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Brouwer, Willem Pieter/0000-0001-8713-1481; van Campenhout, Margo J.H./0000-0003-0460-4920 WOS:000478827400001 PubMed ID: 31135084 Serum Hepatitis B core-related antigen (HBcrAg) level moderately correlates with cccDNA. We examined whether HBcrAg can add value in monitoring the effect of peginterferon (PEG-IFN) therapy for HBeAg-negative chronic hepatitis B (CHB) infection. Thus, serum HBcrAg level was measured in 133 HBeAg-negative, mainly Caucasian CHB patients, treated with 48 weeks of PEG-IFN alfa-2a. We assessed its association with response (ALT normalization & HBV DNA < 2000 IU/mL) at week 72. HBcrAg level strongly correlated with HBV DNA level (r = 0.8, P < 0.001) and weakly with qHBsAg and ALT (both r = 0.2, P = 0.01). At week 48, mean HBcrAg decline was -3.3 log U/mL. Baseline levels were comparable for patients with and without response at week 72 (5.0 vs 4.9 log U/mL, P = 0.59). HBcrAg decline at week 72 differed between patients with and without response (-2.4 vs -1.0 log U/mL, P = 0.001), but no cut-off could be determined. The pattern of decline in responders resembled that of HBV DNA, but HBcrAg decline was weaker (HBcrAg -2.5 log U/mL; HBV DNA: -4.0 log IU/mL, P < 0.001). For early identification of nonresponse, diagnostic accuracy of HBV DNA and qHBsAg decline at week 12 (AUC 0.742, CI-95% [0.0.629-0.855], P < 0.001) did not improve by adding HBcrAg decline (AUC 0.747, CI-95% [0.629-0.855] P < 0.001), nor by replacing HBV DNA decline by HBcrAg decline (AUC 0.754, CI-95% [0.641-0.867], P < 0.001). In conclusion, in Caucasian patients with HBeAg-negative CHB, decline of HBcrAg during PEG-IFN treatment was stronger in patients with treatment response. However, HBcrAg was not superior to HBV DNA and qHBsAg in predicting response during PEG-IFN treatment. Foundation for Liver and Gastrointestinal Research, Rotterdam, the NetherlandsNetherlands Government; Fujirebio Europe, Ghent, Belgium; Dutch government (Health Holland- TKI-LSH) [LSHM15032]; Dutch government [FES0908]; F. HoffmannLa Roche Ltd., Basel, SwitzerlandHoffmann-La Roche This work was supported, initiated and sponsored by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. Financial support was provided by Fujirebio Europe, Ghent, Belgium and the Dutch government (Health Holland- TKI-LSH, [project number LSHM15032]). The studies are part of the Virgo consortium, funded by the Dutch government [project number FES0908]. For the original study, financial support, study medication and drug supply were provided by F. HoffmannLa Roche Ltd., Basel, Switzerland. The funding sources did not have any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication.

Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN +/- lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA

Aliment Pharmacol Ther 2011; 33: 501–513 Summary Background First-line treatment options for chronic hepatitis B (CHB) consist of nucleos(t)ide analogues with a high barrier to resistance (entecavir and tenofovir) or the immunomodulatory agent peginterferon (PEG-IFN). The optimal choice for individual patients remains controversial. Aim To review treatment options for CHB, with a focus on deciding between prolonged nucleos(t)ide analogue therapy or a finite course of PEG-IFN. Methods A comprehensive literature search was undertaken. Results Long-lasting, treatment-maintained suppression of hepatitis B virus (HBV) DNA without resistance is achievable in most patients by entecavir or tenofovir. A sustained off-treatment response is, however, unlikely and long-term therapy must be anticipated. PEG-IFN offers a higher rate of sustained response in a subgroup of patients, but is frequently complicated by side effects. Pre-treatment predictors of response, including HBV genotype, alanine aminotransferase and HBV DNA levels, aid in selecting patients for PEG-IFN therapy. Furthermore, on-treatment markers such as quantitative hepatitis B surface antigen may be applied to identify nonresponders early during the PEG-IFN treatment course, thereby preventing unnecessary treatment. Conclusions Both nucleos(t)ide analogues and PEG-IFN can be prescribed as first-line treatment options for CHB. However, PEG-IFN should only be considered for patients with a high chance of response based on pre-treatment and on-treatment factors.

Background and objectives: Serum Hepatitis B surface Antigen (HBsAg) levels correlate with hepatitis B virus intrahepatic covalently closed circular DNA and may predict response to treatment. Currently, 2 commercial platforms are available for HBsAg quantification in clinical practice, the Architect HBsAg QT and the Elecsys HBsAg. We aimed to directly compare the results of these assays. Study design: HBsAg levels were measured in 1427 serum samples from HBeAg-positive chronic hepatitis B patients who participated in a randomized trial of peginterferon alfa-2b +/- lamivudine. Samples were extracted from our serum bank, thawed, and subsequently analysed for HBsAg levels using both assays. Results: Of 1427 samples, 242 (17%) were taken before and 1185 during the treatment phase of the study. Distribution of HBV genotypes was 447 (31%) genotype A, 125 (9%) B, 210 (15%) C and 534 (37%) D. Correlation between Architect and Elecsys results was high (r = 0.96, p < 0.001). By Bland-Altman analysis, agreement between the two assays was close (mean difference between Architect and Elecsys: -0.01 log IU/mL, 95% CI: -0.55-0.52 log IU/mL), also when analysed separately for HBV genotypes A-D. Additionally, the performance of our recently published stopping rule for HBeAg-positive patients treated with peginterferon was comparable: the negative predictive values were 96% and 98% for Elecsys and Architect, respectively. Conclusions: There is a high correlation and close agreement between quantitative HBsAg measurements conducted with the Architect and the Elecsys. Clinical prediction rules derived from data from one platform can be applied on the other; both can therefore be used in clinical practice. (C) 2011 Elsevier B.V. All rights reserved.

Despite the introduction of new nucleos(t)ide analogues in recent years, peginterferon is still recommended as a potential first-line treatment option by current practice guidelines for the management of chronic hepatitis B. Peginterferon offers the advantage of higher sustained off-treatment response rates compared to nucleos(t)ide analogues because of its immunomodulatory effects. Sustained transition to the inactive hepatitis B surface antigen (HBsAg) carrier state can be achieved in about 30% of hepatitis B e antigen (HBeAg)-positive patients and 20% of HBeAg-negative patients. Recent studies have focused on identification of pretreatment and on-treatment factors that allow the selection of patients who are likely to achieve a sustained response to peginterferon therapy in order to avoid the side-effects and costs associated with unnecessary treatment. Future studies need to address whether specific virologic benchmarks can guide individualized decisions concerning therapy continuation and whether peginterferon combined with new potent nucleos(t)ide analogues improves treatment outcomes.

Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepathis B e antigen (HBeAg) negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB. (HEPATOLOGY 2010;52:454-461)