BACKGROUND AND AIMS: Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma. METHODS: A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up. RESULTS: The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)-positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels <1500, 1500-20,000, and >20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a <10% decline in HBsAg at Week 12 was associated with HBsAg clearance rates of 16% vs 4%. Hepatocellular carcinoma incidence was lower than REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) model predictions. CONCLUSIONS: Sustained off-treatment immune control is achieved with peginterferon alfa-2a in a real-world setting. HBsAg clearance 3 years after completion of peginterferon alfa-2a can be predicted on the basis of on-treatment HBsAg kinetics.

F Hoffmann La Roche Ltd Basel Switzerland

Gastroenterology and Hepatology Prince of Songkla University Songkhla Thailand

Gastroenterology and Hepatology Sungkyunkwan University School of Medicine Seoul South Korea

Gastroenterology and Hepatology University of Milan Milan Italy

Gastroenterology Hepatology and Endocrinology Hannover Medical School Hannover Germany

Gastroenterology Laiko General Hospital Athens Greece

Hepatologie Université Paris Diderot Clichy France

Infectious Disease and Hepatology Medical University of Białystok Białystok Poland

Infectious Diseases Ruijin Hospital Shanghai China

Liver Unit Asklepios Klinik St Georg Hamburg Germany

Liver Unit Queen Mary University of London London United Kingdom

PROMETRIS GmbH Mannheim Germany

Roche Pharma AG Grenzach Wyhlen Germany

Roche s r o Prague Czech Republic

Service d'Hepatologie Institut Arnault Tzanck Saint Laurent du Var France

See more in PubMed

Locarnini S, Hatzakis A, Chen DS, Lok A. Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs. J Hepatol. 2015;62(1 Suppl):S76–86. PubMed

European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98. 10.1016/j.jhep.2017.03.021 PubMed DOI

Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky JM. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol. 2013;58(4):676–83. 10.1016/j.jhep.2012.11.039 PubMed DOI

Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98. 10.1007/s12072-015-9675-4 PubMed DOI PMC

Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352(26):2682–95. 10.1056/NEJMoa043470 PubMed DOI

Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351(12):1206–17. 10.1056/NEJMoa040431 PubMed DOI

Chan HL, Thompson A, Martinot-Peignoux M, Piratvisuth T, Cornberg M, Brunetto MR, et al. Hepatitis B surface antigen quantification: why and how to use it in 2011—a core group report. J Hepatol. 2011;55(5):1121–31. 10.1016/j.jhep.2011.06.006 PubMed DOI

Rijckborst V, Hansen BE, Ferenci P, Brunetto MR, Tabak F, Cakaloglu Y, et al. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a. J Hepatol. 2012;56(5):1006–11. 10.1016/j.jhep.2011.12.007 PubMed DOI

Janssen HL, Sonneveld MJ, Brunetto MR. Quantification of serum hepatitis B surface antigen: is it useful for the management of chronic hepatitis B?. Gut. 2012;61(5):641–5. 10.1136/gutjnl-2011-301096 PubMed DOI

Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137(6):2002–9. 10.1053/j.gastro.2009.08.061 PubMed DOI

Brunetto MR, Moriconi F, Bonino F, Lau GKK, Farci P, Yurdaydin C, et al. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology. 2009;49(4):1141–50. 10.1002/hep.22760 PubMed DOI

Brunetto MR, Marcellin P, Cherubini B, Yurdaydin C, Farci P, Hadziyannis SJ, et al. Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: on-treatment kinetics of HBsAg serum levels vary by HBV genotype. J Hepatol. 2013;59(6):1153–9. 10.1016/j.jhep.2013.07.017 PubMed DOI

Yang HI, Yuen MF, Chan HL, Han KH, Chen PJ, Kim DY, et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol. 2011;12(6):568–74. 10.1016/S1470-2045(11)70077-8 PubMed DOI

Epstein M, International Society of Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2005;14(8):589–95. 10.1002/pds.1082 PubMed DOI

Buster EH, Flink HJ, Cakaloglu Y, Simon K, Trojan J, Tabak F, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008;135(2):459–67. 10.1053/j.gastro.2008.05.031 PubMed DOI

Marcellin P, Bonino F, Lau GK, Farci P, Yurdaydin C, Piratvisuth T, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology. 2009;136(7):2169–79. 10.1053/j.gastro.2009.03.006 PubMed DOI

van Buuren S. Fully conditional specification In: Molenberghs G, Fitmaurice G, Kenward MG, et al., editors. Handbook of Missing Data Methodology. Boca Raton, FL: CRC Press/Chapman & Hall; 2015. pp. 267–89.

van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007;16(3):219–42. 10.1177/0962280206074463 PubMed DOI

Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008;135(4):1192–9. 10.1053/j.gastro.2008.07.008 PubMed DOI

Lim TH, Gane E, Moyes C, Borman B, Cunningham C. Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Māori: results from a 28-year follow-up study. Gut. 2015;64(6):966–72. 10.1136/gutjnl-2013-306247 PubMed DOI

Tseng TC, Liu CJ, Chen CL, Yang WT, Yang HC, Su TH, et al. Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection. Aliment Pharmacol Ther. 2015;41(10):949–60. 10.1111/apt.13170 PubMed DOI

Simonetti J, Bulkow L, McMahon BJ, Homan C, Snowball M, Negus S, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology. 2010;51(5):1531–7. 10.1002/hep.23464 PubMed DOI

Yapali S, Talaat N, Fontana RJ, Oberhelman K, Lok AS. Outcomes of patients with chronic hepatitis B who do not meet criteria for antiviral treatment at presentation. Clin Gastroenterol Hepatol. 2015;13(1):193,201.e1. 10.1016/j.cgh.2014.07.019 PubMed DOI PMC

Liaw YF, Jia JD, Chan HL, Han KH, Tanwandee T, Chuang WL, et al. Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C. Hepatology. 2011;54(5):1591–9. 10.1002/hep.24555 PubMed DOI

Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365(9454):123–9. 10.1016/S0140-6736(05)17701-0 PubMed DOI

Marcellin P, Bonino F, Yurdaydin C, Hadziyannis S, Moucari R, Kapprell HP, et al. Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol Int. 2013;7(1):88–97. 10.1007/s12072-012-9343-x PubMed DOI PMC

Piratvisuth T, Marcellin P, Popescu M, Kapprell HP, Rothe V, Lu ZM. Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. Hepatol Int. 2013;7(2):429–36. 10.1007/s12072-011-9280-0 PubMed DOI

Sonneveld MJ, Hansen BE, Piratvisuth T, Jia JD, Zeuzem S, Gane E, et al. Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology. 2013;58(3):872–80. 10.1002/hep.26436 PubMed DOI