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UniversitiesPhase

    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

     (93-2752-B-002-003-PAE)

    (94-2752-B-002-003-PAE)

    (95-2752-B-002-003-PAE)

     (96-2752-B-002-003-PAE)

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

Project Title:B型和C型肝炎病毒之藥物基因體研究 (The pharmacogenomics of hepatitis B and

    C viruses) (4/4)

    國立台灣大學肝炎研究中心

    Serial No.: 96-2752-B-002-003-PAE Affiliation (Hepatitis Research Center

    National Taiwan University)

    Name Jia-Horng Kao/高嘉宏 Name 鄭惠如

    Tel: 886-2-23123456 ext. 7307 Tel: 886-2-23123456 ext. 7300

    Fax: 886-2-23317624 Fax: 886-2-23317624

    Project Coordinator Principal Investigator E-mail kaojh@ntu.edu.tw E-mail living0510@yahoo.com.tw

    2:Full time/Part Manpower1Expenditures (in NT$1,000) time(Person-Months)

    Projected Actual Projected Actual

    FY2004 NTD 2,338 24

    FY2005 NTD 2,371 24

    FY2006 NTD 2,439 24

    FY2007 NTD 2,389 24

    Overall NTD 9,537

    1,2 Notes: Please explain large differences between projected and actual figures.

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

    Current therapy for chronic hepatitis B or C relied upon interferon-based therapy and/or antiviral compounds. The treatments can eradicate hepatitis C from 50-60% of hepatitis C patients, and can effectively suppress and control hepatitis B in 30-40% of hepatitis B patients. However, there are still about half of chronic hepatitis B or C patients who respond unsatisfactorily. What factors determining the treatment responses for these individuals become important topics to study, as these factors may shed light on the mechanisms of poor response and on the discovery of target molecules or genes for further drug development.

    The treatment response of individual patient will be determined by three critical factors. The first is the drug, which is the interferon-based one for hepatitis B and C treatment. The second is the unique nature of hepatitis virus in the infected individual, including the viral genomics and genotype. The third is the unique nature of genomic characteristics of the individual, including the inherent genomic components or polymorphisms, the expressed gene profiles. As the first factor is the same, only with minor dose adjustment, we will focus on the second and the third, namely, the viral and host genomic uniqueness in relation to treatment response.

    This sub-project is aiming to explore the association of viral factors including genotypes, common naturally occurring or drug-resistant viral mutants and novel single nucleotide polymorphisms (SNPs) with the response to antiviral treatments in patients with chronic hepatitis B or C viral infection.

    We approached the hypothesis by analyzing the genetic polymorphisms or gene expression profiles between the treatment responders versus non-responders. Those SNPs or differentially presented mRNA will be subjected to validation in other groups of patients. Those confirmed genetic markers will be applied and tested in prospectively clinical studies. In addition, their biological functions in hepatitis B and C treatment response will be investigated in appropriate cell lines or animal systems.

     Identify the evolution of HBV precore and basal core promoter mutants during lamivudine

    therapy in HBeAg-positive chronic hepatitis B patients

     HBV genotype B and C have similar YMDD mutation patterns after 1 year of lamivudine

    treatment

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

     Different lamivudine-resistant YMDD mutants have a similar susceptibility to adefovir

    dipivoxil

     Mutations in NS5A and E2-PePHD regions of HCV type 1b have no influence on the

    response to interferon plus ribavirin therapy in chronic hepatitis C patients a. Confirm again that HBV genotype B patients have better virologic, serologic and

    biochemical responses to standard interferon-based therapy compared with genotype C

    patients in a prospective study.

    b. For patients with lamivudine resistant HBV mutants, overlap of lamivudine with adefovir

    for >2 months achieves better virological outcomes than adefovir monotherapy. a. On liver histology, HBV genotype C patients have higher expression levels of intrahepatic

    HBcAg than genotype B patients.

    b. In a cross-sectional study, pre-S deletion mutant is found to be more frequent in HBV

    carriers with genotype C infection, and those with pre-S deletion mutant may have higher

    HCC risk.

    a. HBeAg index ratio is closely correlated with serum HBV DNA level, and the dynamics of

    HBeAg index ratio may predict 1-year on-treatment combined response to lamivudine in

    HBeAg-positive chronic hepatitis B patients.

    b. Viral kinetic parameters in Taiwanese patients were similar to those in Western studies.

    However, the early viral decline pattern and viral negativity rate in Taiwanese patients might

    be different from Caucasian patients.

    c. Pegylated interferon alpha-2a once weekly provides more effective and safer therapy than

    standard interferon alpha-2a thrice weekly for treatment-naive dialysis patients with chronic

    hepatitis C.

    d. For lamivudine-treated HBeAg-positive CH-B patients with pre-therapy ALT levels over 5

    times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however,

    neither ALT levels nor viral factors correlate with higher response rates after 12-18 months of

    treatment. In addition, pre-core stop codon mutation could predict a higher rate of HBeAg

    loss.

    e. HCV genotype, baseline viral load, body mass index, HDL, ALT level and PLT count have

    significant impact on early viral kinetics of CHC patients with interferon-based therapy.

    However, only HCV genotype, baseline viral load and viral load decline at day 29 can

    independently predict SVR.

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

    a. We determined the evolution of HBV precore/basal core promoter and polymerase genes in 13 HBeAg-positive chronic hepatitis B patients during lamivudine therapy. The results showed that HBeAg loss or seroconversion occurred in 11, but 8 relapsed after stopping therapy and 5 had reversion of HBeAg. Before treatment, basal core promoter mutation was found in 1. In the first 3 months of therapy, a rapid decline of serum HBV DNA level accompanied with basal core promoter mutation appeared in 11 of 13 patients (vs. before therapy; P=0.003). However, this mutant was replaced by wild-type virus in 4 of 8 patients who relapsed after treatment. There was no significant change of precore sequences before and during therapy. In summary, lamivudine therapy may result in the rapid development of basal core promoter mutation of HBV, but this mutation may revert to wild type gradually after cessation of therapy.

    b. A recent study indicated that YMDD mutation patterns were different in genotype A and D, genotype A had a higher frequency of YVDD mutation whereas genotype D had a higher frequency of YIDD mutation. We therefore determined the YMDD mutation patterns in 44 chronic hepatitis B patients with lamivudine-resistant YMDD mutations and the results showed that although genotype C had a higher frequency of YVDD mutation than genotype B (69% vs. 50%), the difference was statistically not significant.

    c. Although lamivudine has beneficial antiviral effect accompanied by improvement of liver enzymes and liver histology in the treatment of chronic hepatitis B, long-term lamivudine treatment is associated with the selection of drug resistant YMDD mutants. The clinical issues regarding the hepatitis flare associated with lamivudine resistance have been raised that obviously decreases the initial enthusiasm around lamivudine therapy. Fortunately, new inhibitors with different mechanisms of action and resistance profiles have been discovered and are being evaluated in clinical trials. Among them, adefovir dipivoxil (ADV) is clearly shown to induce a decrease in serum HBV DNA levels in patients with lamivudine resistance. However, whether the susceptibility to ADV varies among different YMDD mutants remains unclear. We therefore studied 11 chronic hepatitis B patients with lamivudine-resistant YMDD mutations (9 YIDD and 2 YVDD), who received ADV for rescue therapy. The results showed that both genotype B and C had a similar reduction of HBV DNA level (3 ~ 4 logs) after ADV therapy. In addition, different YMDD mutations have a comparable susceptibility to ADV (4-log reduction for YVDD and 3-log reduction for YIDD) after 4 weeks of treatment.

    d. Combination therapy with interferon (IFN) and ribavirin is the current standard treatment for chronic hepatitis C, but the efficacy is still not satisfactory, especially for genotype 1b. NS5A and E2 proteins of hepatitis C virus (HCV) may repress the IFN-induced RNA-dependent protein kinase (PKR), and thus have the potential to influence the response of HCV to IFN therapy; however, this issue remains controversial. We determined nucleotide sequences of the PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) and PKR-binding domain (NS5A-PKR bd) of the HCV genome in 30 HCV genotype 1b patients who had been treated with IFN and ribavirin. The results showed that 9 (30%) patients achieved a sustained virological response (SVR) to combination therapy. Pretreatment variables and amino acid substitutions were compared between responders and

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

non-responders. The responders were younger than non-responders (37.2 +/- 10.4 vs. 45.4

    +/- 9.5 years, P = 0.017), whereas no significant statistical differences were found in the

    number of amino acid substitutions in NS5A and E2-PePHD regions between the two

    groups. In summary, genetic heterogeneity in NS5A and E2-PePHD regions of the HCV

    type 1b genome may not serve as a predictor for treatment outcome with combination

    therapy in Taiwanese chronic hepatitis C patients.

    a. To study whether interferon (IFN) alpha and ribavirin combination therapy has a beneficial

    effect for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, we enrolled 119 of

    such patients in the randomized study. Fifty-nine patients received 5 million units (MU) of

    IFN alpha-2b daily for 4 weeks followed by 5 MU thrice weekly for 28 weeks, plus 1200

    mg ribavirin daily. Sixty patients received the same dosage of IFN plus placebo. They were

    followed up for 24 weeks post-treatment and 105 patients (88%) completed the whole

    course of 60 weeks. By intention-to-treat analysis, the rate of combined response (serum

    HBV DNA <2.5 pg/mL and HBeAg seroconversion) was 17% vs. 25% between

    IFN/ribavirin and IFN/placebo group at the end of treatment (P=0.35), and 25% vs. 20% at

    the end of follow-up (P=0.32). By using a quantitative real-time polymerase chain reaction assay, the log(10) reduction of serum HBV DNA was 1.05 ? 1.72 (mean ? SD) vs. 1.29 ?

    1.91 between the two groups at the end of treatment (P=0.49) and was 2.15 ? 2.15 vs. 1.21 ?

    2.48 at the end of follow-up (P=0.04). In the subgroup analysis, patients with genotype B

    seemed to have better virologic, serologic and biochemical responses compared with

    genotype C.

    b. Whether short-term overlap of lamivudine with Adefovir is beneficial for the treatment of

    patients with lamivudine-resistant HBV mutants remains unknown. We enrolled 30 patients

    who received 48-week adefovir (10 mg daily) for hepatitis B exacerbation associated with

    lamivudine-resistant mutants. Nineteen (63.3%) patients had baseline evidence of hepatic

    decompensation. Lamivudine was combined for <1 months in 8 (group I), 2-5 months in 10

    (group II) and >6 months in 12 (group III). We analyzed their serial ALT levels, Child-Pugh

    (CP) score, serum viral load and lamivudine-resistant strains. We found that serum ALT

    became normalized in 20 (66.7%) and HBV DNA decreased to <100 copies/mL in 8 (26.7%)

    at the end of 48-week treatment. The log(10) reduction of serum HBV DNA was

    significantly smaller in group I compared to group II and III patients at week 24 and 48 of

    treatment [median (range): 3.0 (1.5-5.6) vs. 4.5 (1.5-7.4), P=0.032; and 3.4 (0.9-4.7) vs. 5.2

    (2.2-7.7), P=0.008; respectively]. In contrast, the virologic responses at the end of 48-week

    therapy were similar between group II and III patients. The improvement in serum ALT and

    CP score at week 48 was similar irrespective of baseline decompensation, liver cirrhosis and

    the duration of overlap lamivudine therapy.

    a. Expression of hepatitis B core antigen (HBcAg) and mutations of hepatitis B virus (HBV)

    genome are closely related to immunopathogenesis and disease activity of chronic HBV

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

    infection. The role of HBV genotype in subcellular expression of HBcAg remains largely unknown. Thirty-two HBeAg-positive patients with chronic hepatitis (HBV genotype B infection in 19 and genotype C in 12) were consecutively enrolled. Their clinical, virologic and histologic features were compared regarding subcellular localization and expression of intrahepatic HBcAg. Predominant cytoplasmic, mixed cytoplasmic/nuclear, and nuclear localization of intrahepatic HBcAg was found in 16 (50%), 14 (44%) and 2 (6%), respectively. About 69% of these patients expressed high level of HBcAg. Cytoplasmic localization of HBcAg significantly correlated with lower serum viral load but not genotype. High expression level of HBcAg correlated with HBV genotype C in multivariate analysis. In conclusion, HBV genotype contributes to the expression rather than localization of intrahepatic HBcAg in HBeAg-positive patients with chronic active hepatitis.

    b. Pre-S deletion mutant of hepatitis B virus (HBV) affects the expression of middle and small surface proteins, resulting in intracellular accumulation of large surface protein. The correlation between pre-S deletion mutant and risk of hepatocellular carcinoma (HCC) in hepatitis B virus carriers remains unclear. By using molecular assays, pre-S deletion mutant of HBV were determined in 266 patients with chronic HBV genotype B or C infection. They included 202 asymptomatic carriers and 64 HCC patients. The overall prevalence of pre-S deletion mutant was 16.5%. HCC (odds ratio, 3.23; 95% CI, 1.23-8.48, P=0.02) and genotype C (odds ratio, 3.19; 95% CI, 1.54-6.62, P=0.002) were independently associated with the presence of pre-S deletion mutant. The prevalence of pre-S deletion mutant was comparable between HCC patients with genotype B and C infection. Nevertheless, in asymptomatic carriers, patients with genotype C infection were significantly associated with the presence of pre-S deletion mutant than those with genotype B infection (20.8% vs. 7.2%, P=0.007). Compared with age and genotype B-matched asymptomatic carriers, young HCC patients (less than 50 years of age) had a significantly higher frequency of pre-S deletion (3.4% vs. 20%, P=0.04). In summary, pre-S deletion mutant is more frequent in hepatitis B virus carriers with genotype C infection, and those with pre-S deletion mutant may be associated with the development of HCC, irrespective of HBV genotypes.

    c. Clearance of hepatitis C virus (HCV) is attributed to host cellular immune responses, in which T helper cells play a critical role. The purpose of the present paper was therefore to study the serial changes of serum soluble markers released from T helper 1 (Th1) and 2 (Th2) and their correlations with treatment responses in chronic hepatitis C patients receiving interferon-alpha plus ribavirin for 24 weeks. Serum markers (soluble CD26 and CD30 levels) of T helper cells were quantified before and 6 months after combination therapy in 33 chronic hepatitis C patients and in 20 healthy controls. Compared to healthy controls, chronic hepatitis C patients had significantly lower serum soluble CD26 levels before (140.4 +/- 63.9 ng/mL vs 200.6 +/- 60.3 ng/mL, P < 0.0001) and after (115.9 +/- 32.9 ng/mL vs 200.6 +/- 60.3 ng/mL, P < 0.0001) combination therapy. The level was even lower in those with non-sustained virologic response (non-SVR; 139.0 +/- 50.9 ng/mL vs 117.7 +/- 40.3 ng/mL, P = 0.039). In contrast, soluble CD30 levels at 6 months after combination therapy were significantly lower in patients with SVR than those with non-SVR (6.4 +/- 3.5 U/mL vs 10.4 +/- 5.4 U/mL, P = 0.021). These data show that chronic

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

    hepatitis C patients have a weak Th1 response as reflected by lower soluble CD26 levels

    and the levels are even lower in non-sustained responders. In sharp contrast, downregulation

    of Th2 response with serial changes of soluble CD30 level is associated with successful

    treatment of HCV infection.

     Hepatitis B e antigen (HBeAg) seroconversion is an important event in the natural history of chronic hepatitis B virus (HBV) infection. Whether early dynamics of HBeAg index ratio could predict therapeutic endpoint of HBeAg seroconversion in patients receiving lamivudine remains unclear and thus deserves investigation. A total of 52 patients (males/females, 40/12; mean age, 31.1+/-7.5 years) with HBeAg-positive chronic hepatitis B and serum alanine aminotransferase (ALT) level > or = 5 x upper limit of normal were enrolled. They received daily 100 mg lamivudine for at least 1 year. Pretreatment HBeAg index ratio and the dynamics during treatment [early serologic response (ESR) and serologic breakthrough (SB)] between responders and non-responders were compared. Of these 52 patients, mean pretreatment serum ALT level was 580 IU/l and baseline HBeAg index ratio (S/N) was 37.9. The overall 1-year on-treatment combined response rate was 50%. By using linear regression analysis, HBeAg index ratio was positively correlated with serum HBV DNA level (Pearson's correlation coefficient: 0.62, P<0.0001). By using multivariate logistic regression analysis, ESR could predict the success of treatment response (P=0.0302), and SB had a 90% positive predictive value of treatment failure. Our data show that HBeAg index ratio is closely correlated with serum HBV DNA level, and the dynamics of HBeAg index ratio may predict 1-year on-treatment combined response to lamivudine in HBeAg-positive chronic hepatitis B patients.

     Early hepatitis C viral (HCV) kinetics following pegylated interferon-alpha (PEG-IFN) and ribavirin help to assess treatment in the Western world. Whether this functions in Taiwanese patients remains unknown. Studying the early HCV kinetics in Taiwanese patients may clarify this issue. Six chronic hepatitis C patients were enrolled. A PEG-IFN-alpha dose was administered at week 1, then it was administered weekly with daily ribavirin for 24 weeks. Serum HCV RNA levels were determined frequently during the trial and qualitatively at week 49. Kinetic parameters epsilon (effectiveness at inhibiting viral production)and delta (loss rate of infected cells) were estimated from viral loads and alanine aminotransferase (ALT) kinetics, respectively. All serum HCV RNA levels became undetectable at week 12. The epsilon ranged from 0.4128 to 0.9904 and delta from 0.0019 to 0.1245. The log values of viral load differences between day 7 and 14 ranged from 0.15 to 1.21. Only 1 patient had an abnormal ALT level at week 49. These data show that viral kinetic parameters in Taiwanese patients were similar to those in Western studies. However, the early viral decline pattern and viral negativity rate in Taiwanese patients might be different from Caucasian patients. Further large-scale studies to clarify this issue are ongoing.

     Chronic hepatitis C virus (HCV) infection is prevalent in dialysis patients, and standard interferon monotherapy is the current standard of care for such patients. AIM: To investigate whether pegylated interferon has a better therapeutic efficacy and safety profile than standard interferon in dialysis patients with chronic hepatitis C. 50 such patients were randomly assigned

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

    to receive either pegylated interferon alpha-2a 135 microg subcutaneously once per week or standard interferon alpha-2a 3 million units subcutaneously thrice per week for 24 weeks. The primary efficacy and safety end points were sustained virological response (SVR) by intention-to-treat analysis and treatment-related withdrawal rate during the study. In univariate analysis, patients receiving pegylated interferon alpha-2a tended to have a higher sustained virological response (SVR) than those receiving standard interferon alpha-2a (48% vs 20%, p = 0.07). By using multivariate analysis, treatment with pegylated interferon alpha-2a (p = 0.02) and pretreatment HCV RNA level <800 000 IU/ml (p = 0.007) were independently predictive of an SVR. All patients failing to achieve a rapid virological response (RVR) could not achieve an SVR. In addition, patients receiving pegylated interferon alpha-2a had a significantly lower treatment-related withdrawal rate than those receiving standard interferon alpha-2a (0% vs 20%, p = 0.04). These data suggest that pegylated interferon alpha-2a once weekly provides more effective and safer therapy than standard interferon alpha-2a thrice weekly for treatment-naive dialysis patients with chronic hepatitis C.

     A pre-therapy serum alanine aminotransferase level above 5 times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B (CH-B) patients. However, whether an even higher pre-therapy serum ALT value or other viral factors could affect treatment responses remains unclear. A total of 253 HBeAg-positive chronic hepatitis B patients who had pre-therapy serum ALT level over 5 times ULN and received lamivudine for 12-18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non-responders at the end of treatment and 6 months post-treatment. At the end of therapy, overall HBeAg seroconversion rate was 33.6%. For naïve patients, the HBeAg

    seroconversion rate was 37.8%. Subgroup analysis showed that patients with pre-therapy ALT levels over 10 times ULN had significantly higher HBeAg seroconversion rate than those with pre-therapy ALT level between 5 and 10 times ULN at 3 months (P = .045) and 6 months (P

    = .037) of lamivudine treatment. No significant difference was identified in terms of pre-therapy serum ALT values, viral load and genotypes between seroconverters and non-seroconverters. Our data show that for lamivudine-treated HBeAg-positive CH-B patients with pre-therapy ALT levels over 5 times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12-18 months of treatment.

     Except pre-therapy serum alanine aminotransferase (ALT) level, there are no documented factors to predict the on-treatment response in lamivudine-treated hepatitis B e antigen (HBeAg) positive patients. We thus studied the influence of pre-therapy precore (PC) and basal core promoter (BCP) mutations on the response to lamivudine therapy. A total of 103 HBeAg-positive chronic hepatitis B patients who had pre-therapy serum ALT level over 5 times upper limit of normal (ULN) and received lamivudine for 12-18 months were prospectively enrolled. The pre-therapy viral factors, including viral load, genotype, PC/BCP sequences, and status of YMDD were determined to correlate with the HBeAg loss at the end of therapy. The overall HBeAg loss rate was 57.3% at the end of therapy. The number of patients with PC wild

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    Midterm Report of the Program for Promoting Academic Excellence of UniversitiesPhase II

    (1896G)/mutant (1896A) at pre-therapy was 79 and 24, respectively. The rates of HBeAg loss

    for patients with pre-therapy PC wild/mutant were 51.9% and 75.0%, respectively (P = .045).

     Such a trend of higher HBeAg loss rate in patients with PC mutant was also observed at 3

    months (P = .045) and 6 months (P = .060) post-therapy. No significant difference was

    identified in terms of pre-therapy serum ALT values, HBV viral load, genotypes, BCP and

    status of YMDD between responders and non-responders. Thus, for lamivudine-treated

    HBeAg-positive chronic hepatitis B patients with pre-therapy ALT levels over 5 times ULN,

    pre-core stop codon mutation could predict a higher rate of HBeAg loss.

     Early hepatitis C viral kinetics following pegylated interferon alfa and ribavirin therapy is

    known to affect the treatment responses of CHC; however, the influence of host and viral

    factors on early viral kinetics remains largely unknown. Clinical and serial virological data were

    collected from 145 consecutive chronic hepatitis C patients with pegylated interferon plus

    ribavirin therapy. .A dose of pegylated interferon was administered at week 1. Then, it was

    administered weekly with daily oral ribavirin for 24 to 48 weeks. Genotyping and quantification

    of HCV RNA were done by molecular methods. Eighty-one patients were infected by HCV

    genotype 1, 61 by genotype 2 and 3 by both genotypes 1 and 2. At the end of follow-up, 110

    patients attained SVR. In multivariate analysis, body mass index and genotype were related to

    viral load decline at day 3, and baseline viral load and HDL level were correlated with viral load

    decline between day 3 and day 29. HCV Genotype, pretreatment platelet count, ALT level and

    BMI could independently predict RVR, and only genotype 2, lower baseline viral load and more

    substantial viral load decline at day 29 predicted a higher SVR. These data suggest that HCV

    genotype, baseline viral load, body mass index, HDL, ALT level and PLT count have

    significant impact on early viral kinetics of CHC patients with interferon-based therapy. Only

    HCV genotype, baseline viral load and viral load decline at day 29 can independently predict

    SVR.

    In the next year’s project, we will continue to study the association of viral factors with the

    progression of liver disease and the response to antiviral treatments in patients with chronic hepatitis

    B or C viral infection. We will specifically focus on the influence of common HBV molecular

    mutants such as PC/CPM and pre-S deletion on the response to current anti-HBV treatments

    including interferon and oral NAs as well as the possible existence of ISDR in HBV genotype C

    genome. In addition, amino acid substitutions (Arg70 vs. Gln70 and Leu91 vs. Met91)of core gene

    and novel SNPs in the HCV genome that affect the response to combination therapy of pegylated

    interferon plus ribavirin will also be investigated.

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