Chronic hepatitis B virus (HBV) infection constitutes a major global burden [
1]; 295 million individuals are living with chronic HBV, of which 40%, or 115.7 million, are from the World Health Organization (WHO) Western Pacific region [
2]. While long-term nucleoside analogue therapy has greatly reduced the risk of cirrhotic complications and hepatocellular carcinoma, treatment accessibility remains an issue. Currently, only 5.6 million in the Western Pacific region are receiving HBV treatment [
2], with the WHO treatment coverage target of 80% among eligible patients unlikely to be achieved in the near future [
3]. Since 2015, HBV-related death has not been decreasing in countries with a sociodemographic index of middle or higher; with the HBV-related death count actually increasing in the Western Pacific region; possibly a reflection of the ageing of the HBV-infection population [
1]. These epidemiological data reflect the importance of HBV treatment option and availability in achieving the ultimate goal of HBV elimination.
Besifovir dipivoxil maleate is an acyclic nucleotide phosphonate which was developed in Korea. It has potent antiviral efficacy against HBV, noninferior to that of entecavir or tenofovir disoproxil fumarate (TDF) [
4], as demonstrated in the phase III trial comparing besifovir vs. TDF over 48 weeks. Besifovir also has a superior renal and bone safety profiles as compared to TDF as based on estimated glomerular filtration rates and hip and spine bone mineral densities (BMDs) up to 96 weeks [
5]. The long-term safety of an antiviral is particularly vital when the prevalence of comorbidities in increasing in an ageing HBV-infected population [
6]. That being said, a clinical trial setting may not be reflective of genuine real-world practice, and the proportion of patients being treatment-experienced prior to attempting a new antiviral is increasing. Studies investigating the long-term outcomes of patients after antiviral switching are warranted, as illustrated by data on the switching from TDF or entecavir to tenofovir alafenamide (TAF) [
7,
8]; TAF has been well-demonstrated to have superior long-term bone and renal safety as compared to TDF.
The present study by Yim and co-authors [
9] specifically investigated the switching of TDF to besifovir in patients with chronic HBV. A randomized open-label non-inferiority phase 4 trial involving 22 specialist centers in Korea, the study recruited 153 chronic HBV who had been treated with at least 48 weeks of TDF, with successful virological suppression achieved prior to study enrolment. Patients were randomized 1:1 to receive either besifovir with carnitine supplement or TDF continuation. Of note, the study recruited a consideration proportion of cirrhotic patients and was hence more representative of the real-world scenario. Both hepatitis B e antigen-positive and -negative patients were also enrolled. Switching to besifovir was found to be noninferior to continuing TDF in maintaining a virological response, with no significant in HBV DNA levels up to 48 weeks. The reduction in alanine aminotransferase levels was greater in the besifovir-switch group as compared with the TDF-continuation group. Equally important was the data on safety. Spine and hip BMD were performed longitudinally, with the besifovir-switch group an improvement of BMD at week 48, while the TDF-continuation group had a further reduction in hip BMD. The besifovir-switch group also had a significant reduction in bone resorption based on C-type collagen sequence levels. Regarding renal safety, the besifovir-switch group also had improvements in estimated glomerular filtration rate as compared to the TDF-continuation group; other urinary biomarkers of kidney injury also showed comparable results. Besifovir is known to be associated with carnitine depletion, which can be associated with musculoskeletal and cardiac problems [
4]. In this present study, together with carnitine supplementation 660 mg per day, there was no significant decrease in mean carnitine levels in the besifovir-switch group.
It is important to note that the per protocol analysis of 130 patients, and not the intention-to-treat analysis, was presented in both primary and secondary outcomes. A modified intention-to-treat analysis was only briefly described, and hence one can argue the presented study results can still be susceptible to bias via the exclusion of non-adherent patients. That being said, nucleos(t)ide analogues are generally very well-tolerated with excellent safety record, with the majority of on-treatment patients being compliant [
10], and hence the presented results can be largely representative of real-world practice. In addition, a more ideal comparison would be establishing noninferiority versus a switch to TAF [
7,
8] for both treatment efficacy and long-term safety. Nonetheless, the present study strengthens the evidence on the long-term efficacy and safety of besifovir when prescribed together with carnitine supplementation.
The WHO has stated the importance of ensuring worldwide equitable access to essential, safe and effective medicines should be the cornerstone of health policies in treatment noncommunicable diseases [
11]. It is unfortunate that besifovir is currently only approved for chronic HBV in Korea; an additional therapeutic option that is globally-available would diversify the anti-HBV management armamentarium and could aid in enhancing treatment accessibility and geographical reach to a broader population. This will be crucial for increasing chronic HBV treatment coverage to the WHO target of 80% and ultimately eliminating HBV as a global health threat.
FOOTNOTES
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Conflicts of Interest
WKS received speaker’s fees from Echosens, is an advisory board member of and received speaker fees from Abbott, received research funding from Alexion Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Pfizer and Ribo Life Science, and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences.
Abbreviations
tenofovir disoproxil fumarate
World Health Organization
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Citations
Citations to this article as recorded by
- Correspondence to editorial on “Switching to besifovir in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate: A randomized trial”
Hyung Joon Yim, Seong Hee Kang, Young Kul Jung, Jin Mo Yang
Clinical and Molecular Hepatology.2026; 32(1): e55. CrossRef
