IgM anti-preS2 during the prednisolone cycle. The IgM anti-preS2 levels fell dramatically upon steroid withdrawal and were followed by a second peak response of IgM anti-preS2 reactivity during the IFN-alpha 2b treatment. No sustained loss of HBV-DNA or DNA polymerase with concomitant HBe/anti-HBe seroconversion was observed in treated patients, who lacked detectable pretreatment levels of IgM anti-preS2 in circulation.

Quantitative assessment of IgM antibodies towards an immunodominant B-cell epitope within the preS2 domain of HBV in the natural course and during combined prednisone/interferon alpha 2b treatment of chronic hepatitis B virus infection.

A direct binding enzyme-linked immunosorbent assay (ELISA) was established for quantitative determination of serum IgM antibodies towards a synthetic peptide corresponding to a selected segment (14-21) of the preS2-gene product containing an immunodominant linear B-cell epitope. The prevalence of IgM anti-preS2 (14-21) antibody titers > 1,000 for hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) infection was 38% (22/58) and 10% (2/21) for HBeAg-negative subjects (P < 0.005). IgM anti-preS2 (14-21) reactivity was detected during the clinical course of chronic HBV infection and IgM anti-peptide antibody titers declined and disappeared before spontaneous HBe/anti-HBe seroconversion. Recombinant interferon (IFN)-alpha 2b with an antecedent short course of corticosteroids was administered to eight Chinese patients with chronic HBV infection. The IgM anti-preS2 (14-21) reactivity was monitored consecutively during treatment and patients were followed for more than 1 year. A close association between the presence of pretreatment IgM anti-preS2 (14-21) in serum and the capacity to respond favorably to the combined prednisone/IFN-alpha 2b therapy was detected. The IgM anti-preS2 (14-21) titers decreased during treatment with subsequent loss of detectable antibodies 8-16 weeks after the initiation of therapy. This decrease was concomitant with an alanine aminotransferase (ALT) augmentation preceding the disappearance of HBV-DNA and anti-HBe seroconversion. Long-term remission was not observed in treated patients who lacked detectable levels of pretreatment IgM anti-preS2 (14-21) in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative monitoring of serum hepatitis B virus DNA and blood lymphocyte subsets during combined prednisolone and interferon-alpha therapy in patients with chronic hepatitis B.

Several investigators have reported a significantly reduced CD4/CD8 ratio, as defined by monoclonal antibodies, in the peripheral blood of Caucasian patients with chronic active hepatitis B (CAHB). In Asian patients with chronic hepatitis B, quantitative analyses of subpopulations of peripheral blood lymphocytes have not been able to confirm these findings. In this work, we analysed the frequency of peripheral blood lymphocyte subsets in 10 Chinese patients with histologically proven CAHB and seven healthy Chinese individuals. Four of the 10 CAHB patients received combined prednisolone/interferon-alpha2b (IFN-alpha2b) therapy. Peripheral blood samples were consecutively collected for analysis of lymphocyte subpopulations using an indirect immunofluorescence (IF) method, and hepatitis B virus (HBV) DNA was quantified by a chemiluminescent, molecular-hybridization assay. Peripheral blood mononuclear cells from seven Chinese control individuals comprised 63 +/- 3% CD3+ cells, of which 41 +/- 4% were of CD4+ and 23 +/- 2% of CD8+ subsets. The mean CD4/CD8 ratio in the healthy controls was 1.9 (95% confidence interval = 1.1-2.7). The CD4/CD8 ratios were significantly reduced (P < 0.01) in the 10 patients with chronic hepatitis B, compared with those of the controls, owing to a significant increase in the number of CD8+ cells (P < 0.005). During the treatment with prednisolone, a significant increase in the CD4/CD8 ratio was observed in all treated patients. This increase was mainly caused by a decrease in the number of CD8+ cells and was accompanied by an increase in serum HBV DNA levels, which peaked during the latter part of the prednisolone cycle. During the treatment with IFN-alpha2b, a second increase in the CD4/CD8 ratio was observed, which was caused by an increase in CD4+ cells. A marked decrease in viral load was observed, during treatment with IFN-alpha2b, in patients with HBV DNA levels below 10 000 pg ml-1. Our data indicate that the CD4/CD8 ratios in Chinese CAHB patients do not differ from those of Caucasian patients with CAHB, when analysed using similar methods for the enumeration of lymphocyte subsets. Profound effects on cellular distribution and viral replication were noted during the combined prednisolone/IFN-alpha2b therapy. Additional studies of the modulatory effect of the combined therapy on the distribution of lymphocyte subsets and cytokine profiles in relation to the therapeutic outcome of HBV infection are warranted.

A multicenter, randomized, controlled trial of interferon alfacon-1 compared with alpha-2a-interferon in Chinese patients with chronic hepatitis C virus infection.

BACKGROUND: Alpha-interferons are the accepted therapy for patients infected with chronic hepatitis C virus (HCV) in China. However, consensus interferon (CIFN) for HCV treatment is effective in patients with chronic hepatitis C from Western countries. METHODS: This randomized, controlled trial was conducted to determine the safety and efficacy of CIFN at two doses, and to compare it with alpha-2a-interferon (IFN-alpha-2a) in Chinese patients with chronic HCV. Interferon-naive patients with chronic HCV infection (n = 187) were randomly chosen to receive 15 microg CIFN or 9 microg or 3 MU IFN-alpha-2a subcutaneously, three times a week for 24 weeks, followed by a 24 week observation period. Efficacy was evaluated by the normalization of serum alanine aminotransferase (ALT) and the non-detectability disappearance of serum HCV-RNA by using reverse-transcription-polymerase chain reaction. The safety of CIFN was evaluated by recording the type and severity of adverse effects. RESULTS: The combined ALT and HCV-RNA end-of-treatment and sustained responses were observed to be greater for treatment with 15 microg CIFN (59.0% and 55.7%, respectively) compared to IFN alpha-2a (36.1% and 39.3%, respectively; P = 0.01 for the end-of-treatment, P = 0.07 for the sustained response). The combined ALT and HCV-RNA end-of-treatment and sustained responses for treatment with 9 microg CIFN (both 49.2%) were higher than those for IFN-alpha-2a (not statistically significant). Data were analyzed by using a logistic-multiple-variate regression model, which indicated that the higher IFN dose (15 microg or 9 microg CIFN vs 3 MU IFN-alpha-2a; P < 0.01) appeared to be associated with a better sustained response. The type, frequency and severity of adverse effects were comparable across treatment groups. CONCLUSIONS: Consensus interferon appears to be safe and effective at concentrations of 9 and 15 microg, but 15 microg CIFN may be more effective than 3 MU IFN-alpha-2a, without increased toxicity.