Antigen-positive Chronic Hepatitis Research Articles

Interleukin-21 Is Associated with Early Antiviral Response in Patients with Hepatitis B e Antigen-Positive Chronic Hepatitis B and Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) becomes a characteristic of liver disease. Interleukin-21 (IL-21) plays an important role in the control of chronic hepatitis B (CHB). We aimed to investigate the relationship between IL-21 and early (24 weeks) viral response (EVR) to antiviral therapy in patients with coexistence of CHB and NAFLD (CHB + NAFLD). A prospective study was carried out in hepatitis B e antigen (HBeAg)-positive CHB + NAFLD and CHB patients receiving Entecavir for initial antiviral therapy, by recording demographic, anthropometric, and clinical data at baseline 12 and 24 weeks. Univariate analysis, correlation analysis, and receiver operating characteristic curve (ROC) were applied to find related factors with EVR. Forty CHB + NAFLD patients and 20 CHB patients entered final analysis. At baseline, IL-21, triglyceride (TG), cholesterol (CHOL), glutanyltransferase (GGT), body mass index (BMI), and computed tomography (CT) ratio of liver/spleen showed significant difference between the 2 groups. Although no significant difference was found, EVR rates was lower in CHB + NAFLD than CHB (75% vs. 90%, P = 0.053). Baseline IL-21 was associated with BMI, CT ratio of liver/spleen, TG, CHOL, and HBeAg level in CHB + NAFLD patients, whose IL-21, alanine aminotransferase, aspartate aminotransferase, CHOL, BMI, and CT ratio of liver/spleen at baseline was associated with EVR. Only the level of IL-21 exhibited significant increase from 0 to 12 weeks, while the change line of other associated factors was nearly parallel between EVR group and non-EVR group. ROC discovered the level of IL-21 at 12 weeks implied a strong predictive value for EVR. We deduced that IL-21 was associated with EVR, and the elevated level of IL-21 at treatment week 12 can predict EVR in CHB + NAFLD patients.

Increased intrahepatic quasispecies heterogeneity correlates with off-treatment sustained response to nucleos(t)ide analogues in e antigen-positive chronic hepatitis B patients

Finite treatment with nucleos(t)ide analogues (NAs) remains a great challenge for chronic hepatitis B in the clinic. This study aimed to investigate the relationship between intrahepatic quasispecies heterogeneity and the NAs off-treatment outcomes in a prospective cohort. Eighteen HBeAg-positive patients with chronic hepatitis B who achieved the cessation criteria underwent liver biopsy, and stopped treatment thereafter. Patients were followed up prospectively for 1 year. The reverse transcriptase (RT) gene of intrahepatic hepatitis B virus (HBV) was cloned and sequenced. Intrahepatic quasispecies heterogeneity and specific gene mutations were analysed using bioinformatic methods. Ten patients achieved sustained response, and eight patients developed viral relapse. The intrahepatic quasispecies Shannon entropy and nucleotide diversity within either RT or the surface (S) region of patients with sustained response were significantly higher (p < 0.05) than those of patients who had a viral relapse. Intrahepatic quasispecies Shannon entropy at the nucleotide level predicted the sustained off-treatment response (area under receiver operating characteristics curve 0.925; 95% CI 0.807–1.000; p 0.003). More positive selection sites and N-glycosylation mutations within the S region were found in patients with sustained response than in the patients with viral relapse (p < 0.01). Most of the positive selection sites in patients with sustained response were located in reported HLA-I-restricted or HLA-II-restricted epitopes. Intrahepatic quasispecies heterogeneity at the end of treatment was correlated with off-treatment outcomes in HBeAg-positive patients with chronic hepatitis B. More immune escape mutations were found within the S region in patients with sustained response. The higher intrahepatic quasispecies heterogeneity indicated a more robust immune control over HBV, which in turn maintained a sustained response after withdrawal of NAs.

Quantitative hepatitis B surface antigen combined with hepatitis B e antigen as sustained virological response predictors during extended therapy with Peginterferon alfa-2a for hepatitis B e antigen-positive chronic hepatitis B

BackgroundThe best strategy for chronic hepatitis B patients with poor response to 48 weeks of Peginterferon-based therapy has been controversial and the predictive value of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA levels for determining the sustained virological response (SVR) of these patients is uncertain. ObjectivesTo optimize management of these patients and evaluate the use of these serobiomarkers to predict SVR. Study designEighty-one patients with an unsatisfactory response after 48 weeks of Peginterferon-based therapy were treated with extended Peginterferon therapy with or without nucleo(s) tide analogues (NAs), for a total of 96 weeks of Peginterferon treatment. HBsAg, HBeAg and HBV DNA levels were measured serially during the treatment and follow-up. Results and ConclusionsTwenty-six of 81 patients (32.1%) attained SVR during the 72-week follow-up. The SVR rate was not statistically different between groups receiving 1-year prolongation of Peginterferon with or without NAs. The serum HBsAg cut-off of 1800IU/mL at week 48 had area under curve (AUC) of 0.727, and the serum HBsAg cut-off of 1500IU/mL, combined with HBeAg loss at week 72, had AUC of 0.753 to predict SVR during the follow-up. In conclusion, extended treatment with Peginterferon with or without NAs for patients with unsatisfactory response after 48 weeks of Peginterferon-based therapy is a promising strategy to achieve SVR, and quantitative serum HBsAg at week 48 and HBsAg level combined with HBeAg loss at week 72 of therapy can predict SVR to prolongation therapy with Peginterferon.

Improved Efficacy of a pegylated interferon-α-2a stepwise optimization treatment strategy in the treatment of hepatitis B e antigen-positive chronic hepatitis B patients.

Current pegylated interferon-α (PEG-IFN) treatment for chronic hepatitis B (CHB) e-antigen (HBeAg)-positive patients are suboptimal, and effective ways of improving PEG-IFN treatment efficacy are needed.This retrospective cohort study compared the efficacy of a PEG-IFN stepwise optimization treatment (PEG-IFN SOT) strategy with that of a 48-week PEG-IFN standard therapy (PEG-IFN ST) in HBeAg-positive CHB patients.A total of 110 patients were included in our study. Of these, 70 received the PEG-IFN SOT and 40 received the PEG-IFN ST (control group). We based the decision whether to add adefovir and/or extend the PEG-IFN-based treatment to 96 weeks on the patients' 12-week or 24-week early virological response (12W EVR, at least a 2 log10 reduction in HBV DNA copies/mL at week 12; 24W EVR, at least 1 log10 reduction in HBsAg IU/mL or HBsAg <1500 IU/mL at week 24) and their 48-week partial response (48W PR, 1.0 ≤HBeAg ≤10.0 S/CO or HBeAg >10.0 S/CO but HBsAg <1000 IU/mL).The HBeAg seroconversion rate 24 weeks post-PEG-IFN treatment was significantly higher in the PEG-IFN SOT than the PEG-IFN ST group (50% vs 22.5%, P = 0.005). The HBsAg clearance rates in the PEG-IFN SOT and ST groups were 10% and 0% (P = 0.04), respectively. Receiving PEG-IFN SOT (OR = 0.26, P = 0.01), ALT × ULN at baseline (OR = 0.74, P = 0.003), and achieving 12 and 24W EVR (OR = 0.29, P = 0.03) were independent factors associated with HBeAg seroconversion.PEG-IFN SOT is a promising strategy for achieving high rates of serological response in HBeAg-positive CHB patients.

Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study).

Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add-on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg-IFN add-on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6-14.0; P = 0.004). Eleven (13%) of the add-on-treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add-on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg-IFN add-on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. Although the primary endpoint was not reached, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add-on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg-IFN add-on therapy may facilitate the discontinuation of nucleos(t)ide analogs.

Effect and impact factors of entecavir alone or temporary in combination with pegylated interferon alpha-2a for the treatment of hepatitis B e antigen-positive chronic hepatitis B

Objective To investigate the efficacy of pegylated interferon alpha-2a (peg-IFN-α-2a) temporary add-on therapy during entecavir (ETV) treatment by comparing with ETV monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB), and to discuss the differences of efficacy between these two strategies. Methods Sixty-one HBeAg-positive patients with CHB were administered with ETV at initial 24 weeks and were assigned randomly to either receive a 24 weeks addition of peg-IFN-α-2a 180 μg weekly or continue on ETV 0.5 mg daily alone for 24 weeks. Response was assessed at week 48 post-treatment and defined as HBeAg loss with hepatitis B virus (HBV) DNA <200 IU/mL. Then the responders were asked to discontinue the antiviral treatment at week 72. Non-responders continue the antiviral treatment with ETV until 96 weeks. All included patients were followed up until 96 weeks from the baseline. Quantitative data were compared using t test or rank sum test. Categorical data were analyzed using χ2 test. Results Fifty-nine patients accomplished 96 weeks study, 29 with ETV alone and 30 with add-on peg-IFN-α-2a. Response at week 48 was achieved in 20.0% (6 cases) of patients treated with add-on peg-IFN-α-2a, compared to 13.8% (4 cases) of patients treated with ETV alone (χ2=0.083, P=0.773); while the response rates at week 96 was 33.3% (10 cases) in add-on peg-IFN-α-2a group and 20.7% (6 cases) in ETV monotherapy group (χ2=1.193, P=0.275). At week 96, the declines of HBsAg between two regimens were 1.05 lg IU/mL and 0.34 lg IU/mL, respectively (Z=-2.972, P=0.003). The analyses on HBeAg levels showed that there were no significant difference between two regimens at week 24, week 48, week 72 and week 96 (all P>0.05). Serum levels of HBsAg and HBeAg at baseline, week 12 and week 24 were significantly lower in HBeAg clearance group than non-clearance group (all P<0.01). Conclusions A short term add-on of peg-IFN-α-2a during ETV treatment increases HBsAg decline. Baseline HBsAg level and on-treatment HBsAg and HBeAg declines may predict the virological response of CHB patients. Key words: Hepatitis B, chronic; Drug therapy, combination; Peginterferon; Entecavir; add-on

Changes in peripheral blood natural killer T cells in hepatitis B e antigen-positive chronic hepatitis B patients and efficacy prediction after pegylated interferon therapy.

We examined the expression of peripheral blood natural killer T (NKT) cells in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients and predicted its efficacy after pegylated interferon α-2a (Peg-INFα-2a) therapy. Sixty-three cases of HbeAg-positive CHB inpatients and outpatients, treated in the Third Xiangya Hospital of Central South University from January to December 2010, were administrated Peg-INFα-2a 18 myriad international unit intramuscularly once per week for 48 weeks. The number of peripheral NKT cells, 5 quantitative indicators of hepatitis B, and hepatitis B virus DNA capacity were detected at each time point. Forty-eight weeks after Peg-INFα-2a treatment, 26 HBeAg-positive CHB patients exhibited significant effects, 21 cases exhibited effects, and 16 cases showed no effects. The ratio of peripheral blood NKT cells in T lymphocytes before and 4, 8, and 12 weeks after treatment in the significant effect group was significantly increased compared to the effect group and no effect group (P < 0.01); at the 48th week of treatment and 24 weeks after the drug was withdrawn, NKT cell expression in the significant effect group was significantly higher than that in the effect group (t = 32.0, P < 0.01; t = 27.6, P < 0.01, respectively). A total of 27 patients showed HBeAg seroconversion until the 24th week after drug withdrawal. During treatment with Peg-INFα-2a in HBeAg-positive CHB patients, expression of peripheral blood NKT cells could be used to predict efficacy.

HBsAg expression of liver correlates with histological activities and viral replication in chronic hepatitis B

Introduction. The intrahepatic hepatitis B surface antigens (HBsAg) expression is related to disease progression of chronic hepatitis B. We examined the features of intrahepatic HBsAg expression.Material and methods. A total of 181 patients with e antigen positive chronic hepatitis B were enrolled. Patterns and semi-quantitative measurement of intrahepatic HBsAg expression were analyzed. The association of intra-hepatic hepatitis HBsAg expression with clinical, viral, and histological characteristics was evaluated.Results. Higher necroinflammation grade and greater fibrosis stage accompanied with lower serum HBV DNA and HBsAg levels were observed in patients with type II ground glass hepatocytes and 2+/3+ scales of intrahepatic HBsAg expression. Basal core promoter T1762/A1764 mutations were strongly associated with the pattern of type II ground glass hepatocytes expression (P < 0.001) and higher level of HBsAg expression (9.3 ± 8.0% vs. 4.3 ± 5.0%, P = 0.008). In multivariate analysis, basal core promoter mutations (Odds ratio: 6.356, 95% confidence interval: 1.204 ~ 33.356, P = 0.029) was associated with 2+/3+ scale of HBsAg expression.Conclusion. Both pattern and levels of intrahepatic HBsAg expression were associated with severity of liver disease in e antigen positive chronic hepatitis B. Strong relationship between intrahepatic HBsAg expression and basal core promoter 1762/A1764 mutations indicated that HBsAg expression may be the histological manifestation of hepatitis B virus genomic evolution under host immune surveillance.

Glucocorticoid-induced S-Adenosylmethionine Enhances the Interferon Signaling Pathway by Restoring STAT1 Protein Methylation in Hepatitis B Virus-infected Cells

Patients with chronic hepatitis B usually exhibit a low response to treatment with interferon α (IFN-α). An alternative approach to increase the response rate of IFN-α might be to immunologically stimulate the host with glucocorticoids (GCs) before treatment with IFN-α, but the underlying mechanism remains unclear. We hypothesized that the GCs enhance IFN signaling by inducing S-adenosylmethionine (AdoMet) when hepatitis B virus (HBV) replication was effectively suppressed by IFN-α. Here, we investigated the effect of GCs and IFN-α on AdoMet production and methionine adenosyltransferase 1A (MAT1A) expression in vitro. Furthermore, we determined whether post-transcriptional regulation is involved in HBV-repressed MAT1A expression and AdoMet production induced by dexamethasone (Dex). We found that AdoMet homeostasis was disrupted by Dex and that Dex directly regulated MAT1A expression by enhancing the binding of the glucocorticoid receptor (GR) to the glucocorticoid-response element (GRE) of the MAT1A promoter. HBV reduced AdoMet production by increasing methylation at GRE sites within the MAT1A promoter. The X protein of hepatitis B virus led to hypermethylation in the MAT1A promoter by recruiting DNA methyltransferase 1, and it inhibited GR binding to the GRE in the MAT1A promoter. Dex could increase an antiviral effect by inducing AdoMet production via a positive feedback loop when HBV is effectively suppressed by IFN-α, and the mechanism that involves Dex-induced AdoMet could increase STAT1 methylation rather than STAT1 phosphorylation. These findings provide a possible mechanism by which GC-induced AdoMet enhances the antiviral activity of IFN-α by restoring STAT1 methylation in HBV-infected cells.

Decreasing hepatitis B viral load is associated with a risk of significant liver fibrosis in hepatitis B e antigen positive chronic hepatitis B.

Alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA levels and age are used commonly to assess liver histology in chronic hepatitis B. Increasing levels of HBV DNA are associated with the increasing prevalence of significant fibrosis in HBeAg-negative patients. It is unclear whether these data can be applied to HBeAg-positive patients. In present study, liver biopsies were performed and clinical parameters were measured in 234 treatment-naive chronic HBeAg-positive patients. The proportion of significant fibrosis in patients with ALT 1-2 × ULN was similar to in patients with ALT more than 2 × ULN (48.4% vs. 51.8%). Patients over 30 years of age (>30 years) had a higher prevalence of significant fibrosis than patients 30 years of age and younger (61.0% vs. 33.6%). Negative correlation between HBV DNA levels and significant fibrosis was observed in patients >30 years. The optimal level of serum HBV DNA to evaluate low risk of significant fibrosis was ≥6.7 log10 IU/ml. Patients with serum HBV DNA levels ≥8.5 log10 IU/ml all had no significant fibrosis, however, patients with HBV DNA levels <4.7 log10 IU/ml all had significant fibrosis. Logistic regressions showed that age, aspartate aminotransferase, platelet count, and HBV DNA levels were independent predictors of significant fibrosis. In summary, older age, elevated ALT, and lower HBV DNA levels are associated with significant fibrosis. Decreasing levels of HBV DNA are associated with increasing prevalence of significant fibrosis in patients >30 years. The threshold of HBV DNA levels for treatment of HBeAg-positive patients needs to be combined with age.

Vitamin E as therapy for children with E antigen positive chronic hepatitis B: Results of a randomized controlled trial

Vitamin E as therapy for children with E antigen positive chronic hepatitis B: Results of a randomized controlled trial

HBsAg quantification: useful for monitoring natural history and treatment outcome

The template of hepatitis B virus transcription, the covalently closed circular DNA (cccDNA), plays a key role in the life cycle of the virus and permits the persistence of infection. It has been suggested that hepatitis B surface antigen (HBsAg) quantification reflects the concentration of cccDNA in the liver. In hepatitis B e antigen (HBeAg) positive chronic hepatitis B, HBsAg levels are higherduring the immune tolerance phase than during the immune clearance phase. During the natural history of chronic hepatitis B, serum HBsAg declines progressively from the immune-tolerant to the low replicative phase. In HBeAg negative patients, the combination of low hepatitis B virus (HBV) DNA (<2000IU/ml) and low HBsAg levels (<1000IU/ml) can predict inactive carrier status, low risk of hepatocellular carcinoma, and the probability of HBsAg loss. HBsAg in combination with HBV DNA predicts the outcome of Peg-Interferon therapy: An absence of decline at week 12 is a good predictor of non-response and to stop therapy. Any decline at week 24, suggests that therapy should be continued to 48weeks. Although the decrease in HBsAg decline slow with nucleos(t)ide analogue therapy, a rapid decline can predict future HBsAg seroclearance. A level <100IU/ml during six consecutive months could be a marker of a sustained response after treatment cessation.

Chronic viral hepatitis in HIV infected patients

Results Of the 826 HIP evaluated during the study period, chronic HBV infection was found in 198 HIP (23.97%), chronic HCV infection in 6 HIP (0.73%). Chronic HBVHDV coinfection was detected in 6 HIP (9.37%, of 64 HIP evaluated) and chronic HBV-HCV coinfection in 2 HIP (0.24%). The evolution of chronic HBV infection during the study period was as follows: HBs seroconversion in 8 HIP (4.04%), chronic hepatitis-167 HIP (84.34%), cirrhosis-17 HIP (8.59%), undefined (lost to follow-up)-6 HIP (3.03%). Complete data necessary for the evaluation of HBV infection phase were available for 27 HIP; according to these data, the distribution of the evaluated subjects was as follows: HBe antigen negative chronic hepatitis B was detected in 8 HIP (29.63%), HBe antigen positive chronic hepatitis B in 6 HIP (22.22%) and immune control phase in 13 HIP (48.15%). 54 deaths (27.27%) were recorded among chronic HBV infected subjects; 18 deaths (9.10%) were liver related. The evolution of chronic HCV infection during the study period was as follows: chronic hepatitis in 3 HIP (50%) and cirrhosis in 3 HIP (50%). 1 death (16.67%) was recorded among chronic HCV infected subjects; this death was liver related.

Hepatitis B: clinical application of HBsAg quantification

Since its discovery by Blumberg in 1965, hepatitis B virus antigen (HBsAg) is used as the fingerprint of hepatitis B infection. HBsAg level reflects the transcriptional activity of the cccDNA. It is an important marker that might not only indicate active hepatitis B infection, but may also predict clinical and treatment outcomes. Assays for HBsAg quantification are fully automated with a high output capacity. HBsAg titer is higher in HBe antigen (HBeAg) positive chronic hepatitis B than in HBeAg negative patients and is negatively correlated with liver fibrosis in HBeAg positive patients. In HBeAg negative chronic hepatitis B, an HBsAg level < 1,000 IU/mL and an HBV DNA titer < 2,000 IU/mL allow the accurate identification of inactive carriers. On pegylated-interferon (PEG-IFN) treatment, HBsAg quantification allows identifying, as early as week 12 PEG-IFN therapy, patients that will not benefit from therapy and thus stop or switch treatment "week 12 stopping rule". Genotype A and D: stop at week 12 if no HBsAg decrease; Genotype B and C: stop at week 12 if titer > 20,000 UI/mL. With regards to nucleos[t]ides analogues therapy the role of HBsAg quantification remains to be clarified. Several studies indicate that baseline and on-treatment HBsAg levels might allow identifying patients that can end up with treatment with no subsequent risk of reactivation. In clinical practice, HBsAg quantification is a simple and reproducible worthwhile tool that can be used in association with HBV DNA to classify patients during HBV infection and to monitor therapy.

Prediction of response to interferon α-1b in HBeAg-positive chronic hepatitis B

Quantification of hepatitis B surface antigen (HBsAg) in serum may be of clinical importance in predicting treatment response towards interferon α (IFNα). To explore the predictive role of serum quantitative HBsAg in predicting treatment response towards IFNα-1b in hepatitis B e antigen-positive chronic hepatitis B patients. Seventy patients received 5 MU of IFNα-1b three times weekly for 48 weeks; the quantification of HBsAg was carried out at baseline, weeks 12, 24, 36, and 48 during treatment. At the end of treatment, the predictive role of quantitative HBsAg in predicting treatment response towards IFNα-1b was evaluated. From weeks 12 to 48, the serum hepatitis B virus DNA and HBsAg levels were positively correlated; the HBsAg levels were lower in responders than those in nonresponders and the difference was statistically significant (P<0.05). The HBsAg cutoff of 6109.01 IU/ml in serum at week 24 had a positive predictive value of 37.5% and a negative predictive value of 94.7%, and with an area under the receiver operating characteristic curve of 0.816. On-treatment, serum HBsAg had a high predictive value to predict treatment response towards IFNα-1b.

Efficacy of sequential use of telbivudine in hepatitis B e antigen‐positive chronic hepatitis B patients with partial responses to pegylated interferon: a pilot study

The aim of this study was to investigate the efficacy of sequential use of telbivudine in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients with partial responses to pegylated interferon. Patients with partial responses to 48 weeks of pegylated interferon treatment were divided into two groups. In group A, patients stopped pegylated interferon directly without sequential treatment. In group B, patients received sequential treatment with telbivudine 600 mg/day. HBeAg, HBeAb, hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT) and creatine kinase levels were determined at baseline and at weeks 12, 24, 36 and 48. Responses and safety were assessed after 48 weeks of telbivudine treatment. Thirty-six patients were recruited. Eighteen of these patients stopped pegylated interferon without sequential treatment (group A). After 48 weeks of follow-up, five patients (28%) had undergone HBeAg seroconversion, nine patients (50%) had undetectable levels of HBV DNA, and 11 patients (61%) achieved normal alanine aminotransferase (ALT) levels. The other 18 patients received sequential telbivudine treatment (group B). After 48 weeks of treatment, 11 patients (61%) had undergone HBeAg seroconversion, and all patients had undetectable levels of HBV DNA and normal ALT levels. All patients tolerated sequential telbivudine treatment, and only slightly elevated creatine kinase levels were observed. Switching to telbivudine therapy was efficient and safe in HBeAg-positive chronic hepatitis B patients with partial responses to 48 weeks of pegylated interferon. Sequential treatment with telbivudine resulted in an HBeAg seroconversion rate of 61% and an HBV DNA loss rate of 100% after 48 weeks. This promising strategy warrants further investigation.

SHOULD CHRONIC HEPATITIS B BE TREATED AS EARLY AS POSSIBLE?

We studied the cost-effectiveness of tenofovir and entecavir in e antigen positive (CHBe+) and negative (CHBe-) chronic hepatitis B. Using a multicenter survey including 544 patients we measured patient quality of life and attributable costs by clinical disease stage. Natural disease progression was studied in 278 patients in a single center. A Markov model was constructed to follow hypothetical cohorts of treated and untreated 40-year-old CHBe+ and CHBe- patients and 50-year-old patients with compensated cirrhosis. We did not find an improvement in quality of life when viral load was reduced under treatment. Transition rates to liver cirrhosis were found to be age-dependent. Assuming equal effectiveness, tenofovir dominates the entecavir strategy because of its lower price in Belgium. The incremental cost-effectiveness ratio (ICER) of tenofovir after 20 years is more favorable for treating Caucasian cirrhotic patients (mean ICER €29,000/quality-adjusted life-year [QALY]) compared with treating non-cirrhotic patients (mean ICER €110,000 and 131,000/QALY for CHB e+ and e-, respectively). Within the non-cirrhotic patients the ICER decreases with increasing cohort starting age from 30 to 50 years. Results of long-term models for tenofovir or entecavir treatment of CHB need to be interpreted with caution as long-term trials with hard end points are lacking. Especially the effect on HCC remains highly uncertain. Based on cost-effectiveness considerations such antiviral treatment should be targeted at patients with cirrhosis or at risk of rapid progression to this disease stage.

Precore and basal core promoter mutations in Asian American patients with hepatitis B e antigen‐positive chronic hepatitis B

Prior studies have shown that precore mutations abolish and basal core promoter (BCP) mutations down-regulate hepatitis B e antigen (HBeAg) production. Thus, the presence of precore and BCP mutations in HBeAg-positive patients indicates an infection with a mixed viral population of wild-type and precore and/or BCP mutant hepatitis B virus (HBV). To date, there has been limited study of the prevalence and clinical significance of precore and BCP mutations in patients with HBeAg-positive chronic hepatitis B. To determine the prevalence, predictors and clinical characteristics of mixed wild-type and precore/BCP HBV infection, through a cross-sectional study, in a US cohort of patients with chronic hepatitis B. We conducted a retrospective study of 828 chronic hepatitis B patients with HBV genotype and mutation panel testing seen at three US gastroenterology and liver clinics from June 2005 to September 2009. A majority of our patients (92.3%) were either Vietnamese or Chinese American. In the HBeAg-positive cohort, 17% of patients had precore mutations only, 28% had BCP mutations only and 5% had both BCP and precore mutations. On multivariate analyses, HBV genotype C, increasing age, lower HBV DNA level and an ALT quotient >2 were independent predictors for the presence of precore and/or BCP mutations. The current distinction and management recommendations for HBeAg-positive vs. HBeAg-negative patients with chronic hepatitis B should be reassessed. Additional biomarkers and treatment endpoints should be studied for their usefulness in predicting continued viral suppression after treatment discontinuation.

Pegylated interferon α enhances recovery of memory T cells in e antigen positive chronic hepatitis B patients

BackgroundInterferons (IFNs) are a group of cytokines commonly used in the clinical treatment of chronic hepatitis B (CHB) patients. Their therapeutic effects are highly correlated with recovery of host antiviral immunity. Clearance of hepatitis B virus (HBV) is mediated partially by activated functional memory T cells. The aims of the present study were to investigate memory T cell status in patients with different outcomes following pegylated interferon-α (IFN-α) therapy and to identify new biomarkers for predicting antiviral immune responses.MethodsPeripheral blood cells were isolated from 23 CHB patients who were treated with pegylated IFN-α at week 0 (baseline) and week 24. Co-expression of programmed death-1 (PD-1) and CD244 in CD45RO positive T cells, as well as a subset of CD127 and CXCR4 positive memory T cells were assessed. In addition, perforin, granzyme B, and interferon-γ (IFN-γ) expressions were also analyzed by flow cytometric analysis after intracytoplasmic cytokine staining (ICCS). Peripheral blood mononuclear cells (PBMC) isolated at week 24 were re-challenged with exogenous HBV core antigen, and the percentage of IFN-γ expression, serum HBV DNA loads, and ALT (alanine aminotransferase) levels were evaluated.ResultsAt week 24, PD-1 and CD244 expression in CD8 memory T cells were down-regulated (P < 0.05, P < 0.05, respectively), along with decreased HBV DNA loads (P < 0.05), while the expressions of partial effector molecules in CD8 and CD4 memory T cells was up-regulated (P < 0.05,P < 0.05, respectively), especially in the responders. CD127 and CXCR4 were highly expressed in CD8 memory T cells after pegylated IFN-α treatment (P < 0.05), which was inversely correlated with HBV DNA loads (r = −0.47, P = 0.001). The responders had a higher IFN-γ expression in memory T cells than the non-responders did after HBV antigen re-stimulation in vitro.ConclusionPegylated IFN-α treatment enhanced recovery of memory T cells in CHB patients by down-regulating inhibitory receptors and up-regulating effector molecules. The expressions of CXCR4 and CD127 in CD8 memory T cell may be used as biomarkers for predicting the outcome of treatment.

Cost-Effectiveness Analysis of Antiviral Treatments for HBeAg-Positive Chronic Hepatitis B in Canada

ObjectiveTo conduct a cost-effectiveness analysis of currently available nucleos(t)ide antiviral treatments (lamivudine, telbivudine, entecavir, and tenofovir) for chronic hepatitis B in Canada. MethodsMarkov modeling was used to project the lifetime health benefits and costs associated with the antiviral treatments. The hypothetical patient population was hepatitis B e antigen–positive chronic hepatitis B–infected patients aged 34 years. Quality-adjusted life-years were used as a measure of effectiveness. Long-term cumulative incidence of liver complications was also projected. Treatment effectiveness data were derived from the literature; meta-analysis was conducted when there was a large variance in reported effectiveness data. Costs were obtained from a cost analysis of treating chronic hepatitis B–related complications in Canada. Stochastic parameter uncertainty was examined in probabilistic sensitivity analysis by using second-order Monte Carlo simulation. Alternative modeling assumptions were assessed in scenario analysis. One-way sensitivity analysis was used to explore each parameter's impact on the uncertainty of the results. ResultsIn the base-case analysis, telbivudine was dominated by entecavir and tenofovir. Tenofovir strictly dominated lamivudine, telbivudine, and entecavir. Over the 72-year period of the model, the expected life expectancy (undiscounted) of lamivudine, telbivudine, entecavir, and tenofovir was 35.71, 36.94, 37.65, and 37.99 years, respectively. Tenofovir had the highest expected quality-adjusted life-years at 11.86 (discounted) in all comparisons. Scenario and sensitivity analyses proved the robustness of the base-case results. The projected 10-year cumulative incidence of cirrhosis and hepatocellular carcinoma was 11.40% and 3.05%, respectively, for tenofovir, which is significantly lower than that for lamivudine. ConclusionTenofovir generated the best results compared with all other therapies under evaluation.