Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level( 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable( 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.     

Prevalence and clinical features of patients with concurrent HBsAg and anti‐HBs: Evaluation of the hepatitis B research network cohort

The prevalence of concurrent HBsAg and anti‐HBs in plasma of persons with chronic hepatitis B virus (HBV) infection is variable and its clinical significance enigmatic. We examined the prevalence and clinical and virological features of concurrent HBsAg and anti‐HBs in children and adults with chronic HBV infection living in North America. A total of 1462 HBsAg positive participants in the Hepatitis B Research Network paediatric and adult cohorts were included (median age 41 (range 4‐80) years, 48% female, 11% white, 13% black, 73% Asians). Only 18 (1.2%) were found to be anti‐HBs positive (≥10 mIU/mL) at initial study evaluation. Distributions of sex, race, HBV genotype and ALT were similar between participants with and without concurrent anti‐HBs. Those who were anti‐HBs positive appeared to be older (median age 50 vs 41 years, P = .06), have lower platelet counts (median 197 vs 222 × 103/mm³, P = .07) and have higher prevalence of HBeAg (44% vs 26%, P = .10). They also had lower HBsAg levels (median 2.0 vs 3.5 log₁₀ IU/mL, P = .02). Testing of follow‐up samples after a median of 4 years (range 1‐6) in 12 of the 18 participants with initial concurrent anti‐HBs showed anti‐HBs became undetectable in 6, decreased to <10 mIU/mL in 1 and remained positive in 5 participants. Two patients lost HBsAg during follow‐up. In conclusion, prevalence of concurrent HBsAg and anti‐HBs was low at 1.2%, with anti‐HBs disappearing in some during follow‐up, in this large cohort of racially diverse children and adults with chronic HBV infection living in North America. Presence of concurrent HBsAg and anti‐HBs did not identify a specific phenotype of chronic hepatitis B, nor did it appear to affect clinical outcomes.     

HBsAg clearance by Peg-interferon addition to a long-term nucleos(t)ide analogue therapy

The ideal endpoint of hepatitis B virus (HBV) antiviral therapy is HBsAg loss, a difficult goal to obtain, especially in HBeAg negative patients. Herein, we report the results obtained by the addition of peg-interferon α-2a to a long-lasting nucleos(t)ide analogue therapy in a HBeAg negative, genotype D patient with steadily HBV-DNA negative/HBsAg positive values. In 2002, our Caucasian 44-year-old male patient received lamivudine and, 4 years later, added adefovir because of a virological breakthrough. In 2011, considering his young age, liver stiffness (4.3 kPa) and HBsAg levels (3533 IU/mL), we added Peg-interferon α-2a for six months (3 in combination with nucleos(t)ide analogues followed by 3 mo of Peg-interferon α-2a monotherapy). A decrease of HBsAg levels was observed after 1 mo (1.21 log) of Peg-interferon and 3 mo (1.88 log) after the discontinuation of all drugs. Later, a complete clearance of HBsAg was obtained with steadily undetectable HBV-DNA serum levels (< 9 IU/mL). HBsAg clearance by the addition of a short course of Peg-interferon α-2a represents an important result with clinical and pharmaco-economic implications, considering that nucleos(t)ide analogues therapy in HBeAg negative chronic hepatitis B patients is considered a long-lasting/life-long treatment.     

Factors Associated with Hepatitis B Surface Antigen Kinetics and Responses in Pegylated Interferon Alpha-2a Monotherapy for Patients with Chronic Hepatitis B

Objective Pegylated-interferon monotherapy is the standard treatment for patients with chronic hepatitis B; however, the factors associated with its therapeutic effects remain unclear. Methods Patients with chronic hepatitis B were treated with pegylated interferon α-2a for 48 weeks. We evaluated the kinetics of hepatitis B surface antigen (HBsAg) during treatment and follow-up periods and the factors associated with an HBsAg response (defined as a change in HBsAg of ≥-1 log IU/mL from baseline). Results The study population comprised 50 patients. The median baseline levels of hepatitis B virus DNA and HBsAg were 5.00 and 3.40 log IU/mL. The median values of HBsAg reduction from baseline were -0.44 (n=48), -0.41 (n=40), and -0.68 (n=11) log IU/mL at the end of treatment and at 48 and 144 weeks post-treatment, respectively. The rates of HBsAg response were 24.0% and 22.5% at the end of treatment and at 48 weeks post-treatment, respectively. A multivariate analysis identified HBsAg <3.00 log IU/mL as an independent baseline factor contributing to the HBsAg response at the end of treatment and 48 weeks post-treatment (p=1.07×10^-2 and 4.42×10^-2, respectively). There were significant differences in the reduction of the HBsAg levels at 12 weeks of treatment and in the incidence of serum ALT increase during treatment between patients with and without an HBsAg response. Conclusion These findings suggest that the baseline HBsAg level, HBsAg kinetics at 12 weeks of treatment, and ALT increase during treatment are important factors contributing to the HBsAg response in pegylated interferon α-2a monotherapy for patients with chronic hepatitis B.     

Baseline HBsAg predicts response to pegylated interferon-α2b in HBeAg-positive chronic hepatitis B patients

AIM: To evaluate the predictive effect of baseline hepatitis B surface antigen (HBsAg) on response to pegylated interferon (PEG-IFN)-α2b in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.METHODS: This retrospective analysis compared the treatment efficacy of PEG-IFN-α2b alone in 55 HBeAg-positive CHB patients with different baseline HBsAg levels. Serum HBV DNA load was measured at baseline, and at 12, 24 and 48 wk of therapy. Virological response was defined as HBV DNA < 1000 IU/mL. Serum HBsAg titers were quantitatively assayed at baseline, and at 12 and 24 wk.RESULTS: Eighteen patients had baseline HBsAg > 20 000 IU/mL, 26 patients had 1500-20000 IU/mL, and 11 patients had < 1500 IU/mL. Three (16.7%), 11 (42.3%) and seven (63.6%) patients in each group achieved a virological response at week 48, with a significant difference between groups with baseline HBsAg levels > 20000 or < 20000 IU/mL (P = 0.02). Thirteen patients had an HBsAg decline > 0.5 log₁₀ and 30 patients < 0.5 log₁₀ at week 12; and 6 (46.2%) and 10 (33.3%) in each group achieved virological response at week 48, with no significant difference between the two groups (P = 0.502). Eighteen patients had an HBsAg decline > 1.0 log₁₀ and 30 patients < 1.0 log₁₀ at week 24, and 8 (44.4%) and 11 (36.7%) achieved a virological response at week 48, with no significant difference between the two groups (P = 0.762). None of the 16 patients with HBsAg > 20000 IU/mL at week 24 achieved a virological response at week 48.CONCLUSION: Baseline HBsAg level in combination with HBV DNA may become an effective predictor for guiding optimal therapy with PEG-IFN-α2b against HBeAg-positive CHB.     

Impact of Pegylated Interferon-alfa-2a on Perforin Level in Patients With Chronic Hepatitis B; Preliminary Study

Background

Chronic hepatitis B is one of the most common causes of cirrhosis and hepatocellular toxicity in many countries, including Iran. Cytotoxic T lymphocyte (CTL) and Natural killer (NK) cells are the two of main cell populations considered as cytotoxic cells. One of the distinct pathways CTL and NK cells exert cytotoxicity is perforin/granzyme. After the cytotoxic cell/target cell junction, perforin is released from granules by exocytosis. Once it is anchored, perforin forms cylindrical pores through which granzymes and granulysin enter and induce apoptosis.

Objectives

Large controlled trials have demonstrated the efficacy of PEG-IFN-α-2a in treatment of chronic hepatitis B. This study was aimed to examine whether the enhancement of cytotoxicity by PEG-IFN-α-2a is mainly due to the perforin pathway.

Patients and Methods

This research work was performed on 50 patients and five healthy people. Patients with chronic hepatitis B were further subdivided into two groups: patients with inactive chronic hepatitis B (carriers, n = 30), and those with active chronic hepatitis B who were under treatment with PEG-IFN-alfa-2a (n = 20) for minimum six and maximum 12 months. Serum perforin level was measured using ELISA method (CUSABIO Company), HBV viral load was assessed using COBAS Taq-man, and we used Elecsys hepatitis B surface antigen (HBs Ag) II quantitative assay method for HBs Ag determination. HBeAg was evaluated by ELISA method, and AST and ALT were measured by routine laboratorymethods.

Results

Based on the results obtained serum perforin level in healthy group was 0.64 ng/mL, the mean of serum perforin level in inactive HBs Ag carriers was 2.63ng/mL, and 4.63 ng/mL in patients with active chronic hepatitis B under treatment with PEG-IFN-α-2a. The mean of serum perforin level in patients with and without virologic response to treatment were 5.45 ng/mL,and 3.4 ng/mL respectively. Finally in patients with virologic response and seroconverted serum perforin level was 7.23 ng/mL.

Conclusions

Based on our results higher perforin level in patients under treatment with PEG-IFN-α-2a, could be an indication of elevated cytotoxicity via perforin/granzyme pathway.     

Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community‐based real‐world study

Community‐based real‐world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re‐emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti‐HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re‐emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg‐positive and HBeAg‐negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti‐HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on‐treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re‐emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community‐based real‐world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti‐HBs, nearly all patients achieved sustained undetectable virus.     

Identified OAS3 gene variants associated with coexistence of HBsAg and anti‐HBs in chronic HBV infection

The underlying mechanism of coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antigen antibody (anti‐HBs) is still controversial. To identify the host genetic factors related to this unusual clinical phenomenon, a two‐stage study was conducted in the Chinese Han population. In the first stage, we performed a case‐control (1:1) age‐ and gender‐matched study of 101 cases with concurrent HBsAg and anti‐HBs and 102 controls with negative HBsAg and positive anti‐HBs using whole exome sequencing. In the second validation stage, we directly sequence the 16 exons on the OAS3 gene in two dependent cohorts of 48 cases and 200 controls. Although, in the first stage, a genome‐wide association study of 58,563 polymorphism variants in 101 cases and 102 controls found no significant loci (P‐value ≤ .05/58563), and neither locus achieved a conservative genome‐wide significance threshold (P‐value ≤ 5e‐08), gene‐based burden analysis showed that OAS3 gene rare variants were associated with the coexistence of HBsAg and anti‐HBs. (P‐value = 4.127e‐06 ≤ 0.05/6994). A total of 16 rare variants were screened out from 21 cases and 3 controls. In the second validation stage, one case with a stop‐gained rare variant was identified. Fisher’s exact test of all 149 cases and 302 controls showed that the rare coding sequence mutations were more frequent in cases vs controls (P‐value = 7.299e‐09, OR = 17.27, 95% CI [5.01‐58.72]). Protein‐coding rare variations on the OAS3 gene are associated with the coexistence of HBsAg and anti‐HBs in patients with chronic HBV infection in Chinese Han population.     

HBV reactivation in patients with HCV/HBV cirrhosis on treatment with direct‐acting antivirals

Anecdotal reports suggest that patients with chronic hepatitis C virus (HCV) hepatitis and overt or occult hepatitis B virus (HBV) coinfection may reactivate HBV when HCV is suppressed or cleared by direct‐acting antivirals (DAAs). We assessed the prevalence of overt or previous HBV coinfection and the risk of HBV reactivation in patients with HCV cirrhosis treated with DAAs. This was a retrospective cohort of 104 consecutive patients with HCV cirrhosis treated with DAAs. Serum HCV‐RNA and HBV‐DNA were tested at weeks 4, 8 and 12 of DAAs therapy and at week 12 of follow‐up. At the start of DAAs, eight patients (7.7%) were HBsAg positive/HBeAg negative with undetectable HBV‐DNA and low levels of quantitative HBsAg (four on nucleos(t)ide analogues [NUCs] and four inactive carriers), 37 patients (35.6%) had markers of previous HBV infection (25 anti‐HBc positive, 12 anti‐HBc/anti‐HBs positive) and 59 (56.7%) had no evidence of HBV infection. Sixty‐seven patients (64.4%) were HCV‐RNA negative at week 4 and 98 (94.2%) achieved sustained virological response. All four HBsAg‐positive patients treated with NUCs remained HBV‐DNA negative, but three of four untreated patients showed an increase in HBV‐DNA of 2‐3 log without a biochemical flare and achieved HBV‐DNA suppression when given NUCs. During or after DAAs, by conventional assay, HBV‐DNA remained not detectable in all 37 anti‐HBc‐positive patients but in three of them (8.1%) HBV‐DNA became detectable with a highly sensitive PCR. HBV reactivation is likely to occur in untreated HBV/HCV‐coinfected cirrhotic patients when they undergo HCV treatment with DAAs. Pre‐emptive therapy with NUCs should be considered in this setting. Anti‐HBc‐positive patients rarely reactivate HBV without clinical or virological outcomes.     

Clinical Predictors of Functional Cure in Children 1–6 Years-old with Chronic Hepatitis B

Background and AimsHepatitis B surface antigen (HBsAg) clearance is significantly more common in children with chronic hepatitis B (CHB) than in adults; however, the possible influencing factors related to HBsAg loss have yet to be found. This study aimed to explore the efficacy of long-term interferon (IFN)α therapy in treating children with CHB and analyzed the factors influencing functional cure after treatment.MethodsA total of 236 children aged 1–6 years and diagnosed with CHB via liver biopsy were included in the study, all receiving IFNα treatment (IFNα-2b monotherapy, IFNα-2b followed by lamivudine [LAM] or IFNα-2b combined with LAM) and followed up for 144 weeks. A comprehensive analysis was conducted on clinical data, including biochemical items, serum markers of hepatitis B virus (HBV) and immunological indexes, and logistic regression analysis was used to screen the influencing factors related to HBsAg loss.ResultsThe cumulative loss rates of HBsAg were 79.5%, 62.1% and 42.1% at 144 weeks after the start of treatment in the 1–3 years-old group, 3–5 years-old group and 5–7 years-old group, respectively (p<0.05). IFNα-2b combined with LAM treatment displayed the highest HBsAg loss rates compared with monotherapy and sequential treatment (p=0.011). Younger baseline age and lower HBsAg levels were independent factors for the prediction of HBsAg loss (p<0.05). The baseline PreS1 and hepatitis B core antibody levels in the HBsAg loss group were lower than those in the HBsAg non-loss group. In addition, the PreS1 level was positively corelated with the level of HBsAg, HBV DNA and liver inflammation.ConclusionsLong-term treatment with IFNα was effective in achieving HBsAg loss in CHB children aged 1–6 years-old. Age less than 3 years-old and lower HBsAg levels are independent predictors of functional cure in children with CHB.     

Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct‐acting antiviral therapy

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon‐free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co‐infected patients and 765 patients with resolved HBV infection during and after treatment with direct‐acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti‐HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)‐positive patients with an HBV DNA level <2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti‐HBs titres at baseline with those at post‐DAA therapy in 123 patients without HBsAg. There was no significant difference in anti‐HBs levels between the two points (P = .79). In conclusion, HBV reactivation was rare in HBsAg‐negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV‐reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA therapy.     

Epidemiological characteristics of the carriers with coexistence of HBsAg and anti‐HBs based on a community cohort study

The coexistence of HBsAg and anti‐HBs is an atypical serological pattern in HBV infection. There is no epidemiological characteristics of this serological pattern in the community and there is controversy over the molecular mechanisms underlying this pattern. We investigated the epidemiological characteristics of the carriers with HBsAg and anti‐HBs in a longitudinal community cohort study. The prevalence of this atypical serological pattern was 2.93% (122/4169) in HBsAg‐positive populations. The prevalence progressively increased with age from 40 to 70 years old. The rate of HBeAg positive and detectable HBV DNA were both significantly higher in carriers with this pattern than in carriers who were HBsAg positive but anti‐HBs negative (26/122 verse 598/4047, P = 0.046; 86/122 verse 275/529,P < 0.001). After 1 year of follow‐up, 85.19% of the carriers still had coexistence HBsAg and anti‐HBs, 14.81% of the carriers lost their anti‐HBs. Viral sequencing showed that carriers with coexistence of HBsAg and anti‐HBs had higher numbers of residue changes within the S gene than carriers who were HBsAg positive but anti‐HBs negative (2.42 verse 1.33 changes per 100 residues, P < 0.05). Hence, the coexistence of HBsAg and anti‐HBs is a unique serological pattern which may be associated with an increased risk of adverse clinical outcome and may be related to HBsAg immune variants which have genotypic heterogeneity.     

Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients

The impact of prolonged direct antiviral therapy on hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B is poorly understood. We quantitatively assessed serum HBsAg levels during 3 years of telbivudine treatment, as well as their relationship with virologic and biochemical characteristics in 162 hepatitis B e antigen-positive patients who maintained undetectable serum hepatitis B virus (HBV) DNA long-term. Telbivudine treatment progressively reduced serum HBsAg levels (mean ± SD) from baseline (3.8 ± 0.6 log?? IU/mL) to treatment week 24 (3.4 ± 0.7 log?? IU/mL), treatment year 1 (3.3 ± 0.8 log?? IU/mL), and treatment year 3 (3.0 ± 1.4 log?? IU/mL) (P <0.0001). In this patient population, HBsAg loss was observed in nine (6%) of 162 patients through year 3. During the first year of treatment, three patterns of HBsAg decline were observed: rapid (≥ 1 log?? IU/mL) in 32 patients, slow (0-1 log?? IU/mL) in 74 patients, and steady levels in 56 patients. These findings were associated with different likelihoods of HBsAg loss during long-term telbivudine therapy. Eight of 32 patients with rapid HBsAg decline versus none of 56 patients with steady HBsAg levels achieved HBsAg loss at year 3 (P = 0.0024). HBV genotype was a significant determinant for HBsAg kinetics, with the fastest decline in genotype A patients. In patients with subsequent HBsAg loss, viral antigens were already undetectable in liver biopsy samples after 1 year of treatment. This was associated with markedly enhanced antiviral T cell reactivity. CONCLUSION: In patients who have effective suppression of viral replication during telbivudine treatment, a rapid decline in serum HBsAg levels during the first year may identify those with a greater likelihood of achieving HBsAg clearance.     

Persistent and transient hepatitis B virus (HBV) infections in children born to HBV‐infected mothers despite active and passive vaccination

Summary. Combined passive and active immunization for newborns very effectively prevents perinatal hepatitis B virus (HBV) infections. In the Netherlands, babies born to hepatitis B surface antigen (HBsAg)‐positive women receive passive immunization with hepatitis B and at least three active HBsAg vaccinations. Serological testing for the presence of HBV markers was offered for all infants born to HBsAg‐positive mothers between January 2003 and July 2007, after completion of their vaccination schedule. About 75% of the infants (n = 1743) completed their HB‐vaccination schedule and participated in the serologic evaluation. Twelve of them (0.7%) were found to be HBV infected. Furthermore, we identified three older children with high levels of anti‐HBc, anti‐HBs and anti‐HBe, while they were HBsAg and HBV DNA negative. This serologic profile is evidence for a resolved HBV infection. In the group of older children (1.5–5 years of age, n = 728), about half of the HBV‐infected children (3 of 7) had already cleared their infection at the time of sampling. For a proper evaluation of the efficacy of a new intervention programme to prevent vertical HBV transmission, it is also important to analyse the HBV markers in serum collected when the children are older than 1.5 years. In a programmatic setting, all children born to HBV‐infected mothers should be tested not only for the level of anti‐HBs but also for the absence of HBsAg, because 2 of the 12 HBV‐infected children (17%) had a high level of anti‐HBs.     

Analysis of hepatitis B surface antigen (HBsAg) using high‐sensitivity HBsAg assays in hepatitis B virus carriers in whom HBsAg seroclearance was confirmed by conventional assays

Aim

We investigated the utility of high‐sensitivity hepatitis B surface antigen (HBsAg) assays compared with conventional HBsAg assays.

Methods

Using serum samples from 114 hepatitis B virus (HBV) carriers in whom HBsAg seroclearance was confirmed by conventional HBsAg assays (cut‐off value, 0.05 IU/mL), the amount of HBsAg was re‐examined by high‐sensitivity HBsAg assays (cut‐off value, 0.005 IU/mL). Cases negative for HBsAg in both assays were defined as consistent cases, and cases positive for HBsAg in the high‐sensitivity HBsAg assay only were defined as discrepant cases.

Results

There were 55 (48.2%) discrepant cases, and the range of HBsAg titers determined by high‐sensitivity HBsAg assays was 0.005–0.056 IU/mL. Multivariate analysis showed that the presence of nucleos(t)ide analog therapy, liver cirrhosis, and negative anti‐HBs contributed to the discrepancies between the two assays. Cumulative anti‐HBs positivity rates among discrepant cases were 12.7%, 17.2%, 38.8%, and 43.9% at baseline, 1 year, 3 years, and 5 years, respectively, whereas the corresponding rates among consistent cases were 50.8%, 56.0%, 61.7%, and 68.0%, respectively. Hepatitis B virus DNA negativity rates were 56.4% and 81.4% at baseline, 51.3% and 83.3% at 1 year, and 36.8% and 95.7% at 3 years, among discrepant and consistent cases, respectively. Hepatitis B surface antigen reversion was observed only in discrepant cases.

Conclusions

Re‐examination by high‐sensitivity HBsAg assays revealed that HBsAg was positive in approximately 50% of cases. Cumulative anti‐HBs seroconversion rates and HBV‐DNA seroclearance rates were lower in these cases, suggesting a population at risk for HBsAg reversion.     

Incidence of hepatitis B virus infection in young Chinese blood donors born after mandatory implementation of neonatal hepatitis B vaccination nationwide

This study was carried out to determine the incidence of hepatitis B virus (HBV) infection in the young generation born after mandatory implementation of hepatitis B vaccination since 1992. Repeat blood donors born between 1992 and 1997 were enrolled, who gave blood at least twice during the past 3 years. Donors were tested for HBV infection markers of HBsAg, anti‐HBc, anti‐HBs and viral DNA by immunoassays (EIAs) and nucleic acid tests (NAT). A total of 14 937 pre‐donation screening qualified young repeat donors aged 18‐23 years were tested with 9 (0.06%) being HBsAg by EIA and 10 (1:1494) HBV DNA positive by Ultrio NAT (10.4 IU/mL), respectively. HBV DNA was further detected in 1:192 (9/1732) anti‐HBc+ repeat donors with Ultrio Plus NAT (3.4 IU/mL). Most cases were identified as occult HBV infection (OBI). Of 14 937 repeat donors, 20.9% were anti‐HBc+ positive, while approximately 50% of 12 024 repeat donors were anti‐HBs negative or had levels <100 IU/L. HBsAg+ or OBI strains were classified as wild type of genotype B or genotype C. Incident HBV infection in repeat donors was approximately 1:18.5 person‐years (1.1%/year) but significantly less frequent in donors with confirmed HBV vaccination (2.4%‐3.3%) than those unsure of vaccination status (10.5%; P = .0023). Hepatitis B virus vaccination appears largely protective of HBV infection, but incidence of infections increases in young adults with mostly undetectable or low anti‐HBs or occasionally high anti‐HBs. A boost of hepatitis B vaccine for adolescents prior to age 18 years may reduce HBV infection, and implementation of more sensitive NAT in blood donation screening may improve HBV safety in blood transfusion.     

Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: results of a pilot study

Sustained viral suppression using monotherapy with interferon alfa (IFN-alpha) or lamivudine can only be achieved in a small percentage of patients with chronic hepatitis B. The concomitant administration of lamivudine and IFN-alpha does not enhance efficacy. We postulated that the optimal timing of therapy might be sequential treatment with lamivudine and IFN-alpha. The aim of this study was therefore to assess the efficacy of sequential treatment in patients resistant to IFN-alpha alone. Fourteen male patients, with a median age of 40 years, nonresponders to IFN-alpha with hepatitis B virus (HBV) DNA > 100 pg/mL (branched DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg) in 11 of 14 patients, were treated with lamivudine 100 mg/d alone for 20 weeks, then with both IFN-alpha2b 5 MU 3 times per week and lamivudine for 4 weeks, and lastly with IFN-alpha alone for 24 weeks. At the end of lamivudine therapy, all patients had undetectable serum HBV DNA, and none exhibited an emergence of HBV polymerase mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months after the end of sequential treatment was achieved in 8 of 14 patients, HBeAg-to-anti-HBe seroconversion in 5 of 11 patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions in 3 of 14 patients (anti-HBs > 100 IU/mL). All sustained responders had normalized their alanine transaminase (ALT) values and exhibited histologic improvements. In conclusion, the results of this pilot study suggest that sequential treatment with lamivudine and IFN-alpha can induce a sustained virologic response, including HBs seroconversion, in patients with chronic hepatitis B not responding to IFN-alpha alone, without the selection of drug-resistant mutants. This therapeutic schedule warrants further evaluation in clinical trials.     

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 6 months. 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.     

Occult hepatitis B virus infection: a covert operation

Summary. Detection of occult hepatitis B requires assays of the highest sensitivity and specificity with a lower limit of detection of less than 10 IU/mL for hepatitis B virus (HBV) DNA and <0.1 ng/mL for hepatitis B surface antigen (HBsAg). This covert condition is relatively common in patients with chronic hepatitis C virus (HCV) that seems to exert some influence on the replicative capacity and latency of HBV. Detection of virus‐specific nucleic acid does not always translate into infectivity, and the occurrence of primer‐generated HBV DNA that is of partial genomic length in immunocompetent individuals who have significant levels of hepatitis B surface antibody (anti‐HBs) may not be biologically relevant. Acute flares of alanine aminotransferase (ALT) that occur during the early phase of therapy for HCV or ALT levels that remain elevated at the end of therapy in biochemical nonresponders should prompt an assessment for occult hepatitis B. Similarly, the plasma from patients with chronic hepatitis C that is hepatitis B core antibody (anti‐HBc) positive (±anti‐HBs at levels of <100 mIU/mL) should be examined for HBV DNA with the most sensitive assay available. If a liver biopsy is available, immunostaining for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) should be contemplated and a portion of the sample tested for HBV DNA. This is another reason for optimal collection of a specimen (e.g. two passes with a 16‐guage needle under ultrasound guidance). Transmission of HBV to immunosuppressed orthotopic liver transplant recipients by donors with occult hepatitis B (OHB) will continue to occupy the interests of the transplant hepatologist. As patients with OHB may have detectable HBV DNA in serum, peripheral blood mononuclear cells (PBMC) and/or liver that can be reactivated following immunosuppression or intensive cytotoxic chemotherapy, the patient needs to be either monitored or treated depending on the pretreatment serological results such as an isolated anti‐HBc reaction or a detectable HBV DNA.     

A pilot study of extended duration peginterferon alfa-2a for patients with hepatitis B e antigen-negative chronic hepatitis B

OBJECTIVES: Forty-eight weeks of peginterferon alfa-2a is the approved regimen for chronic hepatitis B (CHB). Standard interferon is more effective for hepatitis B e antigen (HBeAg)-negative CHB when given for longer than 1 yr. This study evaluated peginterferon alfa-2a for 60 wk, alone or in combination with lamivudine. METHODS: Thirteen patients with HBeAg-negative CHB received peginterferon alfa-2a (180 microg/week) for 60 wk or peginterferon alfa-2a (180 microg/week) for 12 wk followed by 48 wk of peginterferon alfa-2a plus lamivudine. The primary end point, sustained virologic response (SVR), was defined as a reduction in hepatitis B virus deoxyribonucleic acid (HBV DNA) of >or=2 log10 copies/mL and HBV DNA<20,000 copies/mL at 24 wk of follow-up (week 84). Hepatitis B surface antigen (HBsAg) concentrations were analyzed and compared to changes in HBV DNA. RESULTS: SVR was achieved by 9/13 patients (69%). At week 84, HBV DNA was undetectable by polymerase chain reaction in 5/13 (38%) patients, and 3 additional patients had a sustained 2-3 log reduction in HBV DNA. Five patients demonstrated a >90% decrease in HBsAg concentration at week 60, including 3 with undetectable HBV DNA at week 84 and a fourth who met criteria for SVR. CONCLUSIONS: Sixty weeks of peginterferon alfa-2a with or without lamivudine resulted in a higher rate of SVR compared to historical controls with HBeAg-negative CHB treated with 48 wk of pegylated interferon. Larger studies are necessary to assess if longer duration therapy is more effective than the standard regimen and results in a greater decline in HBsAg concentration.