Besifovir Improves Renal, Bone Health in HBV Patients Receiving Long-Term TDF

New research suggests switching to besifovir dipivoxil maleate (BSV) therapy may improve renal and bone health in patients with chronic hepatitis B virus (HBV) previously receiving long-term tenofovir disoproxil fumarate (TDF) treatment.1

The randomized, open-label, active-controlled, non-inferiority phase 4 clinical trial found switching to a 48-week BSV therapy regimen after long-term TDF demonstrated noninferior antiviral efficacy compared to maintaining TDF. Additionally, findings suggest certain adverse effects of long-term TDF may be reversible with BSV, which was linked to improved kidney function and bone density.1

“TDF is the most widely used potent antiviral agent for the treatment of CHB without the emergence of antiviral resistance. However, estimated glomerular filtration rates and bone mineral density may decrease gradually during long-term therapy,” Hyung Joon Yim, of the department of internal medicine at Korea University Ansan Hospital, and colleagues wrote.1 “Considering that patients with CHB increasingly have diverse comorbid diseases, such drug-related adverse events may hamper the benefit of antiviral therapy for CHB.”

While BSV has been shown to have antiviral efficacy comparable to TDF in a stage 3 clinical trial, with improved kidney and bone safety in treated patients, this study was conducted in individuals who had never received treatment for CHB. Investigators noted that in the real world, most patients with chronic HBV are already being treated with TDF and have been on the therapy for several years, necessitating further research about the use of BSV in TDF-treated patients.1,3

To assess the efficacy and safety of switching from TDF to BSV in patients with chronic HBV and suppressed viral replication, investigators conducted a phase 4 clinical trial at 22 tertiary hospitals in South Korea. For inclusion, patients were required to have a history of chronic HBV or positive HBsAg for > 6 months before screening; TDF monotherapy for ≥48 weeks and TDF use at the time of clinical screening; and HBV DNA <20 IU/mL.1

In total, the trial enrolled 153 patients who were randomly assigned to receive either BSV 150 mg with carnitine 660 mg as a supplement or TDF 300 mg for 48 weeks, with randomization stratified according to hepatitis B e antigen (HBeAg) status. The primary endpoint was the proportion of patients with HBV DNA <20 IU/mL at week 48.1

The per-protocol analysis included 130 patients, including 64 in the BSV group and 66 in the TDF group. In both groups, the mean prior-exposure durations to TDF before enrollment in the study were 4.26 and 4.33 years, respectively.1

In the per-protocol analysis, 100.0% of patients in the BSV group and 98.5% of patients in the TDF group experienced virological response, defined as HBV DNA <20 IU/mL, at week 48, exhibiting a 1.5% difference between the groups (95% CI for difference, -0.01 to 0.04) with a predefined margin of -0.18.1

Investigators noted both groups showed similar rates of adverse events (36.8% for BSV group vs 38.7% for TDF group). Grade 3 and 4 adverse events occurred in 1 and 3 patients, respectively, and serious adverse events occurred in 1 and 4 patients, respectively, none of which were related to the study medication.1

The mean percentage changes in estimated glomerular filtration rate over 48 weeks were persistently greater in the BSV group than in the TDF group (P = .009). The urine protein to creatinine ratio and urine albumin to creatinine ratio (UACR) did not change in the BSV group but were significantly increased in the TDF group. Investigators pointed out the median changes in urine protein to creatinine ratio were significantly different between the groups (-1.48 vs 13.2; P = .027), but median changes in UACR were not (14.3 vs 22.13; P = .548).1

After switching to BSV, the BSV group showed greater improvement in bone turnover markers than the TDF group. Specifically, the hip bone mineral density changes were +0.36 in the BSV group and -0.70 in the TDF group at week 48 (P = .039), while the spine bone mineral density changes were +1.89 and +0.28, respectively (P = .172).1

“These results show that adverse effects of long-term TDF may be potentially reversible with improved kidney function and bone density after switching to BSV," Yim concluded.2 "It seems that long term treatment with BSV would be a viable option for patients with CHB.”

References

1. Yim HJ, Seo YS, Kim JH, et al. Switching to Besifovir in Patients with Chronic Hepatitis B Receiving Tenofovir Disoproxil Fumarate: A Randomized Trial. Clin Mol Hepatol. doi:10.3350/cmh.2024.0819

2. PRNewswire. New Study by Korea University College of Medicine Researchers Reveals a Safer Alternative for Long-Term Hepatitis B Treatment. April 9, 2025. Accessed April 9, 2025. https://www.prnewswire.com/news-releases/new-study-by-korea-university-college-of-medicine-researchers-reveals-a-safer-alternative-for-long-term-hepatitis-b-treatment-302424477.html

3. Ahn SH, Kim W, Jung YK, 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. doi:10.1016/j.cgh.2018.11.001