One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C

Jing-Hang Xu, Sa Wang, Da-Zhi Zhang, Yan-Yan Yu, Chong-Wen Si, Zheng Zeng, Zhong-Nan Xu, Jun Li, Qing Mao, Hong Tang, Ji-Fang Sheng, Xin-Yue Chen, Qin Ning, Guang-Feng Shi, Qing Xie, Xi-Quan Zhang, Jun Dai, Jing-Hang Xu, Sa Wang, Da-Zhi Zhang, Yan-Yan Yu, Chong-Wen Si, Zheng Zeng, Zhong-Nan Xu, Jun Li, Qing Mao, Hong Tang, Ji-Fang Sheng, Xin-Yue Chen, Qin Ning, Guang-Feng Shi, Qing Xie, Xi-Quan Zhang, Jun Dai

Abstract

Background: Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144.

Aim: To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C.

Methods: In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations.

Results: Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV.

Conclusion: Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

Keywords: Chronic hepatitis B; Entecavir maleate; Genotype; Mutation; Randomized controlled trial; Treatment outcome.

Conflict of interest statement

Conflict-of-interest statement: Qing Xie has acted as a consultant for Novar’s, Bristol-Myers Squibb and Roche; Guang-Feng Shi has been a member of advisory committees or review panels, received consulting fees from Novar’s, GlaxoSmithKline and Bristol-Myers Squibb; Guang-Feng Shi has acted as a consultant for Novar’s, Bristol-Myers Squibb, GlaxoSmithKline and Roche; other authors have nothing to declare.

©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.

Figures

Figure 1
Figure 1
Rates of patients with undetectable hepatitis B virus DNA through week 192. A: Proportion of patients with HBV DNA < 20 IU/mL in Group A and B in HBeAg positive (+) patients; B: Proportion of patients with HBV DNA < 20 IU/mL in Groups A and B in HBeAg negative (-) patients. HBeAg: Hepatitis B e antigen.
Figure 2
Figure 2
Rates of undetectable hepatitis B virus DNA levels in patients with different baseline hepatitis B virus DNA levels from 48 wk to 192 wk. HBV: Hepatitis B virus.
Figure 3
Figure 3
Rates of patients with hepatitis B e antigen loss and hepatitis B e antigen seroconversion, and alanine aminotransferase normalization through week 192. A: Percentage of patients with hepatitis B e antigen (HBeAg) loss in Groups A and B; B: Percentage of patients with HBeAg seroconversion in Groups A and B; C: Percentage of patients with alanine aminotransferase (ALT) normalization in Groups A and B in hepatitis B e antigen positive (+) patients; D: Percentage of patients with ALT normalization in Groups A and B in in HBeAg positive (+) patients. HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; ALT: Alanine transaminase.

References

    1. Yuen MF, Chen DS, Dusheiko GM, Janssen HLA, Lau DTY, Locarnini SA, Peters MG, Lai CL. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4:18035.
    1. Seto WK, Lo YR, Pawlotsky JM, Yuen MF. Chronic hepatitis B virus infection. Lancet. 2018;392:2313–2324.
    1. Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, Zhang Y, Liu J, Gong X, Chen Y, Wang F, Zheng H, Guo J, Jia Z, Ma J, Wang H, Luo H, Li L, Jin S, Hadler SC, Wang Y. Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination. Vaccine. 2009;27:6550–6557.
    1. Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. [The guidelines of prevention and treatment for chronic hepatitis B (2019 version)] Zhonghua Gan Zang Bing Za Zhi. 2019;27:938–961.
    1. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–1599.
    1. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–398.
    1. World Health Organization. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva, 2015. Available from: .
    1. Mak LY, Wong DK, Cheung KS, Seto WK, Fung J, Yuen MF. First-line oral antiviral therapies showed similar efficacies in suppression of serum HBcrAg in chronic hepatitis B patients. BMC Gastroenterol. 2021;21:123.
    1. Chon HY, Ahn SH, Kim YJ, Yoon JH, Lee JH, Sinn DH, Kim SU. Efficacy of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide in treatment-naive hepatitis B patients. Hepatol Int. 2021;15:1328–1336.
    1. Marcellin P GE, Flisiak R. Long-term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials. Hepatology. 2014;60:313A–314A.
    1. Jafari A, Khalili H, Dashti-Khavidaki S. Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention. Eur J Clin Pharmacol. 2014;70:1029–1040.
    1. Jung CY, Kim HW, Ahn SH, Kim SU, Kim BS. Tenofovir is Associated With Higher Risk of Kidney Function Decline Than Entecavir in Patients With Chronic Hepatitis B. Clin Gastroenterol Hepatol. 2022;20:956–958.e2.
    1. Chuang WL AK, Hwang JS, Caruntu F, Wong F, Hann HW, et al Continued improvement in renal laboratory parameters in CHB patients treated with tenofovir alfenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) over 96 wk. J Hepatol 2017; 66: S695.
    1. Agarwal K FS, Seto WK, Lim YS, Gane E, Janssen HL. A phase 3 study comparing tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) in patients with HBeAg-positive, chronic hepatitis B (CHB): efficacy and safety results at week 96. J Hepatol . 2017;66:S478.
    1. Brunetto M LY, Gane E, Seto WK, Osipenko M, Ahn SH. A phase 3 study comparing tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) in patients with HBeAg-negative, chronic hepatitis B (CHB): efficacy and safety results at week 96. J Hepatol. 2017;66:S25–S26.
    1. Gupta SK, Post FA, Arribas JR, Eron JJ Jr, Wohl DA, Clarke AE, Sax PE, Stellbrink HJ, Esser S, Pozniak AL, Podzamczer D, Waters L, Orkin C, Rockstroh JK, Mudrikova T, Negredo E, Elion RA, Guo S, Zhong L, Carter C, Martin H, Brainard D, SenGupta D, Das M. Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate: a pooled analysis of 26 clinical trials. AIDS. 2019;33:1455–1465.
    1. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010.
    1. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L BEHoLD AI463027 Study Group. Entecavir vs lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020.
    1. Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HS, Carrilho FJ, Poordad F, Halota W, Horsmans Y, Tsai N, Zhang H, Tenney DJ, Tamez R, Iloeje U. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51:422–430.
    1. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB, Colonno RJ. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–1514.
    1. Lai K, Zhang C, Ke W, Gao Y, Zhou S, Liu L, Yang Y. Cost-Effectiveness Comparison Between the Response-Guided Therapies and Monotherapies of Nucleos(t)ide Analogues for Chronic Hepatitis B Patients in China. Clin Drug Investig. 2017;37:233–247.
    1. Zheng J, Zeng Z, Zhang D, Yu Y, Wang F, Pan CQ. Prevalence and significance of Hepatitis B reverse transcriptase mutants in different disease stages of untreated patients. Liver Int. 2012;32:1535–1542.
    1. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z, Chi YC, Zhang H, Hindes R, Iloeje U, Beebe S, Kreter B. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886–893.
    1. Yao GB, Ren H, Xu DZ, Zhou XQ, Jia JD, Wang YM, Chen CW. Virological, serological and biochemical outcomes through 3 years of entecavir treatment in nucleoside-naive Chinese chronic hepatitis B patients. J Viral Hepat. 2010;17 Suppl 1:51–58.
    1. Yokosuka O, Takaguchi K, Fujioka S, Shindo M, Chayama K, Kobashi H, Hayashi N, Sato C, Kiyosawa K, Tanikawa K, Ishikawa H, Masaki N, Seriu T, Omata M. Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B infection. J Hepatol. 2010;52:791–799.
    1. Yuen MF, Seto WK, Fung J, Wong DK, Yuen JC, Lai CL. Three years of continuous entecavir therapy in treatment-naïve chronic hepatitis B patients: VIRAL suppression, viral resistance, and clinical safety. Am J Gastroenterol. 2011;106:1264–1271.
    1. Ahn J, Lee HM, Lim JK, Pan CQ, Nguyen MH, Ray Kim W, Mannalithara A, Trinh H, Chu D, Tran T, Min A, Do S, Te H, Reddy KR, Lok AS. Entecavir safety and effectiveness in a national cohort of treatment-naïve chronic hepatitis B patients in the US - the ENUMERATE study. Aliment Pharmacol Ther. 2016;43:134–144.
    1. Zoutendijk R, Reijnders JG, Brown A, Zoulim F, Mutimer D, Deterding K, Petersen J, Hofmann WP, Buti M, Santantonio T, van Bömmel F, Pradat P, Oo Y, Luetgehetmann M, Berg T, Hansen BE, Wedemeyer H, Janssen HL VIRGIL Surveillance Study Group. Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of naïve patients with a partial virological response. Hepatology. 2011;54:443–451.
    1. Ono A, Suzuki F, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Suzuki Y, Saitou S, Arase Y, Ikeda K, Watahiki S, Mineta R, Kumada H. Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. J Hepatol. 2012;57:508–514.
    1. Nakashima H, Furusyo N, Kubo N, Kashiwagi K, Etoh Y, Kashiwagi S, Hayashi J. Double point mutation in the core promoter region of hepatitis B virus (HBV) genotype C may be related to liver deterioration in patients with chronic HBV infection. J Gastroenterol Hepatol. 2004;19:541–550.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться