Factors associated with the decrease in hepatitis B surface antigen titers following interferon therapy in patients with chronic hepatitis B: Is interferon and adefovir combination therapy effective?

Yano,Yoshihiko; Seo,Yasushi; Hayashi,Hiroki; Hatazawa,Yuri; Hirano,Hirotaka; Minami,Akihiro; Kawano,Yuki; Saito,Masaya; Ninomiya,Toshiaki; Sugano,Masahiko; Yamada,Hajime; Kitajima,Naoto; Yoon,Seitetsu; Hayashi,Yoshitake

doi:10.3892/br.2017.944

Factors associated with the decrease in hepatitis B surface antigen titers following interferon therapy in patients with chronic hepatitis B: Is interferon and adefovir combination therapy effective?

Authors:
- Yoshihiko Yano
- Yasushi Seo
- Hiroki Hayashi
- Yuri Hatazawa
- Hirotaka Hirano
- Akihiro Minami
- Yuki Kawano
- Masaya Saito
- Toshiaki Ninomiya
- Masahiko Sugano
- Hajime Yamada
- Naoto Kitajima
- Seitetsu Yoon
- Yoshitake Hayashi
View Affiliations

Affiliations: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650‑0017, Japan, Seo Clinic, Himeji 672‑8002, Japan, Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650‑0017, Japan, Saito Internal Clinic, Kobe 651‑2412, Japan, Ninomiya Internal Clinic, Itami 664‑0856, Japan, Sugano Naika Clinic, Himeji 671‑0223, Japan, Department of Gastroenterology, Shinko Hospital, Kobe 651‑0072, Japan, Department of Gastroenterology, Kasai City Hospital, Kasai 675‑2393, Japan, Department of Gastroenterology, Kakogawa Municipal Hospital, Kakogawa 675‑8555, Japan
Published online on: July 18, 2017 https://doi.org/10.3892/br.2017.944
Pages: 257-262

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The purpose of antiviral therapy in chronic hepatitis B (CHB) is generally to achieve a decrease and ultimately disappearance of HBs antigen (HBsAg). Interferon (IFN) therapy of CHB appears to be less effective in Asian countries than in European countries, and the advantage of IFN and nucleotide(s) analog (NA) combination therapy has yet to be fully investigated. The present study focused on the factors associated with a decrease in HBs antigen following IFN monotherapy or IFN + NA combination therapy. A total of 35 patients with CHB who received IFN‑based therapy (mean ± standard deviation age 36.7±8.5 years; 27 males and 8 females) were enrolled in this study. Of the 35 patients, 21 patients received pegylated IFN monotherapy and 14 patients received IFN and adefovir (ADV) combination therapy. We examined the factors associated with reductions in the HBsAg titer of >1.0 log IU/ml from the initial HBsAg titer to the end of treatment and to 24 weeks after treatment. Although 13 patients (37%) had a reduction in HBsAg of >1.0 IU/ml at the end of treatment, it was only maintained to 24 weeks after treatment in 7 patients (20%). The HBV core‑related antigen (HBcrAg) titer before treatment was significantly higher in patients with a decrease in HBsAg at the end of treatment than in patients without a decrease in HBsAg (6.56±0.78 vs. 5.30±1.66 log IU/ml, P<0.05). Moreover, an increase in alanine aminotransferase (ALT) of >2 times from baseline occurred significantly more frequently in patients with a decrease in HBsAg (62 vs. 14%, P<0.05). The proportion of patients with a decrease in HBsAg was significantly greater in patients who received IFN monotherapy than in patients who received IFN and ADV combination therapy (43 vs. 29%, P<0.05). The present results revealed that the HBcr antigen titer before therapy and an on‑treatment elevation of ALT (indicative of host instruction flare) are important factors associated with a decrease in HBsAg titers after IFN‑based therapy. The efficacy of IFN and ADV combination therapy was not apparent in terms of a reduction in the HBsAg titer.

View Figures

View References

1	Lok AS and McMahon BJ: Chronic hepatitis B: Update 2009. Hepatology. 50:661–662. 2009. View Article : Google Scholar : PubMed/NCBI
2	European Association For The Study Of The Liver, . EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 57:167–185. 2012. View Article : Google Scholar : PubMed/NCBI
3	Liaw YF, Kao JH, Piratvisuth T, Chan HLY, Chien RN, Liu CJ, Gane E, Locarnini S, Lim SG, Han KH, et al: Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2012 update. Hepatol Int. 6:531–561. 2012. View Article : Google Scholar : PubMed/NCBI
4	Marcellin P, Martinot-Peignoux M, Asselah T, Batrla R, Messinger D, Rothe V, Lau G and Liaw YF: Serum levels of Hepatitis B surface antigen predict severity of fibrosis in patients with E antigen-positive chronic Hepatitis B. Clin Gastroenterol Hepatol. 13:1532–9.e1. 2015. View Article : Google Scholar : PubMed/NCBI
5	Shouval D: Focus: Quantitative HBsAg measurement as a new surrogate marker for assessment of hepatic fibrosis in HBeAg+ chronic hepatitis B. J Hepatol. 58:1063–1064. 2013. View Article : Google Scholar : PubMed/NCBI
6	Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, Lee HC, Chung YH, Lee YS and Suh DJ: HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: Clinical outcomes and durability. Gut. 63:1325–1332. 2014. View Article : Google Scholar : PubMed/NCBI
7	Hynicka LM, Yunker N and Patel PH: A review of oral antiretroviral therapy for the treatment of chronic hepatitis B. Ann Pharmacother. 44:1271–1286. 2010. View Article : Google Scholar : PubMed/NCBI
8	Lam YF, Yuen MF, Seto WK and Lai CL: Current antiviral therapy of chronic hepatitis B: Efficacy and safety. Curr Hepat Rep. 10:235–243. 2011. View Article : Google Scholar : PubMed/NCBI
9	Shi Y, Wu YH, Shu ZY, Zhang WJ, Yang J and Chen Z: Interferon and lamivudine combination therapy versus lamivudine monotherapy for hepatitis B e antigen-negative hepatitis B treatment: A meta-analysis of randomized controlled trials. Hepatobiliary Pancreat Dis Int. 9:462–472. 2010.PubMed/NCBI
10	Huang R, Hao Y, Zhang J and Wu C: Interferon-alpha plus adefovir combination therapy versus interferon-alpha monotherapy for chronic hepatitis B treatment: A meta-analysis. Hepatol Res. 43:1040–1051. 2013.PubMed/NCBI
11	Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, et al: Peginterferon alfa-2a HBeAg-positive chronic Hepatitis B study group: Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 352:2682–2695. 2005. View Article : Google Scholar : PubMed/NCBI
12	Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, Piratvisuth T, Germanidis G, Yurdaydin C, et al: Peginterferon alfa-2a HBeAg-negative chronic hepatitis B study group: Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 351:1206–1217. 2004. View Article : Google Scholar : PubMed/NCBI
13	Marcellin P, Wursthorn K, Wedemeyer H, Chuang WL, Lau G, Avila C, Peng CY, Gane E, Lim SG, Fainboim H, et al: Telbivudine plus pegylated interferon alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected high rate of peripheral neuropathy. J Hepatol. 62:41–47. 2015. View Article : Google Scholar : PubMed/NCBI
14	Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T, Schirmacher P, Metzler F, Zankel M, et al: Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology. 44:675–684. 2006. View Article : Google Scholar : PubMed/NCBI
15	Takkenberg B, Terpstra V, Zaaijer H, Weegink C, Dijkgraaf M, Jansen P, Beld M and Reesink H: Intrahepatic response markers in chronic hepatitis B patients treated with peginterferon alpha-2a and adefovir. J Gastroenterol Hepatol. 26:1527–1535. 2011. View Article : Google Scholar : PubMed/NCBI
16	Takkenberg RB, Jansen L, de Niet A, Zaaijer HL, Weegink CJ, Terpstra V, Dijkgraaf MG, Molenkamp R, Jansen PL, Koot M, et al: Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with pegylated interferon-α2a and adefovir. Antivir Ther. 18:895–904. 2013. View Article : Google Scholar : PubMed/NCBI
17	Xie QL, Zhu Y, Wu LH, Fu LL and Xiang Y: The efficacy and safety of entecavir and interferon combination therapy for chronic hepatitis B virus infection: A meta-analysis. PLoS One. 10:e01322192015. View Article : Google Scholar : PubMed/NCBI
18	Buster EH, Flink HJ, Cakaloglu Y, Simon K, Trojan J, Tabak F, So TM, Feinman SV, Mach T, Akarca US, et al: Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 135:459–467. 2008. View Article : Google Scholar : PubMed/NCBI
19	Moucari R, Korevaar A, Lada O, Martinot-Peignoux M, Boyer N, Mackiewicz V, Dauvergne A, Cardoso AC, Asselah T, Nicolas-Chanoine MH, et al: High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: A long-term follow-up study. J Hepatol. 50:1084–1092. 2009. View Article : Google Scholar : PubMed/NCBI
20	Seo Y and Yano Y: Short- and long-term outcome of interferon therapy for chronic hepatitis B infection. World J Gastroenterol. 20:13284–13292. 2014. View Article : Google Scholar : PubMed/NCBI
21	Croagh CM, Desmond PV and Bell SJ: Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance. World J Hepatol. 7:289–303. 2015. View Article : Google Scholar : PubMed/NCBI
22	Howard CR: The structure of hepatitis B envelope and molecular variants of hepatitis B virus. J Viral Hepat. 2:165–170. 1995. View Article : Google Scholar : PubMed/NCBI
23	Höner Zu, Siederdissen C and Cornberg M: The role of HBsAg levels in the current management of chronic HBV infection. Ann Gastroenterol. 27:105–112. 2014.PubMed/NCBI
24	Brunetto MR, Moriconi F, Bonino F, Lau GK, Farci P, Yurdaydin C, Piratvisuth T, Luo K, Wang Y, Hadziyannis S, et al: Hepatitis B virus surface antigen levels: A guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology. 49:1141–1150. 2009. View Article : Google Scholar : PubMed/NCBI
25	Moucari R, Mackiewicz V, Lada O, Ripault MP, Castelnau C, Martinot-Peignoux M, Dauvergne A, Asselah T, Boyer N, Bedossa P, et al: Early serum HBsAg drop: A strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology. 49:1151–1157. 2009. View Article : Google Scholar : PubMed/NCBI
26	Dando T and Plosker G: Adefovir dipivoxil: A review of its use in chronic hepatitis B. Drugs. 63:2215–2234. 2003. View Article : Google Scholar : PubMed/NCBI
27	Cheng PN, Liu WC, Tsai HW, Wu IC, Chang TT and Young KC: Association of intrahepatic cccDNA reduction with the improvement of liver histology in chronic hepatitis B patients receiving oral antiviral agents. J Med Virol. 83:602–607. 2011. View Article : Google Scholar : PubMed/NCBI
28	Hansen BE, Rijckborst V, Ter Borg MJ and Janssen HL: HBV DNA suppression in HBeAg-positive chronic hepatitis B patients treated with peginterferon or placebo. J Med Virol. 83:1917–1923. 2011. View Article : Google Scholar : PubMed/NCBI
29	Wong DK, Tanaka Y, Lai CL, Mizokami M, Fung J and Yuen MF: Hepatitis B virus core-related antigens as markers for monitoring chronic hepatitis B infection. J Clin Microbiol. 45:3942–3947. 2007. View Article : Google Scholar : PubMed/NCBI
30	Suzuki F, Miyakoshi H, Kobayashi M and Kumada H: Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol. 81:27–33. 2009. View Article : Google Scholar : PubMed/NCBI