Long-Term Safety and Efficacy of Tenofovir Alafenamide in Chronic Hepatitis B: Raising the Need for Studies on Functional Cure—Editorial on “Long-Term Real-World Outcomes of Tenofovir Alafenamide in Chronic Hepatitis B” (original) (raw)

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Long-Term Safety and Efficacy of Tenofovir Alafenamide in Chronic Hepatitis B: Raising the Need for Studies on Functional Cure—Editorial on “Long-Term Real-World Outcomes of Tenofovir Alafenamide in Chronic Hepatitis B”

만성 B형간염에서 테노포비르 알라페나마이드의 장기 효과와 안전성: 기능적 치유 연구의 필요성

Soon Kyu Lee1,2

이순규1,2

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea1; The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea2, Seoul, Korea

가톨릭대학교 의과대학 인천성모병원 내과학교실 소화기내과1, 가톨릭대학교 의과대학 간연구소2

Correspondence to: Soon Kyu Lee, Division of Hepatology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Tel: +82-32-280-7477, Fax: +82-2-599-3589, E-mail: blackiqq@catholic.ac.kr, ORCID: https://orcid.org/0000-0003-1865-8225

Financial support: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, MSIT) (RS-2024-00451810) (S.K.L). This work was also supported by the Technology Innovation Program (or Industrial Strategic Technology Development Program) (20024163, Development of microbiome-based treatment technology to improve the treatment and prognosis of liver transplant patients) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea) (S.K.L).

Received: June 12, 2025; Accepted: June 16, 2025

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A hepatitis B virus (HBV) infection is a significant global health burden, with an estimated 1.2 million new infections annually and approximately 254 million individuals living with a chronic HBV infection worldwide.1 East Asia, in particular, has one of the highest prevalences of chronic HBV infection. A chronic HBV infection is a well-established risk factor for liver cirrhosis (LC) and hepatocellular carcinoma (HCC), making appropriate treatment essential for disease management.2 The introduction of potent nucleos(t)ide analogues (NAs), such as entecavir and tenofovir, markedly reduced the incidence of adverse liver-related events, including LC and HCC.3 Indeed, the risk of HCC development in patients receiving NA therapy has been reduced by 40–60% compared to untreated individuals.3 Among the available NAs, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are used widely for their potent antiviral efficacy. Nevertheless, TAF is generally preferred over TDF because of its improved renal and bone safety profile.4 Despite this, the long-term efficacy and safety of TAF, particularly in China, remain insufficiently characterized.

Song et al. reported the long-term real-world outcomes of TAF therapy in a Chinese cohort.5 Among treatment-naïve patients, the virological response (VR) rates increased to 100% after 48 to 192 weeks of TAF therapy, with a longer duration required to achieve a complete VR in HBeAg-positive individuals. Moreover, treatment-experienced patients also achieved favorable VR rates, including those who switched to TAF because of persistent low-level viremia while on previous NAs. These findings underscore the high antiviral efficacy of TAF in real-world clinical practice across East Asia. In particular, the cumulative incidence of HCC in this study was only 0.7%, which is substantially lower than the rates following entecavir therapy reported in earlier studies: 7.5% and 14.3% among patients with undetectable HBV DNA and low-level viremia, respectively.6 Further studies involving larger patient populations are needed to evaluate the long-term impact of TAF on HCC development in real-world settings.

Song et al. evaluated the reasons for switching to TAF and assessed its safety profile. The primary reason for switching was renal tubular injury, reported in approximately 30% of treatment-experienced patients. After switching to TAF, most patients experienced normalization of the renal tubular function within 48 to 144 weeks of treatment. Chan et al. also reported an improved renal function, with a median increase in the estimated glomerular filtration rate of 4.9 mL/min/1.73 m² after switching from TDF to TAF.7 Furthermore, TAF use has been associated with improvements in the hip and spine bone mineral density, reinforcing its favorable renal and bone safety profile. On the other hand, concerns remain regarding dyslipidemia associated with TAF. Song et al. reported an increase in the total cholesterol (TC) levels during TAF therapy, but they remained within the normal range. Previous studies have shown that TDF may reduce the TC levels, whereas TAF has been characterized as lipid-neutral or associated with modest lipid increases.8,9 Further research will be needed to clarify the clinical significance of dyslipidemia in patients undergoing long-term TAF therapy.

Song et al. examined the changes in the quantitative hepatitis B surface antigen (HBsAg) levels after TAF therapy. Consistent with a previous study, which reported a significant decline in HBsAg levels during the first year of entecavir or TDF treatment, the HBsAg levels also decreased gradually over the course of the TAF therapy.10 The authors identified a baseline body mass index <25 kg/m² and baseline HBsAg <3.3 log10IU/mL as predictive factors for a significant decrease in HBsAg at 48 weeks of TAF treatment. With the high VR rates achieved during the TAF era, achieving a functional cure, defined as HBsAg loss or seroconversion, is an important unmet need in HBV management.1 Currently, low HBsAg levels, specifically <1,000 IU/mL in the Caucasian populations and <100 IU/mL in Asian populations, are considered predictive of a functional cure.1,10 Furthermore, recent studies have highlighted the utility of hepatitis B core-related antigen as a predictor of a functional cure, with a proposed cut-off level of <2 log10IU/mL.11 Lower baseline HBsAg levels have also been associated with a higher likelihood of achieving a functional cure. Nevertheless, further research is needed to identify and validate predictive markers for functional cure in patients treated with TAF.

In conclusion, Song et al. reported the long-term efficacy of TAF in treatment-naïve and treatment-experienced patients with a chronic HBV infection in a real-world setting in China. In addition, TAF therapy exhibited a favorable long-term safety profile. Considering its efficacy and safety, further studies are needed to identify the predictors of a functional cure after a TAF treatment.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, MSIT) (RS-2024-00451810) (S.K.L). This work was also supported by the Technology Innovation Program (or Industrial Strategic Technology Development Program) (20024163, Development of micro-biome-based treatment technology to improve the treatment and prognosis of liver transplant patients) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea) (S.K.L).

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, MSIT) (RS-2024-00451810) (S.K.L). This work was also supported by the Technology Innovation Program (or Industrial Strategic Technology Development Program) (20024163, Development of microbiome-based treatment technology to improve the treatment and prognosis of liver transplant patients) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea) (S.K.L).

Long-term real-world outcomes of tenofovir alafenamide in chronic hepatitis B: Detailed analysis of treatment-naive and experienced patients (Korean J Gastroenterol 2025;85:64-72)

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