Sustained Hepatitis B E Antigen Seroconversion Research Articles

Relationship between hepatitis B core-related antigen levels and sustained HBeAg seroconversion in patients treated with nucleo(s)tide analogues.

Hepatitis B e antigen (HBeAg) seroconversion experienced during nucleo(s)tide analogue (NUC) therapy is often not sustained. We aimed to study whether hepatitis B core-related antigen (HBcrAg) levels predict sustained HBeAg seroconversion in patients treated with NUCs. We studied HBeAg-positive patients treated with NUCs for at least 6months. We quantified HBcrAg at baseline and at the time of HBeAg seroconversion and studied the relationship with HBeAg seroconversion and subsequent relapse. HBcrAg was quantified at baseline in 196 patients; levels varied significantly by HBV genotype and correlated with HBsAg, HBV DNA and HBeAg. Baseline HBcrAg levels were lower in patients who achieved HBeAg seroconversion than in those who did not; the unadjusted hazard ratio (HR) was 0.802 (95% CI: 0.656-0.980, P=0.031); and this association was not sustained in multivariate analysis. HBcrAg remained detectable in all patients at the time of HBeAg seroconversion. Higher HBcrAg at the time of seroconversion was an independent predictor of relapse (adjusted HR: 1.855 (95% CI: 1.099-3.133, P=0.021), and none of the patients with HBcrAg<4.90 log U/mL experienced relapse. Baseline HBcrAg is not an independent predictor of HBeAg seroconversion during NUC therapy. HBcrAg remains detectable in patients after HBeAg seroconversion. Patients with lower levels at the time of seroconversion have a higher probability of sustained HBeAg seroconversion.

Genetic variation in the vitamin D pathway CYP2R1 gene predicts sustained HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon: A multicenter study.

Evidence of a role of vitamin D in the immune system is increasing. Low serum vitamin D is associated with increased hepatitis B virus replication. Genome-wide association study (GWAS) data has revealed a number of the single nucleotide polymorphisms (SNPs) within the vitamin D synthetic pathway that affect vitamin D functions. We aimed to determine the association between SNPs in the vitamin D gene cascade and response to pegylated interferon (PegIFN) therapy in hepatitis B e-antigen (HBeAg)-positive patients. One hundred and eleven patients treated for 48 weeks with PegIFN-alfa 2a at 13 hospitals were retrospectively evaluated. Thirteen SNPs derived from vitamin D cascade-related genes, including DHCR7 (rs12785878), CYP27B1 (rs10877012), CYP2R1 (rs2060793, rs12794714), GC (rs4588, rs7041, rs222020, rs2282679), and VDR (FokI, BsmI, Tru9I, ApaI, TaqI), were genotyped. Thirty-one patients (27.9%) seroconverted to HBeAg after 24 weeks of treatment. Multivariate analysis found pretreatment qHBsAg <10,000 IU/mL (OR = 7.73, 95% CI: 2.36–25.31, P = 0.001), CYP2R1 rs12794714 TT genotype (OR = 4.16, 95% CI: 1.07–16.25, P = 0.04), and baseline ALT >2 times the upper limit of normal (OR = 3.83, 95% CI: 1.31–11.22, P = 0.014) predicted sustained HBeAg seroconversion after completion of PegIFN treatment. HBV DNA during study period tended to be lower with the rs12794714 CYP2R1 TT than the non-TT genotype. The rs12794714 CYP2R1 polymorphism may be a useful pretreatment factor predictive of sustained HBeAg seroconversion after PegIFN therapy. This study provides evidence that not only vitamin D level but also genetic variation of CYP2R1 in the vitamin D cascade influences host immune response in chronic HBV infection.

Prediction model for sustained hepatitis B e antigen seroconversion to peginterferon alfa-2a in chronic hepatitis B.

Clinically applicable models to predict hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) response to peginterferon (PEG-IFN) are scarce. This study aimed to develop simple scoring systems, based on multiple parameters, for predicting sustained HBeAg seroconversion to PEG-IFN. Eighty-five treatment-naïve patients with HBeAg-positive CHB underwent 52-week PEG-IFN treatment and 24-week follow-up. Logistic regression analysis assessed parameters at baseline and weeks 12, 24, and 52 to predict HBeAg seroconversion at week 24 off-treatment. The best three predictors at each time point were included in prediction models of PEG-IFN therapy efficacy. The three most meaningful predictors were alanine aminotransferase (ALT) > 5 × ULN, HBeAg ≤ 500 S/CO, and antibody to hepatitis B core antigen (anti-HBc) > 10.7 S/CO at baseline; HBeAg ≤ 20 S/CO, anti-HBc > 11.7 S/CO, and HBeAg decline > 1 log10 S/CO at week 12; ALT > 2 × ULN, HBeAg ≤ 15 S/CO, and anti-HBc > 10.4 S/CO at week 24; HBeAg ≤ 5 S/CO, anti-HBc > 11.1 S/CO, and hepatitis B virus DNA decline > 2 log10 copies/mL at week 52. Parameters meeting optimal cutoff thresholds were scored 1 or otherwise scored 0. For total scores of 0 versus 3 at baseline and weeks 12, 24, and 52, response rates were 6.3%, 12.5%, 0%, and 0% versus 90.0%, 83.3%, 76.9%, and 86.4%, respectively. We successfully established prediction models for PEG-IFN response in HBeAg-positive CHB.

Sustained Immune Control in HBeAg-Positive Patients who Switched from Entecavir Therapy to Pegylated Interferon-α2a: 1 Year follow-up of the OSST Study

In the OSST study, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who switched from long-term entecavir (ETV) therapy to pegylated interferon-α2a (PEG-IFN-α2a; 40 kDa) achieved higher rates of HBeAg seroconversion and hepatitis B surface antigen (HBsAg) loss than those who continued ETV. Herein we report the sustainability of serological responses during 1 year of untreated follow-up in patients who switched from ETV to PEG-IFN-α2a therapy. A total of 62 patients who completed 48 weeks of PEG-IFN-α2a therapy were followed-up for 48 weeks off treatment. Primary end points were HBeAg seroconversion and maintenance of HBeAg seroconversion at 48 weeks post-treatment. Secondary end points included HBsAg loss, HBV DNA <1,000 copies/ml and alanine aminotransferase normalization (<1× upper limit of normal). The HBeAg seroconversion rate increased from 17.7% (11/62) at the end of treatment to 38.7% (24/62) 1 year post-treatment. Sustained HBeAg seroconversion was achieved by 63.6% (7/11) patients with end-of-treatment responses, while late HBeAg seroconversion was achieved by 33.3% (17/51) of patients who did not have end-of-treatment responses. Sustained HBsAg loss was documented in 6 of 7 patients, and sustained HBV DNA suppression was achieved in 60% (27/45) of patients with an end-of-treatment response. In patients who do not achieve HBeAg seroconversion during long-term ETV therapy, switching to finite treatment with PEG-IFN-α2a produces HBeAg seroconversion in a substantial proportion of patients at end of treatment and during 1 year of follow-up. Moreover, HBeAg seroconversion and HBsAg loss are sustained in most patients during 1 year of untreated follow-up.

Recent advances in the treatment of chronic hepatitis B

Introduction: At present, two strategies exist for the treatment of chronic hepatitis B (CHB): i) standard or pegylated interferon alpha (IFN) with mainly immune modulatory effects; and ii) nucleos(t)ide analogues (NA) with direct antiviral effects. The optimal treatment for an individual patient remains controversial.Areas covered: The treatment efficacy and prediction of response to antiviral agents for chronic hepatitis B are reviewed and discussed.Expert opinion: The rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss or seroconversion are continuously increasing in CHB patients after stopping a finite course of IFN, whereas long-term NA therapy is usually required to improve the adverse outcomes of CHB. Lower baseline HBV DNA level is a strong predictor for both sustained viral suppression and HBeAg seroconversion in patients receiving IFN-based as well as NAs therapy. In addition, HBeAg-positive patients with genotype A or B infection have better responses to IFN-based therapy than those with genotypes C or D infection. Furthermore, on-treatment predictors such as declines of serum HBV DNA, HBsAg and HBeAg levels may be helpful in making decisions of subsequent therapy. Regarding the association of host genetic factors with responses to antiviral therapy, current evidence is limited.

Quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa‐2b in HBeAg‐positive patients

To evaluate the usefulness of quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) for predicting HBeAg seroconversion in chronic hepatitis B patients treated with conventional interferon (IFN) alfa-2b or PegIFN alfa-2b. Fifty-eight patients were enrolled; 29 for the training group and 29 for the validating group. Quantification of HBsAg and HBeAg was carried out at baseline, week 12, week 24, and then again at 12 and 24 weeks follow up, respectively, for two groups. Sixteen patients in the training group were followed up for 5 years. The cutoff of 1500 IU/mL in serum HBsAg at week 12 had a positive predictive value (PPV) of 33% and a negative predictive value (NPV) of 91%, and 2890 IU/mL at week 24 had a PPV of 43% and an NPV of 95% for HBeAg seroconversion at week 48. The cutoff of 17.55 Paul Ehrlich Institute units/mL (PEI-U/mL) in serum HBeAg at week 12 had a PPV of 38% and an NPV of 95%, and 8.52 PEI-U/mL at week 24 had a PPV of 44% and a NPV of 100% for HBeAg seroconversion at week 48. Moreover the HBsAg and HBeAg levels of PegIFN alfa-2b group were lower than those of the conventional IFN alfa-2b group. During follow up, patients with HBeAg seroconversion remained HBeAg negative and none of them progressed to cirrhosis, but among the patients with non-HBeAg seroconversion, two progressed to cirrhosis. Two additional patients with negative HBeAg were observed. On-treatment serum HBsAg and HBeAg had high predictive values to predict sustained HBeAg seroconversion by PegIFN alfa-2b. Patients who cleared HBeAg had better survival free of hepatic complications during long-term follow-up study.

Extended lamivudine consolidation therapy in hepatitis B e antigen-positive chronic hepatitis B patients improves sustained hepatitis B e antigen seroconversion

Objectives. Longer lamivudine (LAM) consolidation therapy after hepatitis B e antigen (HBeAg) seroconversion has been demonstrated to reduce the cumulative relapse rate. However, the optimal interval of LAM consolidation therapy remains controversial. We evaluated the post-treatment durability of LAM-induced HBeAg seroconversion and the length of LAM consolidation therapy required to maintain sustained HBeAg seroconversion. Material and methods. This retrospective study included 401 naive HBeAg-positive chronic hepatitis B patients who were treated with LAM 100 mg daily for at least 24 weeks (range 24–258 weeks). Among them, 124 patients who achieved a complete response (HBeAg seroconversion, alanine aminotransferase normalization, hepatitis B virus DNA < 200 copies/ml) at the end of LAM therapy were followed up for at least 48 weeks (range 48–350 weeks). Results. Of the 124 complete responders, 42 (33.87%) achieved a sustained response (persistent response ≥ 48 weeks). However, the cumulative relapse rates at 48 and 96 weeks post-treatment were 54.03% and 68.4%, respectively. Multivariate analysis revealed pretreatment age ≤ 34 years [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.40–3.62; p < 0.001] and LAM consolidation therapy ≥ 48 weeks (HR 2.44; 95% CI 1.35–4.40; p = 0.003) to be independent factors for predicting a sustained response. Conclusions. LAM-induced HBeAg seroconversion is not durable in Taiwan. However, a duration of LAM consolidation therapy > 48 weeks may be favorable for maintaining durable HBeAg seroconversion.

HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B

During the natural history of chronic hepatitis B virus (HBV) infection, the loss of serum hepatitis B e antigen (HBeAg) and the development of anti-HBe antibodies (HBeAg seroconversion) mark a transition from the immune-active phase of disease to the inactive carrier state. This review examines the evidence from natural history and cohort studies on the relationship between HBeAg seroconversion and disease progression. The role of HBeAg seroconversion as an important milestone in the management of HBeAg-positive patients with chronic hepatitis B (CHB), as well as the advantages and disadvantages of administering a finite course of therapy for HBeAg-positive CHB, is also discussed. The evidence from natural history and cohort studies indicates that spontaneous or treatment-induced HBeAg seroconversion is associated with lower rates of disease progression to cirrhosis and hepatocellular carcinoma, a potential of hepatitis B surface antigen seroconversion, and improved survival rates. Updated guidelines developed by major liver associations recommend stopping oral therapy for HBeAg-positive patients who achieve sustained HBeAg seroconversion with polymerase chain reaction-undetectable HBV-DNA on two separate occasions for 6 or more months apart, taking into consideration the individual's clinical and virologic response to therapy, as well as the severity of liver disease. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogues has important clinical and socioeconomic implications for the management of CHB.

Sustained Hepatitis B e Antigen Seroconversion in Patients with Chronic Hepatitis B after Adefovir Dipivoxil Treatment: Analysis of Precore and Basal Core Promoter Mutants

This study evaluated the persistence of hepatitis B e antigen (HBeAg) seroconversion (which is considered to be an important therapeutic end point) after adefovir dipivoxil treatment. Forty-five patients who experienced confirmed HBeAg seroconversion and had a serum hepatitis B virus DNA level < 10(5) copies/mL while receiving 10 mg of adefovir dipivoxil in a prior study were enrolled in the present study. At the time of the last dose of adefovir dipivoxil (baseline), the median age of the patients was 35 years, 64% were male, 73% were Asian, 27% were white, the median alanine aminotransferase level was 25 IU/L, and the median serum hepatitis B virus DNA level was 3.0 log copies/mL. The median follow-up time was 150 weeks (range, 13-252 weeks). Forty-one patients maintained sustained seroconversion at the last 2 assessments, and 4 experienced seroreversion at weeks 12 (3 patients) and 16 (1 patient) of follow-up. Approximately 50% of patients had a hepatitis B virus DNA level < 1000 copies/mL at the last visit of the study period. Of 13 patients who were viremic and had available samples at the last visit, 11 had basal core promoter and/or precore mutations. Notably, 8 of these 11 patients had basal core promoter and/or precore mutations before adefovir dipivoxil therapy despite being HBeAg positive. The median duration of adefovir dipivoxil treatment was shorter before seroconversion (48 vs. 108 weeks; P = .03) and longer after seroconversion (41 vs. 22 weeks; P = .02) for patients who experienced sustained seroconversion, compared with the patients who experienced seroreversion. Prolonged adefovir dipivoxil therapy after HBeAg seroconversion appeared to increase the likelihood of sustained HBeAg seroconversion. Most patients who experienced HBeAg seroconversion and had viremia had precore and/or basal core promoter mutants, which usually existed before initiation of adefovir dipivoxil therapy.

Long-Term follow-up of Lamivudine Treatment in Patients with Severe Acute Exacerbation of Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B

The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown. Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine aminotransferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls. Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0-7.1) years and 3.8 (range 3.5-8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for > or =6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment (P=0.02). Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.

Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy

Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy

Intrahepatic Hepatitis B Virus Covalently Closed Circular DNA Can Be a Predictor of Sustained Response to Therapy

This study aimed to determine whether intrahepatic hepatitis B virus (HBV) covalently closed circular (ccc) DNA and total HBV DNA levels at the end of therapy would predict sustained response to therapy. Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients receiving either lamivudine monotherapy or combination of peginterferon and lamivudine had liver biopsy at the end of 1 year therapy and were followed for 52 more weeks after cessation of therapy. Serum HBV DNA, intrahepatic HBV ccc DNA, and total HBV DNA levels were determined. Forty-seven patients, including 34 males and 13 females, were studied. Twenty-seven patients received combination therapy, and 20 patients received lamivudine monotherapy. Twenty-nine patients had end-of-treatment virologic response, and 15 patients had sustained response 52 weeks after therapy. At the end of treatment, log serum HBV DNA levels correlated well with log intrahepatic HBV cccDNA and log intrahepatic total HBV DNA levels. Log intrahepatic cccDNA and log intrahepatic total DNA levels were significantly lower among patients with sustained virologic response. The adjusted odds ratio for log cccDNA was 5.3 (95% CI: 1.5-18.2, P = .009) and, for log intrahepatic HBV DNA, was 4.4 (95% CI: 1.3-14.7, P = .015) to predict sustained virologic response. Using log cccDNA at -0.80 copies/genome equivalent as cutoff, the sensitivity, specificity, and positive and negative predictive values and accuracy of predicting sustained virologic response were 73%, 78%, 56%, 86%, and 77% respectively. Intrahepatic HBV cccDNA and intrahepatic total HBV DNA levels at the end of therapy are superior to serum HBV DNA as surrogates of sustained virologic response.