A comparative network meta-analysis of standard of care treatments in treatment-naïve chronic hepatitis B patients
Publication: Journal of Comparative Effectiveness Research
Abstract
Objective: Published network meta-analyses of chronic hepatitis B (CHB) treatments are either out-of-date or excluded key treatments. Therefore, we aimed to comprehensively update the efficacy evidence for the following end points: Hepatitis B surface antigen (HBsAg) loss, hepatitis B early antigen (HBeAg) seroconversion and hepatitis B virus DNA (HBV DNA) suppression. Materials & methods: Approved treatments in CHB and their combinations were evaluated. A systematic literature review was conducted to identify all randomized controlled trials in treatment-naïve CHB patients. Included studies reported at least one of the end points of interest. A frequentist probability network meta-analysis was performed for each end point. The choice of fixed effect or random-effect model was based on the I-square statistic, a measure of variation in study outcomes between studies. The analyses were performed separately for HBeAg-positive and HBeAg-negative patients. For the primary analyses, end points measured 48 ± 4 weeks after treatment initiation were considered. Results: A total of 47 randomized controlled trials (13,826 patients), covering 23 unique treatment regimens, were included: a total of 29 reported HBsAg loss, 36 reported HBeAg seroconversion and 37 reported HBV DNA suppression. For both HBsAg loss and HBeAg seroconversion, pegylated interferon-based regimens were the most effective strategy in both HBeAg-positive and HBeAg-negative patients. On the other hand, for HBV DNA suppression, nucleosides-based regimens were the most effective strategy in both HBeAg-positive and HBeAg-negative patients. Conclusion: Our findings confirm available evidence around the comparative efficacy of available CHB treatments. Therefore, they can be used to update relevant cost–effectiveness analyses and clinical guidelines.
Supplementary Material
File (suppl_data.zip)
- Download
- 1.41 MB
References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
1.
Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol. Hepatol. 3(6), 383–403 (2018).
2.
WHO. Hepatitis B: key facts (2019). www.who.int/news-room/fact-sheets/detail/hepatitis-b
3.
Stanaway JD, Flaxman AD, Naghavi M et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet 388(10049), 1081–1088 (2016).
• States the large burden of disease and thus, the importance of accurate comparative effectiveness research.
4.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 67(2), 370–398 (2017).
5.
WHO. Hepatitis B—Key Facts (2019). www.who.int/en/news-room/fact-sheets/
6.
Lampertico P. Discontinuation of nucleoside analogues in hepatitis B virus infection. Gastroenterol. Hepatol. (NY). 9(10), 656–658 (2013).
7.
NHS. Conditions hepatitis b; treatment (2019). www.nhs.uk/conditions/hepatitis-b/treatment/
8.
Sokal EM, Conjeevaram HS, Roberts EA, Alvarez F, Bern EM. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology 114(5), 988–995 (1998).
9.
Terrault NA, Lok ASF, McMahon BJ et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67(4), 1560–1599 (2018).
10.
NICE. Hepatitis B (chronic). Appendices H-0 (2013). www.nice.org.uk/guidance/cg165/evidence/cg165-hepatitis-b-chronic-appendices-ho2
•• Previously conducted network meta-analysis (NMA) in the indication of chronic hepatitis B (CHB). Our study aims to update their findings.
11.
Govan L, Wu O, Xin Y, Hutchinson SJ, Hawkins N. Comparative effectiveness of antiviral treatment for hepatitis B: a systematic review and Bayesian network meta-analysis. Eur. J. Gastroenterol. Hepatol. 27(8), 882–894 (2015).
•• Previously conducted NMA in the indication of CHB. Our study aims to update their findings.
12.
Wong WWL, Pechivanoglou P, Wong J et al. Antiviral treatment for treatment-naïve chronic hepatitis B: systematic review and network meta-analysis of randomized controlled trials. Syst. Rev. 8(1), 207 (2019).
•• Previously conducted NMA in the indication of CHB. Our study aims to update their findings.
13.
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 6(7), e1000097 (2009).
14.
Higgins JPT, Altman DG, Gøtzsche PC et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343, d5928 (2011).
15.
Terrault NA, Bzowej NH, Chang K-M, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 63(1), 261–283 (2016).
16.
Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. Hepatology 66(4), 1296–1313 (2017).
17.
Lau GKK, Piratvisuth T, Luo KX et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 352(26), 2682–2695 (2005).
18.
Dakin H, Fidler C, Harper C. Mixed treatment comparison meta-analysis evaluating the relative efficacy of nucleos(t)ides for treatment of nucleos(t)ide-naive patients with chronic hepatitis B. Value Health 13(8), 934–945 (2010).
19.
Rücker G, Schwarzer G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med. Res. Methodol. 15(1), 58 (2015).
20.
Hou J, Yin Y-K, Xu D et al. Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: results at 1 year of a randomized, double-blind trial. Hepatology 47(2), 447–454 (2008).
21.
Sung JJY, Lai J-Y, Zeuzem S et al. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J. Hepatol. 48(5), 728–735 (2008).
22.
Chan HLY, Heathcote EJ, Marcellin P et al. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann. Intern. Med. 147(11), 745–754 (2007).
23.
Ren F-Y, Piao D-M, Piao X-X. A one-year trial of entecavir treatment in patients with HBeAg-positive chronic hepatitis B. World J. Gastroenterol. 13(31), 4264–4267 (2007).
24.
Kaymakoglu S, Oguz D, Gur G et al. Pegylated interferon alfa-2b monotherapy and pegylated interferon alfa-2b plus lamivudine combination therapy for patients with hepatitis B virus E antigen-negative chronic hepatitis B. Antimicrob. Agents Chemother. 51(8), 3020–3022 (2007).
25.
Chan HL-Y, Leung NW-Y, Hui AY et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann. Intern. Med. 142(4), 240–250 (2005).
26.
Tassopoulos NC, Volpes R, Pastore G et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology 29(3), 889–896 (1999).
27.
Dienstag JL, Schiff ER, Wright TL et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N. Engl. J. Med. 341(17), 1256–1263 (1999).
28.
Lai C-L, Shouval D, Lok AS et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 354(10), 1011–1020 (2006).
29.
Janssen HLA, van Zonneveld M, Senturk H et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 365(9454), 123–129 (2005).
30.
Chang T-T, Gish RG, de Man R et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 354(10), 1001–1010 (2006).
31.
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N. Engl. J. Med. 348(9), 800–807 (2003).
32.
Marcellin P, Lau GKK, Bonino F 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. 351(12), 1206–1217 (2004).
33.
Marcellin P, Heathcote EJ, Buti M et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N. Engl. J. Med. 359(23), 2442–2455 (2008).
34.
Lok AS, Trinh H, Carosi G et al. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naive patients with chronic hepatitis B. Gastroenterology 143(3), 619.e1–628.e1 (2012).
35.
Yao G, Chen C, Lu W et al. Efficacy and safety of entecavir compared to lamivudine in nucleoside-naive patients with chronic hepatitis B: a randomized double-blind trial in China. Hepatol. Int. 1(3), 365–372 (2007).
36.
Lai C-L, Gane E, Liaw Y-F et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N. Engl. J. Med. 357(25), 2576–2588 (2007).
37.
Papadopoulos VP, Chrysagis DN, Protopapas AN, Goulis IG, Dimitriadis GT, Mimidis KP. Peginterferon alfa-2b as monotherapy or in combination with lamivudine in patients with HBeAg-negative chronic hepatitis B: a randomised study. Med. Sci. Monit. 15(2), CR56–CR61 (2009).
38.
Leung N, Peng C-Y, Hann H-W et al. Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: a randomized international study of entecavir versus adefovir. Hepatology 49(1), 72–79 (2009).
39.
Jun DW, Ahn SB, Kim TY et al. Efficacy of pegylated interferon monotherapy versus sequential therapy of entecavir and pegylated interferon in hepatitis B e antigen-positive hepatitis B patients: a randomized, multicenter, Phase IIIb open-label study (POTENT Study). Chin. Med. J. (Engl.) 131(14), 1645–1651 (2018).
40.
Luo XD, Chen XF, Zhou Y, Chen XP. Comparison of 208-week sequential therapy with telbivudine and entecavir in HBeAg-positive chronic hepatitis B patients with suboptimal responses to 24 weeks of peg-IFN alpha-2a therapy: an open-labelled, randomized, controlled, “real-life” trial. J. Viral Hepat. 24(Suppl. 1), 36–42 (2017).
41.
Lee KS, Kweon Y-O, Um S-H et al. Efficacy and safety of entecavir versus lamivudine over 5 years of treatment: a randomized controlled trial in Korean patients with hepatitis B e antigen-negative chronic hepatitis B. Clin. Mol. Hepatol. 23(4), 331–339 (2017).
42.
Xu Y, Wang X, Liu Z et al. Addition of nucleoside analogues to peg-IFN alpha-2a enhances virological response in chronic hepatitis B patients without early response to peg-IFNalpha-2a: a randomized controlled trial. BMC Gastroenterol. 17(1), 102 (2017).
43.
de Niet A, Jansen L, Stelma F et al. Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial. Lancet Gastroenterol. Hepatol. 2(8), 576–584 (2017).
44.
Buti M, Gane E, Seto WK et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind,Phase III, non-inferiority trial. Lancet Gastroenterol. Hepatol. 1(3), 196–206 (2016).
45.
Chan HLY, Fung S, Seto WK et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, Phase III, non-inferiority trial. Lancet Gastroenterol. Hepatol. 1(3), 185–195 (2016).
46.
Koike K, Suyama K, Ito H, Itoh H, Sugiura W. Randomized prospective study showing the non-inferiority of tenofovir to entecavir in treatment-naive chronic hepatitis B patients. Hepatol. Res. 48(1), 59–68 (2018).
47.
Krastev Z, Petrova D, Kotzev I et al. Telbivudine vs tenofovir in hepatitis B e antigen-negative chronic hepatitis B patients: OPTIMA roadmap study. World J. Hepatol. 8(32), 1402–1413 (2016).
48.
Zhang K, Cao H, Liang J et al. CONSORT: effects of adding adefovirdipivoxil to peginterferon alfa-2a at different time points on HBeAg-positivepatients: a prospective, randomized study. Medicine (Balt.) 95(31), e4471 (2016).
49.
Sriprayoon T, Mahidol C, Ungtrakul T et al. Efficacy and safety of entecavir versus tenofovir treatment in chronic hepatitis B patients: a randomized controlled trial. Hepatol. Res. 47(3), E161–E168 (2017).
50.
Marcellin P, Ahn SH, Ma X et al. Combination of tenofovir disoproxil fumarate and peginterferon alpha-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology 150(1), 134–144.e10 (2016).
51.
Liang X, Cheng J, Sun Y et al. Randomized, three-arm study to optimize lamivudine efficacy in hepatitis B e antigen-positive chronic hepatitis B patients. J. Gastroenterol. Hepatol. 30(4), 748–755 (2015).
52.
Hou JL, Gao ZL, Xie Q et al. Tenofovir disoproxil fumarate vs adefovir dipivoxil in Chinese patients with chronic hepatitis B after 48 weeks: a randomized controlled trial. J. Viral Hepat. 22(2), 85–93 (2015).
53.
Wen Z, Zhang H, Zhang M et al. Effect of hepatitis B virus genotypes on the efficacy of adefovir dipivoxil antiviral therapy. Hepat. Mon. 14(8), e10813 (2014).
54.
Xie Q, Zhou H, Bai X et al. A randomized, open-label clinical study of combined pegylated interferon alfa-2a (40KD) and entecavir treatment for hepatitis B “e” antigen-positive chronic hepatitis B. Clin. Infect. Dis. 59(12), 1714–1723 (2014).
55.
Liu Y-H, Wu T, Sun N et al. Combination therapy with pegylated interferon alpha-2b and adefovir dipivoxil in HBeAg-positive chronic hepatitis B versus interferon alone: a prospective, randomized study. J. Huazhong Univ. Sci. Tech. Med. Sci. 34(4), 542–547 (2014).
56.
Li C-Z, Hu J-J, Xue J-Y et al. Viral infection parameters not nucleoside analogue itself correlates with host immunity in nucleoside analogue therapy for chronic hepatitis B. World J. Gastroenterol. 20(28), 9486–9496 (2014).
57.
Tseng K-C, Chen C-Y, Tsai H-W et al. Efficacy of entecavir in chronic hepatitis B patients with persistently normal alanine aminotransferase: randomized, double-blind, placebo-controlled study. Antivir. Ther. 19(8), 755–764 (2014).
58.
Sun J, Xie Q, Tan D et al. The 104-week efficacy and safety of telbivudine-based optimization strategy in chronic hepatitis B patients: a randomized, controlled study. Hepatology 59(4), 1283–1292 (2014).
59.
Jia J-D, Hou J-L, Yin Y-K et al. Two-year results of a randomized, Phase III comparative trial of telbivudine versus lamivudine in Chinese patients. Hepatol. Int. 8(1), 72–82 (2014).
60.
Cao ZH, Ma LN, Zhang HW, Liu YL, Chen XY. Extended treatment with peginterferon alpha-2a in combination with lamivudine or adefovir for 96 weeks yields high rates of HBeAg and HBsAg seroconversion. J. Dig. Dis. 14(8), 446–450 (2013).
61.
Wang H, Ji YY, Yao GB et al. Two years efficiency of lamivudine and adefovir dipivoxil combined therapy in chronic hepatitis B patients. Eur. Rev. Med. Pharmacol. Sci. 17(5), 636–643 (2013).
62.
He Z, Wang J, Liu K et al. Randomized trial of lamivudine, adefovir, and the combination in HBeAg-positive chronic hepatitis B. Clin. Res. Hepatol. Gastroenterol. 36(6), 592–597 (2012).
63.
Zhang Shuang Li, Wei Lu, Ping Ma. Clinical efficacy of tenofovir and entecavir in the treatment of chronic hepatitis B infection in patients naïve to nucleosides and their analogues therapy. Int. J. Clin. Exp. Med. 10(8), 12329–12335 (2017).
64.
Marcellin P, Chang T-T, Lim SG et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N. Engl. J. Med. 348(9), 808–816 (2003).
65.
Lai C-L, Leung N, Teo E-K et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 129(2), 528–536 (2005).
66.
Jia J-D, Hou J-L, Yin Y-K et al. Two-year results of a randomized, Phase III comparative trial of telbivudine versus lamivudine in Chinese patients. Hepatol. Int. 8(1), 72–82 (2014).
67.
Sarin SK, Kumar M, Lau GK et al. Asian–Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol. Int. 10(1), 1–98 (2016).
68.
Buster Erik HCJ, Flink HJ, Cakaloglu Y et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology 135(2), 459–467 (2008).
69.
World Health Organization. Hepatitis - fact sheet. [Hepatitis B control]. www.wpro.who.int/china/mediacentre/factsheets/hepatitis/en/
Information & Authors
Information
Published In
Pages: 1051 - 1065
PubMed: 32945178
Copyright
© 2020 Ingress-health Nederland BV. This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License
History
Received: 1 May 2020
Accepted: 19 August 2020
Published online: 18 September 2020
Keywords:
Topics
Authors
Metrics & Citations
Metrics
Article Usage
Article usage data only available from February 2023. Historical article usage data, showing the number of article downloads, is available upon request.
Citations
How to Cite
A comparative network meta-analysis of standard of care treatments in treatment-naïve chronic hepatitis B patients. (2020) Journal of Comparative Effectiveness Research. DOI: 10.2217/cer-2020-0068
Export citation
Select the citation format you wish to export for this article or chapter.
Citing Literature
- Markus Cornberg, Lisa Sandmann, Jerzy Jaroszewicz, Patrick Kennedy, Pietro Lampertico, Maud Lemoine, Sabela Lens, Barbara Testoni, Grace Lai-Hung Wong, Francesco Paolo Russo, EASL Clinical Practice Guidelines on the management of hepatitis B virus infection, Journal of Hepatology, 10.1016/j.jhep.2025.03.018, 83, 2, (502-583), (2025).
- Ying Zhang, Xiaoyu Lin, Huizhen Wu, Jing Chen, Qi Zheng, Systematic review with network meta-analysis: sustained hepatitis B surface antigen clearance after pegylated interferon cessation, European Journal of Gastroenterology & Hepatology, 10.1097/MEG.0000000000002823, 36, 10, (1159-1170), (2024).
- Carol Forbes, Louis Lavoie, Sacha Satram, Ling Shen, Vaidehi Thanawala, Andre Arizpe, Norah Terrault, Global importance of new treatment strategies to efforts to control hepatitis B virus, Expert Review of Anti-infective Therapy, 10.1080/14787210.2023.2225771, 21, 8, (847-862), (2023).
- Piyameth Dilokthornsakul, Ratree Sawangjit, Pisit Tangkijvanich, Maneerat Chayanupatkul, Tawesak Tanwandee, Wattana Sukeepaisarnjaroen, Pajaree Sriuttha, Unchalee Permsuwan, Economic Evaluation of Oral Nucleos(t)ide Analogues for Patients with Chronic Hepatitis B in Thailand, Applied Health Economics and Health Policy, 10.1007/s40258-022-00719-y, 20, 4, (587-596), (2022).
- Valentina Zuccaro, Erika Asperges, Marta Colaneri, Lea Nadia Marvulli, Raffaele Bruno, HBV and HDV: New Treatments on the Horizon, Journal of Clinical Medicine, 10.3390/jcm10184054, 10, 18, (4054), (2021).