Continuing besifovir dipivoxil maleate versus switching from tenofovir disoproxil fumarate for treatment of chronic hepatitis B: Results of 192-week phase 3 trial

Do Seon Song, Won Kim, Sang Hoon Ahn, Hyung Joon Yim, Jae Young Jang, Young Oh Kweon, Yong Kyun Cho, Yoon Jun Kim, Gun Young Hong, Dong Joon Kim, Young Kul Jung, Joo Hyun Sohn, Jin-Woo Lee, Sung Jae Park, Byung Seok Lee, Ju Hyun Kim, Hong Soo Kim, Seung Kew Yoon, Moon Young Kim, Kwan Sik Lee, Young Suk Lim, Wan Sik Lee, Jin Mo Yang, Kyun-Hwan Kim, Kwang-Hyub Han, Soon Ho Um, Do Seon Song, Won Kim, Sang Hoon Ahn, Hyung Joon Yim, Jae Young Jang, Young Oh Kweon, Yong Kyun Cho, Yoon Jun Kim, Gun Young Hong, Dong Joon Kim, Young Kul Jung, Joo Hyun Sohn, Jin-Woo Lee, Sung Jae Park, Byung Seok Lee, Ju Hyun Kim, Hong Soo Kim, Seung Kew Yoon, Moon Young Kim, Kwan Sik Lee, Young Suk Lim, Wan Sik Lee, Jin Mo Yang, Kyun-Hwan Kim, Kwang-Hyub Han, Soon Ho Um

Abstract

Background/aims: Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, shows potent antiviral activity against hepatitis B virus. Our previous 48-week trial revealed that BSV has comparable antiviral efficacy to tenofovir disoproxil fumarate (TDF) and better safety profiles in terms of improved renal and bone safety. This extension study evaluated the prolonged efficacy and safety of BSV in treatment-naive chronic hepatitis B patients.

Methods: Patients continued to participate in an open-label BSV study after an initial 48-week double-blind comparison of BSV and TDF treatment. The antiviral efficacy and drug safety was evaluated up to 192 weeks in two groups: patients continuing BSV treatment (BSV-BSV) and patients switching from TDF to BSV after 48 weeks (TDF-BSV).

Results: Among 197 patients receiving randomized treatments, 170 (86%) entered the open-label phase and 152 (77%) entered the 192-week extension study. Virological response rates over 192 weeks were 92.50% and 93.06% in the BSV-BSV and TDF-BSV groups, respectively (P=0.90). Hepatitis B envelop antigen seroconversion and alanine aminotransferase normalization rates were similar between the groups (P=0.75 and P=0.36, respectively). There were no drug-resistant mutations to BSV. Bone mineral density and renal function were well preserved in the BSV-BSV group, whereas these initially worsened then recovered after switching therapy in the TDF-BSV group.

Conclusion: BSV maintained potent antiviral efficacy after 192 weeks and showed no evidence of drug resistance. BSV was safe, well tolerated, and effective in patients who switched from TDF to BSV. Trial Registration Number: NCT01937806 (date: 10 Sep 2013).

Keywords: Besifovir; Bone mineral density; Drug resistance; Hepatitis B, Chronic; Nephrotoxicity.

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare regarding the content of this manuscript. The sponsor paid for the laboratory analyses and clinical research coordinator expenses and supplied the investigational products. Dr. Um received grants for clinical trials sponsored by Ildong Pharmaceutical Co. outside of the submitted work.

Figures

Figure 1.
Figure 1.
Patient disposition. BSV, besifovir dipivoxil maleate; TDF, tenofovir disoproxil fumarate; HCC, hepatocellular carcinoma; CPK, creatinine phosphokinase; F/U, follow up; FAS, full analysis set; PPS, per protocol set; IP, investigational product.
Figure 2.
Figure 2.
Viral suppression by study visit. (A) Proportions of patients with HBV DNA

Figure 3.

Changes in BMD. (A) Mean…

Figure 3.

Changes in BMD. (A) Mean percentage changes in the hip at week 48,…

Figure 3.
Changes in BMD. (A) Mean percentage changes in the hip at week 48, 96, 144, and 192 of treatment. Bars represent 95% confidence intervals. (B) Mean percentage changes in the spine at week 48, 96, 144, and 192 of treatment. Bars represent 95% confidence intervals. BMD, bone mineral density; BSV, besifovir dipivoxil maleate; TDF, tenofovir disoproxil fumarate.

Figure 4.

Median changes from baseline in…

Figure 4.

Median changes from baseline in eGFR (MDRD) by study week. Data are presented…

Figure 4.
Median changes from baseline in eGFR (MDRD) by study week. Data are presented as median (Q1, Q3) values (mL/min). BSV, besifovir dipivoxil maleate; TDF, tenofovir disoproxil fumarate; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease.
Figure 3.
Figure 3.
Changes in BMD. (A) Mean percentage changes in the hip at week 48, 96, 144, and 192 of treatment. Bars represent 95% confidence intervals. (B) Mean percentage changes in the spine at week 48, 96, 144, and 192 of treatment. Bars represent 95% confidence intervals. BMD, bone mineral density; BSV, besifovir dipivoxil maleate; TDF, tenofovir disoproxil fumarate.
Figure 4.
Figure 4.
Median changes from baseline in eGFR (MDRD) by study week. Data are presented as median (Q1, Q3) values (mL/min). BSV, besifovir dipivoxil maleate; TDF, tenofovir disoproxil fumarate; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8046633/bin/cmh-2020-0307f5.jpg

References

    1. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–1555.
    1. Wong GL, Chan HL, Mak CW, Lee SK, Ip ZM, Lam AT, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;58:1537–1547.
    1. Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky JM. Longterm hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol. 2013;58:676–683.
    1. Seto WK, Hui AJ, Wong VW, Wong GL, Liu KS, Lai CL, et al. Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study. Gut. 2015;64:667–672.
    1. Liaw YF, Sheen IS, Chen TJ, Chu CM, Pao CC. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology. 1991;13:627–631.
    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. Korean Association for the Study of the Liver (KASL) KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol. 2019;25:93–159.
    1. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–1599.
    1. Marcellin P, Wong DK, Sievert W, Buggisch P, Petersen J, Flisiak R, et al. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int. 2019;39:1868–1875.
    1. Lim YS. Management of antiviral resistance in chronic hepatitis B. Gut Liver. 2017;11:189–195.
    1. Liang LY, Wong GL. Unmet need in chronic hepatitis B management. Clin Mol Hepatol. 2019;25:172–180.
    1. Ahn SH, Kim W, Jung YK, Yang JM, Jang JY, Kweon YO, et al. Efficacy and safety of besifovir dipivoxil maleate compared with tenofovir disoproxil fumarate in treatment of chronic hepatitis B virus infection. Clin Gastroenterol Hepatol. 2019;17:1850–1859. e4.
    1. Yim HJ, Kim W, Ahn SH, Yang JM, Jang JY, Kweon YO, et al. Besifovir dipivoxil maleate 144-week treatment of chronic hepatitis B: an open-label extensional study of a phase 3 trial. Am J Gastroenterol. 2020;115:1217–1225.
    1. Kwon SY, Park YK, Ahn SH, Cho ES, Choe WH, Lee CH, et al. Identification and characterization of clevudine-resistant mutants of hepatitis B virus isolated from chronic hepatitis B patients. J Virol. 2010;84:4494–4503.
    1. Park ES, Lee AR, Kim DH, Lee JH, Yoo JJ, Ahn SH, et al. Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients. J Hepatol. 2019;70:1093–1102.
    1. Gordon SC, Krastev Z, Horban A, Petersen J, Sperl J, Dinh P, et al. Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load. Hepatology. 2013;58:505–513.
    1. Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Muñoz AE, Adrover R, et al. Efficacy and safety of long term entecavir in chronic hepatitis B treatment naïve patients in clinical practice. Ann Hepatol. 2014;13:327–336.
    1. Chen CF, Lee WC, Yang HI, Chang HC, Jen CL, Iloeje UH, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology. 2011;141:1240–1248. , 1248.e1-e2.
    1. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381:468–475.
    1. Liang X, Gao Z, Xie Q, Zhang J, Sheng J, Cheng J, et al. Longterm efficacy and safety of tenofovir disoproxil fumarate in Chinese patients with chronic hepatitis B: 5-year results. Hepatol Int. 2019;13:260–269.
    1. Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36:186–194.
    1. Zeuzem S, Gane E, Liaw YF, Lim SG, DiBisceglie A, Buti M, et al. Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B. J Hepatol. 2009;51:11–20.
    1. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261–283.
    1. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531.
    1. Papatheodoridis GV, Dimou E, Dimakopoulos K, Manolakopoulos S, Rapti I, Kitis G, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology. 2005;42:121–129.
    1. Lim YS, Lee YS, Gwak GY, Byun KS, Kim YJ, Choi J, et al. Monotherapy with tenofovir disoproxil fumarate for multiple drug-resistant chronic hepatitis B: 3-year trial. Hepatology. 2017;66:772–783.
    1. Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140:132–143.
    1. Gill US, Zissimopoulos A, Al-Shamma S, Burke K, McPhail MJ, Barr DA, et al. Assessment of bone mineral density in tenofovir-treated patients with chronic hepatitis B: can the fracture risk assessment tool identify those at greatest risk? J Infect Dis. 2015;211:374–382.
    1. Cho YY, Chang Y, Nam JY, Cho H, Cho EJ, Lee JH, et al. Long-term nucleotide analogue treatment has higher levels of renal toxicities than does entecavir in patients with chronic hepatitis B. Gut Liver. 2020;14:225–231.
    1. Rodríguez-Nóvoa S, García-Samaniego J, Prieto M, Calleja JL, Pascasio JM, Delgado Blanco M, et al. Altered underlying renal tubular function in patients with chronic hepatitis B receiving nucleos(t)ide analogs in a real-world setting: the MENTE study. J Clin Gastroenterol. 2016;50:779–789.
    1. Lai CL, Ahn SH, Lee KS, Um SH, Cho M, Yoon SK, et al. Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B. Gut. 2014;63:996–1004.
    1. Yuen MF, Ahn SH, Lee KS, Um SH, Cho M, Yoon SK, et al. Two-year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecavir: results from a multicentre study. J Hepatol. 2015;62:526–532.
    1. Fong TL, Lee BT, Tien A, Chang M, Lim C, Ahn A, et al. Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide. J Viral Hepat. 2019;26:561–567.
    1. Cid-Silva P, Fernández-Bargiela N, Margusino-Framiñán L, Balboa-Barreiro V, Mena-De-Cea Á, López-Calvo S, et al. Treatment with tenofovir alafenamide fumarate worsens the lipid profile of HIV-infected patients versus treatment with tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine. Basic Clin Pharmacol Toxicol. 2019;124:479–490.
    1. Mallon P, Brunet L, Fusco J, Prajapati G, Beyer A, Fusco G, et al. Changes in lipids after a direct switching from TDF to TAF. OPERA web site, < >. Accessed 4 Mar 2019.
    1. Ewers E, Won S, Okulicz J, Ferguson T, Deiss R, Maves R, et al. Changes in lipid profiles for patients to tenofovir alafenamide (TAF)-containing regimens: perspectives from a military HIV-positive cohort. Open Forum Infect Dis. 2018;5:S665.
    1. Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185–195.
    1. Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, 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 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196–206.

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