Tenofovir amibufenamide in chronic hepatitis B: Lipid changes and 144-week safety with tenofovir disoproxil fumarate-to-tenofovir amibufenamide switch

Abstract

BACKGROUND

Tenofovir amibufenamide (TMF) has shown antiviral efficacy comparable to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB), with improved renal and bone safety profiles. While TDF is recognized for its lipid-lowering properties, the long-term effects of TMF on lipid metabolism remain unclear.

AIM

To assess lipid changes and long-term safety of TMF in CHB, including outcomes after TDF-to-TMF switch over 144 weeks.

METHODS

This retrospective analysis utilized data from a phase III randomized, double-blind trial involving 53 patients with CHB treated with either TMF 25 mg (n = 39) or TDF 300 mg (n = 14) once daily for 96 weeks. Following this blinded phase, all participants entered an open-label extension in which they received TMF until week 144. This design enabled assessment of both the comparative effects of TMF and TDF and the impact of switching from TDF to TMF, thereby reflecting real-world treatment scenarios. Virological, biochemical and imaging evaluations were performed throughout the study.

RESULTS

At week 96, both groups achieved comparable virological suppression and maintained stable hepatic and renal function. However, total cholesterol and low-density lipoprotein cholesterol levels were significantly higher in the TMF group compared to the TDF group (P = 0.012 and P = 0.040, respectively). TDF was associated with a transient increase in serum phosphate (P = 0.030). After switching to TMF, lipid profiles in the former TDF group gradually aligned with those of the continuous TMF group by week 144, with no lipid abnormalities observed in either group.

CONCLUSION

TMF provides sustained antiviral efficacy and maintains a favourable long-term lipid and renal safety profile. These findings support TMF as a viable first-line therapy and a switch option for CHB management in clinical practice.

Key Words: Tenofovir amibufenamide; Hepatitis B virus; Lipid profile; Lipoprotein; Cholesterol

Core Tip: This 144-week dual-phase study investigated the long-term lipid and safety profile of tenofovir amibufenamide (TMF) in chronic hepatitis B patients. Through a randomized, double-blind comparison with tenofovir disoproxil fumarate (TDF) followed by a TDF-to-TMF switch, the trial revealed comparable antiviral efficacy, improved renal and bone safety, and a moderate elevation in lipid levels with TMF that stabilized after switch therapy. These findings support TMF as a viable first-line and sequential therapy option in real-world chronic hepatitis B management.

INTRODUCTION

Chronic hepatitis B (CHB) remains a major global health burden, contributing to approximately 55500 deaths annually[1]. Oral nucleoside analogs (NAs) effectively suppress hepatitis B virus (HBV) replication, thereby reducing the risk of liver injury, cirrhosis, hepatic failure and hepatocellular carcinoma (HCC) and improving long-term prognosis[2]. According to current Chinese guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) and tenofovir amibufenamide (TMF) are recommended as first-line NAs for CHB management[3]. Although NAs offer durable antiviral efficacy, hepatitis B surface antigen (HBsAg) clearance is rare, necessitating prolonged or lifelong therapy. This raises concerns about long-term metabolic effects, particularly on bone mineral density, renal function and lipid metabolism.

ETV and TDF have both demonstrated efficacy in suppressing HBV, reversing liver fibrosis and reducing HCC incidence. ETV has a favourable safety profile and a low 5-year resistance rate of 1.2%[4]. TDF achieves higher virologic suppression and a lower risk of HCC than ETV but is associated with long-term adverse effects on bone and renal metabolism, as well as reductions in serum lipid levels[5].

TAF, a novel tenofovir prodrug, results in approximately 90% lower plasma tenofovir concentrations than TDF and is not renally eliminated. Clinical studies have shown that TAF offers comparable antiviral efficacy with improved bone and renal safety. However, its effects on lipid profiles remain debatable[6].

TMF is a newly developed tenofovir prodrug that differs from TAF by an additional methyl group, enhancing lipophilicity and cellular uptake. Preclinical studies suggest greater biological activity than TAF, and clinical trials have demonstrated similar antiviral efficacy with improved renal and bone safety compared to TDF. TMF was approved in China in June 2021. However, its impact on blood lipid profiles still needs to be explored. Therefore, we conducted this clinical trial to evaluate the effect of TMF on lipid profiles in CHB patients, with prolonged 144-week outcomes[3].

MATERIALS AND METHODS

Methods

This retrospective analysis was based on a randomized, controlled phase III clinical trial conducted between July 18, 2018, and April 9, 2020. A total of 84 patients with confirmed CHB were randomized to receive either (TMF, 25 mg once daily) or TDF (300 mg once daily) for 96 weeks. At the end of the double-blind phase, all patients originally assigned to TDF were switched to TMF, and treatment continued through week 144 in an open-label extension.

Of the 84 initially enrolled patients, 31 were excluded due to incomplete follow-up (n = 15), missing serum samples (n = 10), or protocol deviations (n = 6), leaving 53 patients for the final analysis. The details are shown in Figure 1.

Figure 1 Workflow of the clinical trial. TMF: Tenofovir amibufenamide; TDF: Tenofovir disoproxil fumarate.

Inclusion criteria: (1) Male participants aged 18-65 years or non-pregnant, non-lactating females of childbearing potential with a negative serum pregnancy test; (2) Chronic HBV infection, defined as HBsAg positivity for ≥ 6 months; (3) Hepatitis B e antigen (HBeAg)-positive or HBeAg-negative with HBV DNA ≥ 2 × 10⁴ IU/mL and alanine aminotransferase (ALT) > 1 × upper limit of normal (ULN) but ≤ 10 × ULN at screening; and (4) Either treatment-naive (< 12 weeks of prior NA therapy) or treatment-experienced ( ≥ 12 weeks), provided other eligibility criteria were met.

Exclusion criteria: (1) Pregnancy, lactation, or intent to conceive; (2) Coinfection with hepatitis C virus, human immunodeficiency virus or hepatitis delta virus; (3) Imaging-confirmed HCC; (4) Decompensated liver disease (e.g., ascites, hepatic encephalopathy, variceal bleeding); (5) Abnormal haematologic or biochemical values [e.g., haemoglobin < 10 g/dL, platelets ≤ 50 × 10⁹/L, ALT or aspartate aminotransferase (AST) > 10 × ULN, total bilirubin > 2.5 × ULN, albumin < 3.0 g/dL]; (6) History of solid organ or bone marrow transplantation; (7) Significant comorbidities affecting renal, cardiovascular, or neurological function; (8) Severe bone disease or malignancy within the past five years; (9) Use of immunomodulatory or nephrotoxic medications; (10) Known hypersensitivity to study drugs or their components; and (11) Substance abuse likely to affect treatment adherence.

The trial was registered at ClinicalTrials.gov (No. NCT03903796) and conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the Second Xiangya Hospital, and all procedures complied with relevant guidelines and regulations.

Data collection

Demographic variables collected included age, sex, body mass index and the initiation date of antiviral therapy. Fasting lipid profiles were obtained for total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), measured using standardized enzymatic assays. Serum samples were collected after a minimum 12-hour fast. Additional laboratory assessments included HBV-DNA, HBV-RNA, HBV-microRNA-3, HBsAg, HBeAg, haemoglobin, white blood cell count, platelet count, serum phosphate, AST, ALT, uric acid, creatinine, creatinine clearance rate and fasting blood glucose. Liver stiffness measurement and the fibrosis-4 index were assessed via transient elastography. All data were collected and analyzed by the Hepatology Institute of the Second Xiangya Hospital, Central South University. This retrospective study received ethical approval from the Ethics Committee of the Second Xiangya Hospital, Central South University.

Statistical analysis

Clinical raw data were collected and organized in Microsoft Excel and then imported into Python 3.8 for statistical analysis. Continuous variables were presented as mean ± SE. For normally distributed data, Student’s t-test was used for two-group comparisons, while one-way analysis of variance (ANOVA) was used for comparisons among multiple groups. Categorical variables were summarized as frequencies (percentages) and analyzed using the χ² test. Student’s t-test, one-way ANOVA, and the χ² test were conducted using the scipy.stats module. Dynamic changes in each indicator were visualized using the seaborn module to plot curves. Pearson correlation coefficient (R value) was calculated to evaluate associations between variables. Scatter plots and regression lines were used to illustrate relationships between liver fibrosis markers. A significance level of P < 0.05 was considered statistically significant, with a test level of α = 0.05.

RESULTS

Baseline demographic profiles and characteristics

Of the 53 enrolled patients, the mean age was 36.89 years, and 67.9% were male. No statistically significant differences (P > 0.05) were observed between the TDF and TMF groups in baseline laboratory parameters, including lipid profile (TC, TG, HDL and LDL), HBV-DNA, HBV-RNA, HBV-microRNA-3, HBsAg, HBeAg, or other laboratory indices. Detailed baseline characteristics are provided in Table 1.

Table 1 Baseline demographic profiles and characteristics, mean ± SE.

Mark	Total (n = 53)	TDF (n = 14)	TMF (n = 39)	P value
Gender (M/F)	36/17	8/6	28/11	0.314
Age	36.89 ± 1.44	34.50 ± 1.95	37.74 ± 1.83	0.327
BMI 0 week	22.83 ± 0.67	22.01 ± 1.02	23.16 ± 0.85	0.448
WBC 0 week	6.13 ± 0.22	6.27 ± 0.45	6.08 ± 0.26	0.715
Hb 0 week	149.02 ± 2.06	147.79 ± 3.88	149.46 ± 2.45	0.723
PLT 0 week	214.62 ± 10.01	234.00 ± 15.58	207.67 ± 12.31	0.250
ALT 0 week	129.10 ± 17.09	176.42 ± 53.02	112.12 ± 13.01	0.097
AST 0 week	79.79 ± 9.70	99.85 ± 28.31	73.10 ± 8.91	0.236
Cr 0 week	65.84 ± 2.08	67.25 ± 5.17	65.37 ± 2.22	0.699
CLCR 0 week	116.45 ± 3.46	112.04 ± 7.11	117.91 ± 3.98	0.468
PHOS 0 week	1.06 ± 0.03	1.09 ± 0.07	1.05 ± 0.03	0.459
GLU 0 week	4.97 ± 0.11	4.73 ± 0.11	5.06 ± 0.14	0.176
TG 0 week	1.06 ± 0.07	1.15 ± 0.20	1.03 ± 0.06	0.477
CHOL 0 week	4.76 ± 0.15	4.77 ± 0.20	4.76 ± 0.19	0.984
HDL 0 week	1.46 ± 0.05	1.45 ± 0.10	1.46 ± 0.06	0.960
LDL 0 week	2.74 ± 0.11	2.74 ± 0.17	2.74 ± 0.14	0.989
FIB-4 0 week	1.46 ± 0.18	1.28 ± 0.29	1.52 ± 0.22	0.576
CAP 0 week	204.50 ± 5.74	212.07 ± 13.44	201.38 ± 5.99	0.403
RNA 0 week	4.14 ± 0.39	3.99 ± 0.86	4.18 ± 0.44	0.845
DNA 0 week	6.81 ± 0.17	7.20 ± 0.28	6.67 ± 0.21	0.181
miR3 0 week	5.38 ± 0.29	5.33 ± 0.60	5.40 ± 0.34	0.919
HBsAg 0 week	2.94 ± 0.12	3.12 ± 0.25	2.88 ± 0.14	0.381
HBeAg 0 week	0.98 ± 0.27	1.33 ± 0.54	0.85 ± 0.31	0.441

TMF: Tenofovir amibufenamide; TDF: Tenofovir disoproxil fumarate; M: Male; F: Female; BMI: Body mass index; WBC: White blood cells; Hb: Hemoglobin; PLT: Platelet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: Creatinine; CLCR: Creatinine clearance; PHOS: Phosphorus; GLU: Glucose; TG: Triglycerides; CHOL: Cholesterol; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; FIB-4: Fibrosis-4; CAP: C-reactive protein; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; miR3: Hepatitis B virus-microRNA-3.

TDF/TMF effectively inhibit HBV replication

After 96 weeks of treatment, both treatment groups demonstrated significant suppression of HBV replication, as reflected by significant reductions in HBV-DNA, HBV-RNA and HBV-microRNA-3 levels from baseline (Tables 2 and 3). No significant differences were observed between the TDF and TMF groups in HBV-DNA, HBV-RNA, HBV-microRNA-3, HBsAg, or HBeAg levels. The details are shown in Table 4 and Figure 2.

Figure 2 Hepatitis B virus biomarkers dynamic changes between tenofovir amibufenamide group and tenofovir disoproxil fumarate group. A-E: The two groups showed consistent virological performance in terms of hepatitis B surface antigen (A), hepatitis B e antigen (B), hepatitis B virus (HBV)-DNA (C), HBV-RNA (D), HBV-microRNA-3 (E). TMF: Tenofovir amibufenamide; TDF: Tenofovir disoproxil fumarate; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; miR: MicroRNA.

Table 2 Comparison within the tenofovir amibufenamide group after treatment, mean ± SE.

TMF	0 week	96 weeks	(0 week vs 96 weeks)
WBC	6.08 ± 0.26	6.53 ± 0.28	0.247149198
Hb	149.46 ± 2.45	149.21 ± 2.78	0.944983486
PLT	207.67 ± 12.31	213.10 ± 11.67	0.74947324
ALT	112.12 ± 13.01	23.48 ± 2.31	3.09 × 10-9
AST	73.10 ± 8.91	23.22 ± 1.21	4.05 × 10-7
Cr	65.37 ± 2.22	74.05 ± 2.12	0.006031745
CLCR	117.91 ± 3.98	100.63 ± 3.44	0.001543066
PHOS	1.05 ± 0.03	0.88 ± 0.02	1.82 × 10-5
GLU	5.06 ± 0.14	5.65 ± 0.42	0.186321806
TG	1.03 ± 0.06	1.29 ± 0.13	0.069367579
CHOL	4.76 ± 0.19	4.64 ± 0.14	0.613234644
HDL	1.46 ± 0.06	1.37 ± 0.07	0.35635419
LDL	2.74 ± 0.14	2.95 ± 0.13	0.276270192
FIB-4	1.52 ± 0.22	1.28 ± 0.24	0.475793108
CAP	201.38 ± 5.99	202.80 ± 6.26	0.870684054
miR3	5.40 ± 0.34	2.41 ± 0.42	4.27 × 10-7
RNA	4.18 ± 0.44	0.53 ± 0.23	5.19 × 10-10
DNA	6.67 ± 0.21	0.27 ± 0.16	1.69 × 10-28
HBsAg	2.88 ± 0.14	2.94 ± 0.10	0.696890055
HBeAg	0.85 ± 0.31	-0.15 ± 0.18	0.005855419

TMF: Tenofovir amibufenamide; WBC: White blood cells; Hb: Hemoglobin; PLT: Platelet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: Creatinine; CLCR: Creatinine clearance; PHOS: Phosphorus; GLU: Glucose; TG: Triglycerides; CHOL: Cholesterol; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; FIB-4: Fibrosis-4; CAP: C-reactive protein; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; miR3: Hepatitis B virus-microRNA-3.

Table 3 Comparison within the tenofovir disoproxil fumarate group after treatment, mean ± SE.

TDF	0 week	96 weeks	(0 week vs 96 weeks)
WBC	6.27 ± 0.45	6.87 ± 0.63	0.443861557
Hb	147.79 ± 3.88	147.50 ± 5.80	0.967641272
PLT	234.00 ± 15.58	239.14 ± 11.38	0.791953625
ALT	176.42 ± 53.02	20.62 ± 3.63	0.00922277
AST	99.85 ± 28.31	22.75 ± 1.15	0.011908537
Cr	67.25 ± 5.17	77.49 ± 5.63	0.192832703
CLCR	112.04 ± 7.11	90.04 ± 6.85	0.036435267
PHOS	1.09 ± 0.07	1.23 ± 0.27	0.611661657
GLU	4.73 ± 0.11	4.77 ± 0.14	0.80941735
TG	1.15 ± 0.20	2.42 ± 1.32	0.332101848
CHOL	4.77 ± 0.20	3.97 ± 0.19	0.008550427
HDL	1.45 ± 0.10	1.14 ± 0.10	0.033296713
LDL	2.74 ± 0.17	2.23 ± 0.17	0.046729094
FIB-4	1.28 ± 0.29	1.12 ± 0.39	0.742777384
CAP	212.07 ± 13.44	185.17 ± 6.02	0.09703147
miR3	5.33 ± 0.60	2.35 ± 0.69	0.003107141
RNA	3.99 ± 0.86	1.29 ± 0.68	0.024764947
DNA	7.20 ± 0.28	0.29 ± 0.29	4.24 × 10-12
HBsAg	3.12 ± 0.25	2.92 ± 0.13	0.473322675
HBeAg	1.33 ± 0.54	-0.03 ± 0.32	0.040841537

TDF: Tenofovir disoproxil fumarate; WBC: White blood cells; Hb: Hemoglobin; PLT: Platelet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: Creatinine; CLCR: Creatinine clearance; PHOS: Phosphorus; GLU: Glucose; TG: Triglycerides; CHOL: Cholesterol; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; FIB-4: Fibrosis-4; CAP: C-reactive protein; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; miR3: Hepatitis B virus-microRNA-3.

Table 4 Comparison of laboratory finding at 96 weeks in tenofovir disoproxil fumarate/tenofovir amibufenamide groups, mean ± SE.

96 weeks	TDF	TMF	P value
WBC	6.87 ± 0.63	6.53 ± 0.28	0.578
Hb	147.50 ± 5.80	149.21 ± 2.78	0.769
PLT	239.14 ± 11.38	213.10 ± 11.67	0.214
ALT	20.62 ± 3.63	23.48 ± 2.31	0.531
AST	22.75 ± 1.15	23.22 ± 1.21	0.830
Cr	77.49 ± 5.63	74.05 ± 2.12	0.485
CLCR	90.04 ± 6.85	100.63 ± 3.44	0.152
PHOS	1.23 ± 0.27	0.88 ± 0.02	0.026
GLU	4.77 ± 0.14	5.65 ± 0.42	0.236
TG	2.42 ± 1.32	1.29 ± 0.13	0.163
CHOL	3.97 ± 0.19	4.64 ± 0.14	0.011
HDL	1.14 ± 0.10	1.37 ± 0.07	0.077
LDL	2.23 ± 0.17	2.95 ± 0.13	0.005
FIB-4	1.12 ± 0.39	1.28 ± 0.24	0.739
CAP	185.17 ± 6.02	202.80 ± 6.26	0.105
miR3	2.35 ± 0.69	2.41 ± 0.42	0.937
RNA	1.29 ± 0.68	0.53 ± 0.23	0.186
DNA	0.29 ± 0.29	0.27 ± 0.16	0.936
HBsAg	2.92 ± 0.13	2.94 ± 0.10	0.874
HBeAg	-0.03 ± 0.32	-0.15 ± 0.18	0.724

TMF: Tenofovir amibufenamide; TDF: Tenofovir disoproxil fumarate; WBC: White blood cells; Hb: Hemoglobin; PLT: Platelet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: Creatinine; CLCR: Creatinine clearance; PHOS: Phosphorus; GLU: Glucose; TG: Triglycerides; CHOL: Cholesterol; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; FIB-4: Fibrosis-4; CAP: C-reactive protein; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; miR3: Hepatitis B virus-microRNA-3.

Impact of TDF/TMF on CHB blood lipid levels

Lipid parameters remained stable in the TMF group over 96 weeks (Table 2). In contrast, patients receiving TDF showed significant reductions in TG, TC and LDL levels (Table 3). By week 24, a significant difference in TC was noted between the two groups, and by week 96, both TC and LDL levels were significantly lower in the TDF group compared to the TMF group (P = 0.01) (Figure 3 and Table 4).

Figure 3 Dynamic changes in lipid profiles between the tenofovir amibufenamide group and the tenofovir disoproxil fumarate group in chronic hepatitis B. A-E: The two groups exhibited comparable virological performance regarding cholesterol (A), low-density lipoprotein (B), high-density lipoprotein (C), triglycerides (D) and the triglycerides/high-density lipoprotein ratio (E). TMF: Tenofovir amibufenamide; TDF: Tenofovir disoproxil fumarate; CHOL: Cholesterol; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; TG: Triglycerides; TC: Total cholesterol.

TMF ultimately did not affect the CHB’s blood lipid levels

After the week 48 switch from TDF to TMF, all patients continued TMF 25 mg once daily until week 144. Lipid levels (TG, HDL, TC, LDL) were monitored at weeks 72, 96 and 144. No significant changes were observed in lipid parameters compared to baseline, and no cases of dyslipidemia were reported during TMF treatment (Table 5).

Table 5 Comparison of laboratory finding at 144 weeks in tenofovir disoproxil fumarate to tenofovir amibufenamide / tenofovir disoproxil fumarate groups.

144 weeks	TDF to TMF	TMF	P value
WBC	6.20 ± 0.37	6.48 ± 0.27	0.558
Hb	145.57 ± 4.64	148.31 ± 2.92	0.764
PLT	240.50 ± 12.49	224.31 ± 12.05	0.405
ALT	32.71 ± 10.93	28.27 ± 5.24	0.257
AST	24.91 ± 3.67	25.01 ± 2.14	0.845
Cr	72.38 ± 4.95	74.26 ± 2.26	0.414
CLCR	103.07 ± 6.79	101.33 ± 3.50	0.154
PHOS	1.01 ± 0.04	0.97 ± 0.03	0.485
GLU	5.15 ± 0.17	5.82 ± 0.36	0.887
TG	1.56 ± 0.38	1.34 ± 0.14	0.904
CHOL	4.64 ± 0.23	4.47 ± 0.16	0.561
HDL	1.29 ± 0.12	1.29 ± 0.06	0.937
LDL	2.83 ± 0.22	2.78 ± 0.13	0.220
FIB-4	15.38 ± 14.59	1.08 ± 0.13	0.739
CAP	182.22 ± 9.02	189.22 ± 7.8	0.175
miR3	2.27 ± 0.72	2.62 ± 0.44	0.896
RNA	1.46 ± 0.79	0.51 ± 0.25	0.986
DNA	1.24 ± 0.76	0.56 ± 0.33	0.531
HBsAg	3.16 ± 0.17	2.95 ± 0.10	0.849
HBeAg	0.18 ± 0.39	-0.37 ± 0.18	0.865

TMF: Tenofovir amibufenamide; TDF: Tenofovir disoproxil fumarate; WBC: White blood cells; Hb: Hemoglobin; PLT: Platelet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: Creatinine; CLCR: Creatinine clearance; PHOS: Phosphorus; GLU: Glucose; TG: Triglycerides; CHOL: Cholesterol; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; FIB-4: Fibrosis-4; CAP: C-reactive protein; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; miR3: Hepatitis B virus-microRNA-3.

DISCUSSION

NAs inhibit HBV replication by blocking the reverse transcription of pre-genomic RNA into HBV DNA and are widely used for the treatment of chronic HBV infection globally[2,7]. However, NAs do not eliminate covalently closed circular DNA from infected hepatocyte nuclei[8]. Most patients experience viral rebound upon treatment discontinuation, necessitating long-term or even lifelong therapy, posing substantial medical and economic burdens. The long-term safety of NAs has become a growing concern, particularly due to TDF’s potential nephrotoxic effects[9]. TAF, a prodrug of tenofovir with improved renal and bone safety profiles, has demonstrated non-inferior antiviral efficacy compared to TDF in patients with CHB[10]. However, emerging evidence suggests that patients who switch from TDF to TAF may experience weight gain and increased fasting LDL cholesterol, raising concerns about the potential impact of TAF on lipid metabolism[11].

TMF, a methylated derivative of TAF, offers enhanced plasma stability and lipid solubility[12]. In a 24-week clinical trial, TMF yielded a superior virological response in treatment-naive patients with CHB compared to TAF (92% vs 74%, P = 0.033), without adverse effects on renal function or lipid profiles[13]. Our findings align with this conclusion (Figure 4). After 96 weeks of treatment, both TMF and TDF groups achieved significant virological suppression and normalization of ALT and AST levels relative to baseline (Tables 2 and 3). Furthermore, although no clinical abnormalities were observed, a reduction in creatinine clearance rate in the TDF group may indicate early renal impairment, underscoring the need for long-term safety monitoring.

Figure 4 Dynamic changes in renal function between the tenofovir amibufenamide group and the tenofovir disoproxil fumarate group in chronic hepatitis B. A: Creatinine (Cr); B: Cr clearance rate; C: Phosphorus. TMF: Tenofovir amibufenamide; TDF: Tenofovir disoproxil fumarate; Cr: Creatinine; CLCR: Creatinine clearance rate; PHOS: Phosphorus.

In this study, we analyzed real-world data from patients with CHB who received either TMF or TDF for 96 weeks, followed by TMF treatment up to 144 weeks. During the initial 96-week period, significant differences in lipid profiles were observed between the two groups at several time points. Specifically, TC levels were significantly lower in the TDF group at weeks 24, 48 and 96, and LDL levels were also significantly lower at weeks 48 and 96 compared to the TMF group (Supplementary Table 1). However, by week 144, no statistically significant differences in lipid parameters were observed between the groups. Although the early lipid-lowering effects of TDF reached statistical significance, they appeared to have a limited long-term impact and lacked clear clinical relevance, as the lipid profiles converged over time. This suggests that TDF’s transient influence on lipid metabolism does not translate into a sustained or meaningful reduction in cardiovascular risk. These findings are consistent with previous studies reporting no significant difference in the TC to HDL cholesterol (TC/HDL) ratio between TDF and TAF treatment groups, as reductions in TC and HDL levels occurred concurrently in the TDF group. TDF has been reported to modulate serum cholesterol levels through the upregulation of the cluster of differentiation 36/peroxisome proliferators-activated receptor-α axis[14]. However, the molecular mechanism by which TDF treatment regulates HDL levels still requires further investigation. While the mean levels of LDL and TG also showed a decreasing trend during TDF treatment, these differences did not reach statistical significance, possibly due to the limited sample size. Notably, our results revealed a significant reduction in HDL levels during the 96-week TDF treatment period, suggesting that TDF may exert a broader inhibitory effect on lipid metabolic pathways. Plasma lipid parameters are widely recognized as important indicators for assessing cardiovascular risk. According to a recent large-scale epidemiological study, the TC/HDL ratio is considered a more reliable predictor of cardiovascular events than LDL levels alone[15]. Specifically, adding LDL to the TC/HDL ratio does not enhance its predictive value. In our cohort, we also observed no significant difference in the TC/HDL ratio between patients treated with TDF and those treated with TAF for 48 weeks, further supporting the notion that the lipid-modulating effects of these therapies may not substantially alter cardiovascular risk profiles.

After 96 weeks, all patients were switched to TMF 25 mg once daily and continued treatment until week 144, with lipid parameters monitored at weeks 72, 96 and 144. The results showed no statistically significant differences in TG, HDL, cholesterol and LDL levels compared to baseline. Additionally, no patients experienced lipid abnormalities during TMF treatment.

These findings suggest that TMF effectively maintains stable blood lipid levels over the long-term and does not induce dyslipidemia. This may be particularly beneficial for individuals with underlying lipid metabolism concerns, as maintaining stable lipid profiles is essential for cardiovascular health. Moreover, the results underscore the potential safety and efficacy of TMF in preserving lipid homeostasis, supporting its broader clinical application in the management of CHB. However, further research with larger cohorts and extended follow-up is warranted to confirm these findings and to fully elucidate the long-term metabolic safety profile of TMF, which could support further clinical applications[2,16,17]. TDF and TMF are widely used as first-line NAs for antiviral therapy in CHB[18]. However, current evidence regarding the effects of TMF on lipid metabolism is limited, and findings related to TAF remain inconclusive. Moreover, the molecular mechanisms by which NAs influence lipid metabolism are not yet fully understood. Therefore, multicenter, large-scale prospective studies are needed to clarify the metabolic impact of antiviral therapies, elucidate their underlying biological mechanisms and assess their long-term clinical significance.

Our findings indicate that TMF offers antiviral efficacy comparable to TDF while maintaining stable lipid profiles, suggesting it may be a safer alternative for patients requiring lifelong therapy, particularly those with pre-existing metabolic risk factors. Although TDF is associated with lipid-lowering effects, its long-term use is limited by concerns related to renal and bone toxicity. In contrast, TMF achieves effective viral suppression without inducing the lipid-lowering effects that may be undesirable in patients with normal or low baseline lipid levels.

This 144-week study further supports the long-term safety and efficacy of TMF, demonstrating that it sustains virological suppression while preserving lipid homeostasis. The transient lipid-lowering effects observed with TDF were not maintained following the switch to TMF, highlighting TMF as a potentially more suitable option for patients requiring prolonged antiviral treatment without compromising metabolic health.

Nonetheless, this study has certain limitations, most notably the relatively small sample size, which may limit the statistical power to detect subtle differences in lipid profiles. Future multicenter studies with larger and more diverse cohorts are warranted to validate and extend these findings.

CONCLUSION

This study supports TMF as a first-line antiviral agent for CHB, offering a favorable balance of virological efficacy, renal safety, and lipid profile stability, especially for long-term therapy.

ACKNOWLEDGEMENTS

We thank the clinical staff at the Second Xiangya Hospital for their assistance with patient management and data collection. We also acknowledge the statistical support provided by the Department of Public Health, Central South University.