Serum hepatitis B surface antigen (HBsAg) levels may reflect the immunomodulatory efficacy of pegylated interferon (PEG‐IFN). We investigated within a large randomized trial whether quantitative ...HBsAg levels predict response to PEG‐IFN in patients with hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B. Serum HBsAg was measured in samples taken at baseline and weeks 4, 8, 12, 24, 52, and 78 of 221 patients treated with PEG‐IFN alfa‐2b with or without lamivudine for 52 weeks. HBsAg decline was compared between treatment arms and between responders and nonresponders. Response was defined as HBeAg loss with HBV DNA < 10,000 copies/mL at 26 weeks after treatment (week 78); 43 of 221 (19%) patients achieved a response. One year of PEG‐IFN with or without lamivudine resulted in a significant decline in serum HBsAg, which was sustained after treatment (decline 0.9 log IU/mL at week 78, P < 0.001). Patients treated with combination therapy experienced a more pronounced on‐treatment decline, but relapsed subsequently. Responders experienced a significantly more pronounced decline in serum HBsAg compared to nonresponders (decline at week 52: 3.3 versus 0.7 log IU/mL, P < 0.001). Patients who achieved no decline at week 12 had a 97% probability of nonresponse through posttreatment follow‐up and no chance of HBsAg loss. In a representative subset of 149 patients similar results were found for prediction through long‐term (mean 3.0 years) follow‐up. Conclusion: PEG‐IFN induces a significant decline in serum HBsAg in HBeAg‐positive patients. Patients who experience no decline from baseline at week 12 have little chance of achieving a sustained response and no chance of HBsAg loss and should be advised to discontinue therapy with PEG‐IFN. (HEPATOLOGY 2010)
Peginterferon alfa‐2a results in a sustained response (SR) in a minority of patients with hepatitis 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)
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 <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non‐WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non‐WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio OR 2.90, 95% confidence interval CI: 1.15‐7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26‐24.63, P = 0.013) and patients with non‐A genotypes with detectable mutants had a low probability of response. Conclusion: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG‐IFN for HBeAg‐positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG‐IFN therapy. (HEPATOLOGY 2012;56:67–75)
Background & Aims It was recently demonstrated that none of the hepatitis B e antigen (HBeAg)-negative patients without any serum hepatitis B surface antigen (HBsAg) decline and with <2 log hepatitis ...B virus (HBV) DNA decline at week 12 of a 48-week peginterferon alfa-2a (PEG-IFN) treatment course achieved a sustained response (SR). We aimed at validating this stopping rule in two independent trials. Methods HBeAg-negative patients receiving 48 or 96 weeks of PEG-IFN in the phase III registration trial (N = 85) and PegBeLiver study (N = 75) were stratified according to the presence of any HBsAg decline and/or ⩾2 log HBV DNA decline at week 12. SR was defined as HBV DNA <2000 IU/ml and normal alanine aminotransferase 24 weeks after treatment. Results The original PARC trial included 102 patients (genotype A/D/other: 14/81/7), 25 (25%) had an SR. The validation dataset consisted of 160 patients (genotype A/B/C/D/other: 10/18/34/91/7), 57 (36%) achieved an SR. The stopping rule performed well across the two studies ( p = 0.001) and its negative predictive value NPV was 95% in the validation dataset harbouring genotypes A–D. Its performance was best for genotype D. Moreover, among the 34 patients treated for 96 weeks, none of the 7 (21%) without HBsAg decline and with <2 log HBV DNA decline at week 12 achieved an SR (NPV 100%). Conclusions We confirmed in two independent studies that the combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients with a very low chance of SR to either 48 or 96 weeks of PEG-IFN therapy.
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.
Background & Aims We aimed to investigate serum hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B virus (HBV) infection during peginterferon (PEG-IFN) and entecavir ...(ETV) monotherapy. Methods HBsAg was quantified (Abbott ARCHITECT) at baseline and during antiviral therapy (weeks 12, 24, 36, 48) in hepatitis B e antigen (HBeAg-) positive patients treated with ETV ( n = 33) or PEG-IFN ( n = 61) and in HBeAg-negative patients treated with ETV ( n = 37) or PEG-IFN ( n = 69). Results Within the HBeAg-positive population, patients treated with PEG-IFN tended to have a steeper HBsAg decline than ETV-treated patients (mean decline 0.94 versus 0.38 log IU/ml at week 48, p = 0.07 for comparison of the slope of HBsAg decline). The HBsAg decline was larger in those patients who became HBeAg negative, irrespective of the treatment regimen. A decline in HBsAg was confined to ETV-treated patients with elevated baseline alanine aminotransferase (ALT) levels, whereas HBsAg decline was not associated with baseline ALT in patients treated with PEG-IFN. Within the HBeAg-negative population, PEG-IFN induced a significant HBsAg decline, while HBsAg did not decrease in ETV-treated patients (0.56 versus −0.10 log IU/ml, p <0.001). Both in HBeAg-positive and HBeAg-negative patients, the decline in serum HBV DNA was larger in patients who received ETV as compared to patients treated with PEG-IFN. Conclusions In HBeAg-positive patients, the decline in serum HBsAg is mainly confined to patients who clear HBeAg, by either PEG-IFN or ETV treatment. In HBeAg-negative patients, PEG-IFN therapy resulted in a significant reduction in HBsAg levels, whereas HBsAg did not decrease in ETV-treated patients.
Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon alpha-2a with ribavirin might improve ...sustained response rates.
Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon alpha-2a 180 microg weekly plus placebo) or combination therapy (peginterferon alpha-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients.
At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline -3.9 vs. -2.6 log copies/ml, P<0.001 and -0.56 vs. -0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia.
Treatment with peginterferon alpha-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.
Background & Aims Migrants born in countries where hepatitis B is endemic are a risk group for chronic hepatitis B virus (HBV) infection. Treatment options have improved, but due to the asymptomatic ...nature of chronic HBV infection, the majority of patients remain unidentified. Methods In 2009, a campaign targeting the Chinese community was held in the city of Rotterdam, The Netherlands. The campaign combined disease awareness activities with free HBV testing at outreach locations. Chronically HBV infected patients were referred to specialist care based on a referral guideline. Before and after the campaign, knowledge of chronic hepatitis B was measured through questionnaires in a convenience sample of the target population (n = 285 and n = 277). Results In a period of 3 months, 13 outreach activities took place and 1090 Chinese migrants were tested for HBV. Forty-nine percent had serological signs of a past or recent HBV infection and 8.5% (n = 92) were chronically infected. Thirty-eight percent (n = 35) of chronically infected patients were referred for evaluation by a specialist and of these, 15 started antiviral treatment within 1 year of follow-up. Before the campaign, 55% answered correctly to 6 or more out of 10 knowledge items. Knowledge was positively associated with educational level. After the campaign, an increase in knowledge was observed in participants with low levels of education. Conclusions Chinese migrants could be reached with an outreach campaign, and on-site testing was well accepted. A high prevalence of chronic HBV infection was found and referral to specialist care and initiation of treatment was successful.
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